JPH08253465A - Tetracyclic compound - Google Patents

Abstract

PURPOSE: To obtain a new compound useful as an antitumor agent. CONSTITUTION: This taxol derivative is shown by formula I (R<1> is an alkyl, an alkenyl or an alkynyl; R<2> is H, an alkyl, etc.; R<3> is H, OH or OCOR<9> ; R<4> and R<5> are each H, a halogen, an alkyl or OH; R<6> is an alkyl, a cycloalkyl, an aryl, a heterocyclic, etc.; R<7> is an alkyl, an aryl or an alkoxy; R<8> is H or OH; R<7> is an alkyl, a cycloalkyl, an aryl, a heterocyclic, amino, etc.) such as 13-O-[(2R), (3R)-3( (tert-butoxycarbonulamino)-3-phenylpropionyl]-4,10- dideacetyl-4-0-propionylbaccatin III. The compound of formula I is obtained by subjecting a compound of formula II (R<21> and R<22> are each protected OH) as a starting substance to oxidation, reduction, condensation, etc., into a compound of formula III (R<11> is as shown for R<1> ; R<12> is as shown for R<2> ; R<13> is H or OCOR<9> ; R<15> is H, a halogen, etc.; R<16> is as shown for R<6> ; R<17> is R<7> ; R<24> and R<25> are each H, an alkyl or an aryl) and carrying out exchange reaction such as removal of protecting group (in case R<3> is OH).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel taxol derivative having an antitumor activity.

[0002]

2. Description of the Related Art Taxol is a natural product represented by the chemical structural formula shown in Chemical formula 11 and is obtained in trace amounts from the stems of the yew tree.

[0003]

[Chemical 11]

Taxol is known to have an antitumor activity, and its mechanism of action is based on the inhibitory effect of depolymerization of microtubules in cell division, which is different from conventional antitumor agents. Its clinical application is expected as an antitumor agent.

So far, taxol has been obtained from nature only in trace amounts. However, in recent years, 10-deacetylbaccatin III, which is a taxol precursor represented by Chemical formula 12, which can be obtained in a relatively large amount from leaves of yew, etc.

[0006]

[Chemical 12]

A semi-synthesized taxol derivative using as a raw material has been reported (Japanese Patent Laid-Open No. 03-50572).
5). Among them, a compound having a structure represented by Chemical formula 13 (Taxotere) has been attracting attention as a compound having an antitumor activity equal to or higher than that of taxol, and is currently under development as an antitumor agent.

[0008]

[Chemical 13]

[0009]

However, although taxol and the derivative represented by Chemical formula 13 are promising as antitumor agents, they are not very effective against digestive organ cancers, especially colon cancers in clinical tests. Derivatives that have been found and have a stronger antitumor effect are desired.

[0010]

Means for Solving the Problems As a result of diligent studies by the present inventors, a derivative obtained by converting an acyloxy group such as a propanoyloxy group at the 4-position and further converting a 10-position substituent has a strong antitumor activity. We have found this and completed the present invention.

[0011]

The present invention has the general formula (I)

[0012]

Embedded image [Wherein R ¹ is an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group, or an alkynyl group having a substituent (substitution of these alkyl group, alkenyl group, and alkynyl group The group is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group,
A group selected from the group consisting of an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group,
You may have two or more of these. ) Means

R ² is a hydrogen atom, an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group, or an alkynyl group having a substituent (these alkyl groups, alkenyl groups, and alkynyl groups). The substituent of is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group. a group selected from the group, meaning they may have several.), R ³ is a hydrogen atom, a hydroxyl group or a group -OCOR ^9, R ⁴ is a hydrogen atom, a hydroxyl group, a halogen atom Or an alkyl group, and R ⁵ represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group. Meaning,

R ⁶ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a heterocyclic group (these alkyl groups, alkenyl groups, alkynyl groups,
Cycloalkyl group, aryl group, and heterocyclic group, a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, It may have one or more groups selected from the group consisting of an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group as a substituent. ) Means

R ⁷ is an alkyl group, an aryl group or an alkoxyl group (these alkyl groups, aryl groups and alkoxyl groups are halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxyl group, aryloxy group,
One substituent selected from the group consisting of a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group. Or you may have two or more. ), R ⁸ represents a hydrogen atom or a hydroxyl group,

R ⁹ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heterocyclic group or a group.

[0017]

[Chemical 15] (Q ¹ and Q ^{2, which} may be the same or different, each represents a hydrogen atom or an alkyl group. Further, Q ¹ and Q ² are bonded to each other to form a group together with an adjacent nitrogen atom.

[0018]

Embedded image (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. )

(These are alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclic groups and groups.

[0020]

[Chemical 17] Is an alkyl moiety (when Q ¹ and / or Q ² is an alkyl group) is a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group. , An alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, an acyloxy group, and a nitrogen-containing heterocyclic group having a size of a 3- to 8-membered ring (the nitrogen-containing heterocyclic group is One or more alkyl groups may be present on the ring-constituting atoms, and one or more groups selected from the group consisting of: ) Means. ] It is related with the compound and its salt represented.

The general formula (II)

[0022]

Embedded image [Wherein R ¹ is an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group, or an alkynyl group having a substituent (substitution of these alkyl group, alkenyl group, and alkynyl group The group is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group,
A group selected from the group consisting of an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group,
You may have two or more of these. ) Means

R ² is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, or a substituted alkynyl group (these alkyl groups, alkenyl groups, and alkynyl groups). The substituent of is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group. A group selected from the group, which may have a plurality of these groups).

R ⁴ represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group, R ⁵ represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group,

R ⁶ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or a heterocyclic group (these alkyl groups, alkenyl groups, alkynyl groups,
Cycloalkyl group, aryl group, and heterocyclic group, a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, It may have one or more groups selected from the group consisting of an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group as a substituent. ) Means

R ⁷ is an alkyl group, an aryl group or an alkoxyl group (these alkyl groups, aryl groups and alkoxyl groups are halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxyl group, aryloxy group,
One substituent selected from the group consisting of a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group. Or you may have two or more. ), R ⁸ represents a hydrogen atom or a hydroxyl group,

Q ¹ and Q ² may be the same or different and each represents a hydrogen atom or an alkyl group. Also, Q ¹
And Q ² are combined with the adjacent nitrogen atom to form the formula

[0028]

[Chemical 19] (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. (When Q ¹ and / or Q ² is an alkyl group, a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group,
Amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group,
An acyloxy group and a nitrogen-containing heterocyclic group having a size of a 3- to 8-membered ring (the nitrogen-containing heterocyclic group may have one or more alkyl groups on the constituent atoms of the ring. 1) or more than one group selected from the group consisting of 2) may be included as a substituent. ) Means. ] It is related with the compound and its salt represented.

Next, terms used in this specification will be described.

As used below, "C ₁ -C ₆ " means 1 carbon atom.
In the meaning of 1 to 6, for example, “C ₂ -C ₆ alkenyl group” means an alkenyl group having 2 to 6 carbon atoms.

The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The term "alkyl group" refers to straight or branched chain alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl, tetradecyl and the like. Means

Similarly, the term "alkenyl group" refers to straight or branched chain alkenyl, such as vinyl, allyl,
It means isopropenyl, 2-methyl-1-propenyl and the like.

Similarly, the term "alkynyl group" refers to a straight or branched chain alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1,1-dimethyl-
It means 2-propynyl, 2-pentynyl, 2-hexynyl and the like.

Similarly, the term "cycloalkyl group" means cyclopropyl, cyclobutyl, cyclopentyl,
It means cyclohexyl, cycloheptyl and the like.

Similarly, the term "alkoxyl group" refers to
An alkyl group bonded to the group —O— means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy and the like. It also means that a phenyl group (which may have a substituent) such as benzyloxy, phenethyloxy and p-methoxybenzyloxy is bonded to a group —O— via an alkyl group. .

Similarly, the term "alkoxycarbonyl group" means an oxygen atom of the group --COO-- to which an alkyl group is attached, eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tertiary Examples include butoxycarbonyl and the like. Further, for example, a phenyl group (which may have a substituent) such as benzyloxycarbonyl, phenethyloxycarbonyl, and p-methoxybenzyloxycarbonyl is attached to the oxygen atom of the group —COO— via an alkyl group. Also means combined.

Similarly, the term "aryl group" means a monovalent group obtained by removing one hydrogen atom from the nucleus of an aromatic hydrocarbon, for example, phenyl, tolyl, biphenylyl,
Examples include naphthyl.

Similarly, the term "aryloxy group" means a group --O-- to which an aryl group is bonded, and examples thereof include phenoxy and naphthyloxy.

Similarly, "aryloxycarbonyl group"
The term means an aryl group attached to the oxygen atom of the group —COO—, for example phenoxycarbonyl,
Examples include naphthyloxycarbonyl and the like.

Similarly, the term "aminoalkyl group" means an alkyl group substituted with an amino group, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl and 4-aminopropyl. Aminobutyl, 5-aminopentyl, 6-aminohexyl and the like can be mentioned.

Similarly, the term "alkylamino group" means an amino group substituted with one alkyl group or an amino group substituted with two alkyl groups (two alkyl groups may be the same or different). Which means that an amino group is substituted with one alkyl group, for example, methylamino, ethylamino, propylamino,
Examples of isopropylamino, hexylamino and the like in which two alkyl groups are substituted on the amino group include dimethylamino, diethylamino, ethylmethylamino, dihexylamino and the like.

Similarly, the term "alkylaminoalkyl group" means an alkyl group substituted with an alkylamino group, and examples thereof include methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl and the like.

Similarly, the term "acyl group" means a carbonyl group (-CO-) to which a hydrogen atom, an alkyl group or an aryl group is bonded, and examples thereof include formyl, acetyl, propanoyl and benzoyl. To be

Similarly, the term "acylamino group" refers to
Means a substituted amino group with an acyl group, for example,
Acetamino, propanoylamino, benzoylamino and the like can be mentioned.

Similarly, the term "acyloxy group" refers to
The group —COO— means a carbon atom to which a hydrogen atom, an alkyl group or an aryl group is bonded, and examples thereof include acetoxy, propanoyloxy and benzoyloxy.

Similarly, the term "heterocyclic group" means a monocyclic ring containing at least one atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as a constituent atom of the ring structure. Means a substituent derived from a cyclic or bicyclic saturated or unsaturated heterocyclic compound, and as the monocyclic heterocyclic group, for example, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, Pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine,
Pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine, a substituent derived from a monocyclic heterocyclic compound such as thiomorpholine, a bicyclic heterocyclic group, benzofuran, indolizine, benzothiophene, Substituents derived from bicyclic heterocyclic compounds such as indole, naphthyridine, quinoxaline, quinazoline, chroman and the like can be mentioned.

Similarly, the term "nitrogen-containing heterocyclic group" always includes one nitrogen atom as a constituent atom of the heterocyclic group, and one kind of atom consisting of oxygen atom, nitrogen atom and sulfur atom as other constituent atoms. It means a substituent derived from a saturated or unsaturated heterocyclic compound which may include one or more of the above, and examples thereof include pyrrole, pyrrolidine, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole and oxadiazole. , Thiadiazole, pyridine, dihydropyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, thiomorpholine and the like.

Similarly, the "expression

[0050]

Embedded image (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
"A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by" means a 5- to 6-membered ring containing a nitrogen atom as a constituent atom of the heterocyclic group. It means a substituent derived from a saturated heterocyclic compound having a size, and examples thereof include pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolidine, piperidine, piperazine, morpholine and thiomorpholine.

Next, each substituent in the general formula (I) and the general formula (II) will be described.

R ¹ is an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group or an alkynyl group having a substituent.

The "alkyl group" for R ¹ is linear or branched alkyl, for example, C ₁ -such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl and the like. C ₈ alkyl group is preferable.

Similarly, the "alkenyl group" for R ¹ is a straight chain or branched chain alkenyl, for example, C ₂ -C ₆ alkenyl such as vinyl, allyl, isopropenyl, 2-methyl-1-propenyl, butenyl and the like. Groups are preferred.

Similarly, an "alkynyl group" for R ¹ is a straight chain or branched chain alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl, 1,1-
Dimethyl-2-propynyl, 2-pentynyl, is C ₂ -C ₆ alkenyl group of the 2-hexynyl or the like.

The substituent of the alkyl group having a substituent, the alkenyl group having a substituent or the alkynyl group having a substituent is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group or an amino group. It is a group selected from the group consisting of a group, an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group, and may have a plurality of these groups.

Incidentally, the bonding position of the substituent is the alkyl group,
It may be at any position of the alkenyl group or alkynyl group.

Here, the substituent of the alkyl group, alkenyl group or alkynyl group for R ¹ will be described.

"Alkoxyl group" as a substituent of the alkyl group, alkenyl group or alkynyl group for R ¹ .
Is a straight-chain or branched-chain alkoxyl group, and for example, a C ₁ -C ₆ alkoxyl group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy is preferable.

Similarly, as the "aryloxy group",
A phenyloxy group in which a phenyl group is bonded to the group -O- is preferable.

Similarly, as the "alkylamino group",
An amino group substituted with one C ₁ -C ₆ alkyl group,
Alternatively, an amino group in which two C _{1 to} C ₆ alkyl groups are substituted (two alkyl groups may be the same or different), and an amino group is substituted with one C _{1 to} C ₆ alkyl group. as, for example, methylamino, ethylamino, propylamino, isopropylamino, hexylamino, etc. are preferred, and C ₁ -C ₆ alkyl group to an amino group 2
As those substituted individually, dimethylamino, diethylamino, ethylmethylamino, dihexylamino and the like are preferable.

Similarly, the "alkoxycarbonyl group" is a group --COO-- in which a C ₁ -C ₆ alkyl group is bonded to an oxygen atom, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Tertiary butoxycarbonyl and the like are preferred.

Similarly, "aryloxycarbonyl group"
As the above, a phenyloxycarbonyl group in which a phenyl group is bonded to the oxygen atom of the group —COO— is preferable.

Similarly, the “acyl group” is a carbonyl group (group —CO—) to which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded, and examples thereof include formyl and
Acetyl, propanoyl, benzoyl and the like are preferable.

Similarly, as the "acylamino group", an amino group substituted with the above acyl group, for example, acetamino, propanoylamino, benzoylamino and the like are preferable.

Similarly, the "acyloxy group" is a group -COO- in which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded to, for example, acetoxy, propanoyloxy, benzoyloxy. Etc. are preferred.

R ² is a hydrogen atom, an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group or an alkynyl group having a substituent.

The "alkyl group" for R ² is a straight chain or branched chain alkyl, for example, C ₁ -such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl and the like. C ₈ alkyl group is preferable.

Similarly, the "alkenyl group" for R ² is a straight chain or branched chain alkenyl, for example, C ₂ -C ₆ alkenyl such as vinyl, allyl, isopropenyl, 2-methyl-1-propenyl, butenyl and the like. Groups are preferred.

Similarly, an "alkynyl group" for R ² is a straight chain or branched chain alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl, 1,1-
Dimethyl-2-propynyl, 2-pentynyl, is C ₂ -C ₆ alkenyl group of the 2-hexynyl or the like.

As the substituent of the alkyl group having a substituent, the alkenyl group having a substituent, or the alkynyl group having a substituent, a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, It is a group selected from the group consisting of an amino group, an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group, and may have a plurality of these groups.

Incidentally, the bonding position of the substituent is the alkyl group,
It may be at any position of the alkenyl group or alkynyl group.

Here, the substituent of the alkyl group, alkenyl group or alkynyl group for R ² will be described.

"Alkoxyl group" as a substituent of the alkyl group, alkenyl group or alkynyl group for R ² .
Is a straight-chain or branched-chain alkoxyl group, and for example, a C ₁ -C ₆ alkoxyl group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy is preferable.

Similarly, as the "aryloxy group",
A phenyloxy group in which a phenyl group is bonded to the group -O- is preferable.

Similarly, as the "alkylamino group",
An amino group substituted with one C ₁ -C ₆ alkyl group,
Alternatively, an amino group in which two C _{1 to} C ₆ alkyl groups are substituted (two alkyl groups may be the same or different), and an amino group is substituted with one C _{1 to} C ₆ alkyl group. as, for example, methylamino, ethylamino, propylamino, isopropylamino, hexylamino, etc. are preferred, and C ₁ -C ₆ alkyl group to an amino group 2
As those substituted individually, dimethylamino, diethylamino, ethylmethylamino, dihexylamino and the like are preferable.

Similarly, an "alkoxycarbonyl group" is a group --COO-- in which a C ₁ -C ₆ alkyl group is bonded to an oxygen atom, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Tertiary butoxycarbonyl and the like are preferred.

Similarly, "aryloxycarbonyl group"
As the above, a phenyloxycarbonyl group in which a phenyl group is bonded to the oxygen atom of the group —COO— is preferable.

Similarly, the “acyl group” is a carbonyl group (group —CO—) to which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded, for example, formyl,
Acetyl, propanoyl, benzoyl and the like are preferable.

Similarly, as the "acylamino group", an amino group substituted with the above acyl group, for example, acetamino, propanoylamino, benzoylamino and the like are preferable.

Similarly, the "acyloxy group" is a group -COO- in which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded to, for example, acetoxy, propanoyloxy, benzoyloxy. Etc. are preferred.

R ⁴ and R ⁵ are hydrogen atom, hydroxyl group, halogen atom or alkyl group.

The "halogen atom" for R ⁴ and R ⁵ is preferably a fluorine atom, a chlorine atom or a bromine atom.

Similarly, the "alkyl group" for R ⁴ and R ⁵ is preferably a methyl group, an ethyl group or a propyl group.

R ⁶ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group (these alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups and heterocyclic groups are halogen atoms). , Hydroxyl group, carboxyl group, alkyl group, alkoxyl group, phenyl group, amino group, alkylamino group,
One or more groups selected from the group consisting of an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group may be contained as a substituent. ).

The "alkyl group" for R ⁶ is a straight chain or branched chain alkyl, for example, C ₁ -such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl and the like. C ₈ alkyl group is preferable.

Similarly, the "alkenyl group" for R ⁶ is a straight chain or branched chain alkenyl, for example, C ₂ -C ₆ alkenyl such as vinyl, allyl, isopropenyl, 2-methyl-1-propenyl, butenyl and the like. Groups are preferred.

Similarly, the "alkynyl group" for R ⁶ is a straight chain or branched chain alkynyl, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl, 1,1-
Dimethyl-2-propynyl, 2-pentynyl, is C ₂ -C ₆ alkenyl group of the 2-hexynyl or the like.

Similarly, the "cycloalkyl group" for R ⁶ is preferably a C ₃ -C ₇ cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Similarly, the "aryl group" for R ⁶ is preferably a phenyl group.

Similarly, as the “heterocyclic group” for R ⁶ , one or more kinds of atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as a constituent atom of the ring structure is used.
A substituent derived from a saturated or unsaturated heterocyclic compound containing one or more heterocyclic compounds, and these heterocyclic groups may be bonded at any position. The heterocyclic group may be monocyclic or bicyclic, and examples of the monocyclic heterocycle include pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole and oxax. Substituents derived from 4-membered to 9-membered heterocyclic compounds such as diazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine, and thiomorpholine are preferable. . The bicyclic heterocyclic group is preferably a substituent derived from benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, chroman and the like.

Here, the substituent of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group or heterocyclic group for R ⁶ will be described.

The bonding position of the substituent is the alkyl group,
It may be at any position of the alkenyl group, alkynyl group, cycloalkyl group, aryl group or heterocyclic group.

The "alkyl group" as a substituent of the cycloalkyl group, aryl group or heterocyclic group for R ⁶ is a straight chain or branched chain alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
C ₁ -C ₆ alkyl groups such as tertiary butyl, pentyl and hexyl are preferred.

Similarly, as the "aminoalkyl group",
A C ₁ -C ₆ alkyl group substituted with an amino group, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl. Amino C ₁ -C such as
_{A 6} alkyl group is preferred.

Similarly, the "alkylaminoalkyl group" is a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₆ alkylamino group, and examples thereof include methylaminomethyl, 2-methylaminoethyl and dimethyl. Aminomethyl and the like are preferable.

An alkyl group, an alkenyl group in R ⁶ ;
As the "alkoxyl group" as a substituent of an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group,
A straight-chain or branched-chain alkoxyl group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy,
C ₁ -C ₆ alkoxyl groups such as hexyloxy is preferred.

Similarly, as the "aryloxy group",
A phenyloxy group in which a phenyl group is bonded to the group -O- is preferable.

Similarly, as the "alkylamino group",
An amino group substituted with one C ₁ -C ₆ alkyl group,
Alternatively, an amino group in which two C _{1 to} C ₆ alkyl groups are substituted (two alkyl groups may be the same or different), and an amino group is substituted with one C _{1 to} C ₆ alkyl group. Examples thereof include methylamino, ethylamino, propylamino, isopropylamino, hexylamino and the like, and examples of the amino group substituted with two C _{1 to} C ₆ alkyl groups include, for example, dimethylamino, diethylamino, ethylmethyl. Amino, dihexylamino and the like are preferable.

Similarly, the "alkoxycarbonyl group" is a group --COO-- in which an oxygen atom is bonded to a C ₁ -C ₆ alkyl group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Tertiary butoxycarbonyl and the like are preferred.

Similarly, "aryloxycarbonyl group"
As the above, a phenyloxycarbonyl group in which a phenyl group is bonded to the oxygen atom of the group —COO— is preferable.

Similarly, the “acyl group” is a carbonyl group (group —CO—) to which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded, and examples thereof include formyl and
Acetyl, propanoyl, benzoyl and the like are preferable.

Similarly, as the "acylamino group", an amino group substituted with the above-mentioned acyl group, for example, acetamino, propanoylamino, benzoylamino and the like are preferable.

Similarly, the "acyloxy group" is a group -COO- in which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded to, for example, acetoxy, propanoyloxy, benzoyloxy. Etc. are preferred.

R ⁷ is an alkyl group, an aryl group or an alkoxyl group (these alkyl groups, aryl groups or alkoxyl groups are halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxyl group, phenyl group, amino group, alkylamino group, One or more groups selected from the group consisting of an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group may be contained as a substituent.) Is.

The "alkyl group" for R ⁷ is a straight chain or branched chain alkyl, for example, C ₁ -C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl and the like. C ₈ alkyl group is preferable.

Similarly, the "aryl group" for R ⁷ is preferably a phenyl group.

Similarly, an "alkoxyl group" for R ⁷
Is a straight-chain or branched-chain alkoxyl group, and is preferably a C ₁ -C ₈ alkoxyl group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy.

Here, the substituent of the alkyl group, aryl group or alkoxyl group for R ⁷ will be described.

The bonding position of the substituent is the alkyl group,
It may be at any position of the aryl group or the alkoxyl group.

The "alkyl group" as the substituent of the aryl group in R ⁷ includes straight chain or branched chain alkyl,
For example, C ₁ -C ₆ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl are preferable.

"Alkoxyl group" as a substituent of the alkyl group, aryl group or alkoxyl group for R ⁷ .
Is a straight-chain or branched-chain alkoxyl group, and for example, a C ₁ -C ₆ alkoxyl group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy is preferable.

Similarly, as the "aryloxy group",
A phenyloxy group in which a phenyl group is bonded to the group -O- is preferable.

Similarly, as the "alkylamino group",
An amino group substituted with one C ₁ -C ₆ alkyl group,
Alternatively, an amino group in which two C _{1 to} C ₆ alkyl groups are substituted (two alkyl groups may be the same or different), and an amino group is substituted with one C _{1 to} C ₆ alkyl group. Examples thereof include methylamino, ethylamino, propylamino, isopropylamino, hexylamino and the like, and examples of the amino group substituted with two C _{1 to} C ₆ alkyl groups include, for example, dimethylamino, diethylamino, ethylmethyl. Amino, dihexylamino and the like are preferable.

Similarly, as the "aminoalkyl group",
A C ₁ -C ₆ alkyl group substituted with an amino group, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl. Preferred are amino C ₁ -C ₆ alkyl groups such as

Similarly, an "alkylaminoalkyl group" is a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₆ alkylamino group, such as methylaminomethyl, 2
-Methylaminoethyl, dimethylaminomethyl and the like are preferable.

Similarly, the “alkoxycarbonyl group” is a group —COO— having an oxygen atom bonded to a C ₁ -C ₆ alkyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Tertiary butoxycarbonyl and the like are preferred.

Similarly, "aryloxycarbonyl group"
As the above, a phenyloxycarbonyl group in which a phenyl group is bonded to the oxygen atom of the group —COO— is preferable.

Similarly, the “acyl group” is a carbonyl group (group —CO—) to which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded, and examples thereof include formyl and
Acetyl, propanoyl, benzoyl and the like are preferable.

Similarly, as the "acylamino group", an amino group substituted with the above acyl group, for example, acetamino, propanoylamino, benzoylamino and the like are preferable.

Similarly, the “acyloxy group” is a group —COO— having a carbon atom bonded to a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group, such as acetoxy, propanoyloxy and benzoyloxy. Etc. are preferred.

R ⁹ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heterocyclic group or a group.

[0123]

[Chemical 21] (Q ¹ and Q ^{2, which} may be the same or different, each represents a hydrogen atom or an alkyl group. Further, Q ¹ and Q ² are bonded to each other to form a group together with an adjacent nitrogen atom.

[0124]

[Chemical formula 22] (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. )

(These are alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclic groups and groups.

[0126]

[Chemical formula 23] Is an alkyl moiety (when Q ¹ and / or Q ² is an alkyl group) is a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group. , An alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, an acyloxy group, and a nitrogen-containing heterocyclic group having a size of a 3- to 8-membered ring (the nitrogen-containing heterocyclic group is One or more alkyl groups may be present on the ring-constituting atoms, and one or more groups selected from the group consisting of: ).

The "alkyl group" for R ⁹ is a straight chain or branched chain alkyl, for example, C ₁ -C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl and the like. C ₈ alkyl group is preferable.

Similarly, the "alkenyl group" for R ⁹ is a straight chain or branched chain alkenyl, for example, C ₂ -C ₆ alkenyl such as vinyl, allyl, isopropenyl, 2-methyl-1-propenyl, butenyl and the like. Groups are preferred.

Similarly, the "alkynyl group" for R ⁹ is a straight chain or branched chain alkynyl, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl, 1,1-
Dimethyl-2-propynyl, 2-pentynyl, is C ₂ -C ₆ alkenyl group of the 2-hexynyl or the like.

Similarly, the "cycloalkyl group" for R ⁹ is preferably a C ₃ -C ₇ cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Similarly, the "aryl group" for R ⁹ is preferably a phenyl group.

Similarly, as the "heterocyclic group" for R ⁹ , one or more atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as a ring-constituting atom are
A substituent derived from a saturated or unsaturated heterocyclic compound containing one or more heterocyclic compounds, and these heterocyclic groups may be bonded at any position. The heterocyclic group may be monocyclic or bicyclic, and examples of the monocyclic heterocycle include pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole and oxax. Substituents derived from 4-membered to 9-membered heterocyclic compounds such as diazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine, and thiomorpholine are preferable. . The bicyclic heterocyclic group is preferably a substituent derived from benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, chroman and the like.

Similarly, the "group" in R ⁹

[0134]

[Chemical formula 24] (Q ¹ and Q ^{2, which} may be the same or different, each represents a hydrogen atom or an alkyl group. Further, Q ¹ and Q ² are bonded to each other to form a group together with an adjacent nitrogen atom.

[0135]

[Chemical 25] (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. ) "Is a compound in which at least ^one of Q ¹ and Q ² is an alkyl group, or a compound with a nitrogen atom which Q ¹ and Q ² are bonded to and is adjacent to.

[0136]

[Chemical formula 26] (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) Are preferably formed.

When at least ^one of Q ¹ and Q ² is an alkyl group, the alkyl group is C ₁ -C ₆
An alkyl group is preferred, and when Q ¹ and Q ² are both alkyl groups, the two alkyl groups may be different.

As the saturated heterocyclic group having a size of 5 to 6 membered ring, a group derived from pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine is preferable.

Y is preferably a C ₁ -C ₃ alkyl group, and the alkyl group substituting on the carbon atom which is a constituent atom of the heterocyclic group is preferably a C ₁ -C ₃ alkyl group.

Here, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heterocyclic group or group for R ⁹

[0141]

[Chemical 27] Substituents in the alkyl moiety of (when Q ¹ and / or Q ² is an alkyl group) are explained.

The bonding position of the substituent is the alkyl group,
Alkenyl group, alkynyl group, cycloalkyl group, aryl group, heterocyclic group or group

[0143]

[Chemical 28] May be at any position of the alkyl moiety of (when Q ¹ and / or Q ² is an alkyl group).

The "alkyl group" as a substituent of the cycloalkyl group, aryl group or heterocyclic group for R ⁹ includes straight chain or branched chain alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
C ₁ -C ₆ alkyl groups such as tertiary butyl, pentyl and hexyl are preferred.

Similarly, as the "aminoalkyl group",
A C ₁ -C ₆ alkyl group substituted with an amino group, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl. Amino C ₁ -C such as
_{A 6} alkyl group is preferred.

Similarly, "alkylaminoalkyl group"
And then C₁~ C₆C to the alkyl group ₁~ C₆Alkyla
Substituted with a mino group, for example, methylaminomethyi
2-methylaminoethyl, dimethylaminomethyl, etc.
Is preferred.

An alkyl group, an alkenyl group in R ⁹ ;
Alkynyl group, cycloalkyl group, aryl group, heterocyclic group or group

[0148]

[Chemical 29] The "alkoxyl group" as a substituent of the alkyl moiety (when Q ¹ and / or Q ² is an alkyl group) of
A straight-chain or branched-chain alkoxyl group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy,
C ₁ -C ₆ alkoxyl groups such as hexyloxy is preferred.

Similarly, as the "aryloxy group",
A phenyloxy group in which a phenyl group is bonded to the group -O- is preferable.

Similarly, as the "alkylamino group",
An amino group substituted with one C ₁ -C ₆ alkyl group,
Alternatively, an amino group in which two C _{1 to} C ₆ alkyl groups are substituted (two alkyl groups may be the same or different), and an amino group is substituted with one C _{1 to} C ₆ alkyl group. as, for example, methylamino, ethylamino, propylamino, isopropylamino, hexylamino, cyclohexylamino and the like, C ₁ -C amino group ₆
As those having two alkyl groups substituted, for example, dimethylamino, diethylamino, ethylmethylamino, dihexylamino and the like are preferable.

Similarly, "alkoxycarbonyl group"
Is a group --COO-- with an oxygen atom having C ₁~ C₆Alkyl group
Bound to, for example, methoxycarbonyl, etoxy
Sicarbonyl, propoxycarbonyl, isopropoxy
Carbonyl, tertiary butoxycarbonyl and the like are preferable.

Similarly, "aryloxycarbonyl group"
As the above, a phenyloxycarbonyl group in which a phenyl group is bonded to the oxygen atom of the group —COO— is preferable.

Similarly, the “acyl group” is a carbonyl group (group —CO—) to which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded, and examples thereof include formyl and
Acetyl, propanoyl, benzoyl and the like are preferable.

Similarly, as the "acylamino group", an amino group substituted with the above acyl group, for example, acetamino, propanoylamino, benzoylamino and the like are preferable.

Similarly, the "acyloxy group" is a group -COO- in which a hydrogen atom, a C ₁ -C ₆ alkyl group or an aryl group is bonded to, for example, acetoxy, propanoyloxy, benzoyloxy. Etc. are preferred.

Similarly, a nitrogen-containing heterocyclic group having a size of a 3- to 8-membered ring (the nitrogen-containing heterocyclic group may have one or more alkyl groups on the constituent atoms of the ring). Is preferable, for example, a substituent derived from a heterocyclic compound such as pyrrole, pyrrolidine, imidazolidine, pyrazolidine, pyridine, piperidine, piperazine, morpholine and thiomorpholine. A methyl group is preferred as the alkyl group that substitutes on the constituent atoms.

In the present invention, the configuration shown in Chemical formula 30 is preferable.

[0158]

Embedded image

Further, the configuration of the 3'position to which the substituent R ⁶ is bonded includes both configurations, but the configuration of the same as that of natural taxol is more preferred.

The following are preferable substituents for the compound of the present invention.

R ¹ is preferably an alkyl group, an alkyl group having a substituent, or an alkynyl group.

The alkyl group preferably has 1 to 6 carbon atoms, and the alkynyl group preferably has 2 to 6 carbon atoms.

The substituent of the alkyl group is preferably a halogen atom, a phenyl group, a hydroxyl group or an alkylamino group.

The halogen atom is particularly preferably a fluorine atom.

R ¹ is methyl, ethyl, propyl, fluoromethyl, trifluoromethyl, benzyl,
2,3-dihydroxypropyl, allyl and diethylaminoethyl are particularly preferred.

Most preferably, R ¹ is
Examples include methyl, ethyl, propyl and allyl.

R ² is preferably a hydrogen atom, an alkyl group, an alkyl group having a substituent or an alkynyl group.

The alkyl group preferably has 1 to 6 carbon atoms, and the alkynyl group preferably has 2 to 6 carbon atoms.

The substituent of the alkyl group is preferably a halogen atom, a phenyl group or a hydroxyl group.

The halogen atom is particularly preferably a fluorine atom.

R ² is particularly preferably a hydrogen atom or methyl.

The most preferable one as R ² is
An example is a hydrogen atom.

R ³ is a hydrogen atom, a hydroxyl group, or a group —OCOR ⁹ , and R ⁹ is an alkyl group, a heterocyclic group or a group.

[0174]

[Chemical 31] (Q ¹ and Q ^{2, which} may be the same or different, each represents a hydrogen atom or an alkyl group. Further, Q ¹ and Q ² are bonded to each other to form a group together with an adjacent nitrogen atom.

[0175]

Embedded image (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. ) (The alkyl group and group

[0176]

[Chemical 33] The alkyl portion of (when Q ¹ and / or Q ² is an alkyl group) may have a substituent. ) Is preferred.

Alkyl groups and groups for R ⁹

[0178]

Embedded image The substituent of the alkyl moiety (when Q ¹ and / or Q ² is an alkyl group) is an amino group, an alkylamino group, a nitrogen-containing heterocyclic group having a size of 5 to 6-membered ring (the nitrogen-containing heterocyclic group). Heterocyclic groups have 1 alkyl group on each ring atom.
You may have one piece or plural pieces. ) Is preferred.

The alkylamino group as a substituent is preferably an amino group in which two C ₁ -C ₃ alkyl groups are substituted (two alkyl groups may be the same or different), and particularly dimethylamino. Groups are preferred.

Similarly, a nitrogen-containing heterocyclic group having a size of a 5- to 6-membered ring (the nitrogen-containing heterocyclic group may have one or more alkyl groups on the constituent atoms of the ring). Group), a group derived from pyridine, morpholine, or thiomorpholine is particularly preferable.

The alkyl group for R ⁹ is preferably one having 1 to 6 carbon atoms, and particularly preferably a methyl group, an ethyl group or a propyl group.

The heterocyclic group for R ⁹ is preferably a group derived from pyridine.

The group of R ⁹

[0184]

Embedded image (Q ¹ and Q ^{2, which} may be the same or different, each represents a hydrogen atom or an alkyl group. Further, Q ¹ and Q ² are bonded to each other to form a group together with an adjacent nitrogen atom.

[0185]

Embedded image (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. ), When ^one of Q ¹ and Q ² is a C ₁ -C ₃ alkyl group and the other is a hydrogen atom, or when Q ¹ and Q ² are bonded to each other and a neighboring nitrogen atom is piperazine, N—C. when forming the ₁ -C ₃ alkyl piperazines are preferred.

R ⁹ is particularly 2-pyridyl, 3-pyridyl, 4-pyridyl, dimethylaminomethyl, 2-
(Dimethylamino) ethyl, 3- (dimethylamino) propyl, morpholinomethyl, 2- (dimethylamino) ethylamino, (2-pyridyl) methylamino, 4-methylpiperazin-1-yl are preferred.

As R ⁴ , a halogen atom and a hydroxyl group are preferable, and among the halogen atoms, a fluorine atom is particularly preferable.

R ⁵ is preferably a halogen atom, a hydrogen atom or an alkyl group. Among the halogen atoms, a fluorine atom is particularly preferable, and among the alkyl groups, a methyl group is particularly preferable.

Most preferred as R ⁴ and R ⁵ are R
Wherein ⁴ is a fluorine atom and R ⁵ is a combination of fluorine atoms,
Examples thereof include those in which R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom, or those in which R ⁴ is a hydroxyl group and R ⁵ is a methyl group.

R ⁶ is preferably an alkenyl group, an aryl group or a heterocyclic group. 2 among the alkenyl groups
A -methyl-1-propenyl group is particularly preferable, and among aryl groups, a phenyl group is particularly preferable.

Among the heterocyclic groups, monocyclic heterocyclic groups are preferable, and further monocyclic 5- to 6-membered heterocyclic groups such as pyrrole, furan, thiophene, pyrrolidine, and tetrahydrofuran. , A group derived from tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine, etc. Is preferred.

Of the heterocyclic groups, a monocyclic 5-membered to 6-membered heterocyclic group is particularly preferable, and 1 atom of an oxygen atom, a nitrogen atom and a sulfur atom is contained as a constituent atom of the ring structure.
Examples of the heterocyclic group include a group derived from pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyran and the like.

The most preferable heterocyclic group is a monocyclic 5-membered to 6-membered heterocyclic group, which contains 1 atom of an oxygen atom, a nitrogen atom and a sulfur atom as a constituent atom of the ring structure.
Unsaturated heterocyclic groups containing 1 unit.

The most preferred specific examples include groups derived from furan, pyridine and pyrrole.

As R ⁷ , an aryl group and an alkoxyl group are preferable, a phenyl group is particularly preferable among the aryl groups, and a tertiary butoxy group is particularly preferable among the alkoxyl groups.

In the case of the taxol derivative of the present invention, which is capable of forming a salt, it may be in the free form or may be an acid addition salt. Examples of acid addition salts include:
Inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, or acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citric acid Organic salts such as salts, maleates, fumarates and lactates can be mentioned.

Next, the steps for producing the compound of the present invention will be described.

The compounds of the present invention represented by the general formula (I)
If R ³ is a hydroxyl group

[0199]

Embedded image

[0200]

[Chemical 38]

A compound of the present invention represented by the general formula (I)
When R ³ is a hydrogen atom or a group —OCOR ⁹

[0202]

[Chemical Formula 39]

[0203]

[Chemical 40]

[Wherein R ²¹ represents a hydrogen atom or a hydroxyl group protected by a protecting group, and examples of the hydroxyl protecting group include a triethylsilyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyl group and the like. Is preferred.

R ²² means a hydroxyl-protecting group, and is preferably a triethylsilyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyl group or the like.

[0206] R ¹¹ is (as the substituent, if having a hydroxyl group, an amino group) R ¹ protected by R ¹ or a protecting group refers to.

[0207] R ¹² is (as the substituent, a hydroxyl group, if having an amino group) R ² protected by R ² or a protecting group refers to.

R ¹³ is a hydrogen atom or —OCOR ⁹ (provided that when R ⁹ is a group having a hydroxyl group or an amino group as a substituent, these hydroxyl group and amino group are protected by a protecting group). means.

R ¹⁴ represents a hydrogen atom, a halogen atom, an alkyl group or a hydroxyl group protected by a protecting group.

R ¹⁵ represents a hydrogen atom, a halogen atom, an alkyl group or a hydroxyl group protected by a protecting group.

[0211] R ¹⁶ is (as the substituent, if having a hydroxyl group, an amino group) R ⁶ that is protected by R ⁶ or a protecting group refers to.

[0212] R ¹⁷ is (as the substituent, if having a hydroxyl group, an amino group) R ⁷ that is protected by R ⁷ or a protecting group refers to.

R ²⁴ and R ²⁵ each independently represent a hydrogen atom, an alkyl group, or an aryl group, and preferred R ²⁴ and R ²⁵ are those in which both are methyl groups and one is paramethoxyphenyl. And the other is a hydrogen atom.

The protective groups for the hydroxyl groups and amino groups of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ include triethylsilyl group, 2,2,2-trichloroethoxycarbonyl group and 1 -Ethoxyethyl group, benzyloxycarbonyl group and the like are preferable.

R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ are the same as above. ] Each reaction step will be described.

A compound represented by the formula (1) (hereinafter referred to as compound
Compounds represented by (1) and other numbers are also the same.
Represent ) → Compound (2) or Compound (1a) → Chemical
Compound (2a) By oxidizing compound (1) or compound (1a), compound (2) or compound (2a) can be obtained.

The oxidation reaction may be carried out, for example, by treating with manganese dioxide in an inert solvent (for example, dioxane) at room temperature or under heating.

Compound (2) → Compound (3), or
Compound (2a) → compound (3a) Depending on the case of R ¹¹ and R ¹² , it can be divided into the following 3 ways. When R ¹² is a hydrogen atom, the compound (2) or the compound (2a) is reacted in a solvent inert to the reaction (eg, tetrahydrofuran) at a reaction temperature of −.
After reacting with a base at 100 ° C. to 0 ° C., a compound represented by R ¹¹ -Z (Z is a halogen atom such as an iodine atom or a bromine atom, or a leaving group such as a methanesulfonyl group or a paratoluenesulfonyl group) And the reaction temperature -1.
By reacting from 00 ° C. to room temperature, the compound (3) or compound (3a) in which R ¹² is a hydrogen atom can be obtained.

Examples of the base used in this step include lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, tertiary butoxy potassium, sodium hydride and the like. .

The base is the compound (2) or the compound (2
1 to 10 equivalents may be used with respect to a).

The compound represented by R ¹¹ -Z is 1 to 100 relative to the compound (2) or the compound (2a).
The equivalent may be used. R ¹² is not a hydrogen atom and R ¹² is the same as R ^11.
When performing the same reaction as in the case that the amount of base increases from 2 to 20 times, increasing the amount of R ¹¹ -Z 2 to 20 times, or equal to 50 ° C. of about increasing the reaction temperature from 10 ° C., By changing the amount of the compound used in the reaction or the reaction conditions (the degree of change depends on the base used and the compound represented by R ¹¹ -Z to be reacted), the hydrogen atom of R ¹² is substituted with R ¹¹ , compound ¹¹ and R ¹² are the same (3) or R ¹² can be obtained compound (3a) is not hydrogen atom, der which R ¹² is different from R ¹¹
In a solvent inert to the reaction (for example, compound (3) or compound (3a) in which R ¹² is a hydrogen atom,
Tetrahydrofuran, etc., reaction temperature -100 ° C to 0 ° C
And a compound represented by R ¹² -Z (R
¹² is different from R ¹¹ and Z is the same as above. ) At a reaction temperature of −100 ° C. to room temperature to give R
¹² is not hydrogen atom, R ¹² can be obtained compound is different from the R ¹¹ (3) or compound (3a).

[0222] The process for obtaining a compound having R ¹¹ and R ¹² of interest (3) or compound (3a), as described above, the reaction is carried out using R ¹¹ -Z and / or R ¹² -Z Methods and compounds having groups that are easily converted to R ¹¹ and R ¹² (R ¹¹⁰ —Z and / or R ¹²⁰ —
The reaction was carried out using a Z), then performed the organic chemical conversion reaction usually used, the R ¹¹⁰ and R ¹²⁰ R ¹¹
And there is a method of converting into R ¹² .

Compound (3) → Compound (4), or
Compound (3a) → Compound (4a) → Compound (4b) Compound (4) or compound (4a) can be obtained by reducing compound (3) or compound (3a).

The reduction reaction is carried out, for example, in a solvent (for example, methanol or tetrahydrofuran) and a reducing agent (for example,
Sodium borohydride).

The obtained compound (4a) was treated with R ⁹ COOH in the presence of a base catalyst such as 4-dimethylaminopyridine (provided that R ⁹ is a hydroxyl group or a group having an amino group as a substituent, these hydroxyl groups and Amino group is protected by a protecting group) or a carboxylic acid represented by R is reacted with a condensing agent such as dicyclohexylcarbodiimide or di (2-pyridyl) carbonate, or R
⁹ COCl (provided that R ⁹ is a group having a hydroxyl group or an amino group as a substituent, these hydroxyl group and amino group are protected by a protecting group), and then the acid chloride is represented by a base such as pyridine or triethylamine. R ¹³ is —OCOR ⁹ by reacting with (provided that when R ⁹ is a group having a hydroxyl group or an amino group as a substituent, these hydroxyl group and amino group are protected by a protecting group) The compound (4b) can be obtained.

It is to be noted that R ⁹ is a group

[0227]

Embedded image (Q ¹ and Q ^{2, which} may be the same or different, each represents a hydrogen atom or an alkyl group. Further, Q ¹ and Q ² are bonded to each other to form a group together with an adjacent nitrogen atom.

[0228]

Embedded image (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. ), R ⁹ is a phenyl group, p
After synthesizing the compound of the -nitrophenyl group, the formula

[0229]

[Chemical 43] (Q ¹ and Q ² are the same as the above), and can be obtained by reacting with an amine.

The compound (4b) in which R ¹³ is a hydrogen atom is
Compound (4a) can be obtained by carrying out a reaction similar to the method described in the literature (J. Org. Chem., 58, 5028 (1993) or Tetrahedron Lett., 34, 4921 (1993) etc.).

Various compounds can be synthesized by incorporating various side chains at the 13-position of the compound (4) or compound (4b) thus obtained.

Compound (4) → Compound (5) or compound
(6), or compound (4b) → compound (5a)
Is compound (6a) compound (4) or compound (4b) and compound (7),
By condensing the compound (8) or the compound (9), the compound (5) or the compound (6), or the compound (5a) or the compound (6a) can be obtained.

When the compound (7) or the compound (8) is used in the condensation reaction for obtaining the compound (5) or the compound (5a) from the compound (4) or the compound (4b),
A method of using a carboxylic acid activator such as di (2-pyridyl) carbonate or dicyclohexylcarbodiimide in the presence of a base catalyst such as 4-dimethylaminopyridine is known (Tetrahedron Lett., 33, 5185 ( 199
2), J. Am. Chem. Soc., 110, 5917 (1988) etc.).

When the compound (9) is used, a method using a base such as sodium hexamethyldisilazide is known (Tetrahedron Lett., 34, 4149 (1993).
etc).

Compound (5) or Compound (6) → Compound
(I), or compound (5a) or compound (6a)
→ Compound (I) of the present invention can be obtained by carrying out a commonly used organic chemical conversion reaction such as removing the protecting group of compound (I).

The compound (I) of the present invention in which R ³ is a group —OCOR ⁹ is a compound of the formula (5) or the compound (6).
The protecting group R ²² at the 0-position is removed to convert the 10-position to a hydroxyl group, and then the compound (4a) described above is converted to the compound (4
It can also be obtained by converting the 10-position to —OCOR ⁹ using the method of converting to b), and then performing a conversion reaction such as removing the protecting group.

The compound (1) or compound (1a) as a starting material can be synthesized from 10-deacetylbaccatin III, R ²¹ is a hydroxyl group protected by a triethylsilyl group, and R ²² is a triethylsilyl group. (WO 93/06079 etc.), R ²¹ is a hydroxyl group protected by a 2,2,2-trichloroethoxycarbonyl group, R
Compounds in which ²² is a 2,2,2-trichloroethoxycarbonyl group (Tetrahedron, 42, 4451 (1986) and the like) are known.

Compound (7), compound (8), and compound (9), which are also raw materials for production, are
According to the method described in trahedron Lett., 33 , 5185 (1992),
Compound (8) was prepared according to the method described in J. Am. Chem. Soc., 110 , 5917 (1988), and compound (9) was prepared by Tetrahedron Lett.
34 , 4149 (1993).

Next, a detailed description will be given with reference to Examples.

[0240]

【Example】

 Example 1

[0241]

[Chemical 44]

Step 1: 10-deacetyl-13-deoxy-13-
Oxo-7,10-bis-O-triethylsilylbaccatin II
The I 2.91 g of 10-deacetyl-7,10-bis -O- (triethylsilyl) baccatin III was dissolved in dioxane 80 ml, and stirred for 40 hours at room temperature was added activated manganese dioxide 11.4 g. The reaction solution was filtered through Celite, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (elution solvent; ethyl acetate: hexane = 1: 4 (v / v)),
2.35 g of the title compound was obtained as a colorless solid.

Melting point: 217-219 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.76 (m, 12H), 0.94-
1.04 (m, 18H), 1.21 (s, 3H), 1.28 (s, 3H), 1.65 (s, 3H), 1.
85-1.91 (m, 1H), 2.05 (s, 3H), 2.19 (s, 3H), 2.51-2.59 (m,
1H), 2.63 (d, 1H, J = 20Hz), 2.92 (d, 1H, J = 20Hz), 3.93 (d, 1
H, J = 7Hz), 4.12 (d, 1H, J = 9Hz), 4.32 (d, 1H, J = 9Hz), 4.41
(dd, 1H, J = 7Hz, 10Hz), 4.91 (d, 1H, J = 9Hz), 5.37 (s, 1H),
5.68 (d, 1H, J = 7Hz), 7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8H
z), 8.08 (d, 2H, J = 8Hz) .IR (KBr): 3504, 2960, 2916, 2884, 2744, 1730, 167
6, 1606, 1456 cm ^-1 MS-FAB: 771 (MH ⁺ )

Step 2: 13-deoxy-4,10-dideacetyl-
13-oxo-4-O-propionyl-7,10-bis-O-triethyl
Lusilylbaccatin III Lithium bis (triethylsilyl) amide (1M tetrahydrofuran solution) (1.04 ml) was added to anhydrous tetrahydrofuran (3 ml) and cooled to -45 ° C. Then, 200 mg of the compound obtained in Step 1 above was treated with 2 m of anhydrous tetrahydrofuran.
The solution dissolved in l was added dropwise, and after 10 minutes, methyl iodide was added.
0.10 ml was added dropwise with a syringe and stirred at the same temperature for 1 hour. A saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to give the title compound 14
7 mg was obtained as a colorless solid.

Melting point: 189-191 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.77 (m, 12H), 0.94-
1.04 (m, 18H), 1.20 (s, 3H), 1.23 (t, 3H, J = 7Hz), 1.28 (s, 3
H), 1.65 (s, 3H), 1.86-1.92 (m, 1H), 2.04 (s, 3H), 2.40-
2.56 (m, 3H), 2.60 (d, 1H, J = 20Hz), 2.92 (d, 1H, J = 20Hz),
3.93 (d, 1H, J = 7Hz), 4.13 (d, 1H, J = 9Hz), 4.32 (d, 1H, J = 9H
z), 4.44 (dd, 1H, J = 7Hz, 10Hz), 4.86 (d, 1H, J = 8Hz), 5.37
(s, 1H), 5.68 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.61 (t,
1H, J = 8Hz), 8.07-8.09 (m, 2H) .IR (KBr): 3664, 3512, 2960, 2884, 2344, 1874, 173
0, 1676, 1606, 1456 cm ^-1 MS-FAB: 785 (MH ⁺ )

Step 3: 4,10-dideacetyl-4-O-propyi
Onyl-7,10-bis-O-triethylsilyl baccatin
III 175 mg of the compound obtained in the above step 2 was added to 10 ml of methanol.
The mixture was dissolved in water, and 169 mg of sodium borohydride was added at room temperature, followed by stirring for 4 hours. The reaction solution was diluted with chloroform and washed with a saturated ammonium chloride aqueous solution. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 3 (v / v))
Purification gave 113 mg of the title compound as a colorless solid.

Melting point: 177-179 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.73 (m, 12H), 0.95-
1.02 (m, 18H), 1.05 (s, 3H), 1.19 (s, 3H), 1.24 (t, 3H, J = 7H
z), 1.66 (s, 3H), 1.86-1.92 (m, 1H), 2.02 (s, 3H), 2.22-
2.25 (m, 2H), 2.51-2.65 (m, 3H), 3.91 (d, 1H, J = 7Hz), 4.15
(d, 1H, J = 8Hz), 4.29 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 1
0Hz), 4.82 (m, 1H), 4.90 (d, 1H, J = 8Hz), 5.22 (s, 3H), 5.6
1 (d, 1H, J = 7Hz), 7.46 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz),
8.10-8.12 (m, 2H) .MS-FD: 786 (M ⁺ )

Step 4: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Isoserinyl] -4,10-dideacetyl-4-O-propionyl
-7,10-Bis-O-triethylsilylbaccatin III (2R, 3S) -N- (tert-butoxycarbonyl) -N, O-isopropylidene-3-phenylisoserine 77.2 mg in toluene
Dissolve in 4 ml and dicyclohexylcarbodiimide 53.
0 mg was added and the mixture was stirred at room temperature for 10 minutes. To this solution, 63.0 mg of the compound obtained in Step 3 above and 10 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at 80 ° C. for 1 hour.
After allowing to cool, the mixture was diluted with ethyl acetate and washed with a 1N hydrochloric acid aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated saline solution in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent; ethyl acetate:
Hexane = 1: 4 (v / v)) to give the title compound (87.0 mg) as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.68 (m,
12H), 0.93-1.04 (m, 21H), 1.11 (br s, 9H), 1.22 (s, 6H),
1.64 (s, 3H), 1.78 (s, 3H), 1.80 (s, 3H), 1.87 (s, 3H), 2.
01-2.07 (m, 2H), 2.11 (d, 2H, J = 9Hz), 2.45-2.53 (m, 1H),
3.78 (d, 1H, J = 7Hz), 4.10 (d, 1H, J = 8Hz), 4.22 (d, 1H, J = 8H)
z), 4.38 (dd, 1H, J = 7Hz, 10Hz), 4.41 (d, 1H, J = 7Hz), 4.79
(d, 1H, J = 8Hz), 5.02 (br, 1H), 5.16 (s, 1H), 5.63 (d, 1H, J =
7Hz), 6.22 (t, 1H, J = 9Hz), 7.30-7.39 (m, 5H), 7.49 (t, 2H,
J = 8Hz), 7.63 (t, 1H, J = 8Hz), 8.05 (d, 2H, J = 8Hz).

Step 5: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenylpropionyl] -4,10-
Dideacetyl-4-O-propionylbaccatin III 87.0 mg of the compound obtained in the above step 4 was dissolved in 5 ml of formic acid and stirred at room temperature for 1 hour. Formic acid was distilled off under reduced pressure, and the residue was mixed solvent of chloroform and methanol (10: 1 (v / v)
) And washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 5 ml of tetrahydrofuran, 40 μl of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 20: 1 (v / v)) to give 38.6 mg of the title compound.
Was obtained as a colorless solid.

Melting point: 185-188 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.23 (t, 3H, J =
7Hz), 1.25 (s, 3H), 1.33 (s, 9H), 1.75 (s, 3H), 1.86 (s, 3
H), 2.27-2.29 (m, 2H), 2.54-2.67 (m, 3H), 3.39 (br, 1H),
3.91 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.25 (m, 1H), 4.
32 (d, 1H, J = 8Hz), 4.62 (br s, 1H), 4.89 (d, 1H, J = 8Hz), 5.
21 (s, 1H), 5.37 (br d, 1H, J = 9Hz), 5.68 (d, 1H, J = 7Hz), 6.
21 (t, 1H, J = 9Hz), 7.31-7.45 (m, 5H), 7.50 (t, 2H, J = 8Hz),
7.62 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz) .IR (KBr): 3664, 3452, 3068, 2984, 2944, 1716, 1604,
1588, 1496 cm ^-1 MS-FAB: 822 (MH ⁺ )

Example 2

[0253]

Embedded image

Step 1: 13-deoxy-4,10-dideacetyl-
4-O-isobutyryl-13-oxo-7,10-bis-O-triethyl
Lusilylbaccatin III Lithium bis (triethylsilyl) amide (1M tetrahydrofuran solution) 2.59 ml anhydrous tetrahydrofuran
It was added to 2 ml and cooled to -45 ° C. Then, Example 1
A solution prepared by dissolving 200 mg of the compound obtained in step 1 in 2 ml of anhydrous tetrahydrofuran was added dropwise, and after 10 minutes, 0.26 ml of methyl iodide was added by a syringe and stirred for 2 hours.
A saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to give 63 mg of the title compound.
Was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.57-0.77 (m,
12H), 0.95-1.04 (m, 18H), 1.19 (s, 3H), 1.25 (d, 3H, J = 7H
z), 1.28 (s, 3H), 1.35 (d, 3H, J = 7Hz), 1.66 (s, 3H), 1.86-
1.92 (m, 1H), 2.04 (s, 3H), 2.51-2.66 (m, 2H), 2.61 (d, 1H,
J = 20Hz), 2.93 (d, 1H, J = 20Hz), 3.95 (d, 1H, J = 7Hz), 4.14
(d, 1H, J = 9Hz), 4.32 (d, 1H, J = 9Hz), 4.45 (dd, 1H, J = 7Hz, 10
Hz), 4.76 (d, 1H, J = 8Hz), 5.37 (s, 1H), 5.68 (d, 1H, J = 7H
z), 7.47 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09-8.11
(m, 2H).

Step 2: 4,10-dideacetyl-4-O-isobu
Tyryl-7,10-bis-O-triethylsilyl baccatin II
I The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 1 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.70 (m,
12H), 0.93-1.04 (m, 18H), 1.05 (s, 3H), 1.20 (s, 3H), 1.2
6 (d, 3H, J = 7Hz), 1.38 (d, 3H, J = 7Hz), 1.67 (s, 3H), 1.85-
1.91 (m, 1H), 2.02 (s, 3H), 2.22-2.28 (m, 2H), 2.51-2.58
(m, 1H), 2.77-2.85 (m, 1H), 3.93 (d, 1H, J = 7Hz), 4.16 (d, 1
H, J = 8Hz), 4.29 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 10Hz),
4.79 (m, 1H), 4.79 (d, 1H, J = 7Hz), 5.22 (s, 3H), 5.61 (d, 1
H, J = 7Hz), 7.45 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.12-
8.14 (m, 2H).

Step 3: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4,10-dideacetyl-4-O-isobutyryl-7,
10-Bis-O-triethylsilylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 4 of Example 1 to obtain the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.70 (m,
12H), 0.94-1.04 (m, 18H), 1.08 (br s, 9H), 1.10 (d, 3H, J
= 7Hz), 1.21 (d, 3H, J = 7Hz), 1.23 (s, 6H), 1.64 (s, 3H), 1.
77 (s, 3H), 1.79 (s, 3H), 1.87 (s, 3H), 2.10-2.19 (m, 3H),
2.45-2.53 (m, 1H), 3.79 (d, 1H, J = 7Hz), 4.10 (d, 1H, J = 8H
z), 4.22 (d, 1H, J = 8Hz), 4.40 (dd, 1H, J = 7Hz, 10Hz), 4.43
(d, 1H, J = 7Hz), 4.69 (d, 1H, J = 8Hz), 5.04 (br, 1H), 5.16
(s, 1H), 5.64 (d, 1H, J = 7Hz), 6.21 (t, 1H, J = 8Hz), 7.30-7.
39 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.05-
8.07 (m, 2H).

Step 4: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenylpropionyl] -4,10-
Dideacetyl-4-O-isobutyrylbaccatin III The compound obtained in Step 3 above was reacted in the same manner as in Step 5 of Example 1 to give the title compound as a colorless solid.

Melting point: 174-177 ° C. ¹ H-NMR (CDCl ₃ /TMS)δ(ppm):1.13(s,3H), 1.20 (d, 3H, J = 7
Hz), 1.26 (s, 3H), 1.33 (s, 9H), 1.37 (d, 3H, J = 7Hz), 1.76
(s, 3H), 1.87 (s, 3H), 2.28-2.33 (m, 2H), 2.54-2.62 (m, 1
H), 2.85-2.89 (m, 1H), 3.31 (br, 1H), 3.92 (d, 1H, J = 7H
z), 4.20 (d, 1H, J = 8Hz), 4.28 (m, 1H), 4.32 (d, 1H, J = 8Hz),
4.63 (br s, 1H), 4.79 (d, 1H, J = 8Hz), 5.20 (s, 1H), 5.31
(d, 1H, J = 10Hz), 5.70 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 9Hz),
7.31-7.45 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8H
z), 8.14 (d, 2H, J = 8Hz) .IR (KBr): 3452, 3068, 2980, 2936, 1722, 1604, 1586,
1496 cm ^-1 MS-FAB: 836 (MH ⁺ )

Example 3: 13-Deoxy-4,10-dideacetyl-4-O-isobutyryl-13-oxo-7,10-bis-O-triethylsilylbaccatin III

[0263]

Embedded image

2.00 ml of lithium bis (triethylsilyl) amide (1M tetrahydrofuran solution) was added to 2 ml of anhydrous tetrahydrofuran and cooled to -45 ° C. Then, a solution prepared by dissolving 104 mg of the compound obtained in Step 2 of Example 1 in 2 ml of anhydrous tetrahydrofuran was added dropwise, 10 minutes later, 0.20 ml of methyl iodide was added dropwise with a syringe, and the mixture was stirred for 2 hours. A saturated ammonium chloride aqueous solution was added to this solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to give the same title compound as the compound of Step 1 of Example 2.
5 mg was obtained as a colorless amorphous solid.

Example 4

[0266]

[Chemical 47]

Step 1: 4-O-butyryl-13-deoxy-4,10
-Dideacetyl-13-oxo-7,10-bis-O-triethyloxy
Rilbaccatin III The reaction of Step 2 of Example 1 was similarly performed using sodium bis (triethylsilyl) amide in place of lithium bis (triethylsilyl) amide and ethyl iodide in place of methyl iodide to obtain the title compound. Was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.
57-0.77 (m, 12H), 0.95-1.04
(M, 18H), 1.07 (t, 3H, J = 7H
z), 1.20 (s, 3H), 1.28 (s, 3)
H), 1.65 (s, 3H), 1.71-1.76.
(M, 2H), 1.85-1.92 (m, 1H),
2.03 (s, 3H), 2.33-2.49 (m, 2
H), 2.52-2.60 (m, 1H), 2.61.
(D, 1H, J = 20 Hz), 2.92 (d, 1H, J
= 20 Hz), 3.93 (d, 1H, J = 7 Hz),
4.13 (d, 1H, J = 9 Hz), 4.31 (d,
1H, J = 9 Hz), 4.43 (dd, 1H, J = 7)
Hz, 10 Hz), 4.87 (d, 1H, J = 8H
z), 5.37 (s, 1H), 5.68 (d, 1H,
J = 7 Hz), 7.48 (t, 2H, J = 8 Hz),
7.62 (t, 1H, J = 8Hz), 8.08 (d,
2H, J = 8 Hz).

Step 2: 4-O-butyryl-4,10-dideacease
Tyl-7,10-bis-O-triethylsilylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 1 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.73 (m,
12H), 0.95-1.02 (m, 18H), 1.02 (s, 3H), 1.05 (t, 3H, J = 7H
z), 1.19 (s, 3H), 1.66 (s, 3H), 1.78 (q, 2H, J = 7Hz), 1.82-
1.92 (m, 1H), 2.02 (s, 3H), 2.24 (d, 2H, J = 8Hz), 2.51-2.58
(m, 3H), 3.91 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.29 (d,
1H, J = 8Hz), 4.43 (dd, 1H, J = 7Hz, 10Hz), 4.82 (m, 1H), 4.90
(d, 1H, J = 8Hz), 5.22 (s, 3H), 5.61 (d, 1H, J = 7Hz), 7.46 (t,
2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.10-8.12 (m, 2H).

Step 3: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4-O-butyryl-4,10-dideacetyl-7,10-
Bis-O-triethylsilylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 4 of Example 1 to obtain the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.55-0.72 (m, 1
2H), 0.91-1.02 (m, 21H), 1.13 (br s, 9H), 1.21 (s, 6H),
1.64 (s, 3H), 1.77 (s, 3H), 1.81 (s, 3H), 1.89 (s, 3H), 2.
02-2.07 (m, 2H), 2.11-2.14 (m, 2H), 2.47-2.55 (m, 1H),
3.81 (d, 1H, J = 7 Hz), 4.11 (d, 1)
H, J = 8Hz), 4.23 (d, 1H, J = 8H
z), 4.39 (dd, 1H, J = 7Hz, 10H
z), 4.42 (d, 1H, J = 7 Hz), 4.81
(D, 1H, J = 9 Hz), 5.09 (br, 1
H), 5.17 (s, 1H), 5.63 (d, 1H,
J = 7 Hz), 6.21 (t, 1H, J = 8 Hz),
7.30-7.36 (m, 5H), 7.48 (t, 2
H, J = 8Hz), 7.62 (t, 1H, J = 8H
z), 8.05 (d, 2H, J = 8Hz).

Step 4: 13-O-[(2R, 3S) -3- (tert-but
Xycarbonylamino) -3-phenylpropionyl] -4-O
-Butyryl-4,10-dideacetylbaccatin III The compound obtained in Step 3 above was reacted in the same manner as in Step 5 of Example 1 to give the title compound as a colorless solid.

Melting point: 164-168 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.94 (t, 3H, J = 7Hz), 1.13
(s, 3H), 1.24 (s, 3H), 1.34 (s, 9H), 1.75 (s, 3H), 1.84 (s,
3H), 1.70-1.86 (m, 3H), 2.26-2.28 (m, 2H), 2.44-2.62
(m, 3H), 3.41 (br, 1H), 3.91 (d, 1H, J = 7Hz), 4.19 (d, 1H, J =
8Hz), 4.25 (m, 1H), 4.31 (d, 1H, J = 8Hz), 4.62 (br s, 1H),
4.89 (d, 1H, J = 8Hz), 5.21 (s, 1H), 5.40 (br d, 1H, J = 9Hz),
5.67 (d, 1H, J = 7Hz), 6.17 (t, 1H, J = 8Hz), 7.29-7.45 (m, 5
H), 7.49 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.11 (d, 2H, J
= 8Hz) .IR (KBr): 3456, 3072, 2980, 2944, 1720, 1604, 1586,
1496 cm ^-1 MS-FAB: 836 (MH ⁺ )

Example 5

[0276]

Embedded image

Step 1: 13-deoxy-4,10-dideacetyl
-13-oxo-4-O- (4-pentenoyl) -7,10-bis-O-tri
Ethylsilylbaccatin III A reaction similar to step 2 of Example 1 was carried out using sodium bis (triethylsilyl) amide in place of lithium bis (triethylsilyl) amide and allyl iodide in place of methyl iodide. The title compound was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.5
6-0.77 (m, 12H), 0.95-1.04
(M, 18H), 1.20 (s, 3H), 1.28
(S, 3H), 1.65 (s, 3H), 1.85-
1.92 (m, 1H), 2.03 (s, 3H),
2.44-2.66 (m, 5H), 2.62 (d, 1)
H, J = 20 Hz), 2.91 (d, 1H, J = 20)
Hz), 3.93 (d, 1H, J = 7 Hz), 4.1
2 (d, 1H, J = 8Hz), 4.31 (d, 1H,
J = 8 Hz), 4.42 (dd, 1H, J = 7 Hz,
10Hz), 4.85 (d, 1H, J = 8Hz),
5.10 (dd, 1H, J = 1.5Hz, 10Hz),
5.17 (dd, 1H, J = 1.5Hz, 17Hz),
5.37 (s, 1H), 5.68 (d, 1H, J =
7 Hz), 5.87-5.97 (m, 1H), 7.4
8 (t, 2H, J = 8Hz), 7.62 (t, 1H,
J = 8 Hz), 8.07-8.09 (m, 2H).

Step 2: 4,10-dideacetyl-4-O- (4
-Pentenoyl) -7,10-bis-O-triethylsilylbac
Catin III The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 1 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.73 (m,
12H), 0.95-1.02 (m, 18H), 1.05 (s, 3H), 1.19 (s, 3H), 1.6
6 (s, 3H), 1.85-1.91 (m, 1H), 2.01 (s, 3H), 2.23-2.30 (m,
2H), 2.47-2.58 (m, 2H), 2.68 (t, 2H, J = 7Hz), 3.91 (d, 1H, J
= 7Hz), 4.15 (d, 1H, J = 8Hz), 4.29 (d, 1H, J = 8Hz), 4.43 (dd,
1H, J = 7Hz, 10Hz), 4.82 (m, 1H), 4.90 (d, 1H, J = 8Hz), 5.08
(dd, 1H, J = 1.5Hz, 10Hz), 5.16 (dd, 1H, J = 1.5Hz, 17Hz), 5.2
2 (s, 3H), 5.61 (d, 1H, J = 7Hz), 5.86-5.96 (m, 1H), 7.46 (t,
2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.10-8.12 (m, 2H).

Step 3: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4,10-dideacetyl-4-O- (4-pentenoy
) -7,10-Bis-O-triethylsilylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 4 of Example 1 to obtain the title compound as a colorless amorphous solid. .

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-0.72 (m,
12H), 0.94-1.02 (m, 21H), 1.12 (br s, 9H), 1.21 (s, 6H),
1.64 (s, 3H), 1.77 (s, 3H), 1.81 (s, 3H), 1.89 (s, 3H), 2.
12-2.17 (m, 4H), 2.31 (m, 2H), 2.49 (m, 1H), 3.81 (d, 1H, J =
7Hz), 4.10 (d, 1H, J = 8Hz), 4.22 (d, 1H, J = 8Hz), 4.38 (dd, 1
H, J = 7Hz, 10Hz), 4.42 (d, 1H, J = 7Hz), 4.80 (d, 1H, J = 8Hz),
5.00 (d, 1H, J = 10Hz), 5.05 (d, 1H, J = 17Hz), 5.17 (s, 1H),
5.63 (d, 1H, J = 7Hz), 5.74-5.77 (m, 1H), 6.21 (t, 1H, J = 7H
z), 7.30-7.39 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J =
8Hz), 8.05 (d, 2H, J = 8Hz).

Step 4: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenylpropionyl] -4,10-
Dideacetyl-4-O- (4-pentenoyl) baccatin III The compound obtained in Step 3 above was reacted in the same manner as in Step 5 of Example 1 to obtain the title compound as a colorless solid.

Melting point: 168-172 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.24 (s, 3H),
1.35 (s, 9H), 1.75 (s, 3H), 1.84 (s, 3H), 2.25-2.27 (m, 2
H), 2.43-2.50 (m, 2H), 2.52-2.64 (m, 2H), 2.76 (m, 1H),
3.33 (br, 1H), 3.91 (d, 1H, J = 7Hz), 4.12 (d, 1H, J = 8Hz),
4.19 (m, 1H), 4.31 (d, 1H, J = 8Hz), 4.60 (br s, 1H), 4.88
(d, 1H, J = 8Hz), 4.99 (d, 1H, J = 10Hz), 5.07 (d, 1H, J = 17Hz),
5.20 (s, 1H), 5.38 (br d, 1H, J = 10Hz), 5.67 (d, 1H, J = 7H
z), 5.73-5.77 (m, 1H), 6.17 (t, 1H, J = 8Hz), 7.30-7.40 (m,
5H), 7.50 (t, 2H, J = 8Hz), 7.63 (t, 1H, J = 8Hz), 8.11 (d, 2H,
J = 8Hz) .IR (KBr): 3800, 3456, 3072, 2984, 2944, 1968, 1726,
1644, 1604, 1586 cm ^-1 MS-FAB: 848 (MH ⁺ )

Example 6: 13-O-[(2R, 3S) -3- (tert-but
Xycarbonylamino) -3-phenylpropionyl] -4,10
-Dideacetyl-4-O-pentanoylbaccatin III

[0286]

[Chemical 49]

10.2 mg of the compound obtained in step 4 of example 5
Was dissolved in 2 ml of ethyl acetate, 5 mg of 10% (w / w) palladium on carbon was added, and the mixture was stirred under hydrogen gas for 2 hours at room temperature. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (developing solvent;
Chloroform: methanol = 20: 1 (v / v)) to obtain 7.5 mg of the title compound as a colorless solid.

Melting point: 157-160 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.89 (t, 3H, J = 7Hz), 1.13 (s,
3H), 1.24 (s, 3H), 1.29-1.31 (m, 2H), 1.35 (s, 9H), 1.68-
1.71 (m, 2H), 1.75 (s, 3H), 1.84 (s, 3H), 2.27-2.29 (m, 2
H), 2.45-2.68 (m, 3H), 3.35 (br, 1H), 3.91 (d, 1H, J = 7H
z), 4.19 (d, 1H, J = 8Hz), 4.20 (m, 1H), 4.31 (d, 1H, J = 8Hz),
4.63 (br s, 1H), 4.88 (d, 1H, J = 8Hz), 5.21 (s, 1H), 5.38
(br d, 1H, J = 9Hz), 5.68 (d, 1H, J = 7Hz), 6.18 (t, 1H, J = 8H
z), 7.32-7.40 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.62 (t, 1H, J =
8Hz), 8.12 (d, 2H, J = 8Hz) .IR (KBr): 3460, 3068, 2968, 2940, 2880, 1722, 1604,
1586, 1496 cm ^-1 MS-FAB: 850 (MH ⁺ )

Example 7

[0290]

Embedded image

Step 1: 13-deoxy-4,10-dideacetyl-
13-oxo-4-O- (3-phenylpropionyl) -7,10-bis-
O-Triethylsilylbaccatin III A reaction similar to step 2 of Example 1 was repeated except that sodium bis (triethylsilyl) amide was used instead of lithium bis (triethylsilyl) amide and benzyl bromide was used instead of methyl iodide. The title compound was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.5
7-0.77 (m, 12H), 0.95-1.04
(M, 18H), 1.21 (s, 3H), 1.28
(S, 3H), 1.64 (s, 3H), 1.83-
1.90 (m, 1H), 2.07 (s, 3H),
2.49-2.57 (m, 1H), 2.63 (d, 1)
H, J = 20 Hz), 2.67-2.83 (m, 2
H), 2.93 (d, 1H, J = 20Hz), 2.9.
2-3.09 (m, 2H), 3.93 (d, 1H, J
= 7 Hz), 4.09 (d, 1H, J = 8 Hz),
4.24 (d, 1H, J = 8 Hz), 4.43 (d
d, 1H, J = 7 Hz, 10 Hz), 4.77 (d,
1H, J = 8 Hz), 5.38 (s, 1H), 5.6
8 (d, 1H, J = 7 Hz), 7.34-7.38
(M, 5H), 7.46 (t, 2H, J = 8Hz),
7.60 (t, 1H, J = 8Hz), 8.05 (d,
2H, J = 8 Hz).

Step 2: 4,10-dideacetyl-4-O- (3
-Phenylpropionyl) -7,10-bis-O-triethylsilyl
Lubaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 1 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.56-0.73 (m,
12H), 0.95-1.02 (m, 18H), 1.05 (s, 3H), 1.19 (s, 3H),
1.65 (s, 3H), 1.83-1.91 (m, 1H), 2.01 (s, 3H), 2.19-
2.31 (m, 2H), 2.48-2.56 (m, 1H), 2.87-2.97 (m, 2H), 3.
03-3.09 (m, 2H), 3.91 (d, 1H, J = 7Hz), 4.12 (d, 1H, J
= 8Hz), 4.22 (d, 1H, J = 8Hz), 4.43 (dd, 1H, J = 7Hz, 10H
z), 4.80 (d, 1H, J = 8Hz), 4.82 (br, 1H), 5.21 (s, 3H), 5.
61 (d, 1H, J = 7Hz), 7.19-7.36 (m, 5H), 7.46 (t, 2H, J =
8Hz), 7.59 (t, 1H, J = 8Hz), 8.10-8.12 (m, 2H).

Step 3: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4,10-dideacetyl-4-O- (3-phenylpro
(Pionyl) -7,10-bis-O-triethylsilylbaccatin I
II The compound obtained in Step 2 above was reacted in the same manner as in Step 4 of Example 1 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.79
(m, 12H), 0.93-1.02 (m, 18H), 1.13 (br s, 9H), 1.21
(s, 6H), 1.62 (s, 3H), 1.74 (s, 3H), 1.76 (s, 3H), 1.9
0 (s, 3H), 2.14-2.16 (m, 2H), 2.37-2.49 (m, 3H), 2.89-
2.91 (m, 2H), 3.80 (d, 1H, J = 7Hz), 4.04 (d, 1H, J = 8H
z), 4.09 (d, 1H, J = 8Hz), 4.36 (dd, 1H, J = 7Hz, 10Hz),
4.40 (d, 1H, J = 7Hz), 4.51 (d, 1H, J = 9Hz), 5.17 (s, 1
H), 5.62 (d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz), 7.15-7.3
6 (m, 10H), 7.49 (t, 2H, J = 8Hz), 7.63 (t, 1H, J = 8Hz),
8.05 (d, 2H, J = 8Hz).

Step 4: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenylpropionyl] -4,10-
Dideacetyl-4-O- (3-phenylpropionyl) baccati
Compound III The compound obtained in Step 3 above was reacted in the same manner as in Step 5 of Example 1 to give the title compound as a colorless solid.

Melting point: 162-165 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.22 (s, 3
H), 1.37 (s, 9H), 1.72 (s, 3H), 1.83 (s, 3H), 2.17-2.1
9 (m, 2H), 2.45-2.53 (m, 1H), 2.80-2.86 (m, 1H), 3.00-
3.09 (m, 3H), 3.37 (br, 1H), 3.87 (d, 1H, J = 7Hz), 4.13
(d, 1H, J = 8Hz), 4.18 (m, 1H), 4.20 (d, 1H, J = 8Hz), 4.
51 (br s, 1H), 4.59 (d, 1H, J = 8Hz), 5.18 (s, 1H), 5.32
(br d, 1H, J = 9Hz), 5.65 (d, 1H, J = 7Hz), 6.15 (t, 1H,
J = 8Hz), 7.19-7.36 (m, 10H), 7.52 (t, 2H, J = 8Hz), 7.6
4 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz) .IR (KBr): 3452, 3068, 2984, 1716, 1606, 1586 cm ^-1 MS-FAB: 898 (MH ⁺ )

Example 8

[0300]

[Chemical formula 61]

Step 1: 10-deacetyl-13-deoxy-13-
Oxo-7-O-triethylsilylbaccatin III 10-deacetyl-7-O-triethylsilylbaccatin III
Was reacted in the same manner as in Step 1 of Example 1 to obtain the title compound as a colorless solid.

Melting point: 238-246 ° C. (decomposition) ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.48-0.61 (m, 6H), 0.93
(t, 9H, J = 8Hz), 1.17 (s, 3H), 1.23 (s, 3H), 1.73 (s,
3H), 1.86-1.93 (m, 1H), 2.11 (s, 3H), 2.19 (s, 3H), 2.
45-2.52 (m, 1H), 2.65 (d, 1H, J = 20Hz), 2.94 (d, 1H, J =
20Hz), 3.96 (d, 1H, J = 7Hz), 4.14 (d, 1H, J = 8Hz), 4.31
(d, 1H, J = 3Hz), 4.34 (d, 1H, J = 8Hz), 4.39 (dd, 1H, J =
7Hz, 10Hz), 4.92 (d, 1H, J = 10Hz), 5.33 (s, 1H), 5.66
(d, 1H, J = 7Hz), 7.49 (t, 2H, J = 8Hz), 7.63 (t, 1H, J =
8Hz), 8.06-8.08 (m, 2H) .IR (KBr): 3480, 2964, 2888, 1730, 1714, 1676, 1454
cm ^-1 MS-FAB: 657 (MH ⁺ )

Step 2: 13-deoxy-4,10-dideacetyl-
13-oxo-4-O-propionyl-7-O-triethylsilyl
Baccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Example 1 to obtain the title compound as a colorless solid.

Melting point: 181-184 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.48-0.63 (m, 6H), 0.93
(t, 9H, J = 8Hz), 1.16 (s, 3H), 1.21 (s, 3H), 1.22 (t,
3H, J = 7Hz), 1.73 (s, 3H), 1.86-1.93 (m, 1H), 2.10 (s,
3H), 2.38-2.54 (m, 3H), 2.62 (d, 1H, J = 20Hz), 2.93
(d, 1H, J = 20Hz), 3.96 (d, 1H, J = 7Hz), 4.14 (d, 1H, J =
8Hz), 4.31 (d, 1H, J = 2Hz), 4.32 (d, 1H, J = 8Hz), 4.41
(dd, 1H, J = 7Hz, 10Hz), 4.88 (d, 1H, J = 8Hz), 5.32 (s,
1H), 5.65 (d, 1H, J = 7Hz), 7.48 (t, 2H, J = 8Hz), 7.62
(t, 1H, J = 8Hz), 8.06-8.09 (m, 2H) .IR (KBr): 3800, 3464, 3072, 2964, 2888, 1730, 1676,
1606, 1454 cm ^-1 MS-FAB: 671 (MH ⁺ )

Step 3: 4,10-dideacetyl-4-O-propyi
Onyl-7-O-triethylsilylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 3 of Example 1 to give the title compound as a colorless solid.

Melting point: 202-204 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.48-0.63 (m, 6H), 0.94
(t, 9H, J = 8Hz), 1.07 (s, 3H), 1.24 (t, 3H, J = 7Hz), 1.
26 (s, 3H), 1.73 (s, 3H), 1.86-1.93 (m, 1H), 2.07 (s, 3
H), 2.22-2.28 (m, 2H), 2.45-2.51 (m, 1H), 2.52-2.67
(m, 2H), 3.94 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz),
4.27 (d, 1H, J = 2Hz), 4.31 (d, 1H, J = 8Hz), 4.42 (dd, 1H,
J = 7Hz, 10Hz), 4.84 (t, 1H, J = 8Hz), 4.91 (d, 1H, J = 8H
z), 5.18 (s, 1H), 5.59 (d, 1H, J = 7Hz), 7.46 (t, 2H, J =
8Hz), 7.60 (t, 1H, J = 8Hz), 8.10-8.12 (m, 2H) .IR (KBr): 3476, 3072, 2960, 2888, 1986, 1728, 1712,
1604, 1586 cm ^-1 MS-FAB: 673 (MH ⁺ )

Step 4: 4,10-dideacetyl-4-O-propyi
Onyl-10-O- (2,2,2-trichloroethoxycarbonyl)-
7-O-Triethylsilylbaccatin III 36.0 mg of the compound obtained in the above step 3 was dissolved in 2 ml of pyridine, and 2,2,2-trichloroethyl chloroformate 0.0
14 ml was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: acetone = 20: 1 (v / v)) to give the title compound 38.6.
Obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.62
(m, 6H), 0.93 (t, 9H, J = 8Hz), 1.07 (s, 3H), 1.21 (s, 3
H), 1.22-1.26 (m, 3H), 1.70 (s, 3H), 1.85-1.92 (m, 1
H), 2.19 (s, 3H), 2.26-2.28 (m, 2H), 2.51-2.67 (m, 3
H), 3.72 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.31 (d,
1H, J = 8Hz), 4.50 (dd, 1H, J = 7Hz, 10Hz), 4.81 (AB type
q, 2H, J = 12Hz), 4.85 (br, 1H), 4.91 (d, 1H, J = 8Hz),
5.63 (d, 1H, J = 7Hz), 6.30 (s, 1H), 7.47 (t, 2H, J = 8H
z), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).

Step 5: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4,10-dideacetyl-4-O-propionyl-10
-O- (2,2,2-trichloroethoxycarbonyl) -7-O-tri
Ethylsilylbaccatin III The compound obtained in Step 4 above was reacted in the same manner as in Step 4 of Example 1 to obtain the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.60
(m, 6H), 0.92 (t, 9H, J = 8Hz), 1.06 (t, 3H, J = 7Hz), 1.
07 (br s, 9H), 1.23 (s, 3H), 1.24 (s, 3H), 1.67 (s, 3
H), 1.76 (s, 3H), 1.80 (s, 3H), 1.86-2.00 (m, 2H), 2.0
4 (s, 3H), 2.12-2.17 (m, 2H), 2.47-2.54 (m, 1H), 3.71
(d, 1H, J = 7Hz), 4.10 (d, 1H, J = 8Hz), 4.25 (d, 1H, J = 8
Hz), 4.42 (d, 1H, J = 7Hz), 4.45 (dd, 1H, J = 7Hz, 10Hz),
4.81 (s, 2H), 5.03 (br, 1H), 5.65 (d, 1H, J = 7Hz), 6.2
5 (t, 1H, J = 8Hz), 6.26 (s, 1H), 7.30-7.38 (m, 5H), 7.5
0 (t, 2H, J = 8Hz), 7.64 (t, 1H, J = 8Hz), 8.06 (d, 2H, J =
8Hz).

Step 6: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4,10-dideacetyl-4-O-propionyl-7-
O-Triethylsilylbaccatin III 50.7 mg of the compound obtained in Step 5 above was added to acetic acid-methanol.
(1: 1 (v / v)) Dissolved in 4 ml of mixed solvent, activated zinc powder 100 m
g was added, and the mixture was stirred at 60 ° C for 15 minutes. After cooling, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: acetone = 40: 1 (v / v)) to obtain 36.4 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.46-0.61
(m, 6H), 0.93 (t, 9H, J = 8Hz), 1.04 (t, 3H, J = 7Hz), 1.
07 (br s, 9H), 1.10 (s, 3H), 1.24 (s, 3H), 1.71 (s, 3
H), 1.77 (s, 3H), 1.80 (s, 3H), 1.94 (s, 3H), 2.04-2.1
2 (m, 2H), 2.40-2.48 (m, 1H), 3.80 (d, 1H, J = 7Hz), 4.1
1 (d, 1H, J = 8Hz), 4.25 (d, 1H, J = 8Hz), 4.28 (s, 1H),
4.38 (dd, 1H, J = 7Hz, 10Hz), 4.40 (d, 1H, J = 7Hz), 4.81
(d, 1H, J = 9Hz), 5.04 (br, 1H), 5.11 (s, 1H), 5.61 (d,
1H, J = 7Hz), 6.26 (t, 1H, J = 8Hz), 7.34-7.39 (m, 5H),
7.50 (t, 2H, J = 8Hz), 7.64 (t, 1H, J = 8Hz), 8.05 (d, 2H,
J = 8Hz).

Step 7: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4,10-dideacetyl-10-O-nicotinoyl-4
-O-propionyl-7-O-triethylsilylbaccatin II
I Dissolve 46.0 mg of nicotinic acid in 4 ml of toluene, add 42.0 mg of dicyclohexylcarbodiimide, and add 10
After stirring for 3 minutes, 36.4 mg of the compound obtained in Step 6 above and 4
-Add 5 mg of dimethylaminopyridine and 24 at 80 ° C
Stirred for hours. After allowing to cool, the mixture was diluted with ethyl acetate and the insoluble matter was filtered off. The filtrate was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)),
41 mg of the title compound were obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-0.61
(m, 6H), 0.89 (t, 9H, J = 8Hz), 1.07 (t, 3H, J = 7Hz), 1.
09 (br s, 9H), 1.24 (s, 3H), 1.33 (s, 3H), 1.69 (s, 3
H), 1.76 (s, 3H), 1.81 (s, 3H), 1.84-1.98 (m, 2H), 2.1
1 (s, 3H), 2.14-2.18 (m, 2H), 2.50-2.57 (m, 1H), 3.81
(d, 1H, J = 7Hz), 4.12 (d, 1H, J = 8Hz), 4.27 (d, 1H, J = 8
Hz), 4.43 (d, 1H, J = 7Hz), 4.54 (dd, 1H, J = 7Hz, 10Hz),
4.84 (d, 1H, J = 8Hz), 5.03 (br, 1H), 5.70 (d, 1H, J = 7H
z), 6.25 (t, 1H, J = 8Hz), 6.70 (s, 1H), 7.34-7.39 (m, 5
H), 7.45 (dd, 1H, J = 5Hz, 8Hz), 7.51 (t, 2H, J = 8Hz),
7.64 (t, 1H, J = 8Hz), 8.07 (d, 2H, J = 8Hz), 8.37-8.40
(m, 1H), 8.82 (dd, 1H, J = 1.5Hz, 5Hz), 9.32 (d, 1H, J =
1.5Hz).

Step 8: 1 3-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenylpropionyl] -4,10-
Dideacetyl-10-O-nicotinoyl-4-O-propionyl
Baccatin III The compound obtained in Step 7 above was reacted in the same manner as in Step 5 of Example 1 to give the title compound as a colorless solid.

Melting point: 176-180 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.22-1.26 (m, 3H), 1.24
(s, 3H), 1.33 (s, 9H), 1.36 (s, 3H), 1.71 (s, 3H), 1.9
2 (s, 3H), 2.34 (m, 2H), 2.57-2.69 (m, 3H), 3.86 (d, 1
H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8H
z), 4.51 (dd, 1H, J = 7Hz, 10Hz), 4.64 (br s, 1H), 4.93
(d, 1H, J = 9Hz), 5.23 (br, 1H), 5.35 (br d, 1H, J = 9H
z), 5.73 (d, 1H, J = 7Hz), 6.26 (t, 1H, J = 8Hz), 6.59
(s, 1H), 7.33-7.42 (m, 5H), 7.45 (dd, 1H, J = 5Hz, 8Hz),
7.51 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.14 (d, 2
H, J = 8Hz), 8.33-8.36 (m, 1H), 8.83 (dd, 1H, J = 1.5Hz,
5Hz), 9.29 (d, 1H, J = 1.5Hz) .MS-FAB: 927 (MH ⁺ ).

Example 9

[0318]

Embedded image

Step 1: 4,10-dideacetyl-10-O- (pen
Tafluorophenyloxy) thiocarbonyl-4-O-pro
Pionyl-7-O-triethylsilylbaccatin III 227 mg of the compound obtained in Step 3 of Example 8 was dissolved in 4 ml of anhydrous tetrahydrofuran and cooled to -45 ° C. Next, 0.256 ml of n-butyllithium (1.71M hexane solution) was added dropwise, 40 minutes later, 0.059 ml of pentafluorophenylchlorothionocarbonate was added dropwise with a syringe, and the mixture was stirred at the same temperature for 90 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)) to obtain 205 mg of the title compound as a colorless solid.

Melting point: 207-210 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.53-0.63 (m, 6H), 0.93
(t, 9H, J = 8Hz), 1.10 (s, 3H), 1.22 (s, 3H), 1.25 (t,
3H, J = 7Hz), 1.74 (s, 3H), 1.87-1.93 (m, 1H), 2.28-2.3
2 (m, 2H), 2.31 (s, 3H), 2.54-2.68 (m, 3H), 3.83 (d, 1
H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz),
4.53 (dd, 1H, J = 7, 10Hz), 4.92 (br, 1H), 4.93 (d, 1H, J
= 8Hz), 5.66 (d, 1H, J = 7Hz), 6.81 (s, 1H), 7.49 (t, 2H,
J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.11-8.14 (m, 2H) .MS-FAB: 899 (MH ⁺ ).

Step 2: 4-deacetyl-10-deacetoxy-4
-O-propionyl-7-O-triethylsilyl baccatin
III 190 mg of the compound obtained in the above step 1 was dissolved in 5 ml of toluene, and a catalytic amount of 2,2'-azobis (isobutyronitrile)
Was added, and tributyltin hydride 0.085 ml under a nitrogen stream was added.
Was added dropwise with a syringe, and the mixture was heated with stirring at 90 ° C. for 20 minutes.
The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)) to obtain 133 mg of the title compound as a colorless solid.

Melting point: 200-203 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.51-0.66 (m, 6H), 0.91-
0.97 (m, 9H), 1.03 (s, 3H), 1.13 (s, 3H), 1.24 (t, 3H,
J = 7Hz), 1.62 (s, 3H), 1.83-1.90 (m, 1H), 1.96 (s, 3H),
2.23-2.27 (m, 2H), 2.46-2.57 (m, 1H), 2.59-2.67 (m,
2H), 3.38 (d, 1H, J = 15Hz), 3.78 (d, 1H, J = 15Hz), 4.09
(d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.29 (d, 1H, J = 8
Hz), 4.52 (dd, 1H, J = 7Hz, 10Hz), 4.79 (br, 1H), 4.91
(d, 1H, J = 8Hz), 5.60 (d, 1H, J = 7Hz), 7.45 (t, 2H, J =
8Hz), 7.59 (t, 1H, J = 8Hz), 8.10-8.12 (m, 2H) .MS-FAB: 657 (MH ⁺ ).

Step 3: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenyl-2- (triethylsilyl
Luoxy) propionyl] -4-deacetyl-10-deacetoxy
Ci-4-O-propionyl-7-O-triethylsilyl baccati
Compound III 69.5 mg of the compound obtained in Step 2 above was dissolved in 1.5 ml of anhydrous tetrahydrofuran and cooled to -45 ° C. Then
0.074 ml of n-butyllithium (1.71M hexane solution) was added dropwise, and after 30 minutes, (3R, 4S) -1- (tert-butoxycarbonyl) -4-phenyl-3-triethylsilyloxy-2-azetidinone 59.5 0.5 mg anhydrous tetrahydrofuran
The solution dissolved in
Stir for minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to obtain 91 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.31-0.50
(m, 6H), 0.53-0.60 (m, 6H), 0.79 (t, 9H, J = 8Hz), 0.95
(t, 9H, J = 8Hz), 1.18 (s, 3H), 1.22 (s, 3H), 1.34 (br
s, 9H), 1.38 (t, 3H, J = 7Hz), 1.64 (s, 3H), 1.80 (s, 3
H), 1.86-1.92 (m, 1H), 2.20 (m, 1H), 2.35-2.42 (m, 1
H), 2.46-2.54 (m, 1H), 2.70-2.84 (m, 2H), 3.38 (d, 1H,
J = 15Hz), 3.76 (d, 1H, J = 15Hz), 4.01 (d, 1H, J = 7Hz),
4.20 (d, 1H, J = 8Hz), 4.33 (d, 1H, J = 8Hz), 4.48-4.51
(m, 2H), 4.91 (d, 1H, J = 8Hz), 5.24 (br d, 1H, J = 9Hz),
5.49 (br d, 1H, J = 9Hz), 5.69 (d, 1H, J = 7Hz), 6.15 (t,
1H, J = 8Hz), 7.28-7.40, (m, 5H), 7.49 (t, 2H, J = 8Hz),
7.59 (t, 1H, J = 8Hz), 8.12-8.14 (m, 2H).

Step 4: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenylpropionyl] -4-dea
Cetyl-10-deacetoxy-4-O-propionyl baccatin
III Compound 91 mg obtained in Step 3 above was added to acetonitrile 2 ml.
It was dissolved in and cooled to -10 ° C. Then, 0.035 ml of 12N hydrochloric acid aqueous solution was added, and the mixture was stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 1 (v / v)) to give the title compound 57.0.
Obtained mg as a colorless solid.

Melting point: 172-176 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.17 (s, 3H), 1.21 (t, 3
H, J = 7Hz), 1.23 (s, 3H), 1.34 (brs, 9H), 1.64 (s, 3H),
1.74 (s, 3H), 2.26-2.33 (m, 2H), 2.58-2.70 (m, 3H),
3.42 (br, 1H), 3.43 (d, 1H, J = 15Hz), 3.80 (d, 1H, J = 15
Hz), 4.05 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz), 4.31
(d, 1H, J = 8Hz), 4.28-4.32 (m, 1H), 4.61 (brs, 1H), 4.8
9 (d, 1H, J = 8Hz), 5.23 (br, 1H), 5.36 (br, 1H), 5.70
(d, 1H, J = 7Hz), 6.11 (t, 1H, J = 8Hz), 7.31-7.41 (m, 5
H), 7.50 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.12 (d,
2H, J = 8Hz) .MS-FAB: 806 (MH ⁺ ).

Example 10

[0328]

[Chemical formula 63]

Step 1: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triethylsilyloxy)
Ci) Propionyl] -4-O-butyryl-4,10-dideacetyl-
7,10-Bis-O-triethylsilylbaccatin III 82 mg of the compound obtained in Step 2 of Example 4 and cis-1- (tert-
Butoxycarbonyl) -4- (2-furyl) -3-triethylsilyloxy-2-azetidinone (92 mg) was dissolved in 4 ml of tetrahydrofuran under a nitrogen gas atmosphere, and cooled to -55 ° C. At the same temperature, 0.26 ml of sodium bis (triethylsilyl) amide in tetrahydrofuran (concentration 1
M) was added and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (developing solvent; ethyl acetate: hexane =
1: 4 (v / v)) to give 111 mg of the title compound as a mixture of diastereoisomers in which the relative configuration at the 2'position and the 3'position is threo (syn).

Step 2: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2-hydroxypropionyl]
-4-O-Butyryl-4,10-dideacetylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 4 of Example 9 and post- treated . Then, silica gel column chromatography (developing solvent; chloroform: acetone = 4: 1).
(v / v), then 3: 1 (v / v), then 2: 1 (v / v))
Then, the 2′-position and 3′-position diastereoisomer A, which elutes first, and the later-eluting isomer B, respectively, were obtained as white solids.

Isomer A Melting point: 155-159 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.05 (t, 3H, J = 7.5Hz), 1.1
2 (s, 3H), 1.21 (s, 3H), 1.42 (s, 9H), 1.68-1.79 (m, 1H),
1.76 (s, 3H), 1.79-1.88 (m, 2H), 2.04 (s, 3H), 2.18 (dd, 1
H, J = 15Hz, 7.5Hz), 2.31-2.64 (m, 4H), 3.32 (br, 1H), 3.99
(d, 1H, J = 7Hz), 4.19 (d, 1H, J = 9Hz), 4.31 (d, 1H, J = 9Hz),
4.23 (s, 1H), 4.25-4.36 (m, 1H), 4.62 (dd, 1H, J = 5Hz, 2Hz),
4.90 (dd, 1H, J = 9.5Hz, 2Hz), 5.25 (br s, 1H), 5.24 (br s,
1H), 5.33 (br d, 1H, J = 10.5Hz), 5.67 (d, 1H, J = 7Hz), 6.16
(m, 1H), 6.33 (d, 1H, J = 3.5Hz), 6.38 (dd, 1H, J = 3Hz, 1.5H
z), 7.40 (s, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.62 (t, 1H, J = 6H
z), 8.07 (d, 2H, J = 7.5Hz).

Isomer B Melting point: 141-144 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.99 (t, 3
H, J = 7.5 Hz), 1.13 (s, 3H),
1.23 (s, 3H), 1.35 (s, 9H),
1.75 (s, 3H), 1.71-1.95 (m, 3
H), 1.91 (s, 3H), 2.23-2.40.
(M, 2H), 2.52-2.73 (m, 3H),
3.33 (d, 1H, J = 6 Hz), 3.94 (d,
1H, J = 7Hz), 4.19 (d, 1H, J = 9H)
z), 4.32 (d, 1H, J = 9 Hz), 4.70
(Dd, 1H, J = 5.5Hz, 2Hz), 4.90
(Dd, 1H, J = 9 Hz, 1.5 Hz), 5.22
(M, 2H), 5.31 (br d, 1H, J = 9H
z), 5.68 (d, 1H, J = 7 Hz), 6.2
0 (t, 1H, J = 8Hz), 6.34 (d, 1H, J
= 3 Hz), 6.38 (dd, 1H, J = 3 Hz, 2
Hz), 7.41 (d, 1H, J = 2 Hz), 7.4
9 (t, 2H, J = 8Hz), 7.60 (t, 1H,
J = 8 Hz), 8.12 (d, 2H, J = 8 Hz).

Example 11

[0334]

[Chemical 64]

Step 1: 13-deoxy-4,10-dideacetyl
Ru-4-O- (2-ethylbutyryl) -13-oxo-7,10-bis-O-
Triethylsilylbaccatin III 1.57 ml of sodium bis (triethylsilyl) amide (1 M solution in tetrahydrofuran) was added to 5.5 ml of anhydrous tetrahydrofuran and cooled to -82 ° C. Then
A solution prepared by dissolving 298 mg of the compound obtained in Step 2 of Example 1 in 2 ml of anhydrous tetrahydrofuran was added dropwise, 6 minutes later, 0.20 ml of ethyl iodide was added dropwise at the same temperature, and the mixture was stirred for 1 hour.
A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (developing solvent; ethyl acetate: hexane = 1: 5 (v / v), changed to 2: 5 (v / v) from the middle)
The title compound (132 mg) was obtained as a colorless syrup-like substance. Also, 114 mg of the compound of Step 1 of Example 4
Also got at the same time.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.52-0.75
(m, 12H), 0.90-1.14 (m, 24H), 1.18 (s, 3H), 1.27 (s, 3H),
1.54 (s, 3H), 1.50-1.93 (m, 5H), 2.01 (m, 1H), 2.02 (s, 3
H), 2.30 (m, 1H), 2.54 (m, 1H), 2.58 (d, 1H, J = 19.5Hz), 2.
91 (d, 1H, J = 19.5Hz), 3.92 (d, 1H, J = 7Hz), 4.12 (d, 1H, J = 8.
5Hz), 4.31 (d, 1H, J = 8.5Hz), 4.44 (d, 1H, J = 11Hz, 6.5Hz),
4.82 (d, 1H, J = 9Hz), 5.36 (s, 1H), 5.68 (d, 1H, J = 7Hz), 7.4
7 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.00 (d, 2H, J = 7.
5Hz).

Step 2: 4,10-dideacetyl-4-O- (2-ethyl
Rubutyryl) -7,10-bis-O-triethylsilyl baccati
Compound III The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 1 to give the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.52-0.75
(m, 12H), 0.92-1.09 (m, 27H), 1.20 (s, 3H), 1.67 (s, 3H),
1.53-1.70 (m, 2H), 1.75-1.97 (m, 5H), 2.02 (s, 3H), 2.24
(m, 2H), 2.54 (m, 2H), 3.91 (d, 1H, J = 7.5Hz), 4.16 (d, 1H, J
= 8.5Hz), 4.29 (d, 1H, J = 8.5Hz), 4.42 (d, 1H, J = 10.5Hz, 7H
z), 4.82 (m, 1H), 4.86 (d, 1H, J = 8.5Hz), 5.22 (s, 1H), 5.6
1 (d, 1H, J = 7.5Hz), 7.45 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J =
7.5Hz), 8.13 (d, 2H, J = 7.5Hz).

Step 3: 13-O-[(2R, 3S) -N- (tert-butoxy)
Cycarbonyl) -N, O-isopropylidene-3-phenylyl
Soserinyl] -4,10-dideacetyl-4-O- (2-ethylbutyri
) -7,10-Bis-O-triethylsilylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 4 of Example 1 to obtain the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.52-0.77
(m, 12H), 0.83 (t, 3H, J = 7Hz), 0.87 (t, 3H, J = 7Hz), 0.97
(t, 9H, J = 8Hz), 1.01 (t, 9H, J = 8Hz), 1.22 (s, 3H), 1.23
(s, 3H), 1.55-1.95 (m, 5H), 1.66 (s, 3H), 1.74 (s, 3H), 1.
91 (s, 3H), 2.13 (m, 2H), 2.31 (m, 1H), 2.50 (m, 1H), 3.85
(d, 1H, J = 7Hz), 4.13 (d, 1H, J = 8.5Hz), 4.25 (d, 1H, J = 8.5H
z), 4.39 (d, 1H, J = 6Hz), 4.44 (dd, 1H, J = 10Hz, 7Hz), 4.77
(d, 1H, J = 9.5Hz), 5.18 (s, 2H), 5.66 (d, 1H, J = 8Hz), 6.20
(t, 1H, J = 8.5Hz), 7.31 (m, 5H), 7.43 (t, 2H, J = 8Hz), 7.59
(t, 1H, J = 8Hz), 8.05 (d, 2H, J = 8Hz).

Step 4: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenylpropionyl] -4,10-
Dideacetyl-4-O- (2-ethylbutyryl) baccatin II
I The compound obtained in Step 3 above was reacted in the same manner as in Step 5 of Example 1 to give the title compound as a colorless solid.

Melting point: 128-130 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.83-1.00 (m, 6H), 1.11
(s, 3H), 1.24 (s, 3H), 1.35 (m, 2H), 1.45 (s, 9H), 1.60-1.
96 (m, 5H), 1.76 (s, 3H), 1.81 (s, 3H), 2.30 (d, 2H, J = 8.5H
z), 2.56 (m, 2H), 3.35 (br, 1H), 3.93 (d, 1H, J = 7Hz), 4.21
(d, 1H, J = 8.5Hz), 4.31 (d, 1H, J = 8.5Hz), 4.26 (m, 2H), 4.6
1 (br, 1H), 4.82 (dd, 1H, J = 10Hz, 2.5Hz), 5.18 (m, 1H), 5.2
0 (s, 1H), 5.39 (d, 1H, J = 9Hz), 5.69 (d, 1H, J = 7.5Hz), 6.11
(t, 1H, J = 8.5Hz), 7.30 (m, 5H), 7.47 (t, 2H, J = 8Hz), 7.60
(t, 1H, J = 8Hz), 8.11 (d, 2H, J = 7.5Hz).

Example 12

[0344]

Embedded image

Step 1: 13-O- [3- (tert-butoxycarbo
Nylamino) -2,2-difluoro-3- (2-furyl) propioni
] -10-Deacetoxy-4-deacetyl-4-O-propionyl
-7-O-triethylsilylbaccatin III 3- (tert-butoxycarbonylamino) -2,2-difluoro-
Dissolve 3- (2-furyl) propionic acid 112 mg in toluene 3 ml, add di-2-pyridyl carbonate 83.0 mg,
After stirring at room temperature for 10 minutes, the compound obtained in Step 2 of Example 9 was used.
40.0 mg and 4-dimethylaminopyridine 15 mg were added, and the mixture was stirred at 70 ° C. for 18 hours. After allowing to cool, the mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: acetone = 40: 1 (v / v)) to obtain 48.4 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.50-0.65
(m, 6H), 0.95 (t, 9H, J = 8Hz), 1.18 (s, 3H), 1.19 (s, 3
H), 1.26-1.32 (m, 3H), 1.42 and 1.44 (each s, total
9H), 1.63 (s, 3H), 2.24-2.26 (m, 2H), 2.45-2.58 (m, 3
H), 3.37 (d, 1H, J = 13Hz), 3.73-3.78 (m, 1H), 3.97 (d, 1
H, J = 7Hz), 4.14 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.
49 (dd, 1H, J = 7Hz, 10Hz), 4.88 (d, 1H, J = 9Hz), 5.38 (b
rd, 1H, J = 8Hz), 5.61 (m, 1H), 5.66 (d, 1H, J = 7Hz), 6.
12 (m, 1H), 6.38-6.43 (m, 2H), 7.43 (d, 1H, J = 3Hz), 7.
48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09-8.12
(m, 2H).

Step 2: 13-O- [3- (tert-butoxycarbo
Nylamino) -2,2-difluoro-3- (2-furyl) propioni
] -10-Deacetoxy-4-deacetyl-4-O-propionyl
Baccatin III 48.4 mg of the compound obtained in the above step 1 was added to acetonitrile 1.
It was dissolved in 2 ml and cooled to -10 ° C. Next, 0.020 ml of 12N hydrochloric acid was added, and the mixture was stirred for 1 hour. To the reaction solution was added a saturated aqueous solution of multi-layers, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 27.5 mg of a mixture of two 3'position diastereoisomers. Then
The obtained mixture was subjected to high performance liquid chromatography (used column; C ₁₈ reverse phase column, developing solvent; methanol: water =
It was separated and purified at 19:11 (v / v). The first eluting fraction (isomer A) 10.0 mg and the later eluting fraction (isomer B) 10.0 mg were each dissolved in dioxane and lyophilized to give the title compound as a colorless solid. It was

Isomer A Melting point: 152-155 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.17 (s, 3H), 1.20 (s, 3
H), 1.27 (t, 3H, J = 7Hz), 1.45 (s, 9H), 1.64 (s, 3H), 1.
76 (s, 3H), 1.79-1.83 (m, 1H), 2.25-2.28 (m, 2H), 2.51
-2.60 (m, 2H), 2.61-2.67 (m, 1H), 3.44 (dd, 1H, J = 1.5
Hz, 17Hz), 3.81 (d, 1H, J = 17Hz), 4.04 (d, 1H, J = 7Hz),
4.12 (d, 1H, J = 7Hz), 4.32 (d, 1H, J = 7Hz), 4.31-4.36
(m, 1H), 4.89 (d, 1H, J = 8Hz), 5.36 (br d, 1H, J = 10H
z), 5.55-5.63 (m, 1H), 5.70 (d, 1H, J = 7Hz), 6.11 (t, 1
H, J = 8Hz), 6.38 (dd, 1H, J = 2Hz, 3.5Hz), 6.42 (d, 1H,
J = 3.5Hz), 7.42 (d, 1H, J = 2Hz), 7.49 (t, 2H, J = 8Hz),
7.62 (t, 1H, J = 8Hz), 8.09-8.11 (m, 2H) .MS-FAB: 816 (MH ⁺ )

Isomer B Melting point: 155-158 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.17 (s, 3H), 1.21 (s, 3
H), 1.29 (t, 3H, J = 7Hz), 1.41 (s, 9H), 1.64 (s, 3H), 1.
75 (s, 3H), 1.79-1.84 (m, 1H), 2.21-2.35 (m, 2H), 2.60
-2.67 (m, 3H), 3.44 (d, 1H, J = 16Hz), 3.82 (d, 1H, J = 1
6Hz), 4.04 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.32
(d, 1H, J = 7Hz), 4.31-4.36 (m, 1H), 4.90 (d, 1H, J = 8H
z), 5.36 (br d, 1H, J = 10Hz), 5.52-5.65 (m, 1H), 5.70
(d, 1H, J = 7Hz), 6.16 (t, 1H, J = 8Hz), 6.39-6.43 (m, 2
H), 7.44 (d, 1H, J = 1.5Hz), 7.49 (t, 2H, J = 8Hz), 7.62
(t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz) .MS-FAB: 816 (MH ⁺ )

Example 13

[0351]

[Chemical formula 66]

Step 1: 4-O-butyryl-13-deoxy-4,10
-Dideacetyl-13-oxo-7-O-triethylsilylbac
Catin III The compound obtained in Step 1 of Example 8 was reacted in the same manner as in Step 1 of Example 4 to obtain the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.47-0.64
(m, 6H), 0.93 (t, 9H, J = 8.5Hz), 1.08 (t, 3H, J = 7Hz),
1.16 (s, 3H), 1.21 (s, 3H), 1.66-1.83 (m, 2H), 1.72
(s, 3H), 1.89 (m, 1H), 2.09 (s, 3H), 2.31-2.55 (m, 3
H), 2.61 (d, 1H, J = 20Hz), 2.92 (d, 1H, J = 20Hz), 3.96
(d, 1H, J = 7Hz), 4.13 (d, 1H, J = 8Hz), 4.32 (m, 3H), 4.
40 (dd, 1H, J = 11Hz, 6.5Hz), 4.89 (d, 1H, J = 9Hz), 5.32
(d, 1H, J = 2.5Hz), 5.65 (d, 1H, J = 7Hz), 7.49 (t, 2H, J
= 7.5Hz), 7.62 (t, 1H, J = 7.5Hz), 8.09 (d, 2H, J = 8Hz).

Step 2: 4-O-Butyryl-4,10-dideacetyl
Le-7-O-triethylsilylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 1 to obtain the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.48-0.64
(m, 6H), 0.94 (t, 9H, J = 8.5Hz), 1.05 (t, 3H, J = 7.5H
z), 1.08 (s, 3H), 1.73 (s, 3H), 1.76 (m, 2H), 1.90 (ddd,
1H, J = 14.5Hz, 10.5Hz, 2.5Hz), 1.97 (br, 1H), 2.08
(s, 3H), 2.25 (d, 2H, J = 8.5HZz), 2.49 (ddd, 1H, J = 14.
5Hz, 9.5Hz, 6.5Hz), 2.56 (t, 2H, J = 7.5Hz), 3.95 (d, 1
H, J = 7Hz), 4.17 (d, 1H, J = 8.5Hz), 4.26 (d, 1H, J = 2.5H
z), 4.31 (d, 1H, J = 8.5Hz), 4.52 (dd, 1H, J = 7.5Hz, 10.
5Hz), 4.86 (t, 1H, J = 8.5Hz), 4.92 (dd, 1H, J = 9Hz, 2.5
Hz), 5.17 (d, 1H, J = 3Hz), 5.60 (d, 1H, J = 7Hz), 7.47
(t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8
Hz).

Step 3: 4-O-butyryl-4,10-dideacetyl
Le-10-O- (pentafluorophenyloxy) thiocarbo
Nyl-7-O-triethylsilylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 1 of Example 9 to give the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.52-0.64
(m, 6H), 0.92 (t, 9H, J = 8Hz), 1.06 (t, 3H, J = 7.5Hz),
1.09 (s, 3H), 1.58-1.84 (m, 3H), 1.73 (s, 3H), 1.90 (dd
d, 1H, J = 14.5Hz, 11Hz, 2Hz), 2.08 (br d, 1H, J = 6H
z), 2.29 (d, 1H, J = 7.5Hz), 2.30 (s, 3H), 2.57 (d, 1H,
J = 7.5Hz), 2.51-2.63 (m, 2H), 3.82 (d, 1H, J = 7Hz), 4.1
7 (d, 1H, J = 8.5Hz), 4.31 (d, 1H, J = 8.5Hz), 4.52 (dd, 1
H, J = 7.5Hz, 11Hz), 4.98 (d, 1H, J = 8.5Hz), 5.65 (d, 1
H, J = 7Hz), 6.80 (s, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.61
(t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).

Step 4: 4-O-butyryl-4-deacetyl-10-
Deacetoxy-7-O-triethylsilylbaccatin III The compound obtained in Step 3 above was reacted in the same manner as in Step 2 of Example 9 to give the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.50-0.68
(m, 6H), 0.95 (t, 9H, J = 8Hz), 1.05 (t, 3H, J = 7.5Hz),
1.12 (s, 3H), 1.25-1.40 (m, 1H), 1.61 (s, 6H), 1.78 (se
xtet, 2H, J = 7.5Hz), 1.86 (ddd, 1H, J = 14.5Hz, 10.5H
z, 2.5Hz), 1.96 (s, 3H), 2.00 (t, 1H, J = 5Hz), 2.24 (d,
2H, J = 8Hz), 2.50 (ddd, 1H, J = 14.5Hz, 10Hz, 6.5Hz),
2.56 (t, 2H, J = 7.5Hz), 3.38 (dd, 1H, J = 14Hz, 3Hz), 3.
78 (d, 1H, J = 14Hz), 4.09 (d, 1H, J = 7Hz), 4.15 (d, 1H,
J = 8Hz), 4.29 (d, 1H, J = 8Hz), 4.52 (dd, 1H, J = 10.5Hz,
6.5Hz), 4.80 (br, 1H), 4.92 (dd, 1H, J = 10Hz, 2.5Hz),
5.60 (d, 1H, J = 7Hz), 7.46 (t, 2H, J = 7.5Hz), 7.59 (t, 1
H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).

Step 5: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2-triethylsilyloxy
Propionyl] -4-O-butyryl-10-deacetoxy-4-dea
Cetyl-7-O-triethylsilylbaccatin III The compound obtained in Step 4 above was treated with cis-1- (tert-butoxycarbonyl) -4- (2-furyl) -3-triethyl in the same manner as in Step 1 of Example 10. By reacting with silyloxy-2-azetidinone, the title compound was obtained as a mixture of diastereoisomers in which the relative configuration at the 2'position and the 3'position was threo (syn).

Step 6: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2-hydroxypropionyl]
-4-O-Butyryl-10-deacetoxy-4-deacetylbacca
Chin III The compound obtained in Step 5 above was reacted in the same manner as in Step 4 of Example 9 and post-treated. After that, silica gel column chromatography (developing solvent; chloroform: acetone = 8: 1)
(v / v)) to obtain the diastereoisomer A at the 2'-position and the diastereoisomer A at the 3'-position which are eluted first and the isomer B which is eluted later as white solids.

Isomer A Melting point: 137-142 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.06 (t, 3H, J = 7Hz), 1.17
(s, 3H), 1.19 (s, 3H), 1.52 (s, 9H), 1.71-1.96 (m, 3H), 1.
92 (s, 3H), 2.21 (dd, 1H, J = 14.5Hz, 9Hz), 2.37 (dd, 1H, J = 1
4.5Hz, 9Hz), 2.42-2.59 (m, 2H), 2.65 (ddd, 1H, J = 17Hz, 11H
z, 7Hz), 3.32 (br t, 1H, J = 4Hz), 3.45 (br d, 1H, J = 16Hz),
3.85 (d, 1H, J = 16Hz), 4.13 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 9H
z), 4.31 (d, 1H, J = 9Hz), 4.34 (m, 1H), 4.63 (d, 1H, J = 4H
z), 4.91 (dd, 1H, J = 7Hz, 2.5Hz), 5.24 (br d, 1H, J = 9Hz),
5.34 (br d, 1H, J = 9Hz), 5.69 (d, 1H, J = 7Hz), 6.10 (br, 1H),
6.33 (d, 1H, J = 3Hz), 6.38 (t, 1H, J = 3Hz), 7.41 (d, 1H, J = 3H
z), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J
= 8Hz).

Isomer B Melting point: 129-135 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.00 (t, 3H, J = 7.5Hz), 1.1
8 (s, 3H), 1.20 (s, 3H), 1.36 (s, 9H), 1.50-1.89 (m, 5H),
1.64 (s, 3H), 1.79 (s, 3H), 2.29 (dd, 1H, J = 14.5Hz, 8.5Hz),
2.39 (dd, 1H, J = 14.5Hz, 9Hz), 2.48-2.73 (m, 3H), 3.31 (br
d, 1H, J = 5.5Hz), 3.44 (d, 1H, J = 16Hz), 3.82 (d, 1H, J = 16H
z), 4.08 (d, 1H, J = 7.5Hz), 4.18 (d, 1H, J = 8.5Hz), 4.31 (d,
1H, J = 8.5Hz), 4.37 (m, 1H), 4.70 (dd, 1H, J = 5.5Hz, 2.5H
z), 4.90 (dd, 1H, J = 9.5Hz, 3Hz), 5.21 (br d, 1H, J = 10.5H
z), 5.31 (br d, 1H, J = 10.5Hz), 5.70 (d, 1H, J = 7.5Hz), 6.1
0 (br t, 1H, J = 7Hz), 6.34 (d, 1H, J = 4Hz), 6.38 (dd, 1H, J = 4H
z, 2.5Hz), 7.41 (d, 1H, J = 2.5Hz), 7.49 (t, 2H, J = 7.5Hz),
7.61 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).

Example 14

[0365]

Embedded image

Step 1: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-10-O-isonico
Tinoyl-4-O-propionyl-7-O-triethylsilyl
Lubaccatin III Dissolve 58.0 mg isonicotinic acid in 5 ml toluene,
Add 100 mg of dicyclohexylcarbodiimide at room temperature
After stirring for 10 minutes, the compound 45.8 obtained in step 6 of Example 8
80 mg and 4-dimethylaminopyridine 6 mg were added.
The mixture was stirred at ℃ for 24 hours. After allowing to cool, the mixture was diluted with ethyl acetate and the insoluble matter was filtered off. The filtrate was washed with water, saturated aqueous layer solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)) to obtain 37.5 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.53-0.60
(m, 6H), 0.89 (t, 9H, J = 8Hz), 1.08 (t, 3H, J = 7Hz), 1.09
(s, 9H), 1.24 (s, 3H), 1.33 (s, 3H), 1.69 (s, 3H), 1.76 (s,
3H), 1.81 (s, 3H), 1.84-2.00 (m, 2H), 2.11 (s, 3H), 2.13-
2.19 (m, 2H), 2.49-2.57 (m, 1H), 3.81 (d, 1H, J = 7Hz), 4.12
(d, 1H, J = 8Hz), 4.27 (d, 1H, J = 8Hz), 4.43 (d, 1H, J = 7Hz),
4.54 (dd, 1H, J = 7Hz, 10Hz), 4.84 (d, 1H, J = 8Hz), 5.05 (br, 1
H), 5.71 (d, 1H, J = 7Hz), 6.25 (t, 1H, J = 8Hz), 6.67 (s, 1
H), 7.33-7.40 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.64 (t, 1H, J =
8Hz), 7.92 (dd, 2H, J = 1.5Hz, 4.5Hz), 8.06-8.08 (m, 2H), 8.
83 (dd, 2H, J = 1.5Hz, 4.5Hz)

Step 2: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -2-hydroxy-3-phenylpropyi
Onyl] -4,10-dideacetyl-10-O-isonicotinoyl
-4-O-Propionylbaccatin III 37.5 mg of the compound obtained in the above step 1 was dissolved in 3 ml of formic acid and stirred at room temperature for 1 hour. Formic acid was distilled off under reduced pressure, and the residue was dissolved in a mixed solvent of chloroform and methanol (10: 1 (v / v)) and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 3 ml of tetrahydrofuran, 20 μl of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel thin layer chromatography (developing solvent; chloroform: methanol = 20: 1).
(v / v)) to obtain 13.0 mg of the title compound as a white solid.

Melting point: 178-182 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.24 (t, 3H, J = 7Hz), 1.26
(s, 3H), 1.33 (s, 9H), 1.36 (s, 3H), 1.71 (s, 3H), 1.92 (s,
3H), 2.35 (m, 2H), 2.57-2.72 (m, 3H), 3.34 (br, 1H), 3.86
(d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8Hz),
4.51 (m, 1H), 4.63 (s, 1H), 4.92 (d, 1H, J = 9Hz), 5.23 (br,
1H), 5.29 (d, 1H, J = 9Hz), 5.73 (d, 1H, J = 7Hz), 6.26 (t, 1
H, J = 8Hz), 6.58 (s, 1H), 7.31-7.42 (m, 5H), 7.51 (t, 2H, J
= 8Hz), 7.63 (t, 1H, J = 8Hz), 7.88 (dd, 2H, J = 1.5Hz, 4.5H
z), 8.14 (d, 2H, J = 8Hz), 8.83 (dd, 2H, J = 1.5Hz, 4.5Hz) IR (KBr): 3804, 3668, 3532, 3452, 3072, 2984, 290
4, 1724, 1604, 1564 cm ^-1 MS-FAB: 927 (MH ⁺ )

Example 15

[0371]

[Chemical 68]

Step 1: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-10-O-picolino
Ile-4-O-propionyl-7-O-triethylsilylva
Katchin III The compound obtained in Step 6 of Example 8 was reacted in the same manner as in Step 1 of Example 14 using picolinic acid instead of isonicotinic acid to obtain the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-0.61
(m, 6H), 0.88 (t, 9H, J = 8Hz), 1.07 (t, 3H, J = 7Hz), 1.09
(s, 9H), 1.22 (s, 3H), 1.36 (s, 3H), 1.71 (s, 3H), 1.76 (s,
3H), 1.81 (s, 3H), 1.84-2.01 (m, 2H), 2.14 (s, 3H), 2.13-
2.17 (m, 2H), 2.49-2.57 (m, 1H), 3.84 (d, 1H, J = 7Hz), 4.13
(d, 1H, J = 8Hz), 4.27 (d, 1H, J = 8Hz), 4.42 (d, 1H, J = 7Hz),
4.56 (dd, 1H, J = 7Hz, 10Hz), 4.85 (d, 1H, J = 8Hz), 5.04 (br, 1
H), 5.71 (d, 1H, J = 7Hz), 6.23 (t, 1H, J = 8Hz), 6.73 (s, 1
H), 7.34-7.38 (m, 5H), 7.48-7.52 (m, 3H), 7.64 (t, 1H, J = 7
Hz), 7.86-7.90 (m, 1H), 8.06-8.08 (m, 2H), 8.23 (d, 1H, J =
8Hz), 8.80-8.81 (m, 1H)

Step 2: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -2-hydroxy-3-phenylpropyi
Onyl] -4,10-dideacetyl-10-O-picolinoyl-4-
O-Propionylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Example 14 to give the title compound as a white solid.

Melting point: 184-188 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.24 (t, 3H, J = 7Hz), 1.29
(s, 3H), 1.33 (s, 9H), 1.37 (s, 3H), 1.72 (s, 3H), 1.94 (s,
3H), 2.36 (m, 2H), 2.55-2.69 (m, 3H), 3.79 (br, 1H), 3.86
(d, 1H, J = 7Hz), 4.21 (d, 1H, J = 8Hz), 4.33 (d, 1H, J = 8Hz),
4.55 (m, 1H), 4.69 (s, 1H), 4.93 (d, 1H, J = 9Hz), 5.24 (br,
1H), 5.38 (d, 1H, J = 9Hz), 5.74 (d, 1H, J = 7Hz), 6.26 (t, 1H,
J = 8Hz), 6.63 (s, 1H), 7.32-7.41 (m, 5H), 7.49-7.53 (m, 3
H), 7.62 (t, 1H, J = 8Hz), 7.86-7.91 (m, 1H), 8.13-8.17
(m, 3H), 8.77 (d, 1H, J = 4Hz) IR (KBr): 3804, 3452, 3072, 2908, 1874, 1724, 160
4, 1586 cm ^-1 MS-FAB: 927 (MH ⁺ )

Example 16

[0377]

[Chemical 69]

Step 1: 4,10-dideacetyl-10-O- (N,
N-dimethylglycyl) -4-O-propionyl-7-O-to
Liethylsilylbaccatin III 100 mg of the compound obtained in Step 3 of Example 8, N, N-dimethylglycine hydrochloride 104 mg, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 143 mg and triethylamine 0.208 ml was dissolved in 4 ml of dichloromethane, 20 mg of 1-hydroxybenzotriazole was added, and the mixture was stirred at room temperature for 24 hours. After concentration under reduced pressure, ethyl acetate and water were added, and the organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 2: 1 (v / v)) to give the title compound 19.0.
Obtained mg as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.62
(m, 6H), 0.92 (t, 9H, J = 7Hz), 1.03 (s, 3H), 1.18 (s, 3H),
1.24 (t, 3H, J = 7Hz), 1.68 (s, 3H), 1.84-1.92 (m, 1H), 2.1
8 (s, 3H), 2.21-2.31 (m, 2H), 2.42 (s, 6H), 2.50-2.67 (m, 3
H), 3.34 (s, 2H), 3.88 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz),
4.30 (d, 1H, J = 8Hz), 4.51 (dd, 1H, J = 7Hz, 10Hz), 4.81 (t, 1
H, J = 8Hz), 4.92 (d, 1H, J = 8Hz), 5.63 (d, 1H, J = 7Hz), 6.51
(s, 1H), 7.46 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10-8.
13 (m, 2H)

Step 2: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-10-O- (N, N-
Dimethylglycyl) -4-O-propionyl-7-O-trier
Cylsilylbaccatin III (2R, 3S) -N- (tert-butoxycarbonyl) -N, O-isopropylidene-3-phenylisoserine 24.1 mg was dissolved in toluene 2 ml to give dicyclohexylcarbodiimide 1
After adding 7.0 mg and stirring at room temperature for 10 minutes, 19.0 mg of the compound obtained in the above step 1 and 6 m of 4-dimethylaminopyridine
g was added, and the mixture was stirred at 80 ° C for 1 hr. After allowing to cool, the mixture was diluted with ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous layer solution, and saturated brine in this order, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 23.0 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-
0.62 (m, 6H), 0.92 (t, 9H, J = 7
Hz), 1.06 (t, 3H, J = 7Hz), 1.
12 (s, 9H), 1.21 (s, 6H), 1.66
(S, 3H), 1.76 (s, 3H), 1.80
(S, 3H), 2.03 (s, 3H), 2.13
2.15 (m, 2H), 2.41 (s, 6H),
2.46-2.54 (m, 1H), 3.33 (s, 2
H), 3.76 (d, 1H, J = 7Hz), 4.10
(D, 1H, J = 8Hz), 4.24 (d, 1H, J
= 8 Hz), 4.41 (d, 1H, J = 7 Hz),
4.47 (dd, 1H, J = 7Hz, 10Hz),
4.81 (d, 1H, J = 8Hz), 5.05 (br,
1H), 5.65 (d, 1H, J = 7Hz), 6.
22 (t, 1H, J = 8 Hz), 6.49 (s, 1
H), 7.34-7.37 (m, 5H), 7.50.
(T, 2H, J = 8Hz), 7.64 (t, 1H, J
= 8 Hz), 8.05 (d, 2H, J = 8 Hz)

Step 3: 13-O-[(2R, 3S) -3- (tert-but
Xycarbonylamino) -2-hydroxy-3-phenylpro
Pionyl] -4,10-dideacetyl-10-O- (N, N-dimethyl)
Luglycyl) -4-O-propionylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 2 of Example 14 to give the title compound as a colorless solid.

Melting point: 174-177 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.25 (t, 3H,
J = 7Hz), 1.27 (s, 3H), 1.33 (s, 9H), 1.68 (s, 3H), 1.87 (s,
3H), 2.34 (s, 6H), 2.25-2.35 (m, 2H), 2.48-2.57 (m, 1H),
2.58-2.72 (m, 2H), 3.38 (s, 2H), 3.79 (d, 1H, J = 7Hz), 4.1
9 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.46 (br, 1H), 4.65
(s, 1H), 4.91 (d, 1H, J = 8Hz), 5.21 (br, 1H), 5.40 (d, 1H, J =
10Hz), 5.69 (d, 1H, J = 7Hz), 6.21 (t, 1H, J = 8Hz), 6.37 (s,
1H), 7.33-7.41 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.62 (t, 1H,
J = 8Hz), 8.13 (d, 2H, J = 8Hz) IR (KBr): 3460, 3072, 2984, 2948, 2948, 2788, 222
8, 1722, 1604,1588 cm ^-1 MS-FAB: 907 (MH ⁺ ).

Example 17

[0385]

Embedded image

Step 1: 4,10-dideacetyl-4-O-pro
Pionyl-10-O- (2,2,2-trichloroethoxycarbonyl
) -7-O-Triethylsilylbaccatin III 2.00 g of the compound obtained in Step 3 of Example 8 was added to pyridine 40
A solution prepared by dissolving 1.03 ml of 2,2,2-trichloroethyl chloroformate in 4 ml of dichloromethane was added dropwise under ice cooling and stirred for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. 0.5N hydrochloric acid aqueous solution obtained by cooling the extract,
The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 60 ml of tetrahydrofuran, 282 mg of sodium borohydride was added under ice cooling, and after 5 minutes, methanol 3
ml was added and the mixture was stirred for 2.5 hours. The reaction solution was diluted with chloroform, washed with a saturated aqueous solution of ammonium chloride, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (elution solvent; ethyl acetate: hexane = 1: 2 (v / v)) to give 2.05 g of the title compound.
Was obtained as white crystals.

Melting point: 227-228 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.56-0.62 (m, 6H), 0.93
(t, 9H, J = 8Hz), 1.07 (s, 3H), 1.21 (s, 3H), 1.22-1.26 (m, 3
H), 1.70 (s, 3H), 1.85-1.92 (m, 1H), 2.19 (s, 3H), 2.26-
2.28 (m, 2H), 2.51-2.67 (m, 3H), 3.72 (d, 1H, J = 7Hz), 4.16
(d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.50 (dd, 1H, J = 7Hz, 1
0Hz), 4.78 and 4.82 (each d, 1H, J = 12Hz), 4.85 (br, 1H),
4.91 (d, 1H, J = 8Hz), 5.63 (d, 1H, J = 7Hz), 6.30 (s, 1H), 7.
47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz) IR (KBr): 3560, 2960, 2888, 1764, 1728, 1604, 158
6, 1454 cm ^-1 MS-FAB: 849 (MH ⁺ )

Step 2: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenyl-2- (triethylsilyl)
Oxy) propionyl] -4,10-dideacetyl-4-O-propyl
Ropionyl-10-O- (2,2,2-trichloroethoxycarbonyl
) -7-O-triethylsilylbaccatin III 500 mg of the compound obtained in the above step 1 and (3R, 4S) -1- (te
rt-Butoxycarbonyl) -4-phenyl-3- (triethylsilyloxy) azetidin-2-one (445 mg) was dissolved in anhydrous tetrahydrofuran (10 ml) and cooled to -78 ° C. Then sodium bis (trimethylsilyl) amide (1M
Tetrahydrofuran solution, 1.77 ml) was added dropwise and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel chromatography (elution solvent; ethyl acetate: hexane =
It was purified by 1: 9 (v / v)) to obtain 709 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.39-0.49
(m, 6H), 0.56-0.62 (m, 6H), 0.79 (t, 9H, J = 7Hz), 0.93 (t, 9
H, J = 7Hz), 1.25 (s, 3H), 1.26 (s, 3H), 1.32 (brs, 9H), 1.3
8 (t, 3H, J = 7Hz), 1.72 (s, 3H), 1.88-1.95 (m, 1H), 2.02
(s, 3H), 2.19-2.38 (m, 2H), 2.51-2.59 (m, 1H), 2.71-2.84
(m, 2H), 3.80 (d, 1H, J = 7Hz), 4.20 (d, 1H, J = 8Hz), 4.34 (d,
1H, J = 8Hz), 4.49 (dd, 1H, J = 7Hz, 10Hz), 4.52 (br-s, 1H),
4.81 (AB type q, 2H), 4.90 (d, 1H, J = 8Hz), 5.25 (d, 1H, J = 1
0Hz), 5.47 (d, 1H, J = 10Hz), 5.72 (d, 1H, J = 7Hz), 6.23 (t, 1
H, J = 8Hz), 6.29 (s, 1H), 7.28-7.32 (m, 3H), 7.38 (t, 2H, J
= 8Hz), 7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.13 (d, 2
(H, J = 8Hz)

Step 3: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenyl-2- (triethylsilyl)
Oxy) propionyl] -4,10-dideacetyl-4-O-propyl
Ropionyl-7-O-triethylsilylbaccatin III 709 mg of the compound obtained in the above step 2 was dissolved in 30 ml of a mixed solvent of acetic acid and methanol (1: 1 (v / v)), and 2 g of active zinc was added and the temperature was 50 ° C. And stirred for 20 minutes. After removing the insoluble matter by filtration, the filtrate was evaporated under reduced pressure. After toluene was added and the solvent was distilled off again under reduced pressure, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (eluting solvent: chloroform: acetone = 40: 1 (v / v)) to obtain 540 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.31-0.50
(m, 6H), 0.52-0.63 (m, 6H), 0.78 (t, 9H, J = 7Hz), 0.94 (t, 9
H, J = 7Hz), 1.12 (s, 3H), 1.27 (s, 3H), 1.32 (s, 9H), 1.37
(t, 3H, J = 7Hz), 1.75 (s, 3H), 1.92 (s, 3H), 1.90-1.96 (m,
1H), 2.19-2.38 (m, 2H), 2.44-2.52 (m, 1H), 2.71-2.85 (m,
2H), 3.89 (d, 1H, J = 7Hz), 4.21 (d, 1H, J = 8Hz), 4.28 (d, 1H,
J = 2Hz), 4.34 (d, 1H, J = 8Hz), 4.41 (dd, 1H, J = 7Hz, 10Hz),
4.53 (s, 1H), 4.90 (d, 1H, J = 8Hz), 5.13 (d, 1H, J = 2Hz), 5.2
3 (d, 1H, J = 10Hz), 5.47 (d, 1H, J = 10Hz), 5.68 (d, 1H, J = 7H
z), 6.28 (t, 1H, J = 8Hz), 7.30 (t, 3H, J = 8Hz), 7.37 (t, 2H, J
= 8Hz), 7.48 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.12 (d,
2H, J = 8Hz)

Step 4: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3-phenyl-2- (triethylsilyl)
(Oxy) propionyl] -4,10-dideacetyl-10-O-
(N, N-methylglycyl) -4-O-propionyl-7-O-
Triethylsilylbaccatin III The compound (540 mg) obtained in Step 3 above and N, N-dimethylglycine (265 mg) were added to dichloromethane (20 ml), and dicyclohexylcarbodiimide (583 mg) was added at room temperature, and after 10 minutes,
4-Dimethylaminopyridine (62.8 mg) was added, and the mixture was stirred at room temperature for 65 hours. After concentration, the mixture was diluted with ethyl acetate, the insoluble material was filtered off, washed with water and a saturated aqueous solution of sodium hydrogencarbonate in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (elution solvent; ethyl acetate: hexane = 1: 2).
(v / v)) to obtain 476 mg of the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.33-0.49
(m, 6H), 0.57-0.63 (m, 6H), 0.78 (t, 9H, J = 7Hz), 0.93 (t, 9
H, J = 7Hz), 1.22 (s, 6H), 1.32 (s, 9H), 1.37 (t, 3H, J = 7H
z), 1.70 (s, 3H), 1.87-1.94 (m, 1H), 2.00 (s, 3H), 2.22-
2.40 (m, 2H), 2.42 (s, 6H), 2.48-2.54 (m, 1H), 2.72-2.83
(m, 2H), 3.34 (s, 2H), 3.84 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8
Hz), 4.33 (d, 1H, J = 8Hz), 4.49-4.53 (m, 2H), 4.90 (d, 1H, J
= 8Hz), 5.24 (d, 1H, J = 10Hz), 5.46 (d, 1H, J = 10Hz), 5.71
(d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz), 6.52 (s, 1H), 7.28-7.
40 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.13
(d, 2H, J = 8Hz)

Step 5: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -2-hydroxy-3-phenylpropyi
Onyl] -4,10-dideacetyl-10-O- (N, N-dimethyl
Glycyl) -4-O-propionylbaccatin III 420 mg of the compound obtained in the above step 4 was added to acetonitrile 20
After dissolving in ice-water, 1 ml of pyridine and 3 ml of 48% hydrofluoric acid were added under ice cooling, and the mixture was reacted at 0 ° C for 2 hours and at room temperature for 4 hours. The reaction solution was ice-cooled and made weakly alkaline with a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted 3 times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent: ethyl acetate) to obtain 248 mg of the title compound as a white solid.

Melting point: 174-177 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.25 (t, 3H,
J = 7Hz), 1.27 (s, 3H), 1.33 (s, 9H), 1.68 (s, 3H), 1.87 (s,
3H), 2.34 (s, 6H), 2.25-2.35 (m, 2H), 2.48-2.57 (m, 1H),
2.58-2.72 (m, 2H), 3.38 (s, 2H), 3.79 (d, 1H, J = 7Hz), 4.1
9 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.46 (br, 1H), 4.65
(s, 1H), 4.91 (d, 1H, J = 8Hz), 5.21 (br, 1H), 5.40 (d, 1H, J =
10Hz), 5.69 (d, 1H, J = 7Hz), 6.21 (t, 1H, J = 8Hz), 6.37 (s,
1H), 7.33-7.41 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.62 (t, 1H,
J = 8Hz), 8.13 (d, 2H, J = 8Hz) IR (KBr): 3460, 3072, 2984, 2948, 2948, 2788, 222
8, 1722, 1604,1588 cm ^-1 MS-FAB: 907 (MH ⁺ ).

Example 18

[0397]

Embedded image

Step 1: 4-O-butyryl-4,10-dideacetyl
Ru-10-O- (2,2,2-trichloroethoxycarbonyl) -7-O
-Triethylsilylbaccatin III The compound obtained in step 2 of example 13 was used in step 1 of example 17
The reaction was performed in the same manner as in (1) to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.60 (q, 6H,
J = 8Hz), 0.93 (t, 9H, J = 8Hz), 1.06 (t, 3H, J = 8Hz), 1.08
(s, 3H), 1.20 (s, 3H), 1.70 (s, 3H), 1.79 (m, 2H), 1.89 (dd
d, 1H, J = 3Hz, 10.5Hz, 14Hz), 2.01 (dd, 1H, J = 3Hz, 5.5Hz),
2.19 (s, 3H), 2.27 (d, 2H, J = 8.5Hz), 2.51-2.60 (m, 3H), 3.
83 (d, 1H, J = 7.5Hz), 4.15 (d, 1H, J = 9Hz), 4.30 (d, 1H, J = 9H
z), 4.49 (dd, 1H, J = 5.5Hz, 10.5Hz), 4.78 and 4.82 (each
d, 1H, J = 12Hz), 4.87 (br, 1H), 4.88 (dd, 1H, J = 3Hz, 10.5H
z), 5.63 (d, 1H, J = 7.5Hz), 6.30 (s, 1H), 7.47 (t, 2H, J = 7.5
Hz), 7.61 (t, 1H, J = 7.5Hz), 8.11 (d, 2H, J = 7.5Hz)

Step 2: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triethylsilyloxy
Si) Propionyl] -4-O-butyryl-4,10-dideacetyl
-10-O- (2,2,2-trichloroethoxycarbonyl) -7-O-
Triethylsilylbaccatin III The compound obtained in Step 1 above was treated with cis-1- (tert-butoxycarbonyl) -4- (2-furyl) -3- in the same manner as in Step 2 of Example 17.
Condensation with (triethylsilyloxy) azetidin-2-one gave the title compound as a mixture of diastereoisomers in which the relative configuration at the 2'and 3'positions is threo (syn).

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.40-0.62
(m, 12H), 0.73-1.09 (m, 24H), 1.22 and 1.24 (each s, to
tal 6H), 1.33 and 1.43 (each s, total 9H), 1.70 and
1.71 (each s, total 3H), 1.79-1.98 (m, 3H), 2.03 and 2.
08 (each s, total 2H), 2.18-2.85 (m, 5H), 3.81 and 3.85
(each d, total 1H, J = 7Hz), 4.12-4.21 (m, 1H), 4.25-4.34
(m, 1H), 4.48 (dd, 1H, J = 7Hz, 10.5Hz), 4.68-4.94 (m, 3H),
5.23-5.43 (m, 2H), 5.61-5.73 (m, 1H), 6.11-6.41 (m, 4H),
7.34-7.63 (m, 4H), 8.11 (t, 2H, J = 7Hz).

Step 3: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triethylsilyloxy
Si) Propionyl] -4-O-butyryl-4,10-dideacetyl
-10-O-nicotinoyl-7-O-triethylsilylbacca
Chin III The compound obtained in Step 2 above was reacted and purified in the same manner as in Step 3 of Example 17. The obtained compound was reacted in the same manner as in Step 1 of Example 14 using nicotinic acid instead of isonicotinic acid, and the title compound was purified to give the title compound in the relative threo configuration at the 2'position and the 3'position ( Syn.) Was obtained as a mixture of diastereoisomers.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.41-0.63
(m, 12H), 0.81-0.92 (m, 18H), 1.04 and 1.06 (each t, tot
al 3H, J = 7.5Hz), 1.22 (s, 3H), 1.32 and 1.35 (each s, to
tal 9H), 1.44 (s, 3H), 1.56-1.74 (m, 1H), 1.72 (s, 3H),
1.83-1.99 (m, 2H), 2.11 and 2.14 (each s, total 3H), 2.
21-2.88 (m, 5H), 3.91 and 3.96 (each d, total 1H, J = 7H
z), 4.10 (br-d, 1H, J = 7Hz), 4.16-4.26 (m, 1H), 4.30-4.39
(m, 1H), 4.57 (dd, 1H, J = 7Hz, 10Hz), 4.76 and 4.80 (each
s, total 1H), 4.92 (d, 1H, J = 10.5Hz), 5.26-5.44 (m, 2H),
5.74 (d, 1H, J = 7Hz), 6.26-6.23 (m, 1H), 6.24 (d, 1H, J = 4H
z), 6.37 (dd, 1H, J = 3Hz, 4Hz), 6.72 and 6.74 (each s, tot
al 1H), 7.37 and 7.39 (each s, toatl 1H), 7.40-7.54
(m, 3H), 7.57-7.67 (m, 1H), 8.12 (t, 2H, J = 7Hz), 8.28-8.
43 (m, 1H), 8.76-8.86 (m, 1H), 9.21-9.36 (m, 1H).

Step 4: 13-O- [3- (tert-butoxycarbo
Nylamino) -2-hydroxy-3- (2-furyl) propioni
] -4-O-Butyryl-4,10-dideacetyl-10-O-nicoti
Noilbaccatin III 69.8 mg of the compound obtained in the above step 3 was dissolved in 2.44 ml of acetonitrile, 0.02 ml of concentrated hydrochloric acid was added under cooling to -9 ° C, and the mixture was stirred for 1.5 hours. Then, 0.02 ml of concentrated hydrochloric acid was added, and the mixture was further stirred for 0.5 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel thin layer chromatography (developing solvent; chloroform:
High Rf value after purification with acetone = 6: 1 (v / v)
Obtained were 10.1 mg of 2′-position and 3′-position diastereoisomer A and 22.7 mg of isomer B having a small Rf value as white solids.

Isomer A ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.06 (t, 3H, J = 7Hz), 1.25
(s, 3H), 1.26 (s, 3H), 1.32 (s, 3H), 1.40 (s, 9H), 1.71 (s,
3H), 1.77-1.97 (m, 4H), 2.09 (s, 3H), 2.33 (dd, 1H, J = 8H
z, 15Hz), 2.39-2.69 (m, 3H), 3.94 (d, 1H, J = 7Hz), 4.18 (d,
1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.52-4.60 (br, 1H), 4.63
(br-s, 1H), 4.93 (dd, 1H, J = 2Hz, 9.5Hz), 5.21 (br-d, 1H, J =
9Hz), 5.34 (br-d, 1H, J = 9Hz), 5.71 (d, 1H, J = 7Hz), 6.18 (b
rt, 1H, J = 7Hz), 6.33 (d, 1H, J = 3.5Hz), 6.38 (dd, 1H, J = 1.5
Hz, 3.5Hz), 6.62 (s, 1H), 7.41 (d, 1H, J = 1.5Hz), 7.42-7.5
2 (m, 1H), 7.49 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.08
(d, 2H, J = 8Hz), 8.35 (d, 1H, J = 8Hz), 8.83 (br, 1H), 9.30
(br, 1H) .MS-FAB: 931 (MH ⁺ )

Isomer B ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.00 (t, 3H, J = 7Hz), 1.27
(s, 3H), 1.34 (s, 12H), 1.71 (s, 3H), 1.74-1.96 (m, 3H),
1.95 (s, 3H), 2.32-2.77 (m, 6H), 3.90 (d, 1H, J = 7Hz), 4.20
(d, 1H, J = 8Hz), 4.33 (d, 1H, J = 8Hz), 4.53 (br, 1H), 4.71
(s, 1H), 4.93 (dd, 1H, J = 1.5Hz, 8Hz), 5.20 (d, 1H, J = 10Hz),
5.32 (br-d, 1H, J = 10Hz), 5.72 (d, 1H, J = 7Hz), 6.24 (br-t,
1H, J = 9Hz), 6.35 (d, 1H, J = 3Hz), 6.39 (dd, 1H, J = 1.5Hz, 3H
z), 6.61 (s, 1H), 7.42 (d, 1H, J = 1.5Hz), 7.42-7.54 (m, 1
H), 7.50 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.13 (d, 2H, J
= 8Hz), 8.34 (td, 1H, J = 3Hz, 7.5Hz), 8.83 (dd, 1H, J = 3Hz, 5
Hz), 9.29 (d, 1H, J = 3Hz) .MS-FAB: 931 (MH ⁺ ).

Example 19

[0408]

Embedded image

Step 1: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-4-O- (3-formy
Lepropionyl) -7,10-bis-O- (triethylsilyl)
Baccatin III 118 mg of the compound obtained in Step 3 of Example 5 and 36.9 mg of N-methylmorpholine-N-oxide were added to 10 ml of acetone.
And 3 ml of water and water at room temperature.
0.5 mg was added and stirred for 2 hours. Sodium sulfite was added and the mixture was stirred for 15 minutes, and anhydrous sodium sulfate was further added for 30 minutes, and then the insoluble matter was filtered off. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in 3 ml of methanol. Under ice-cooling, a solution of 45.0 mg of sodium metaperiodate in 1 ml of water was added dropwise, and the mixture was stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v).
) And 106 mg of the title compound was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.74
(m, 12H), 0.93-1.02 (m, 18H), 1.07 (s, 9H), 1.21 (s, 6H),
1.64 (s, 3H), 1.77 (s, 3H), 1.84 (s, 3H), 1.86 (s, 3H), 2.
09-2.17 (m, 2H), 2.40-2.54 (m, 1H), 2.59 (br, 2H), 2.80 (b
r, 2H), 3.78 (d, 1H, J = 7Hz), 4.10 (d, 1H, J = 8Hz), 4.23 (d, 1
H, J = 8Hz), 4.35 (dd, 1H, J = 7Hz, 10Hz), 4.42 (d, 1H, J = 7Hz),
4.83 (d, 1H, J = 8Hz), 5.11 (br, 1H), 5.15 (s, 1H), 5.64 (d,
1H, J = 7Hz), 6.24 (t, 1H, J = 8Hz), 7.35-7.39 (m, 5H), 7.50
(t, 2H, J = 8Hz), 7.63 (t, 1H, J = 8Hz), 8.03 (d, 2H, J = 8Hz),
9.77 (s, 1H)

Step 2: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-4-O- (4-hydro
Xybutyryl) -7,10-bis-O- (triethylsilyl) bar
Katchin III 60.4 mg of the compound obtained in the above step 1 was added to tetrahydrofuran.
Dissolve in 4 ml and cool with ice, sodium borohydride 5 mg
Was added and stirred for 30 minutes. It was diluted with chloroform, washed with a saturated aqueous solution of ammonium chloride, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)) to give 51.0 mg of the title compound.
Was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-
0.73 (m, 12H), 0.94 to 1.02 (m,
18H), 1.13 (s, 9H), 1.22 (s,
6H), 1.64 (s, 3H), 1.76 (s, 3)
H), 1.83 (s, 3H), 1.90 (s, 3)
H), 2.14 (d, 2H, J = 9 Hz), 2.22
-2.26 (m, 2H), 2.40-2.52 (m,
1H), 3.62 (m, 2H), 3.81 (d, 1)
H, J = 7 Hz), 4.12 (d, 1H, J = 8H
z), 4.23 (d, 1H, J = 8 Hz), 4.3
9 (dd, 1H, J = 7Hz, 10Hz), 4.50
(D, 1H, J = 7 Hz), 4.85 (d, 1H, J
= 8 Hz), 5.12 (br, 1H), 5.17
(S, 1H), 5.64 (d, 1H, J = 7Hz),
6.23 (t, 1H, J = 8Hz), 7.36-7.
38 (m, 5H), 7.48 (t, 2H, J = 8H
z), 7.61 (t, 1H, J = 8 Hz), 8.0
5 (d, 2H, J = 8Hz)

Step 3: 4-O- (4-acetoxybutyryl)-
13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -N,
O-isopropylidene-3-phenylisoselinyl] -4,10
-Dideacetyl-7,10-bis-O- (triethylsilyl) va
Katchin III 24.8 mg of the compound obtained in Step 2 above, triethylamine
Add 0.015 ml and acetic anhydride 0.010 ml to methylene chloride 2
It was dissolved in 0.5 ml of 4-dimethylaminopyridine and the mixture was stirred at room temperature for 1 hour. After concentration, dilute with ethyl acetate
The extract was washed with 1N aqueous hydrochloric acid solution and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to give the title compound 23.
4 mg was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-0.72
(m, 12H), 0.94-1.02 (m, 18H), 1.05 (s, 9H), 1.22 (s, 6H),
1.64 (s, 3H), 1.76 (s, 3H), 1.82 (s, 3H), 1.88 (s, 3H), 2.
02 (s, 3H), 2.12-2.23 (m, 4H), 2.46-2.54 (m, 1H), 3.80 (d,
1H, J = 7Hz), 4.00-4.09 (m, 2H), 4.12 (d, 1H, J = 8Hz), 4.23
(d, 1H, J = 8Hz), 4.39 (dd, 1H, J = 7Hz, 10Hz), 4.42 (d, 1H, J = 7
Hz), 4.83 (d, 1H, J = 8Hz), 5.12 (br, 1H), 5.17 (s, 1H), 5.6
4 (d, 1H, J = 7Hz), 6.23 (t, 1H, J = 8Hz), 7.33-7.41 (m, 5H),
7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.02-8.04 (m, 2
H)

Step 4: 4-O- (4-acetoxybutyryl) -13
-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-
Hydroxy-3-phenylpropionyl] -4,10-didease
Cilbaccatin III The compound obtained in Step 3 above was reacted in the same manner as in Step 2 of Example 14 to give the title compound as a white solid.

Melting point: 144-147 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.24 (s, 3
H), 1.35 (s, 9H), 1.76 (s, 3H), 1.83 (s, 3H), 2.00 (s, 3H),
2.06-2.08 (m, 2H), 2.22 (m, 2H), 2.52-2.65 (m, 2H), 2.73
(m, 1H), 3.41 (br, 1H), 3.91 (d, 1H, J = 7Hz), 4.02-4.11
(m, 2H), 4.20 (d, 1H, J = 8Hz), 4.21 (m, 1H), 4.31 (d, 1H, J = 8
Hz), 4.62 (s, 1H), 4.89 (d, 1H, J = 8Hz), 5.20 (s, 1H), 5.21
(br, 1H), 5.45 (br-d, 1H, J = 10Hz), 5.68 (d, 1H, J = 7Hz), 6.
19 (t, 1H, J = 8Hz), 7.31-7.40 (m, 5H), 7.50 (t, 2H, J = 8Hz),
7.62 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz) IR (KBr): 3456, 3068, 2984, 1724, 1604, 1588, 149
6, 1454 cm ^-1 MS-FAB: 894 (MH ⁺ )

Example 20

[0418]

[Chemical 43]

Step 1: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-4-O- [4- (die
Cylamino) butyryl] -7,10-bis-O- (triethylsi
Ril) baccatin III 43.0 mg of the compound obtained in Step 1 of Example 19, 0.040 ml of diethylamine and 0.022 ml of acetic acid were added to 4 m of ethanol.
The resulting mixture was dissolved in l, and sodium cyanoborohydride (24.0 mg) was added, followed by stirring at room temperature for 2 hours. The mixture was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to give 28.4 mg of the title compound as a colorless amorphous solid. Got as.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.84
(m, 12H), 0.94-1.02 (m, 24H), 1.12 (s, 9H), 1.21 (s, 6H),
1.64 (s, 3H), 1.77 (s, 3H), 1.82 (s, 3H), 1.89 (s, 3H), 2.
05-2.08 (m, 2H), 2.13 (d, 2H, J = 9Hz), 2.36-2.39 (m, 2H),
2.40-2.52 (m, 5H), 3.81 (d, 1H, J = 7Hz), 4.11 (d, 1H, J = 8H
z), 4.23 (d, 1H, J = 8Hz), 4.38 (dd, 1H, J = 7Hz, 10Hz), 4.43
(d, 1H, J = 7Hz), 4.83 (d, 1H, J = 8Hz), 5.09 (br, 1H), 5.17
(s, 1H), 5.63 (d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz), 7.34-7.
38 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.05
(d, 2H, J = 8Hz)

Step 2: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -2-hydroxy-3-phenylpropyi
Onyl] -4,10-dideacetyl-4-O- [4- (diethylamido
B) Butyryl] baccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Example 14 to give the title compound as a white solid.

Melting point: 147-142 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.88 (s, 6H), 1.12 (s, 3
H), 1.26 (s, 3H), 1.39 (s, 9H), 1.75 (s, 3H), 1.93 (s, 3H),
2.15-2.25 (m, 2H), 2.40 (br, 4H), 2.51-2.62 (m, 3H), 2.6
3-2.78 (m, 2H), 3.89 (d, 1H, J = 7Hz), 4.20 (d, 1H, J = 8Hz),
4.26 (m, 1H), 4.31 (d, 1H, J = 8Hz), 4.54 (s, 1H), 4.91 (d, 1
H, J = 8Hz), 5.21 (s, 1H), 5.24 (br, 1H), 5.70 (d, 1H, J = 7H
z), 5.76 (br, 1H), 6.20 (t, 1H, J = 8Hz), 7.32-7.40 (m, 5H),
7.47 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.07 (d, 2H, J = 8
Hz) IR (KBr): 3800, 3668, 3452, 3068, 2980, 2940, 1
976, 1726, 1604, 1586 cm ^-1 MS-FAB: 907 (MH ⁺ )

Example 21

[0424]

[Chemical 74]

Step 1: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-4-O- [4- (2,2,2
-Trichloroethoxycarbonyloxy) butyryl] -7,
10-Bis-O- (triethylsilyl) baccatin III 43.2 mg of the compound obtained in Step 2 of Example 19 was treated with pyridine.
It was dissolved in 2.5 ml, and under ice cooling, 0.010 ml of 2,2,2-trichloroethyl chloroformate was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate.
It was washed with a saturated aqueous solution of sodium bicarbonate in this order and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to give 42.2 mg of the title compound as a colorless amorphous substance. Obtained as a solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-0.72
(m, 12H), 0.96-1.02 (m, 18H), 1.14 (s, 9H), 1.22 (s, 6H),
1.65 (s, 3H), 1.76 (s, 3H), 1.82 (s, 3H), 1.88 (s, 3H), 2.
13 (d, 2H, J = 9Hz), 2.15-2.30 (m, 2H), 2.46-2.54 (m, 1H),
3.80 (d, 1H, J = 7Hz), 4.12 (d, 1H, J = 8Hz), 4.23 (d, 1H, J = 8H
z), 4.21-4.25 (m, 2H), 4.38 (dd, 1H, J = 7Hz, 10Hz), 4.43
(d, 1H, J = 7Hz), 4.70 and 4.77 (each AB type d, 1H, J = 12H
z), 4.86 (d, 1H, J = 8Hz), 5.11 (br, 1H), 5.17 (s, 1H), 5.64
(d, 1H, J = 7Hz), 6.24 (t, 1H, J = 8Hz), 7.35-7.38 (m, 5H), 7.
49 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.02-8.04 (m, 2H)

Step 2: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -2-hydroxy-3-phenylpropyi
Onyl] -4,10-dideacetyl-4-O- [4- (2,2,2-trick
Loroethoxycarbonyloxy) butyryl] baccatin
III The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Example 14 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3
H), 1.24 (s, 3H), 1.35 (s, 9H), 1.75 (s, 3H), 1.82 (s, 3
H), 2.04-2.22 (m, 4H), 2.54-2.62 (m, 1H), 2.72-2.79 (m, 1
H), 3.43 (br, 1H), 3.89 (d, 1H, J = 7Hz), 4.12 (d, 1H, J = 8H
z), 4.17-4.23 (m, 3H), 4.29 (d, 1H, J = 8Hz), 4.63 (s, 1H),
4.72 and 4.76 (each AB type d, 1H, J = 12Hz), 4.95 (d, 1
H, J = 10Hz), 5.19 (s, 1H), 5.20 (br, 1H), 5.44 (br, 1H), 5.
67 (d, 1H, J = 7Hz), 6.19 (t, 1H, J = 8Hz), 7.31-7.45 (m, 5H),
7.51 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8H
z)

Step 3: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -2-hydroxy-3-phenylpropyi
Onyl] -4,10-dideacetyl-4-O- (4-hydroxybutyrate
Lil) baccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 3 of Example 17 to give the title compound as a white solid.

Melting point: 168-172 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.25 (s, 3
H), 1.34 (s, 9H), 1.75 (s, 3H), 1.86 (s, 3H), 1.98 (br, 2
H), 2.11-2.35 (m, 4H), 2.54-2.69 (m, 3H), 2.90 (br, 1H),
3.64 (br, 2H), 3.80 (br, 1H), 3.90 (d, 1H, J = 7Hz), 4.19
(d, 1H, J = 8Hz), 4.23 (m, 1H), 4.31 (d, 1H, J = 8Hz), 4.67 (s,
1H), 4.91 (d, 1H, J = 8Hz), 5.20 (s, 1H), 5.25 (br, 1H), 5.5
0 (br, 1H), 5.68 (d, 1H, J = 7Hz), 6.23 (t, 1H, J = 8Hz), 7.31-
7.40 (m, 5H), 7.51 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.
10 (d, 2H, J = 8Hz) IR (KBr): 3816, 3456, 3072, 2980, 2944, 1980, 171
6, 1604, 1586, 1496 cm ^-1 MS-FAB: 852 (MH ⁺ )

Example 22: 13-O- [3- (tert-butoxyca
Rubonylamino) -2-hydroxy-3- (4-pyridyl) propyi
Onyl] -4,10-dideacetyl-4-O-propionyl bacca
Chin III

[0432]

[Chemical 75]

38 mg sodium hydride (60% oil sus
pended) was washed with dry hexane, 1 ml of dry tetrahydrofuran was added, and the solution of 25 mg of the compound obtained in Step 3 of Example 1 in dry tetrahydrofuran (1 ml) and cis-1 was added with stirring at 0 ° C. -(tert-Butoxycarbonyl) -4- (4-pyridyl) -3- (triethylsilyloxy) azetidin-2-one 24 mg of a dry tetrahydrofuran solution (1 ml) was sequentially added, and then at the same temperature for 40 minutes. Further, the mixture was stirred at room temperature for 2 hours. After adding 15 ml of 10% ammonium chloride aqueous solution to the reaction solution, the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel thin-layer chromatography (developing solvent; chloroform: ethyl acetate = 9: 1 (v / v)) to obtain the relative 2'position and 3'position. Three-dimensional configuration is threo type (thin type)
2 diastereoisomers were obtained (low polar isomer A 5 mg, high polar isomer B 6 mg). Isomer A (5 mg) was dissolved in pyridine (1 ml), and 0.2 ml of hydrogen fluoride-pyridine was added at 0 ° C under a nitrogen stream, followed by stirring at room temperature for 2 minutes.
The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and the obtained organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel thin layer chromatography (developing solvent; chloroform containing 8% (v / v) of methanol) to obtain 2 mg of isomer A of the title compound. . By performing the same operation, 4 mg of isomer B of the title compound was obtained.

Isomer A ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.15 (3H, s), 1.24 (3H,
s), 1.25 (3H, t, J = 7Hz), 1.40 (9H, s), 1.78 (3H, s), 1.87
(1H, m), 2.09 (3H, s), 2.16 (1H, dd, J = 8Hz, 16Hz), 2.40 (2
H, m), 2.52 (1H, dd, J = 8Hz, 16Hz), 2.63 (1H, m), 3.97 (1H,
d, J = 7Hz), 4.19 (1H, d, J = 8Hz), 4.32 (1H, m), 4.33 (1H, d, J
= 8Hz), 4.47 (1H, br-s), 4.91 (1H, dd, J = 2Hz, 10Hz), 5.22
(1H, br-d, J = 9Hz), 5.26 (1H, s), 5.39 (1H, br-d, J = 9Hz),
5.70 (1H, d, J = 7Hz), 6.18 (1H, br), 7.39 (2H, d, J = 6Hz), 7.
48 (2H, t, J = 7Hz), 7.62 (1H, t, J = 7Hz), 8.07 (2H, d, J = 7Hz),
8.64 (2H, d, J = 6Hz).

Isomer B ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (3H, s), 1.24 (3H, t,
J = 7Hz), 1.26 (3H, s), 1.33 (9H, s), 1.77 (3H, s), 1.86 (1
H, m), 1.89 (3H, s), 2.26 (1H, dd, J = 9Hz, 16Hz), 2.33 (1H,
m), 2.60 (1H, m), 2.66 (2H, m), 3.92 (1H, d, J = 7Hz), 4.20
(1H, d, J = 8Hz), 4.27 (1H, dd, J = 6Hz, 11Hz), 4.33 (1H, d, J = 8
Hz), 4.69 (1H, br-s), 4.90 (1H, dd, J = 2Hz, 10Hz), 5.26 (1
H, br-d, J = 10Hz), 5.40 (1H, br-d, J = 10Hz), 5.69 (1H, d, J = 7
Hz), 6.29 (1H, br), 7.35 (2H, d, J = 6Hz), 7.50 (2H, t, J = 7H
z), 7.61 (1H, t, J = 7Hz), 8.12 (2H, d, J = 7Hz), 8.64 (2H, d, J
= 6Hz).

Example 23: 13-O- [3- (tert-butoxyca
Rubonylamino) -2-hydroxy-3- (4-pyridyl) propyi
Onyl] -10-deacetoxy-4-deacetyl-4-O-propio
Nilbaccatin III

[0437]

[Chemical 76]

The compound obtained in Step 2 of Example 9 was used in Example 2
Similar to 2, cis-1-tert-butoxycarbonyl-4
-(4-Pyridyl) -3- (triethylsilyloxy) azetidin-2-one condensed and purified, two types of relative configuration of 2'-position and 3'-position is threo type (syn type) To obtain the diastereoisomer (low polar isomer A, high polar isomer B).
Each isomer was deprotected and purified in the same manner as in Example 22 to obtain isomers A and B of the title compound as white solids.

Isomer A ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.18 (3H, s), 1.20 (3H,
s), 1.27 (3H, t, J = 7Hz), 1.40 (9H, s), 1.66 (3H, s), 1.83
(1H, m), 1.95 (3H, s), 2.19 (1H, dd, J = 8Hz, 15Hz), 2.35-
2.45 (2H, m), 2.50 (1H, m), 2.66 (1H, m), 3.47 (1H, br-d, J =
16Hz), 3.86 (1H, d, J = 16Hz), 4.11 (1H, d, J = 7Hz), 4.18 (1
H, d, J = 8Hz), 4.31 (1H, d, J = 8Hz), 4.35 (1H, m), 4.47 (1H, b
rs), 4.92 (1H, br-d, J = 8Hz), 5.23 (1H, br-d, J = 9Hz), 5.4
2 (1H, br-d, J = 9Hz), 5.71 (1H, d, J = 7Hz), 6.10 (1H, br), 7.
39 (2H, d, J = 6Hz), 7.47 (2H, t, J = 7Hz), 7.61 (1H, t, J = 7H
z), 8.07 (2H, d, J = 7Hz), 8.64 (2H, d, J = 6Hz).

Isomer B ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.18 (3H, s), 1.22 (3H,
s), 1.25 (3H, t, J = 7Hz), 1.35 (9H, s), 1.65 (3H, s), 1.75
(3H, s), 1.82 (1H, m), 2.20-2.40 (2H, m), 2.55-2.70 (3H,
m), 3.46 (1H, br-d, J = 16Hz), 3.82 (1H, d, J = 16Hz), 4.12 (1
H, d, J = 7Hz), 4.19 (1H, d, J = 8Hz), 4.31 (1H, m), 4.32 (1H,
d, J = 8Hz), 4.68 (1H, br-s), 4.89 (1H, dd, J = 2Hz, 10Hz), 5.
26 (1H, br-d, J = 10Hz), 5.39 (1H, br-d, J = 10Hz), 5.71 (1H,
d, J = 7Hz), 6.18 (1H, br), 7.35 (2H, d, J = 6Hz), 7.49 (2H,
t, J = 7Hz), 7.61 (1H, t, J = 7Hz), 8.12 (2H, d, J = 7Hz), 8.64
(2H, d, J = 6Hz).

Example 24

[0442]

Embedded image

Step 1: 4,10-dideacetyl-10-O- [3- (
Dimethylamino) propionyl] -4-O-propionyl-7
-O-Triethylsilylbaccatin III The reaction obtained in the same manner as in Step 16 of Example 16 using N, N-dimethyl-β-alanine in place of N, N-dimethylglycine for the compound obtained in Step 3 of Example 8 The title compound was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.55-0.62
(m, 6H), 0.92 (t, 9H, J = 7Hz), 1.04 (s, 3H), 1.19 (s, 3H),
1.24 (t, 3H, J = 7Hz), 1.68 (s, 3H), 1.83-1.93 (m, 1H), 2.1
8 (s, 3H), 2.26 (s, 6H), 2.22-2.27 (m, 2H), 2.50-2.73 (m, 5
H), 3.88 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.30 (d, 1H, J
= 8Hz), 4.50 (dd, 1H, J = 7Hz, 10Hz), 4.81 (t, 1H, J = 8Hz), 4.
91 (d, 1H, J = 8Hz), 5.63 (d, 1H, J = 7Hz), 6.47 (s, 1H), 7.46
(t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10-8.13 (m, 2H)

Step 2: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phenyl
Luisoselinyl] -4,10-dideacetyl-10-O- [3- (dim
Cylamino) propionyl] -4-O-propionyl-7-O
-Triethylsilylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Example 16 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.53-0.59
(m, 6H), 0.91 (t, 9H, J = 7Hz), 1.05 (t, 3H, J = 7Hz), 1.11
(s, 9H), 1.21 (s, 6H), 1.66 (s, 3H), 1.76 (s, 3H), 1.80 (s,
3H), 2.03 (s, 3H), 2.12-2.15 (m, 2H), 2.27 (s, 6H), 2.46-
2.53 (m, 1H), 2.60-2.73 (m, 4H), 3.76 (d, 1H, J = 7Hz), 4.10
(d, 1H, J = 8Hz), 4.24 (d, 1H, J = 8Hz), 4.41 (d, 1H, J = 7Hz),
4.46 (dd, 1H, J = 7Hz, 10Hz), 4.81 (d, 1H, J = 8Hz), 5.03 (br, 1
H), 5.65 (d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz), 6.44 (s, 1
H), 7.33-7.39 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.64 (t, 1H, J =
8Hz), 8.05-8.07 (m, 2H)

Step 3: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -2-hydroxy-3-phenylpropyi
Onyl] -4,10-dideacetyl-10-O- [3- (dimethylamido
B) Propionyl] -4-O-propionyl baccatin III The compound obtained in the above Step 2 was reacted in the same manner as in Step 2 of Example 14 to obtain the title compound as a white solid.

Melting point: 149-152 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.15 (s, 3H), 1.22 (t, 3H, J =
7Hz), 1.27 (s, 3H), 1.33 (s, 9H), 1.67 (s, 3H), 1.86 (s, 3
H), 2.25 (m, 2H), 2.28 (s, 6H), 2.47-2.75 (m, 7H), 3.79
(d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.45 (dd, 1H, J = 7Hz, 10Hz), 4.62 (s, 1H), 4.90 (d, 1H, J = 8H
z), 5.20 (br, 1H), 5.32 (d, 1H, J = 9Hz), 5.68 (d, 1H, J = 7H
z), 6.23 (t, 1H, J = 8Hz), 6.30 (s, 1H), 7.33-7.41 (m, 5H),
7.50 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8H
z) IR (KBr): 3464, 3072, 2984, 2948, 2828, 2784, 17
26, 1604, 1588 cm ^-1 MS-FAB: 921 (MH ⁺ )

Example 25

[0450]

Embedded image

Step 1: 4,10-dideacetyl-10-O- [4-
(Dimethylamino) butyryl] -4-O-propionyl-7-O-
Triethylsilylbaccatin III The compound obtained in Step 3 of Example 8 was reacted in the same manner as in Step 16 of Example 16 using 4- (dimethylamino) butyric acid instead of N, N-dimethylglycine to give the title compound. Obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.54-0.64 (m,
6H), 0.93 (t, 9H, J = 7Hz), 1.03 (s, 3H), 1.19 (s, 3H), 1.24
(t, 3H, J = 7Hz), 1.68 (s, 3H), 1.84-1.92 (m, 3H), 2.18 (s,
3H), 2.27 (s, 6H), 2.24-2.31 (m, 2H), 2.39-2.65 (m, 5H),
3.89 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8H)
z), 4.50 (dd, 1H, J = 7Hz, 10Hz), 4.82 (t, 1H, J = 8Hz), 4.91
(d, 1H, J = 8Hz), 5.63 (d, 1H, J = 7Hz), 6.48 (s, 1H), 7.47 (t,
2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.11 (m, 2H)

Step 2: 13-O-[(2R, 3S) -N- (tert-but
Xycarbonyl) -N, O-isopropylidene-3-phen
Nyl isoserinyl] -4,10-dideacetyl-10-O- [4- (di
Methylamino) butyryl] -4-O-propionyl-7-O-
Triethylsilylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Example 16 to give the title compound as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.53-0.60 (m,
6H), 0.92 (t, 9H, J = 7Hz), 1.05 (t, 3H, J = 7Hz), 1.11 (s, 9
H), 1.20 (s, 3H), 1.21 (s, 3H), 1.65 (s, 3H), 1.76 (s, 3H),
1.80 (s, 3H), 1.92-1.98 (m, 2H), 2.00 (s, 3H), 2.12-2.15
(m, 2H), 2.42 (s, 6H), 2.43-2.64 (m, 5H), 3.75 (d, 1H, J = 7H
z), 4.10 (d, 1H, J = 8Hz), 4.24 (d, 1H, J = 8Hz), 4.41 (d, 1H, J
= 7Hz), 4.46 (dd, 1H, J = 7Hz, 10Hz), 4.81 (d, 1H, J = 8Hz), 5.
05 (br, 1H), 5.64 (d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz), 6.45
(s, 1H), 7.32-7.39 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.64 (t,
1H, J = 8Hz), 8.04-8.06 (m, 2H)

Step 3: 13-O-[(2R, 3S) -3- (tert-but
Xycarbonylamino) -2-hydroxy-3-phenylpro
Pionyl] -4,10-dideacetyl-10-O- [4- (dimethyla
Mino) butyryl] -4-O-propionylbaccatin III The compound obtained in Step 2 above was reacted in the same manner as in Step 2 of Example 14 to give the title compound as a white solid.

Melting point: 153-157 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.23 (t, 3H, J =
7Hz), 1.27 (s, 3H), 1.33 (s, 9H), 1.67 (s, 3H), 1.85 (s, 3
H), 2.31 (s, 6H), 2.28-2.31 (m, 2H), 2.46-2.64 (m, 7H),
3.80 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8H
z), 4.46 (dd, 1H, J = 7Hz, 10Hz), 4.62 (s, 1H), 4.90 (d, 1H, J
= 8Hz), 5.24 (br, 1H), 5.30 (d, 1H, J = 9Hz), 5.67 (d, 1H, J =
7Hz), 6.23 (t, 1H, J = 8Hz), 6.30 (s, 1H), 7.34-7.41 (m, 5
H), 7.50 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.13 (d, 2H, J
= 8Hz) IR (KBr): 3804, 3448, 2980, 2940, 2828, 2780, 182
2, 1722, 1604,1588 cm ^-1 MS-FAB: 935 (MH ⁺ )

Example 26

[0458]

Embedded image

Step 1: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triethylsilyloxy
Si) Propionyl] -4,10-dideacetyl-4-O-propyi
Onyl-10-O- (2,2,2-trichloroethoxycarbonyl)-
7-O-Triethylsilylbaccatin III The compound obtained in Step 1 of Example 16 was used in Step 2 of Example 17.
Similarly to cis-1- (tert-butoxycarbonyl) -4- (2-
Furyl) -3- (triethylsilyloxy) azetidine-2-
A condensation reaction with on was carried out to obtain a mixture of diastereoisomers in which the relative configuration of the 2′-position and the 3′-position of the title compound was threo (syn), as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.42-0.62
(m, 12H), 0.77-0.99 (m, 18H), 1.23 (s, 3H), 1.25 (s, 3H),
1.34 and 1.44 (each s, total 9H), 1.37-1.42 (m, 3H),
1.71 (s, 3H), 2.03 and 2.09 (each s, total 3H), 2.20-2.
41 (m, 2H), 2.48-2.60 (m, 1H), 2.66-2.69 (m, 2H), 3.80 an
d 3.85 (each d, total 1H, J = 7Hz), 4.19-4.23 (m, 1H), 4.3
0-4.34 (m, 1H), 4.48-4.53 (m, 1H), 4.73-4.82 (m, 3H), 4.8
7 (d, 1H, J = 8Hz), 5.31-5.36 (m, 2H), 5.70-5.72 (m, 1H),
6.20-6.25 (m, 2H), 6.30 (s, 1H), 6.34-6.38 (m, 1H), 7.37
and 7.40 (each s, total 1H), 7.43-7.48 (m, 2H), 7.57-7.
61 (m, 1H), 8.09-8.13 (m, 2H)

Step 2: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triethylsilyloxy
Si) Propionyl] -4,10-dideacetyl-4-O-propyi
Onyl-7-O-triethylsilylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 17 to determine the relative configuration at the 2′-position and the 3′-position of the title compound as a threo type (syn). Form) a mixture of diastereoisomers was obtained as a colorless amorphous solid.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.42-0.61
(m, 12H), 0.83-0.96 (m, 18H), 1.11 (s, 3H), 1.24 (s, 3H),
1.33 and 1.43 (each s, total 9H), 1.36-1.41 (m, 3H),
1.75 (s, 3H), 1.93 and 2.02 (each s, total 3H), 2.20-2.
41 (m, 2H), 2.45-2.52 (m, 1H), 2.65-2.79 (m, 2H), 3.89 an
d 3.94 (each d, total 1H, J = 7Hz), 4.19-4.21 (m, 1H), 4.2
7 (s, 1H), 4.31-4.33 (m, 1H), 4.40-4.43 (m, 1H), 4.72 and
4.76 (each s, total1H), 4.90 (d, 1H, J = 8Hz), 5.13 and
5.16 (each s, total 1H), 5.31-5.37 (m, 2H), 5.64-5.68
(m, 1H), 6.22-6.25 (m, 2H), 6.35-6.37 (m, 1H), 7.37 and
7.40 (each s, total 1H), 7.46-7.49 (m, 2H), 7.56-7.60
(m, 1H), 8.08-8.13 (m, 2H)

Step 3: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2-hydroxypropioni
] -4,10-Deacetyl-4-O-propionylbaccatin
III The compound obtained in Step 2 above is reacted in the same manner as in Step 5 of Example 17 to give two diastereomers whose relative configuration at the 2′-position and the 3′-position of the title compound is threo (syn). The isomers (low polar isomer A, high polar isomer B) were each obtained as a white solid.

Isomer A Melting point: 179-184 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.22 (s, 3
H), 1.31 (t, 3H, J = 7Hz), 1.42 (s, 9H), 1.76 (s, 3H), 1.81-
1.88 (m, 1H), 2.06 (s, 3H), 2.15-2.21 (m, 1H), 2.36-2.42
(m, 1H), 2.47-2.64 (m, 3H), 3.33 (br, 1H), 3.98 (d, 1H, J = 7
Hz), 4.19 (d, 1H, J = 8Hz), 4.24-4.31 (m, 2H), 4.32 (d, 1H,
J = 8Hz), 4.62 (s, 1H), 4.90 (d, 1H, J = 8Hz), 5.23 (d, 1H, J = 1
0Hz), 5.25 (s, 1H), 5.32 (d, 1H, J = 10Hz), 5.69 (d, 1H, J =
7Hz), 6.14 (t, 1H, J = 8Hz), 6.32 (d, 1H, J = 3.5Hz), 6.37 (d
d, 1H, J = 2Hz, 3.5Hz), 7.41 (d, 1H, J = 2Hz), 7.48 (t, 2H, J = 8H
z), 7.62 (t, 1H, J = 8Hz), 8.62-8.08 (m, 2H) IR (KBr): 3456, 2984, 2944, 1728, 1604, 1586 cm ^-1 MS-FAB: 812 (MH ⁺ )

Isomer B Melting point: 177-181 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.25 (s, 3
H), 1.28 (t, 3H, J = 7Hz), 1.33 (s, 9H), 1.75 (s, 3H), 1.82-
1.89 (m, 1H), 1.91 (s, 3H), 2.24-2.39 (m, 2H), 2.55-2.63
(m, 1H), 2.70-2.72 (m, 2H), 3.37 (br, 1H), 3.93 (d, 1H, J = 7
Hz), 4.20 (d, 1H, J = 8Hz), 4.24-4.28 (m, 2H), 4.33 (d, 1H,
J = 8Hz), 4.70 (s, 1H), 4.91 (d, 1H, J = 8Hz), 5.22 (s, 1H),
5.24 (d, 1H, J = 10Hz), 5.30 (d, 1H, J = 10Hz), 5.69 (d, 1H, J
= 7Hz), 6.24 (t, 1H, J = 8Hz), 6.34 (d, 1H, J = 3.5Hz), 6.39 (d
d, 1H, J = 2Hz, 3.5Hz), 7.43 (d, 1H, J = 2Hz), 7.49 (t, 2H, J = 8H
z), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz) IR (KBr): 3468, 2984, 2948, 1724, 1604, 1588 cm ^-1 MS-FAB: 812 (MH ⁺ )

Example 27

[0467]

Embedded image

Step 1: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triethylsilyloxy
Si) Propionyl] -4,10-dideacetyl-10-O- (N, N
-Dimethylglycyl) -4-O-propionyl-7-O-tri
Ethylsilylbaccatin III The compound obtained in Step 2 of Example 26 was used in Step 4 of Example 17.
Similarly, react with N, N-dimethylglycine to give a mixture of diastereoisomers in which the relative configuration of the 2'position and 3'position of the title compound is threo (syn) as colorless amorphous solid. Obtained.

¹ H-NMR (CDCl ₃ / TMS) δ
(ppm): 0.42-0.63 (m, 12H), 0.82-0.95 (m, 18H), 1.20
(s, 3H), 1.22 (s, 3H), 1.33 and 1.43 (each s, total 9H),
1.37-1.42 (m, 3H), 1.70 (s, 3H), 2.02 and 2.07 (each s,
total 3H), 2.23-2.26 (m, 1H), 2.35-2.42 (m, 1H), 2.40 a
nd 2.42 (each s, total 6H), 2.54-2.62 (m, 1H), 2.66-2.
78 (m, 2H), 3.33 (s, 2H), 3.84 and 3.89 (each d, total 1
H, J = 7Hz), 4.17-4.20 (m, 1H), 4.30-4.35 (m, 1H), 4.51 (d
d, 1H, J = 7Hz, 10Hz), 4.73 and 4.77 (each s, total1H), 4.
89-4.92 (m, 1H), 5.30-5.35 (m, 1H), 5.68-5.71 (m, 1H), 6.
19-6.25 (m, 2H), 6.36-6.38 (m, 1H), 6.52 (s, 1H), 7.36 an
d 7.40 (each s, total 1H), 7.47-7.49 (m, 2H), 7.56-7.6
1 (m, 1H), 8.10-8.13 (m, 2H)

Step 2: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2-hydroxypropioni
] -4,10-Dideacetyl-10-O- (N, N-dimethylglycol
Syl) -4-O-propionylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 5 of Example 17, and the relative configuration at the 2′-position and the 3′-position of the title compound was the threo type ( Two diastereoisomers (syn type) (low polar isomer A and high polar isomer B) were obtained as white solids.

Isomer A Melting point: 151-154 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.24 (s, 3
H), 1.31 (t, 3H, J = 7Hz), 1.42 (s, 9H), 1.68 (s, 3H), 1.84-
1.91 (m, 1H), 2.03 (s, 3H), 2.16-2.22 (m, 1H), 2.43 (s, 6
H), 2.49-2.63 (m, 3H), 3.40 and 3.45 (each d, 1H, J = 17H
z), 3.85 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.31 (d, 1H,
J = 8Hz), 4.50 (dd, 1H, J = 7Hz, 10Hz), 4.62 (d, 1H, J = 2.5Hz),
4.91 (d, 1H, J = 8Hz), 5.24 (d, 1H, J = 10Hz), 5.29 (d, 1H, J = 1
0Hz), 5.68 (d, 1H, J = 7Hz), 6.12 (t, 1H, J = 8Hz), 6.33 (d, 1
H, J = 3.5Hz), 6.37-6.39 (m, 2H), 7.42 (s, 1H), 7.48 (t, 2
H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.07 (d, 2H, J = 8Hz) IR (KBr): 3460, 2984, 2948, 2788, 1726, 1604, 1588
cm ^-1 MS-FAB: 897 (MH ⁺ )

Isomer B Melting point: 153-156 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.15 (s, 3H), 1.25 (s, 3
H), 1.32 (t, 3H, J = 7Hz), 1.34 (s, 9H), 1.70 (s, 3H), 1.91
(s, 3H), 2.29-2.54 (m, 2H), 2.31 (s, 6H), 2.73-2.80 (m, 2
H), 2.96 (br, 1H), 3.34 and 3.40 (each d, 1H, J = 17Hz),
3.81 (d, 1H, J = 7Hz), 4.20 (d, 1H, J = 8Hz), 4.33 (d, 1H, J = 8H
z), 4.47 (br, 1H), 4.81 (d, 1H, J = 2Hz), 4.93 (d, 1H, J = 8H
z), 5.28 (d, 1H, J = 10Hz), 5.39 (d, 1H, J = 10Hz), 5.70 (d, 1
H, J = 7Hz), 6.19 (t, 1H, J = 8Hz), 6.32 (d, 1H, J = 3.5Hz), 6.3
8 (dd, 1H, J = 2Hz, 3.5Hz), 6.42 (s, 1H), 7.41 (s, 1H), 7.49
(t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz) IR (KBr): 3688, 3532, 2984, 2948, 2788, 1722, 160
4, 1586 cm ^-1 MS-FAB: 897 (MH ⁺ )

Example 28

[0474]

[Chemical 81]

Step 1: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3- (2-furyl) -2- (triisopro
Pyrsilyloxy) propionyl] -4,10-dideacetyl
-4-O-propionyl-10-O- (2,2,2-trichloroethoxy
Cycarbonyl) -7-O-triethylsilylbaccatin III The compound obtained in Step 1 of Example 16 was used in Step 2 of Example 17.
As in (3R, 4S) -1- (tert-butoxycarbonyl) -4- (2
Condensation reaction with -furyl) -3- (triisopropylsilyloxy) azetidin-2-one gave the title compound.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm) 0.54-0.63 (6H, m), 0.90-1.05 (30H, m), 1.09 (3H, s), 1.1
1 (3H, s), 1.24 (3H, t, J = 7Hz), 1.34 (9H, s), 1.41 (3H, s),
1.71 (3H, s), 1.79-1.95 (2H, m), 2.35 (1H, m), 2.55 (1H,
m), 2.76 (2H, m), 3.80 (1H, d, J = 7Hz), 4.19 (1H, d, J = 8Hz),
4.32 (1H, d, J = 8Hz), 4.50 (1H, m), 4.78 (1H, d, J = 12Hz),
4.84 (1H, d, J = 12Hz), 4.90 (1H, d, J = 8Hz), 4.99 (1H, s), 5.
28-5.31 (2H, m), 5.71 (1H, d, J = 9Hz), 6.18 (1H, m), 6.25-
6.40 (2H, m), 6.30 (1H, s), 7.36-7.41 (1H, m), 7.47 (2H, t,
J = 7Hz), 7.58 (1H, m), 8.12 (2H, d, J = 7Hz).

Step 2: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3- (2-furyl) -2- (triisopro
Pyrsilyloxy) propionyl] -4,10-dideacetyl
-4-O-propionyl-7-O-triethylsilylbacca
Chin III The compound obtained in Step 1 above was reacted in the same manner as in Step 3 of Example 17 to give the title compound.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm) 0.50-0.63 (6H, m), 0.90-1.05 (30H, m), 1.11 (3H, s), 1.2
4 (3H, s), 1.33 (9H, s), 1.35 (3H, t, J = 8Hz), 1.41-1.52 (1
H, m), 1.68-1.78 (1H, m), 1.75 (3H, s), 1.94 (3H, s), 2.31
(1H, m), 2.48 (1H, m), 2.75 (2H, m), 3.89 (1H, d, J = 7Hz),
4.21 (1H, d, J = 8Hz), 4.27 (1H, s), 4.32 (1H, d, J = 8Hz), 4.4
2 (1H, m), 4.90 (1H, d, J = 8Hz), 4.97-5.00 (1H, m), 5.13 (1
H, s), 5.28 (2H, m), 5.67 (1H, d, J = 7Hz), 6.20-6.38 (3H,
m), 7.47 (2H, t, J = 8Hz), 7.57 (1H, t, J = 7Hz), 8.11 (2H, d, J
= 7Hz).

Step 3: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3- (2-furyl) -2- (triisopro
Pyrsilyloxy) propionyl] -4,10-dideacetyl
-10-O- (2-morpholinoacetyl) -4-O-propionyl-7
-O-Triethylsilylbaccatin III The title compound was obtained by reacting the compound obtained in Step 2 above with morpholinoacetic acid in place of N, N-dimethylglycine in the same manner as in Step 4 of Example 17.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm) 0.55-0.63 (6H, m), 0.90-1.02 (30H, m), 1.19 (3H, s), 1.2
2 (3H, s), 1.34 (9H, s), 1.35 (3H, m), 1.69 (3H, s), 1.66-
1.78 (1H, m), 1.89-1.98 (1H, m), 2.03 (3H, s), 2.34 (1H,
m), 2.54 (1H, m), 2.58-2.73 (4H, m), 2.75 (2H, m), 3.36 (2
H, s), 3.74-3.80 (4H, m), 3.83 (1H, d, J = 7Hz), 4.19 (1H, d,
J = 8Hz), 4.32 (1H, d, J = 8Hz), 4.50 (1H, m), 4.90 (1H, d, J = 8
Hz), 4.98 (1H, s), 5.24-5.28 (2H, m), 5.70 (1H, d, J = 7H
z), 6.15 (1H, br-t, J = 9Hz), 6.27 (1H, d, J = 3.5Hz), 6.37 (1
H, dd, J = 1.5Hz, 3Hz), 6.51 (1H, s), 7.39 (1H, d, J = 1Hz), 7.
47 (2H, t, J = 8Hz), 7.58 (1H, t, J = 7Hz), 8.12 (2H, d, J = 7Hz).

Step 4: 13-O-[(2R, 3S) -3- (tert-butoxy)
Cycarbonylamino) -3- (2furyl) -2-hydroxypropyi
Onyl] -4,10-dideacetyl-10-O- (2-morpholinoacetate
Tyl) -4-O-propionyl baccatin III pyridine obtained by distilling 93 mg of the compound obtained in the above Step 3 in 2 m
It was dissolved in l and 0.4 ml of hydrogen fluoride-pyridine was added under ice cooling. After the dropping was completed, the temperature was raised to room temperature and the mixture was stirred for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate) to obtain 68 mg of the title compound.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm) 1.15 (3H, s), 1.26 (3H, s),
1.31 (3H, t, J = 7Hz), 1.34 (9
H, s), 1.56-1.73 (1H, m), 1.6
9 (3H, s), 1.88-1.95 (1H, m),
1.92 (3H, s), 2.47 (1H, m),
2.53 (1H, m), 2.66 (4H, m),
2.74 (2H, m), 3.42 (2H, s), 3.
63-3.79 (4H, m), 3.81 (2H, d,
J = 7 Hz), 4.19 (1H, d, J = 8 Hz),
4.33 (1H, d, J = 8Hz), 4.46 (1
H, m), 4.78 (1H, d, J = 1.5 Hz),
4.92 (1H, d, J = 8Hz), 5.29-5.
38 (2H, m), 5.70 (1H, d, J = 7H
z), 6.18 (1H, br-t, J = 9 Hz),
6.33 (1H, d, J = 3.5Hz), 6.39
(2H, m), 7.43 (1H, m), 7.49
(2H, t, J = 8Hz), 7.61 (1H, t, J =
7 Hz), 8.12 (2H, d, J = 7 Hz).

Example 29

[0484]

[Chemical formula 82]

Step 1: 13-O- [3- (tert-butoxycal
Bonylamino) -3- (2-furyl) -2- (triisopropyloxy)
Ryloxy) propionyl] -4,10-dideacetyl-10-O
-(p-nitrophenoxycarbonyl) -4-O-propionyl
-7-O-Triethylsilylbaccatin III 269 mg of the compound obtained in Step 2 of Example 26 was dissolved in 5 ml of dried pyridine, and triethylamine (345 µl) was added.
, P-nitrophenoxycarbonyl chloride (501 mg) and a catalytic amount of dimethylaminopyridine were added, and the mixture was added at 50 ° C for 1 hour.
Stir for 5 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and a 1N aqueous hydrochloric acid solution, and subjected to silica gel column chromatography (developing solvent; chloroform: hexane: acetone = 70: 30: 0.3 (v / v)). Purified, 27
Obtained 4 mg of the title compound as a white solid.

Melting point: 154-157 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.59 (m, 6H), 0.95 (m, 30
H), 1.22 (m, 6H), 1.35 (m, 3H), 1.58 (s, 9H), 1.74 (s, 3H),
1.92 (m, 1H), 2.03 (s, 3H), 2.37 (m, 2H), 2.56 (m, 1H), 2.
76 (m, 2H), 3.80 (d, 1H, J = 7Hz), 4.20 (d, 1H, J = 7Hz), 4.31
(d, 1H, J = 7Hz), 4.50 (dd, 1H, J = 6.5Hz, 10.5Hz), 4.90 (d, 1
H, J = 7Hz), 4.99 (s, 1H), 5.28 (m, 2H), 5.72 (d, 1H, J = 7Hz),
6.18 (t, 1H, J = 9Hz), 6.28 (m, 1H), 6.35 (s, 1H), 6.38 (m, 1
H), 7.40 (m, 1H), 7.43 (m, 2H), 7.48 (t, 2H, J = 7.5Hz), 7.5
9 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz), 8.31 (m, 2H) .IR (KBr): 3456, 3128, 2952, 2880, 2292, 1764, 172
6, 1618, 1596, 1532, 1494, 1466, 1394 cm ^-1 .MASS-FAB: 1247 (M ⁺ )

Step 2: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triisopropylsilyl
Luoxy) propionyl] -4,10-dideacetyl-10-O-
[(2-Pyridyl) methylaminocarbonyl] -4-O-pro
Pionyl-7-O-triethylsilylbaccatin III 20 mg of the compound obtained in the above step 1 was dissolved in 600 μl of dry acetonitrile to give 2-aminomethylpyridine 1
6 μl was added and the mixture was stirred at room temperature for 20 minutes. Concentrated under reduced pressure,
Purification by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 97: 3 (v / v)) gave 19 mg of the title compound as an oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.57 (m, 6
H), 0.89 (t, 9H, J = 8Hz), 0.98 (m, 21H), 1.20 (br-s, 3H),
1.22 (m, 3H), 1.25 (m, 3H), 1.33 (s, 9H), 1.71 (s, 3H), 1.
92 (m, 1H), 2.08 (s, 3H), 2.35 (m, 2H), 2.53 (m, 1H), 2.75
(m, 2H), 3.85 (d, 1H, J = 7Hz), 4.20 (d, 1H, J = 8Hz), 4.31 (d,
1H, J = 8Hz), 4.50 (m, 2H), 4.60 (m, 1H), 4.91 (d, 1H, J = 9H
z), 4.99 (s, 1H), 5.28 (s, 2H), 5.72 (d, 1H, J = 7Hz), 6.01
(m, 1H), 6.18 (br-s, 1H), 6.27 (m, 1H), 6.38 (s, 1H), 6.4
3 (m, 1H), 7.23 (m, 1H), 7.35 (d, 1H, J = 8Hz), 7.39 (s, 1H),
7.48 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 7.72 (m, 1H),
8.13 (m, 2H), 8.55 (d, 1H, J = 4.5Hz). MASS-FAB: 1216 (M ⁺ )

Step 3: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2-hydroxypropioni
]]-4,10-Dideacetyl-10-O-[(2-pyridyl) methyl
Aminocarbonyl] -4-O-propionylbaccatin III The compound obtained in Step 2 above was deprotected and purified in the same manner as in Step 4 of Example 29 to give the title compound as a white powder.

Melting point: 154-157 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.16 (s, 3H), 1.26 (m, 3
H), 1.28 (m, 3H), 1.33 (s, 9H), 1.68 (s, 3H), 1.80 (m, 1H),
1.90 (s, 3H), 2.30 (m, 2H), 2.55 (m, 1H), 2.71 (m, 2H), 3.
80 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8H
z), 4.53 (m, 3H), 4.72 (m, 1H), 4.93 (d, 1H, J = 8Hz), 5.22
(d, 1H, J = 10Hz), 5.29 (m, 1H), 5.68 (d, 1H, J = 7Hz), 6.25
(m, 3H), 6.34 (d, 1H, J = 3Hz), 6.38 (d, 1H, J = 1.5Hz), 7.22
(m, 1H), 7.32 (d, 1H, J = 7Hz), 7.43 (s, 1H), 7.49 (t, 2H, J =
7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 7.70 (m, 1H), 8.12 (d, 2H, J
= 7Hz), 8.54 (d, 1H, J = 4Hz) .IR (KBr): 3920, 3424, 2980, 2940, 1716, 1600, 157
4, 1506, 1454, 1442,1394, 1370 cm ^-1 .MASS-FAB: 946 (M ⁺ )

Example 30

[0492]

[Chemical 83]

Step 1: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2- (triisopropylsilyl
Luoxy) propionyl] -4,10-dideacetyl-10-O-
[(4-Methylpiperazin-1-yl) carbonyl] -4-O-
Propionyl-7-O-triethylsilylbaccatin III 17 mg of the compound obtained in Step 1 of Example 29 was dissolved in 600 μl of dry acetonitrile, 15 μl of N-methylpiperazine was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure and purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 97: 3 (v / v)) to obtain 10 mg of the title compound as an oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.60 (m, 6
H), 0.93 (m, 9H), 0.96-0.99 (m, 21H), 1.20 (m, 3H), 1.22
(m, 3H), 1.34 (s, 9H), 1.36 (m, 3H), 1.70 (s, 3H), 1.89 (m,
1H), 2.08 (s, 3H), 2.33 (s, 3H), 2.50 (m, 3H), 2.75 (m, 2
H), 3.41-3.66 (m, 8H), 3.85 (d, 1H, J = 7Hz), 4.20 (d, 1H, J =
8Hz), 4.31 (d, 1H, J = 8Hz), 4.50 (dd, 1H, J = 6.5Hz, 10.5Hz),
4.90 (d, 1H, J = 8Hz), 4.98 (s, 1H), 5.27 (m, 2H), 5.70 (d, 1
H, J = 7Hz), 6.18 (m, 1H), 6.26 (d, 1H, J = 3Hz), 6.36 (t, 1H, J
= 1.5Hz), 6.37 (s, 1H), 7.39 (s, 1H), 7.48 (t, 2H, J = 7.5H
z), 7.58 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz). MASS-FAB: 1208 (M ⁺ )

Step 2: 13-O- [3- (tert-butoxycarbo
Nylamino) -3- (2-furyl) -2-hydroxypropioni
]]-4,10-Dideacetyl-10-O-[(4-methylpiperazine
1-yl) carbonyl] -4-O-propionylbaccatin
III The compound obtained in Step 1 above was deprotected and purified in the same manner as in Step 4 of Example 28 to give the title compound as a white powder.

Melting point: 168-170 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.25 (s, 3H),
1.26 (m, 3H), 1.31 (s, 9H), 1.65 (s, 3H), 1.70 (m, 1H), 1.9
0 (s, 3H), 2.35 (s, 3H), 2.50 (m, 3H), 2.70 (m, 2H), 3.40-
3.70 (m, 8H), 3.80 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.3
0 (d, 1H, J = 8Hz), 4.50 (dd, 1H, J = 6.5Hz, 10.5Hz), 4.70 (d,
1H, J = 2.5Hz), 4.92 (d, 1H, J = 8Hz), 5.17 (d, 1H, J = 10Hz),
5.30 (d, 1H, J = 10Hz), 5.68 (d, 1H, J = 7Hz), 6.25 (m, 2H), 6.
32 (m, 1H), 6.39 (m, 1H), 7.41 (m, 1H), 7.48 (t, 2H, J = 7.5H
z), 7.59 (t, 1H, J = 7.5Hz), 8.10 (d, 2H, J = 7.5Hz) .IR (KBr): 3892, 3452, 2936, 1718, 1496, 1464, 143
8, 1394, 1370, 1316, 1264, 1176 cm ^-1 .MASS-FAB: 938 (M ⁺ )

[0497]

The following examples show the antitumor effect of the compounds of the present invention. Experimental Example Three types of tumor cells, P388, PC-6 and PC-12,
5.0 × 10 ² cells / 150 μl / well for P388, 5.0 × 10 for PC-6
³ cells / 150 μl / well, PC-12 1.0 × 10 ³ cells / 150
96 well-microplates were seeded so as to have a concentration of μl / well, and the sample was added 50 μl / well after 2 hours for P388 and after 24 hours for the other two. Then, the cells were cultured for 3 days, and MTT [3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyl-
2H-tetrazolium bromide] 5 mg / ml solution 20 μl / wel
l was added. After 4 hours, the culture solution was removed, 150 μl / well of dimethyl sulfoxide was added, and the absorbance was measured at 540 nm. The antitumor effect was compared with the cell growth of the drug-added group in the control group
The drug concentration at 50% was shown as the GI ₅₀ value (ng / ml).

[0498]

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 405/12 213 C07D 405/12 213 405/14 213 405/14 213 // A61K 31/335 ADU A61K 31/335 ADU (C07D 405/12 305: 14 307: 36) (C07D 405/14 305: 14 213: 16 307: 36)

Claims (32)

[Claims] 1. A compound of the general formula (I) [Wherein R ¹ is an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group, or an alkynyl group having a substituent (substitution of these alkyl group, alkenyl group, and alkynyl group The group is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group,
A group selected from the group consisting of an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group,
You may have two or more of these. R ² represents a hydrogen atom, an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group,
Or an alkynyl group having a substituent (the substituents of these alkyl group, alkenyl group, and alkynyl group are a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group). A group selected from the group consisting of a group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group, and may have a plurality of these groups, R ³ is a hydrogen atom,
A hydroxyl group or a group -OCOR ⁹ , R ⁴ is a hydrogen atom,
R ⁵ means a hydroxyl group, a halogen atom or an alkyl group, and R ⁵
Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group, and R ⁶ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group (these alkyl groups, alkenyl groups, alkynyl groups, cyclo The alkyl group, aryl group, and heterocyclic group include halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxyl group, aryloxy group, phenyl group, amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxy group. A carbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group, which may have one or more groups as a substituent.), And R ⁷ is an alkyl group, Aryl group or alkoxyl group (these alkyl groups, aryl groups And alkoxyl groups are halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxyl group, aryloxy group, phenyl group, amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxycarbonyl group, aryloxycarbonyl group. , An acyl group, an acylamino group, and an acyloxy group may be present as one or more substituents.), R ⁸ represents a hydrogen atom or a hydroxyl group, and R ⁹ Is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heterocyclic group or a group (Q ¹ and Q ^{2, which} may be the same or different, each represents a hydrogen atom or an alkyl group. Further, Q ¹ and Q ² are combined with adjacent nitrogen atoms to form a compound represented by the formula: (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. ) (These are alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclic groups and groups. Is an alkyl moiety (when Q ¹ and / or Q ² is an alkyl group) is a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group. , An alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, an acyloxy group, and a nitrogen-containing heterocyclic group having a size of a 3- to 8-membered ring (the nitrogen-containing heterocyclic group is One or more alkyl groups may be present on the ring-constituting atoms, and one or more groups selected from the group consisting of: ) Means. ] The compound and its salt represented by 2. A compound or a salt thereof according to claim 1, wherein R ³ is a hydrogen atom or a hydroxyl group. 3. The compound according to claim 1, wherein R ³ is a group —OCOR ⁹ and R ⁹ is an alkyl group (the alkyl group may have one or more substituents) and the compound thereof. salt 4. A substituent for the alkyl group of R ⁹ is an amino group,
Alkylamino group or nitrogen-containing heterocyclic group having a size of 5 to 6-membered ring (the nitrogen-containing heterocyclic group may have one or more alkyl groups on the constituent atoms of the ring). And a salt thereof. 5. The compound according to claim 1, wherein R ³ is a group —OCOR ⁹ and R ⁹ is a heterocyclic group (the heterocyclic group may have one or more substituents). And its salt 6. The heterocyclic group of R ⁹ is a monocyclic 5-membered ring to 6
A compound or a salt thereof according to claim 5, which is a heterocyclic group having a member ring. 7. The heterocyclic group for R ⁹ is a monocyclic 5-membered ring to 6-membered ring.
The compound or a salt thereof according to claim 5, which is a heterocyclic group having a member ring size and containing at least one nitrogen atom as a constituent atom of the ring structure. 8. A compound represented by the general formula (II): [Wherein R ¹ is an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group, or an alkynyl group having a substituent (substitution of these alkyl group, alkenyl group, and alkynyl group The group is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group,
A group selected from the group consisting of an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group,
You may have two or more of these. R ² is a hydrogen atom, an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group,
Or an alkynyl group having a substituent (the substituents of these alkyl group, alkenyl group, and alkynyl group are a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group). Group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group, and may have a plurality of these), and R ⁴ is a hydrogen atom,
R ⁵ means a hydroxyl group, a halogen atom or an alkyl group.
Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group, and R ⁶ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group (these alkyl groups, alkenyl groups, alkynyl groups, cyclo The alkyl group, aryl group, and heterocyclic group include halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxyl group, aryloxy group, phenyl group, amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxy group. A carbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group, which may have one or more as a substituent), and R ⁷ is an alkyl group, Aryl group or alkoxyl group (these alkyl groups, aryl The group and the alkoxyl group are halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxyl group, aryloxy group, phenyl group, amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxycarbonyl group, aryloxycarbonyl group. Group, an acyl group, an acylamino group, and an acyloxy group, may have one or a plurality of groups selected from the group as substituents, R ⁸ represents a hydrogen atom or a hydroxyl group, and Q ¹ and Q ² may be the same or different and each represents a hydrogen atom or an alkyl group. In addition, Q ¹ and Q ² are combined with adjacent nitrogen atoms to form a compound represented by the formula: (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) .) May be formed. (When Q ¹ and / or Q ² is an alkyl group, a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group,
Amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group,
An acyloxy group and a nitrogen-containing heterocyclic group having a size of a 3- to 8-membered ring (the nitrogen-containing heterocyclic group may have one or more alkyl groups on the constituent atoms of the ring. 1) or more than one group selected from the group consisting of 2) may be included as a substituent. ) Means. ] The compound and its salt represented by 9. The method according to claim 1, wherein at least ^one of Q ¹ and Q ² is an alkyl group.
And the salt thereof 10. Q ¹ and Q ² together with the adjacent nitrogen atom have the formula: (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
A saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by (the heterocyclic group may have an alkyl group on a carbon atom which is a constituent atom of the ring) 9.) and a salt thereof according to any one of claims 1 to 8. 11. The formula: (X is an oxygen atom, a sulfur _{atom, CH 2, CH-Y,} NH
Or, it means N-Y, and Y means an alkyl group. )
11. The compound and salt thereof according to claim 10, wherein the saturated heterocyclic group having a size of a 5- to 6-membered ring containing a nitrogen atom represented by is a group derived from piperazine or N-alkylpiperazine. 12. The compound and salt thereof according to claim 1, wherein R ⁴ and R ⁵ are fluorine atoms. 13. The compound or a salt thereof according to claim 1, wherein R ⁴ is a hydroxyl group and R ⁵ is a hydrogen atom. 14. The compound and salt thereof according to claim 1, wherein R ⁴ is a hydroxyl group and R ⁵ is a methyl group. 15. The compound and salt thereof according to claim 1, wherein R ⁷ is a phenyl group. 16. The compound and salt thereof according to any one of claims 1 to 14, wherein R ⁷ is a tertiary butoxy group. 17. The compound and salt thereof according to any one of claims 1 to 16, wherein R ⁶ is an aryl group. 18. The compound and salt thereof according to claim 1, wherein R ⁶ is a phenyl group. 19. The compound and salt thereof according to claim 1, wherein R ⁶ is a heterocyclic group. 20. The compound and salt thereof according to claim 19, wherein the heterocyclic group is a monocyclic heterocyclic group. 21. The compound according to claim 19, wherein the heterocyclic group is a monocyclic heterocyclic group having a size of a 5- to 6-membered ring, and a salt thereof. 22. The heterocyclic group having a size of a monocyclic 5- to 6-membered ring and containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure. Item 1
9. The compound and its salt according to 9 23. The unsaturated heterocyclic group having a size of a monocyclic 5- to 6-membered heterocyclic group and containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure. 20. The compound according to claim 19 and a salt thereof 24. The compound according to any one of claims 1 to 16 and a salt thereof, wherein R ⁶ is a 2-furyl group, a 2-pyridyl group or a 4-pyridyl group. 25. The compound according to any one of claims 1 to 16 and a salt thereof, wherein R ⁶ is a 2-methyl-1-propenyl group. 26. R ¹ is an alkyl group, an alkenyl group or an alkyl group having one or more groups selected from the group consisting of a halogen atom, a phenyl group, an alkylamino group, an alkoxycarbonyl group and a hydroxyl group as a substituent. A compound according to any one of claims 1 to 25 and a salt thereof 27. The compound and salt thereof according to any one of claims 1 to 25, wherein R ¹ is an alkyl group, an allyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkylaminoalkyl group or a benzyl group. 28. The compound according to any one of claims 1 to 25 and a salt thereof, wherein R ¹ is a methyl group, an ethyl group, a propyl group or an allyl group. 29. The compound according to any one of claims 1 to 28 and a salt thereof, wherein R ² is a hydrogen atom, a methyl group, an ethyl group or an allyl group. 30. The compound and salt thereof according to claim 1, wherein R ² is a hydrogen atom. 31. Formula (III): And the salts thereof 32. Formula (IV): And the salts thereof