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WO2007013592A1 - Nouveau procédé pour la synthèse d'un intermédiaire dans la synthèse d'un carbapénème utilisant un sucre comme matrice - Google Patents

Nouveau procédé pour la synthèse d'un intermédiaire dans la synthèse d'un carbapénème utilisant un sucre comme matrice Download PDF

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Publication number
WO2007013592A1
WO2007013592A1 PCT/JP2006/314992 JP2006314992W WO2007013592A1 WO 2007013592 A1 WO2007013592 A1 WO 2007013592A1 JP 2006314992 W JP2006314992 W JP 2006314992W WO 2007013592 A1 WO2007013592 A1 WO 2007013592A1
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Prior art keywords
group
optionally substituted
hydrogen atom
methyl
lower alkyl
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PCT/JP2006/314992
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English (en)
Japanese (ja)
Inventor
Kinichi Tadano
Kenichi Takao
Masayuki Okue
Shinjiro Sumi
Keiichi Ajito
Original Assignee
Meiji Seika Kaisha, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Meiji Seika Kaisha, Ltd. filed Critical Meiji Seika Kaisha, Ltd.
Priority to JP2007526909A priority Critical patent/JP5143556B2/ja
Publication of WO2007013592A1 publication Critical patent/WO2007013592A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids

Definitions

  • the present invention provides a synthetic intermediate acetoxazetidinone as a starting material, and 1 ⁇ -methyl
  • the purpose is to provide a novel method for efficiently synthesizing ⁇ -methylcarboxylic acid, an intermediate useful for constructing a strong rubapenem skeleton!
  • Another object of the present invention is to provide a novel synthetic intermediate useful for the construction of a 1 j8 -methylcarbapenem skeleton.
  • the method according to the present invention is a method for producing a compound represented by the following formula ( ⁇ ):
  • R 2 represents an optionally substituted lower alkyl group, an optionally substituted lower alkyl group, or a substituted aralkyl group
  • R 3 and R 4 may be joined together to form (CH 2) n—, where n represents 1 to 3,
  • R 5 represents a hydrogen atom, a halogen atom, an R3 ⁇ 40 group, or an OR 7 group, where R 6 is a substituted
  • R 2 represents an optionally substituted lower alkyl group, an optionally substituted lower alkyl group, or a substituted or unsubstituted aralkyl group,
  • R 5 represents a hydrogen atom, a halogen atom, a group R 0, or a group OR 7 where R 6 is a substituted
  • R 7 represents a hydrogen atom, an optionally substituted lower alkyl group, a substituted A lower alkenyl group which may be substituted, an aralkyl group which may be substituted, or a silyl protecting group
  • the production cost is low because it is not necessary to protect the nitrogen atom of the acetoxazetidinone ring having high stereoselectivity.
  • the compound represented by the formula (I) can be quantitatively converted to methyl carboxylic acid (IV) without using harmful chemicals, and the advantage is that the sugar template can be recovered. It is done.
  • Halogen atom means a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
  • silica protecting group examples include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, and the like.
  • Alkyl group means a linear, branched or cyclic lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl. And hexyl.
  • alkyl group means a chain or branched alkenyl group having 2 to 6 carbon atoms.
  • bur 1-probe, aryl, iso-probe, butenyl, iso-butyr And so on.
  • the “aralkyl group” means an aryl group having a lower alkyl having 1 to 6 carbon atoms.
  • aryl group include phenol and naphthyl. “Substituted, may be an alkyl group”, “Substituted, may be an alkyl group”, “Substituted, may be an aralkyl group”, “Substituted, may be, As the “substituent” in the “aryl group”, a halogen atom, amino group, nitro group, cyano group, hydroxyl group, lower alkyl group, lower alkoxy group (for example, methoxy, ethoxy, propoxy group, isopropoxy group, butoxy, And an alkoxy group having 1 to 6 carbon atoms such as an isobutoxy group).
  • the compound synthesized by the method according to the present invention is a azetidinone derivative represented by the above formula (I) and formula ().
  • R 1 represents a hydrogen atom or a silyl-type protecting group.
  • the group that may be described in the above definition is preferred, and more preferably A hydrogen atom, a trimethylsilyl group, and a tert-butyldimethylsilyl group.
  • R 2 represents a substituted !, may represent a lower alkyl group, be substituted !, a lower alkenyl group, or an optionally substituted aralkyl group.
  • the group which may be described in (1) is mentioned as a preferable thing, More preferably, they are a methyl group and a benzyl group.
  • R 3 and R 4 may be the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkyl group, or a substituted Represents an aralkyl group or a silyl protecting group which may be substituted.
  • Preferable examples include groups that may be described in the above definition, and more preferable examples include a hydrogen atom, a methyl group, a benzyl group, a p-methoxyphenylmethyl group, a p-chlorobenzoyl group, and tert-butyl. Examples thereof include a dimethylsilyl group and a ⁇ -naphthylmethyl group.
  • R 3 and R 4 may be joined together to form (CH 2) ⁇ —.
  • ⁇ represents 1 to 3, preferably
  • R 5 represents a hydrogen atom, a halogen atom, an R 6 SO group, or an OR 7 group. Where R 6 is a substitution
  • R 0 group is more preferably methanesulfol group, benzenesulfol group, p-
  • R 7 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, or a silyl protecting group, preferably the above
  • the group which may be described in the definition is mentioned, More preferably, they are a hydrogen atom, a trimethylsilyl group, a trifluoromethyl group, a t_butyldimethylsilyl group, and a tert-butyldiphenylsilyl group.
  • R 3 and R 4 are introduced into the 2-position and 3-position hydroxyl groups of 1-substituted-4,6- 0-protected-a-D-darcobilanoside.
  • the 4- and 6-position hydroxyl-protecting groups are not limited as long as they protect the hydroxyl groups in the following reactions. Examples thereof include benzylidene group, isopropylidene group, cyclohexylidene group, ethylidene group, and the like. And the like.
  • Examples of the substituent introduced into the hydroxyl groups at the 2-position and the 3-position include an alkyl group, an alkenyl group, and Alternatively, when an aralkyl group is introduced, a halogenated alkyl, a halogenated alkyl or a halogenated aralkyl is reacted at room temperature or under heating conditions in the presence of a base in an organic solvent.
  • the halide may be chloride, bromide, or iodide, and preferably salt. From the viewpoint of improving the yield, a phase transfer catalyst may be used as necessary.
  • phase transfer catalyst examples include halogenated tetrabutyl ammonium, halogenated tetrabenzyl ammonium, and halogenated tetraethyl ammonium, preferably tetranormal butyl ammonium iodide. It is.
  • reaction solvent examples include dimethylformamide, dimethylacetamide, or dimethyl sulfoxide, and preferably dimethylformamide.
  • base examples include organic bases such as diisopropylethylamine and triethylamine, and inorganic bases such as sodium carbonate and sodium hydride, preferably sodium hydride.
  • silylation reagent When a silyl group (silyl protecting group) is introduced as a substituent to be introduced into the hydroxyl groups at the 2-position and the 3-position, the silylation reagent is used in an organic solvent in the presence of a base. Is allowed to react under room temperature or heating conditions.
  • reaction solvent examples include dimethylformamide, dimethylacetamide, and tetrahydrofuran. Tetrahydrofuran is preferable.
  • base examples include organic bases such as diisopropylethylamine, triethylamine and imidazole, and inorganic bases such as sodium carbonate and sodium hydride, preferably sodium hydride.
  • silyl reagent examples include salt, trimethylsilyl, salt, triethylsilyl, tertiary butyldimethylsilyl chloride, and salt, tertiary butyldiphenylsilyl. It is tertiary butyl dimethyl silyl.
  • reaction solvent which is preferably carried out under heating, it is preferably heated to reflux.
  • the substituent introduced into the hydroxyl group at the 2-position and the substituent introduced into the hydroxyl group at the 3-position may be the same or different, that is, the reactivity difference between the 2-position and 3-position hydroxyl groups. It is possible to introduce different substituents into the hydroxyl group at the 2-position and the hydroxyl group at the 3-position by utilizing a primary hydroxyl-protecting group or the like.
  • R 3 and R 4 are joined together to form one (CH 2) n — (where n represents 1 to 3).
  • a cyclic ether such as a cyclic acetal or cyclic ketal having a corresponding structure is selected as the first 4,6-0-protected-a-D-darcoviranoside and subjected to the following steps.
  • the protecting group of 4,6- 0-protected-a-D-darcobilanoside having a substituent introduced at the 2-position and 3-position, respectively, is removed.
  • the protecting group is a benzylidene group
  • the benzylidene group can be removed quantitatively and easily under acidic conditions or by hydrogenation reduction.
  • the substituents at the 2- and 3-position hydroxyl groups are alkyl groups, alkenyl groups, or aralkyl groups, it is preferable to remove the benzylidene group under acidic conditions.
  • the substituents at the 2-position and 3-position hydroxyl groups are preferred.
  • Acidic conditions include diluted formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, or sulfuric acid, respectively, and preferably heated to reflux in 80% acetic acid.
  • hydrogenation reduction hydrogen is reacted in the presence of a metal catalyst in an organic solvent that may be mixed with water.
  • the reaction solvent include tetrahydrofuran, 1,4-dioxane, methanol, ethanol and the like, preferably ethanol.
  • the metal catalyst include noradium black, palladium carbon, palladium hydroxide carbon, platinum, Raney nickel, and the like, and preferably hydrogen is reacted in the presence of palladium hydroxide carbon.
  • These compounds have free hydroxyl groups at the 4- and 6-positions, but the 6-position, which is the primary hydroxyl group, is more reactive than the 4-position, which is the secondary hydroxyl group. Using this, it is possible to introduce the desired functional group into the hydroxyl group at the 6-position regioselectively.
  • a sulfonylating reagent having a structure may be a lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group).
  • the sulfonyl group can be obtained by regioselectively introducing the 6-position hydroxyl group.
  • examples of the sulfo group introduced into the hydroxyl group at the 6-position include a methane sulfo group, a benzene sulfo group, a p-toluene sulfonyl group, and a benzyl sulfo group.
  • reaction solvent examples include methylene chloride, tetrahydrofuran, dimethylformamide, 1,4-dioxane and the like, preferably methylene chloride.
  • base examples include organic bases such as diisopropylethylamine triethylamine, and inorganic bases such as sodium carbonate and sodium hydride.
  • methylene chloride is used as a reaction solvent, it is preferable to add a small amount of dimethylaminopyridine using triethylamine as a base. For example, selective 6-position P-toluenesulfolation often proceeds quantitatively, depending on the structure of the atomic group introduced into the hydroxyl group at the 3-position.
  • R 70 is an alkylating reagent, alkenylating reagent, aralkylating reagent having a corresponding structure in the presence of a base in an organic solvent, It can be obtained by reacting a silylation reagent to introduce an alkyl group, an alkenyl group, an aralkyl group, or a silyl protecting group into the hydroxyl group at the 6-position regioselectively.
  • examples of the substituent introduced into the hydroxyl group at the 6-position include a methyl group, a benzyl group, a trifluoromethyl group, a trimethylsilyl group, and a tertiary butyldimethylsilyl group. Preferred are a trimethyl group and a tertiary butyldimethylsilyl group.
  • examples of the reaction solvent include methylene chloride, tetrahydrofuran, dimethylformamide, 1,4-dioxane, pyridine and the like. Preferred are dimethylformamide and pyridine.
  • examples of the base include organic bases such as diisopropylethylamine, triethylamine and dimethylaminopyridine, and inorganic bases such as sodium carbonate and sodium hydride, with organic bases being preferred.
  • a propionyl group is introduced into the free hydroxyl group at the 4-position.
  • the reaction can be carried out in an organic solvent in the presence of a base group at room temperature or under heating conditions.
  • the propionylation reagent used include propionic acid anhydrides and various propionic acid halides, and propionic acid anhydrides are preferred.
  • the reaction solvent include methylene chloride, tetrahydrofuran, pyridine, dimethylformamide, and the like, and preferably pyridine.
  • the base include diisopropylethylamine, triethylamine, organic bases such as dimethylaminopyridine, and inorganic bases such as sodium carbonate and sodium hydride.
  • the production steps are described in the order of the construction of the 6-position hydroxyl group after the introduction of substituents at the 2-position and 3-position, but the order is not limited to this. That is, the 6-position hydroxyl group with the functional group introduced first may be constructed, and then the 2- and 3-positions may be constructed.
  • the compound in which R 5 is a halogen atom is a compound in which a substituent is introduced into the 2- and 3-position hydroxyl groups obtained by the above-described process, and a P-toluenesulfonyl group is introduced into the 6-position hydroxyl group. Convert the 6th position of a-D-Dalcobilanoside in (VI). That is, the compound of the formula (VI) in which the hydroxyl group at the 6-position is sulfo-reduced can be obtained by reacting with a salt containing a halogen element in an organic solvent at room temperature or under heating conditions.
  • Examples of the salt containing a halogen element include sodium iodide, lithium bromide, and potassium salt, and sodium iodide is preferable.
  • Examples of the reaction solvent include acetone, 2-butanone, or dimethylformamide, and 2-butanone is preferable. The reaction is carried out at room temperature or under heating conditions. When 2-butanone is used as the reaction solvent, it should be heated to reflux.
  • the 6-position obtained as described above was iodinated (X-D-darcobilanoside was hydrogenated in an organic solvent in the presence of a metal catalyst.
  • the organic solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, etc., preferably ethanol, and the metal catalyst is palladium black, Examples thereof include palladium carbon, palladium hydroxide carbon, platinum, and Raney nickel, and Raney nickel is preferably used.
  • the compound in which R 5 is a hydrogen atom is obtained by the above-described method of obtaining hydroxyl group 6-position sulphonyl-sulfurized a-D-darcobilanoside, lithium aluminum hydride, etc. in tetrahydrofuran. It can also be obtained by directly reducing the P-toluenesulfol form.
  • the 6th position can be deoxylated by a known established method, for example, the method described in “Organic Reactions” can also be used.
  • a propionyl group is introduced into the 4-position free hydroxyl group.
  • the reaction can be carried out in an organic solvent in the presence of a base at room temperature or under heating conditions with a propionylation reagent.
  • the propionyl reagent used include propionic acid anhydrides and various propionic acid halides, with propionic acid anhydrous being preferred.
  • the reaction solvent include methylene chloride, tetrahydrofuran, pyridine, or dimethylformamide, and pyridine is preferred.
  • the base include diisopropylpyrutylamine triethylamine, organic bases such as dimethylaminopyridine, and inorganic bases such as sodium carbonate and sodium hydride. When the reaction solvent is pyridine, dimethylamino as the base. Preference is given to using pyridine.
  • reaction solvent examples include tetrahydrofuran, jetyl ether, toluene, and the like. These solvents can be used alone, or two or more kinds can be used in an appropriate ratio. In the case of using a mixture of two or more, for example, a mixture of tetrahydrofuran and dimethyl ether, a mixture of tetrahydrofuran and toluene, a mixture of tetrahydrofuran and dimethylformamide, and the like are preferably used.
  • Examples of the base include lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide, and lithium hexamethyldisilazide is preferable.
  • the amount added is preferably about 1.2 to 5 equivalents.
  • Additives that can be prepared as necessary include lithium chloride, tin tetrachloride, tetrasalt titanium, tetrasalt zirconium, salt sodium, zinc chloride, lithium bromide, fluoride. Lithium chloride, calcium chloride and the like, and lithium chloride is preferable. Add 5 to 10 equivalents of these.
  • the reaction temperature is such that a binding reaction is possible in the range from ⁇ 78 ° C. to room temperature, preferably the power to maintain ⁇ 78 ° C. The temperature is raised moderately from ⁇ 78 ° C.
  • the molar ratio of the compound of formula (II) to the compound of formula (III) in the above reaction is not particularly limited, but it will generally be used in an equal amount.
  • a compound represented by the formula (I) is obtained, and in particular, the configuration of the formula ( ⁇ )
  • the compound is obtained in high yield.
  • the compound of the formula ( ⁇ ) may be purified and isolated as necessary. Examples of the method include silica gel column chromatography, cephadex column chromatography, resin chromatography, and recrystallization. Is a purification method by recrystallization, more preferably a recrystallization method using hexane and isopropyl ether. In this stage, it is possible to purify at the j8-methylcarboxylic acid stage after proceeding to the next step without completely isolating the ⁇ -form.
  • the compound of formula (IV) can be obtained by reacting the compound of formula ( ⁇ ) with an inorganic base in a reaction solvent. At this time, the compound of the formula (VI) can be recovered quantitatively. According to a preferred embodiment of the present invention, a small amount of peracid is added to the reaction system during this reaction.
  • reaction solvent examples include hydrous methanol, hydrous ethanol, hydrous tetrahydrofuran, and hydrous 1,4-dioxane, preferably hydrous methanol, and more preferably 50% methanol.
  • Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • 0.2 M lithium hydroxide aqueous solution is mixed with the same amount of methanol and used.
  • the peroxide added in a small amount for the purpose of preventing the reversal of stereochemistry is preferably a small amount of hydrogen peroxide.
  • Tildisilazide (1M tetrahydrofuran solution) was added. After stirring at -78 ° C for 30 minutes, 30.4 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 30 minutes, 1 ml of saturated aqueous solution of ammonium chloride was added and the temperature was gradually raised to room temperature. The mixture was diluted with 10 ml of ethyl acetate and washed 3 times with 5 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • R 1 is a t-butyldimethylsilyl group
  • R 2 acetyl group
  • R 3 force S methyl group
  • R 4 is methyl group
  • R 5 is t-butyldimethylsilyloxy group
  • R 1 is a t-butyldimethylsilyl group
  • R 2 acetyl group
  • R 3 force S methyl group
  • R 4 is methyl group
  • R 5 is t-butyldimethylsilyloxy group
  • R 1 is a t-butyldimethylsilyl group
  • R 2 is a methyl group
  • R 3 is a P-chlorobenzyl group
  • R 4 is a P-chlorobenzyl group
  • R 5 is a hydrogen atom.
  • R 1 is a t-butyldimethylsilyl group
  • R 2 cation group R 3 is a t-butyldimethylsilyl group
  • R 4 is a t-butyldimethylsilyl group
  • R 5 is a hydrogen atom.
  • H é ⁇ ( ⁇ : / ⁇ 4S: be ⁇ nabe ⁇ ) one 4 mu ci ⁇ ma / f, 3 ⁇ 43 ⁇ 4) ⁇ ⁇ 8 ⁇ ⁇ , ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ 3 ⁇ 4
  • Me methyl group
  • Bn benzyl group
  • MPM p-methoxyphenyl methyl
  • PCB p-chlorophenyl
  • NAP ⁇ -naphthylmethyl
  • Tr triphenylmethyl
  • Ts p-toluenesulfur
  • TBS T-Butyldimethylsilyl

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Abstract

Il est exposé un procédé servant à produire avec un bon rendement un intermédiaire dans la synthèse d'un agent antibactérien utile de type carbapénème, plus précisément le procédé décrit ci-dessus qui permet l'introduction d'un groupe méthyle en position 1 du squelette de carbapénème d'une manière extrêmement stéréosélective et qui ne requiert pas d'utiliser un quelconque groupe auxiliaire asymétrique onéreux, un quelconque catalyseur qui peut provoquer une réaction à très basse température ou avoir une quelconque toxicité vis-à-vis du corps humain ou similaire et permettre de récupérer le groupe auxiliaire asymétrique. Dans ce procédé, on fait réagir un sucre servant de matrice et contenant une unité propionate, représenté par la formule (II), avec une acétoxyazétidinone représentée par la formule (III) pour former une liaison carbone-carbone entre ceux-ci, ce par quoi on introduit un groupe méthyle en position 1 du squelette de carbapénème de la manière β-stéréosélective souhaitée.
PCT/JP2006/314992 2005-07-29 2006-07-28 Nouveau procédé pour la synthèse d'un intermédiaire dans la synthèse d'un carbapénème utilisant un sucre comme matrice WO2007013592A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013064A1 (fr) * 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Procede de production d'un derive d'azetidinone substitue en position 4

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2958834B2 (ja) * 1991-12-09 1999-10-06 高砂香料工業株式会社 アゼチジン−２−オン誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013064A1 (fr) * 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Procede de production d'un derive d'azetidinone substitue en position 4

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
NAGATSUKA T. ET AL.: "Highly Diastereoselective Diels-Alder Reactions of Acrylic Esters Incorporated into A variety of Hexopyranosides", JOURNAL OF CARBOHYDRATE CHEMISTRY, vol. 20, no. 7/8, 2001, pages 519 - 535, XP003005143 *
TOTANI K. ET AL.: "Highly Stereoselective 1,4-Conjugate Addition of Organocopper Reagents to Methyl alfa-D-Glucopyranoside Derivatives Tethering an Unsaturated Ester Moiety at C-4 or C-6", ORGANIC LETTERS, vol. 1, no. 9, 1999, pages 1447 - 1450, XP003006583 *
TOTANI K. ET AL.: "Highly stereoselective alfa-alkylations, 1,4-additions, and one-pot 1,4-addition/alfa-methylations achieved on 4-O-acyl and 4-O-crotonyl derivatives of methyl 6-deoxy-2,3-di-O-(t-butyldimethylsilyl)-alfa-Dglucopyranoside", SYNLETT, no. 11, 2001, pages 1772 - 1776, XP003006582 *

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