CN104177394B - Entecavir midbodies and preparation method thereof - Google Patents
Entecavir midbodies and preparation method thereof Download PDFInfo
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- CN104177394B CN104177394B CN201310198729.XA CN201310198729A CN104177394B CN 104177394 B CN104177394 B CN 104177394B CN 201310198729 A CN201310198729 A CN 201310198729A CN 104177394 B CN104177394 B CN 104177394B
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- entecavir
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- 229960000980 entecavir Drugs 0.000 title claims abstract description 66
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 97
- 239000003960 organic solvent Substances 0.000 claims abstract description 58
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims abstract description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 35
- 239000002253 acid Substances 0.000 claims abstract description 28
- 229940125773 compound 10 Drugs 0.000 claims abstract description 28
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims abstract description 28
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims abstract description 21
- 229940125797 compound 12 Drugs 0.000 claims abstract description 21
- 238000006722 reduction reaction Methods 0.000 claims abstract description 19
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 52
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
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- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000001424 substituent group Chemical group 0.000 claims description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- -1 chloroethenes Alkane Chemical class 0.000 claims description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
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- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 12
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- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
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- 239000003440 toxic substance Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of entecavir midbodies and preparation method thereof.The invention provides a kind of preparation method of entecavir midbodies compound 10, it comprises the following steps：In organic solvent, in the presence of reducing agent, ester type compound 11 is subjected to reduction reaction, obtains compound 10.Present invention also offers a kind of preparation method of entecavir midbodies compound 11, it comprises the following steps：In organic solvent, under the conditions of acid is existing, compound 12 and hydroxy protecting agent is carried out to the reaction of upper hydroxyl protecting group, obtain compound 11.The preparation method raw material of the present invention is cheap and easy to get, and reaction condition is gentle, and product yield is higher.Atom economy is good, environment-friendly, is suitable for industrialized production.
Description
Technical field
The present invention relates to entecavir midbodies and preparation method thereof.
Background technology
Nucleotide analog is as a kind of important compound, in the obtained extensive pass of medicinal chemistry art
Note.Relative research has created large quantities of significant medicines, especially in antiviral drugs field.Quite
The anti-AIDS drug and anti-hbv drug of quantity all benefit from the further investigation in the field.
There are 3.5 hundred million~4.0 hundred million hepatitis type B virus (HBV) the infecteds in the whole world, wherein there is nearly 1,000,000 patient to die from every year
Hepatic sclerosis caused by HBV infection and liver cancer.There are more than 1.2 hundred million HBV infection persons in China, account for more than the 1/3 of the world total, occupy generation
The 1st, boundary, chronic hepatitis B (hepatitis B) patient 30,000,000, and also this numeral is just in rising trend at present.Chronic second
Till now also without the method that can be cured completely, patient needs long-term or in most cases needed for hepatovirus infection
HIV suppression is carried out throughout one's life.The clinical guidelines recommended therapy course for the treatment of is at least 1 year.Ucleosides medicine in the medicine of hepatitis B at present
The occupation rate of market of thing is more than 80%.In nucleoside medicine, Entecavir by its it is notable the effect of and good overriding resistance
Property, since two thousand seven, having substituted Lamivudine turns into the anti-hepatic-B virus medicine of a line.Entecavir is applied by U.S.A during the U.S. hundred
Gui Bao companies develop, and U.S. FDA was ratified to list on March 29th, 2005.State food medicine is obtained on November 15th, 2005
Surveillance Authority SFDA ratifies Discussion on Chinese Listed.The drug patent expired in 2008, but because its synthesis difficulty is huge,
Its active component (API) existing market price is high, and manufacturer is few.
The bulk drug of Entecavir causes extensive concern because its synthesis difficulty is big in scientific circles.On entecavir
Therefore the synthetic methodology research of Wei has also obtained deep development.Wherein more representational synthetic route is in Shen Guobing et al. institutes
Write《Entecavir route illustrates》(Chinese Journal of Pharmaceuticals 2007 year 749-752 pages of phase of volume 38 10) and the paper are drawn
There is detailed introduction in document.Other related documents also have a lot, such as CN1861602A, CN101050216A,
CN101182322A、CN101210015A、CN101235034A、CN101245067A、CN101531660A、
CN101723945A、CN101756890A、CN101759698A、CN101781301A、CN101805339A、
CN101830856A、CN101838207A、CN101838270A、CN101863842A、CN101891741A、
CN101906113A、CN102002023A、CN102225938A、CN102229608A、DE102009060194A1、
EP2433941A1、SG171963A1、TW201118097A、US2006106216A1、US2010286089A1、
The pertinent literature that WO2011102806A1, WO2011150513A1, WO2012006964A1 and these documents the inside are quoted.
Larger problem existing for current most synthetic routes, such as equivalent use Dess-Martin reagents or two
The raw material and reagent costly such as firpene borine, and severe reaction conditions, purification procedures are complicated, it is necessary to chromatographic column point
From the means of purification of contour cost, atom utilization is low, and post processing is seriously polluted, is not suitable for large-scale industrial production.Its
In a comparatively practical production line be WO2005118585 reports, its synthetic route is shown below.The route
Also having the raw materials such as the defects of its is corresponding, such as phenyldimethylchlorosilane production difficulty to cause, price is high, cost is higher；It is and high
The use of toxic agent such as boron trifluoride；And the intermediate of the overwhelming majority is all caused by oily liquids in process of production
Purification difficult.
Chinese patent CN101050216A reports the synthetic route similar to WO2005118585, but in production cost
On decrease, employ the relatively low diphenyl methyl chloro silane of price as initiation material.But because two phenyl ring and silicon
The connected caused huge steric effect of atom so that the route can not be still avoided using height in last deprotection base
The boron trifluoride of malicious high pollution, and it is unfavorable for industrialized production.
The content of the invention
The technical problems to be solved by the invention be in order to overcome existing Entecavir preparation method reaction raw materials price compared with
It is expensive, it is difficult to obtain, severe reaction conditions, product yield is relatively low, and post-processing operation is cumbersome, and atom utilization is low, and environmental pollution is tight
The defects of being not suitable for industrialized production again, and provide entecavir midbodies and preparation method thereof.The preparation method of the present invention
Raw material is cheap and easy to get, and reaction condition is gentle, and product yield is higher.Atom economy is good, environment-friendly, is suitable for industrial metaplasia
Production.
The invention provides a kind of preparation method of entecavir midbodies compound 10, it comprises the following steps：Having
In solvent, in the presence of reducing agent, ester type compound 11 is subjected to reduction reaction, obtains compound 10；
Entecavir 1 is prepared again；
Wherein, P1For the hydroxyl protecting group that can be hydrolyzed under acid condition conventional in the art, its acid resistance compares P2
It is weak, be preferablyWherein R8For hydrogen, or C1~C6Straight or branched alkyl (preferably methyl, ethyl or propyl group)；R9
For C1~C6Straight or branched alkyl (preferably methyl, ethyl or propyl group), trimethyl silicon substrate, triethyl group silicon substrate, trityl group
Or t-Butyldimethylsilyl.
R2The substituent being as follows：
Wherein, R21For substituted or unsubstituted pyridine radicals, or substituted or unsubstituted C6~C10Aryl, described substitution
Pyridine radicals in substituent be C1~C3Alkyl, halogen and C1~C3One or more in alkoxy, per the number of class substituent
Mesh can be one or more；Described substituted C6~C10Substituent in aryl is C1~C3Alkyl, halogen and C1~C3Alcoxyl
One or more in base, the number per class substituent can be one or more；Described every class refers to above-mentioned C1~C3Alkane
Base, halogen and C1~C3One kind in alkoxy.
Described R21Preferably following any substituent：
Y is connection or 3~9 carbon atoms for being not connected to substituent, so as to form substituted or unsubstituted 4~10 yuan with Si
Saturation or undersaturated silicon-carbon ring；Or Y for connection or is not connected to substituent, sum is the carbon atom of 3~9 and miscellaneous
Atom, so as to form substituted or unsubstituted 4~10 yuan of saturation or undersaturated carbon sila ring with Si, the hetero atom be O,
S or N, heteroatomic number are 1~3；Substituent in described substitution is C1~C3Alkyl；Described silicon-carbon ring or carbon silicon
Heterocycle be a ring or simultaneously together two rings (such as
Described R2Preferably following any substituent：
In substituent IIa, n is that 0~2, p is that 0~2, q is that 1~2, X and Y is independently each carbon, oxygen or nitrogen, R3Take
Subrogate the position that can arbitrarily substitute being set on heterocycle in addition to silicon atom；R3It can be monosubstituted or polysubstituted, work as R3For
When polysubstituted, substituent can be with identical or different, R3Selected from methyl, ethyl, propyl group or isopropyl；When n is 0, X is carbon,
When p is 0, Y is carbon.
Described substituent IIa is preferably following any substituent：
R10For C1~C4Straight chained alkyl (preferably methyl)；Described reducing agent be diisobutyl aluminium hydride, lithium aluminium hydride reduction,
Red aluminum (double (2- methoxy ethoxies) sodium aluminum hydrides) or sodium borohydride, when reducing agent is sodium borohydride, the reaction exists
Carried out in the presence of lithium chloride and/or lithium bromide.
In the method for prepare compound 10, described organic solvent is normal not influence such reduction reaction that reaction is carried out
Solvent, such as dichloromethane, toluene, 1,2- dichloroethanes, tetrahydrofuran and one kind or more in 2- methyltetrahydrofurans
Kind.Described organic solvent and the volume mass of described compound 11 are more preferably than preferably 3mL/g~20mL/g
5mL/g~12mL/g.
In the method for prepare compound 10, the dosage of described reducing agent can be the routine of the such reduction reaction in this area
Dosage, such as 1~5 times that mole is described compound 11, following ranges specifically preferred according to the invention：Described reducing agent with
The molar ratio of described compound 11 is preferably 1.1~3.When reducing agent is sodium borohydride, described reduction reaction exists
Carried out in the presence of lithium chloride and/or lithium bromide, described lithium chloride and/or lithium bromide and the mol ratio of described compound 11
Value is preferably 0.1~2.
In the method for prepare compound 10, the temperature of described reduction reaction is preferably -78 DEG C~100 DEG C, more preferably
Be -20 DEG C~40 DEG C.The time of described reduction reaction can be by detecting untill reacting no longer progress, generally 0.5 hour
~12 hours.
In the method for prepare compound 10, described compound 11 can be prepared by following methods, and it includes following
Step：In organic solvent, under the conditions of acid is existing, compound 12 and hydroxy protecting agent are subjected to the anti-of upper hydroxyl protecting group
Should, obtain compound 11；
Again successively according to the method for described prepare compound 10, the method for described prepare compound 9, described preparation
The method of compound 8, the method for described prepare compound 6, the method for described prepare compound 5, described prepares chemical combination
The method of thing 4, the method for described prepare compound 3, the method for described prepare compound 2, described prepares Entecavir 1
Method be made Entecavir 1；
Wherein R2、R10And P1Definition it is same as above；Wherein R8For hydrogen, or C1~C6Straight or branched alkyl (preferably
Methyl, ethyl or propyl group)；R9For C1~C6Straight or branched alkyl (preferably methyl, ethyl or propyl group), trimethyl silicon substrate, three
Ethyl silicon substrate, trityl group or t-Butyldimethylsilyl.
In the method for prepare compound 11, the described reaction for carrying out protection group can be nucleophilic substitution or
Coupling reaction.
Described hydroxy protecting agent is the hydroxyl protecting group that can be hydrolyzed under acid condition conventional in the art, compared with
Good isWherein R8For hydrogen, or C1~C6Straight or branched alkyl (preferably methyl, ethyl or propyl group)；R9For C1~
C6Straight or branched alkyl (preferably methyl, ethyl or propyl group), trimethyl silicon substrate, triethyl group silicon substrate, trityl group or uncle
Butyldimethyl silicon substrate.
In the method for prepare compound 11, described organic solvent is preferably aromatic hydrocarbon solvent, halogenated hydrocarbon solvent
With the one or more in alkane solvents；Described aromatic hydrocarbon solvent is preferably toluene；Described halogenated hydrocarbon solvent compared with
It is good for dichloromethane and/or dichloroethanes；Described alkane solvents are preferably n-hexane, pentane, petroleum ether and just
One or more in heptane；The volume mass of described organic solvent and described compound 12 than preferably 3mL/g~
20mL/g, more preferably 5mL/g~15mL/g.Described acid is preferably organic acid, described organic acid preferred pair toluene sulphur
Acid.The described sour molar ratio with described compound 12 is preferably 0.01~10, and more preferably 0.01~1.Described
Hydroxy protecting agent and the molar ratio of described compound 12 are preferably 1~100, and more preferably 1~20.
In the method for prepare compound 11, the temperature of the reaction of described upper hydroxyl protecting group is preferably -20 DEG C~
100 DEG C, more preferably -20 DEG C~40 DEG C.The time of the reaction of described upper hydroxyl protecting group can no longer be entered by detecting reaction
Behavior stops, generally 0.5 hour~12 hours.
In the method for prepare compound 11, described compound 12 can be prepared by following methods, and it includes following
Step：
Step (1)：In organic solvent, by compound 13 and (1R, 2R) -2- amino -1- (4- nitrobenzophenones) propane -1,3-
Glycol is reacted；
Step (2)：In organic solvent, in the presence of the concentrated sulfuric acid, material and R that step (1) is obtained10OH is esterified
Reaction, obtains compound 12；
Again successively according to the method for described prepare compound 11, the method for described prepare compound 10, described system
The method of standby compound 9, the method for described prepare compound 8, the method for described prepare compound 6, described preparation
The method of compound 5, the method for described prepare compound 4, the method for described prepare compound 3, described prepare compound 2
Method and the described method for preparing Entecavir 1 be made Entecavir 1；
Wherein, R2And R10Definition it is same as above；
Prepare compound 12 the step of in (1), the method and condition of described reaction can be this kind of reaction in this area
Conventional method and condition, following conditions specifically preferred according to the invention：Described organic solvent can be isopropanol, methanol, ethanol,
Water, DMF, dimethyl sulfoxide (DMSO), acetonitrile, in tetrahydrofuran, 2- methyltetrahydrofurans and 1-METHYLPYRROLIDONE
One or more.Described organic solvent and the volume mass of described compound 13 are than preferably 1mL/g~100mL/
G, more preferably 3mL/g~20mL/g.Described (1R, 2R) -2- amino -1- (4- nitrobenzophenones) propane -1,3- glycol and institute
The molar ratio for the compound 13 stated is preferably 0.25~10, and more preferably 0.4~3.The time of described reaction can pass through
Untill detection reaction is no longer carried out, generally 0.25 hour~72 hours, more preferably 0.5 hour~24 hours.Described is anti-
The temperature answered is preferably 0~150 DEG C, more preferably 25 DEG C~80 DEG C.
Prepare compound 12 the step of in (2), the method and condition of described esterification can be that this area is this kind of
The conventional method and condition of reaction, following conditions specifically preferred according to the invention：Described organic solvent can be C1~C4Alkylol is molten
Agent.Described organic solvent and the volume mass of described compound 13 are more preferably than preferably 1mL/g~100mL/g
3mL/g~20mL/g.The percetage by weight of the described concentrated sulfuric acid can be 60%~98% (such as 98%wt).The described concentrated sulfuric acid with
The molar ratio of described compound 13 is preferably 0.01~100, and more preferably 0.05~30.The time of described reaction can
By detecting untill reacting no longer progress, generally 0.5 hour~72 hours, more preferably 1 hour~48 hours.Described is anti-
The temperature answered is preferably -20 DEG C~100 DEG C, more preferably -10 DEG C~60 DEG C.
In the method for prepare compound 12, described compound 13 can be made by following methods, and it includes following
Step：In a solvent, compound 14 and reducing agent are subjected to the reaction that carbonyl reduction is hydroxyl, obtain compound 13；
Again successively according to the method for described prepare compound 12, the method for described prepare compound 11, described system
The method of standby compound 9, the method for described prepare compound 8, the method for described prepare compound 6, described preparation
The method of compound 5, the method for described prepare compound 4, the method for described prepare compound 3, described prepare compound 2
Method and the described method for preparing Entecavir 1 be made Entecavir 1；
Wherein, R2It is defined as above described.
In the method for prepare compound 13, described carbonyl reduction is the method for the reaction of hydroxyl and condition can be this
The conventional method and condition of this kind of reaction in field, following conditions specifically preferred according to the invention：Described preferred solvents have for alcohols
Solvent and/or water；Or the one or more in toluene, dichloromethane and tetrahydrofuran.Described solvent and described change
The volume mass of compound 14 is than preferably 1mL/g~100mL/g, more preferably 3mL/g~20mL/g.When solvent has for alcohols
When solvent and/or water, described reducing agent can be LiBH4、CsBH4、KBH4And NaBH4In one or more, reducing agent with
The molar ratio of compound 14 is preferably 0.5~10, and more preferably 1~3, described alcohol organic solvent can be isopropanol,
Methanol, ethanol, the one or more in the tert-butyl alcohol and n-butanol.When solvent is one in toluene, dichloromethane and tetrahydrofuran
When planting or be a variety of, described reducing agent can be lithium aluminium hydride reduction, diisobutyl aluminium hydride or red aluminum (double (2- methoxy ethoxies)
Sodium aluminum hydride)), reducing agent and the molar ratio of compound 14 are preferably 0.5~10, and more preferably 1~3.Described carbonyl
The time for being reduced to the reaction of hydroxyl can be by detecting untill reacting no longer progress, generally 0.25 hour~12 hours, more preferably
For 0.5 hour~10 hours.Described carbonyl reduction is preferably -78 DEG C~120 DEG C for the temperature of the reaction of hydroxyl, more preferably
Be -60 DEG C~60 DEG C.
In the method for prepare compound 13, described compound 14 can be prepared by following methods, and it includes following
Step：In solvent, in the presence of alkali, compound 15 is subjected to isomerization reaction, obtains compound 14；
Again successively according to the method for described prepare compound 13, the method for described prepare compound 12, described system
The method of standby compound 11, the method for described prepare compound 9, the method for described prepare compound 8, described preparation
The method of compound 6, the method for described prepare compound 5, the method for described prepare compound 4, described prepare compound 3
Method, Entecavir 1 is made in the method for described prepare compound 2 and the described method for preparing Entecavir 1；
Wherein, R2It is defined as above described.
In the method for prepare compound 14, the method and condition of described isomerization reaction can be that this area is this kind of anti-
The conventional method and condition answered, following conditions specifically preferred according to the invention：Described solvent can be isopropanol, methanol, ethanol, tertiary fourth
Alcohol, n-butanol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, N- methylpyrroles
One or more in alkanone and water.The volume mass of described solvent and described compound 15 than preferably 1mL/g~
100mL/g, more preferably 3mL/g~20mL/g.Described alkali is preferably triethylamine, diisopropylethylamine, 1,8- diaza
Carbon -7- the alkene of two rings [5.4.0] 11, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide
With the one or more in cesium hydroxide.Described alkali and the molar ratio of described compound 15 are preferably 0.5~10, more
It is good for 1~3.Untill the time of described isomerization reaction can no longer be carried out by detection reaction, generally 0.25 hour~
72 hours, more preferably 0.5 hour~12 hours.The temperature of described isomerization reaction is preferably -50 DEG C~100 DEG C, more
Good is -10 DEG C~80 DEG C.
In the method for prepare compound 14, described compound 15 can be prepared by following methods, and it includes following
Step：In the mixed solution of organic solvent and water, in the presence of alkali, compound 16 is carried out to hydrolysis as follows,
Obtain compound 15；
Again successively according to the method for described prepare compound 14, the method for described prepare compound 13, described system
The method of standby compound 12, the method for described prepare compound 11, the method for described prepare compound 9, described preparation
The method of compound 8, the method for described prepare compound 6, the method for described prepare compound 5, described prepares chemical combination
The method of thing 4, the method for described prepare compound 3 and described prepare Entecavir at the method for described prepare compound 2
Entecavir 1 is made in 1 method；
Wherein, R2It is defined as above described.
In the method for prepare compound 15, the method and condition of described hydrolysis can be this kind of reaction in this area
Conventional method and condition, following conditions specifically preferred according to the invention：Described organic solvent can be isopropanol, methanol, ethanol, uncle
Butanol, n-butanol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, one kind in tetrahydrofuran and 1-METHYLPYRROLIDONE
It is or a variety of.The volume mass of described organic solvent and described compound 16 is than preferably 0.5mL/g~100mL/g, more
It is good for 1mL/g~20mL/g.The volume mass of described water and described compound 16 than preferably 0.25mL/g~
100mL/g, more preferably 0.5mL/g~20mL/g.Described alkali is preferably triethylamine, diisopropylethylamine, 1,8- phenodiazine
Miscellaneous carbon -7- the alkene of two ring [5.4.0] 11, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, potassium hydroxide, lithium hydroxide, hydroxide
One or more in sodium and cesium hydroxide.Described alkali and the molar ratio of described compound 16 be preferably 0.5~
100, more preferably 1~50.The time of described hydrolysis can be by the way that untill detecting reaction no longer progress, generally 0.25 is small
When~72 hours, more preferably 0.5 hour~12 hours.The temperature of described hydrolysis is preferably -10 DEG C~150 DEG C,
More preferably 0~120 DEG C.
In the method for prepare compound 15, described compound 16 can be made by following methods, and it includes following
Step：In organic solvent, in the presence of alkali, compound 17 and dichloroacetyl chloride are subjected to addition reaction as follows, obtained
To compound 16；
Again successively according to the method for described prepare compound 15, the method for described prepare compound 14, described system
The method of standby compound 13, the method for described prepare compound 12, the method for described prepare compound 11, described preparation
The method of compound 9, the method for described prepare compound 8, the method for described prepare compound 6, described prepares chemical combination
The method of thing 5, the method for described prepare compound 4, the method for described prepare compound 3, described prepare compound 2
Entecavir 1 is made in method and the described method for preparing Entecavir 1；
Wherein, R2It is defined as above described.
In the method for prepare compound 16, the method and condition of described addition reaction can be this kind of reaction in this area
Conventional method and condition, following conditions specifically preferred according to the invention：
Described organic solvent is preferably n-hexane, toluene, dimethylbenzene, trimethylbenzene, benzene, chlorobenzene, petroleum ether, tetrahydrochysene furan
Mutter, 2- methyltetrahydrofurans, the one or more in pentane and normal heptane.Described organic solvent and described compound 17
Volume mass than preferably 1mL/g~100mL/g, more preferably 3mL/g~20mL/g.Described alkali is preferably two different
One or more in propylethylamine, the carbon -7- alkene of 1,8- diazabicylos [5.4.0] 11, triethylamine and pyridine.Described alkali
Molar ratio with described compound 17 is preferably 0.5~100, and more preferably 1~50.Described dichloroacetyl chloride and institute
The molar ratio for the compound 17 stated is preferably 0.5~10, and more preferably 0.8~3.The time of described addition reaction can lead to
Untill crossing detection reaction no longer progress, generally 0.25 hour~72 hours, more preferably 0.5 hour~24 hours.Described
The temperature of addition reaction is preferably -50 DEG C~100 DEG C, more preferably -30 DEG C~30 DEG C.
In the method for prepare compound 16, described compound 17 can be made by following either method, indifferent gas
Under body protection, in organic solvent, by compound R2The alkali metal salt of X and cyclopentadiene (such as sodium cyclopentadiene) or cyclopentadiene
Alkali salt carries out nucleophilic substitution, you can；
Wherein, X F, Cl, Br, OTf orR2It is as defined above described.
In the method for prepare compound 17, the method and condition of described nucleophilic substitution can be that this area is this kind of
The conventional method and condition of reaction, following conditions specifically preferred according to the invention：Described organic solvent is preferably tetrahydrofuran, stone
Oily ether, 2- methyltetrahydrofurans, n-hexane, the one or more in pentane and normal heptane.Described organic solvent with it is described
Compound R2X volume mass is than preferably 1mL/g~100mL/g, more preferably 3mL/g~20mL/g.Described ring
The alkali metal salt (such as sodium cyclopentadiene) of pentadiene or the alkali salt of described cyclopentadiene and described compound R2X's
Molar ratio is preferably 0.5~10, and more preferably 0.8~3.The time of described nucleophilic substitution can be reacted by detecting
Untill no longer carrying out, generally 0.25 hour~72 hours, more preferably 0.5 hour~24 hours.Described nucleophilic displacement of fluorine is anti-
The temperature answered is preferably -78 DEG C~50 DEG C, more preferably -60 DEG C~30 DEG C.
After obtained entecavir midbodies compound 10, entecavir midbodies compound 9 can also be prepared, it is wrapped
Include following steps：In aprotic organic solvent, under alkalescence condition, compound 10 and hydroxy protecting agent are subjected to upper hydroxyl guarantor
The reaction of base is protected, obtains compound 9；
Entecavir 1 is prepared again；
Wherein, P1And R2Definition it is same as above.P2For the hydroxyl protection of stable under acidic conditions conventional in the art
Group, it is particularly preferred in of the inventionThe C of alkoxy substitution1~C6Alkyl (preferably
Methoxyl methyl or ethoxymethyl) or trimethyl silicane ethoxymethyl；Wherein described alkoxy is C1~C6Alkoxy, R4For one
Individual or multiple substituents, R5For one or two substituent, R4Selected from hydrogen, halogen, C1~C6Straight or branched alkyl (preferably
One or more of methyl, ethyl, propyl group, isopropyl or the tert-butyl group) and nitro；R5Selected from hydrogen, halogen, C1~C6Straight chain
Or one or two in branched alkyl (preferably methyl, ethyl, propyl group, isopropyl or the tert-butyl group) and nitro.
Described hydroxy protecting agent is hydroxy protecting agent conventional in the art, in the present invention particularly preferablyThe C substituted by alkoxy1~C6Haloalkyl (preferably methoxyl methyl or ethoxy
Methyl) or trimethyl silicane ethoxymethyl alkyl halide, wherein, described alkoxy is C1~C6Alkoxy；Described halogen is
Chlorine, bromine or iodine；R4For one or more substituents, R5For one or two substituent, R4Selected from hydrogen, halogen, C1~C6Straight chain
Or one or more of branched alkyl (preferably methyl, ethyl, propyl group, isopropyl or the tert-butyl group) and nitro；R5Selected from hydrogen, halogen
Element, C1~C6Straight or branched alkyl (preferably methyl, ethyl, propyl group, isopropyl or the tert-butyl group) and nitro in one or two
It is individual；
In the method for prepare compound 9, described upper hydroxyl protecting group reaction method and condition can be this area this
The conventional method and condition of class reaction, following conditions specifically preferred according to the invention：Described aprotic organic solvent can be this area
Conventional aprotic organic solvent, such as DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 2- methyl tetrahydrochysene furans
Mutter and the one or more in 1-METHYLPYRROLIDONE.Described organic solvent is compared with the volume mass of described compound 10
It is good for 1mL/g~100mL/g, more preferably 3mL/g~20mL/g.Described alkali is preferably DMAP, three
Ethamine, diisopropylethylamine, potassium carbonate, the one or more in sodium carbonate, cesium carbonate, hydrofining and sodium hydride；More preferably
Sodium hydride；Described hydrofining or sodium hydride is preferably that weight/mass percentage composition is 10%~90% to be scattered in mineral oil
Hydrofining or hydrogenation sodium reagent, more preferably weight/mass percentage composition are 60% hydrofining or sodium hydride that are scattered in mineral oil
Reagent；Described weight/mass percentage composition refers to the quality of hydrofining or sodium hydride, and to account for hydrofining or sodium hydride total with mineral oil mixture
The percentage composition of quality.Described alkali and the molar ratio of described compound 10 are preferably 0.5~10, more preferably 1~
5.Described hydroxy protecting agent and the molar ratio of described compound 10 are preferably 0.5~10, and more preferably 1~3.Institute
The time of the reaction for the upper hydroxyl protecting group stated can be by detecting untill reacting no longer progress, generally 0.5 hour~72 hours,
More preferably 1 hour~36 hours.The temperature of the reaction of described upper hydroxyl protecting group is preferably -20 DEG C~80 DEG C, more preferably
Be -20 DEG C~50 DEG C.
After obtained entecavir midbodies compound 9, entecavir midbodies compound 8 can also be prepared, it is wrapped
Include following steps：In a solvent, under acid condition, compound 9 is carried out to the reaction of eliminating hydroxide protection group, obtains compound 8；
Entecavir 1 is prepared again；
Wherein, P1、P2And R2Definition be the same as those described above.
In the method for prepare compound 8, the method and condition of the reaction of described eliminating hydroxide protection group can be ability
The conventional method and condition that such in domain reacts, following conditions specifically preferred according to the invention：Described preferred solvents to be organic molten
Agent and/or water, wherein described organic solvent is preferably dichloromethane, methanol, ethanol, isopropanol, the tert-butyl alcohol, tetrahydrochysene furan
Mutter, acetonitrile, the one or more in DMF and dimethyl sulfoxide (DMSO).The solvent and the volume mass ratio of described compound 9 are preferable
For 2mL/g~20mL/g, more preferably 5mL/g~15mL/g.Described Bronsted acid is preferably hydrochloric acid, sulfuric acid, nitric acid, and three
One or more in fluoroacetic acid, methanesulfonic acid and p-methyl benzenesulfonic acid.Described Bronsted acid and the molar ratio of described compound 9
Preferably 0.01~100, more preferably 0.1~20.Untill the time of described reaction can no longer be carried out by detection reaction,
Generally 0.5 hour~24 hours.The temperature of described reaction is preferably 0~100 DEG C, more preferably 20 DEG C~80 DEG C.
After obtained entecavir midbodies compound 8, entecavir midbodies compound 6 can also be prepared, it is wrapped
Include following steps：In organic solvent, compound 8 is subjected to Sharpless chiral epoxy reactions, obtains compound 6；
Entecavir 1 is prepared again；
Wherein, P2And R2Definition be the same as those described above.
In the method for prepare compound 6, the method and condition of the reaction of described Sharpless chiral epoxies can be this
The conventional method and condition that such in field reacts, such as can refer in document (Pfenninger, A.Synthesis 1986,89)
Method and condition carry out, can be following methods：, will in the presence of tetraisopropoxy titanium and chiral ligand in organic solvent
Compound 8 and peroxide carry out Sharpless chiral epoxy reactions, obtain compound 6.
Following conditions specifically preferred according to the invention：Described organic solvent can be dichloromethane and/or 1,2- dichloroethanes.Institute
The volume mass of the organic solvent stated and described compound 8 than preferably 1mL/g~100mL/g, more preferably 3mL/g~
20mL/g.Described chiral ligand is preferably (2S, 3S)-ethyl tartrate or (2S, 3S)-tartaric acid diisopropyl ester.Institute
The chiral ligand stated and the molar ratio of described compound 8 are preferably 0.0001~1, and more preferably 0.001~0.3.Institute
The tetraisopropoxy titanium stated and the molar ratio of described compound 8 are preferably 0.0001~1, more preferably 0.001~
0.3.Described peroxide is preferably one in tert-Butanol peroxide, hydrogen peroxide, Peracetic acid and metachloroperbenzoic acid
Kind is a variety of.Described peroxide and the molar ratio of described compound 8 are preferably 0.5~10, and more preferably 1~5.
The time of described chiral epoxy reaction can be by detecting untill reacting no longer progress, generally 0.25 hour~24 hours,
More preferably 1 hour~16 hours.The temperature of described chiral epoxy reaction is preferably -78 DEG C~25 DEG C, more preferably -
60 DEG C~0 DEG C.
After obtained entecavir midbodies compound 6, entecavir midbodies compound 5 can also be prepared, it is wrapped
Include following steps：In aprotic organic solvent, compound 6 and compound 7 are subjected to ring-opening reaction, obtain compound 5；
Entecavir 1 is prepared again；
Wherein P2It is defined as above described；R6C is selected from for hydrogen, or one or more1~C6Straight or branched alkoxyl
(preferably methoxyl group), C1~C6Straight or branched alkyl (preferably methyl) and halogen atom (such as fluorine, chlorine or bromine) substituent.
The method of prepare compound 5, preferably carry out in the presence of a base.
In the method for prepare compound 5, the method and condition of described ring-opening reaction can be that such in this area is anti-
The conventional method and condition answered, following conditions specifically preferred according to the invention：Described aprotic organic solvent can be that this area is conventional
Aprotic organic solvent, such as DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 1-METHYLPYRROLIDONE and
One or more in 2- methyltetrahydrofurans.Described organic solvent and the volume mass ratio of described compound 6 are preferable
For 1mL/g~100mL/g, more preferably 3mL/g~20mL/g.The molar ratio of described compound 7 and described compound 6
Preferably 0.5~10, more preferably 1~3.Untill the time of described ring-opening reaction can no longer be carried out by detection reaction,
Generally 0.5 hour~24 hours, more preferably 3 hours~20 hours.The temperature of described ring-opening reaction is preferably 0~
150 DEG C, more preferably 25 DEG C~120 DEG C.
In 5 preferable method of prepare compound, described alkali is preferably lithium hydroxide and/or lithium hydride.Described
Alkali and the molar ratio of compound 6 are preferably 0.01~10, and more preferably 0.05~5.
After obtained entecavir midbodies compound 5, entecavir midbodies compound 4 can also be prepared, it is wrapped
Include following steps：In a solvent, under acid condition, compound 5 and compound 18 is subjected to transketalation reaction, obtain compound
4；
Entecavir 1 is prepared again；
Wherein, R2、R6And P2Definition it is same as above；R7For hydrogen atom, or C1~C6Straight or branched alkyl；R11For
C1~C8Straight or branched alkyl, or C1~C8Cycloalkyl；R12For C1~C8Straight or branched alkyl, or C1~C8Ring
Alkyl.
In the method for prepare compound 4, the reaction of described transketalation is that the routine of such reaction occurs in this area
Method, particularly preferred following reaction condition and method in of the invention：
In the method for prepare compound 4, the preferred non-protonic solvent of described solvent, described non-protonic solvent is excellent
Select the one or more in halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent and alkane solvents；Described halogenated hydrocarbon is molten
The preferred chlorinated hydrocarbon solvent of agent；The preferred dichloromethane of described chlorinated hydrocarbon solvent and/or dichloroethanes；Described aromatic hydrocarbons are molten
The preferred toluene of agent；The preferred tetrahydrofuran of described ether solvent and/or 2- methyltetrahydrofurans；Described alkane solvents are preferred
One or more in n-hexane, normal heptane and petroleum ether.
In the method for prepare compound 4, described acid condition can be realized by acidic materials, described acidity
Material is the one or more in organic acid, inorganic acid and strong acid weak base salt；The preferred strong acid weak base salt of described acidic materials, institute
The acid condition stated preferably is realized by strong acid weak base salt, i.e., realizes that described transketalation is anti-by strong acid weak base salt
Should.The preferred p-methyl benzenesulfonic acid of described organic acid and/or methanesulfonic acid；In the preferred hydrochloric acid of described inorganic acid, sulfuric acid and phosphoric acid
It is one or more；Described strong acid weak base salt refers to that strong acid reacts the aobvious weakly acidic salt to be formed, preferred pair toluene sulphur with weak base
One or more in sour pyridiniujm (PPTS), p-methyl benzenesulfonic acid triethylamine salt, methanesulfonic acid pyridiniujm and methanesulfonic acid triethylamine salt,
Further preferred para-methylbenzenepyridinsulfonate sulfonate (PPTS) and methanesulfonic acid pyridiniujm, still further preferably para-methylbenzenepyridinsulfonate sulfonate.
Described acidic materials and the molar ratio of described compound 5 are preferably 0.01~5；The solvent and described compound
5 volume mass is than preferably 1mL/g~20mL/g.As described R11For C1~C8Straight or branched alkyl when, it is described
C1~C8The preferred C of straight or branched alkyl1~C6Straight or branched alkyl, further preferred C1~C4Straight or branched
Alkyl, still further preferably ethyl；As described R11For C1~C8Cycloalkyl when, described C1~C8The preferred C of cycloalkyl1
~C6Cycloalkyl；As described R12For C1~C8Straight or branched alkyl when, described C1~C8Straight or branched alkyl
It is preferred that C1~C6Straight or branched alkyl, further preferred C1~C4Straight or branched alkyl, still further preferably ethyl；
As described R12For C1~C8Cycloalkyl when, described C1~C8The preferred C of cycloalkyl1~C6Cycloalkyl.Described chemical combination
Thing 18 is preferably as follows shown compound, i.e.,：
Wherein, R7For hydrogen atom, or C1~C6Straight or branched alkyl.
The molar ratio of described compound 5 and described compound 18 is preferably 0.5~10.Described reaction when
Between can by detection to reaction no longer progress untill, generally 1 hour~24 hours.The temperature of described reaction be preferably-
20 DEG C~80 DEG C.
After obtained entecavir midbodies compound 4, entecavir midbodies compound 3 can also be prepared, it is wrapped
Include following steps：In a solvent, compound 4 is subjected to reduction reaction, obtains compound 3；
Entecavir 1 is prepared again；
Wherein R2、R6、R7And P2Definition it is same as above.
The method for preparing above-claimed cpd 3, carried out preferably under the conditions of existing for acid；In acid and it can also more preferably add
Carried out under the conditions of adding agent existing, described additive is preferably selected from 2,6- di-tert-butyl-4-methy phenols, butylhydroxy fennel
Fragrant ether (BHA), dibutyl hydroxy toluene (BHT), propylgallate (PG), TBHQ (TBHQ), hydroquinones
With the one or more in 2.6- dinitro-p-cresols.The effect of described additive is to prevent raw material, product or its reaction
Intermediate state is degraded at high temperature.
In the method for preparing above-claimed cpd 3, described preferred solvents for the anhydrides described in anhydrides solvent it is molten
Agent is preferably acetic anhydride and/or benzoyl oxide；
In the method for preparing above-claimed cpd 3, the time of described reaction can no longer enter behavior by detection to reaction
Only, generally 1 hour~72 hours.The temperature of described reaction changes with the species of acid and changed, preferably 20 DEG C~180
℃。
In the preferable method of above-claimed cpd 3 is prepared, described acid is preferably organic acid and/or inorganic acid, institute
The organic acid stated is preferably glacial acetic acid, and described inorganic acid is preferably hydrochloric acid, and described hydrochloric acid is conventional in the art
Hydrochloric acid reagent, generally mass percent are 1%~37% aqueous hydrochloric acid solution, and preferred mass percentage is 37% dense salt
Acid, described mass percent refer to that the quality of hydrogen chloride accounts for the percentage of aqueous hydrochloric acid solution gross mass.The solvent with it is described
Compound 4 volume mass than preferably 1mL/g~20mL/g.Preparing above-mentioned entecavir midbodies compound 3
In preferable method, the described sour molar ratio with described compound 4 is preferably 1~200.
In the more preferably method of above-claimed cpd 3 is prepared, described additive and the molar ratio of described compound 4
Preferably 0.1~100, more preferably 0.5~30.
After obtained entecavir midbodies compound 3, entecavir midbodies compound 2 can also be prepared, it is wrapped
Include following steps：In a solvent, under the action of an acid, reaction is hydrolyzed in compound 3, obtains compound 2；
Entecavir 1 is prepared again；
R2And P2It is as defined above described, R1ForY is 3~9 carbon atoms for connecting or being not connected to substituent,
So as to form substituted or unsubstituted 4~10 yuan of saturation or undersaturated silicon-carbon ring with Si；Or Y for connection or is not connected to
Substituent, sum is the carbon atom and hetero atom of 3~9, so as to form substituted or unsubstituted 4~10 yuan of saturation with Si
Or undersaturated carbon sila ring, the hetero atom are O, S or N, heteroatomic number is 1~3；Substitution in described substitution
Base is C1~C3Alkyl；Described silicon-carbon ring or carbon sila ring be a ring or simultaneously together two rings (such as
Described R1Preferably following any substituent： Wherein, R3The position of substitution be the position that can arbitrarily substitute on heterocycle in addition to silicon atom；R3Can be
It is monosubstituted or polysubstituted, work as R3For it is polysubstituted when, substituent can be with identical or different, R3Selected from methyl, ethyl, propyl group or
Isopropyl；
In substituent Ia, n is that 0~2, p is that 0~2, q is that 1~2, X and Y is independently each carbon, oxygen or nitrogen；When n is 0
When, X is carbon, and when p is 0, Y is carbon.
Substituent Ia is preferably following any substituent：
In the method for preparing above-claimed cpd 2, described solvent can be conventional organic solvent and/or water；Described
Organic solvent can be dichloromethane, 1,2- dichloroethanes, tetrahydrofuran, 2- methyltetrahydrofurans, acetonitrile, methanol, ethanol, isopropyl
Alcohol, the one or more in toluene and t-butyl methyl ether.The solvent and the volume mass ratio of described compound 3 are preferably
1mL/g~20mL/g.Described acid can be Bronsted acid or lewis acid, preferably Bronsted acid；Described Bronsted acid is preferable
For hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, the one or more in methanesulfonic acid and trifluoromethanesulfonic acid；Described lewis acid is preferable
For boron trifluoride and/or titanium tetrachloride.Described hydrochloric acid is hydrochloric acid reagent conventional in the art, generally mass percent
For 1%~37% aqueous hydrochloric acid solution, preferred mass percentage is 37% concentrated hydrochloric acid, and described mass percent refers to chlorination
The quality of hydrogen accounts for the percentage of aqueous hydrochloric acid solution gross mass.Described sulfuric acid is sulphate reagent conventional in the art, generally
Mass percent be 1%~98% aqueous sulfuric acid, preferred mass percentage be 98% the concentrated sulfuric acid, described quality percentage
Quality than referring to sulfuric acid accounts for the percentage of aqueous sulfuric acid gross mass.The described sour molar ratio with described compound 3
Preferably 1~200.Untill the time of described reaction can be by detection to reaction no longer progress, generally 0.5 hour~24
Hour.The temperature of described reaction changes with the species of acid and changed, preferably 0 DEG C~120 DEG C, more preferably 10 DEG C~80
℃。
After obtained entecavir midbodies compound 2, Entecavir 1 can also be prepared, it comprises the following steps：
In solvent, compound 2 is subjected to Tamao-Fleming oxidation reactions, obtains Entecavir as shown in Equation 1；
Wherein, R1ForY is connection or 3~9 carbon atoms for being not connected to substituent, is substituted so as to be formed with Si
Or unsubstituted 4~10 yuan of saturation or undersaturated silicon-carbon ring；Or Y for connection or is not connected to substituent, sum is 3
The carbon atom and hetero atom of~9, so as to form substituted or unsubstituted 4~10 yuan of saturation or undersaturated carbon sila with Si
Ring, the hetero atom are O, S or N, and heteroatomic number is 1~3；Substituent in described substitution is C1~C3Alkyl；Institute
The silicon-carbon ring or carbon sila ring stated be a ring or simultaneously together two rings (such asOr
Described R1Preferably following any substituent： Wherein, R3The position of substitution be the position that can arbitrarily substitute on heterocycle in addition to silicon atom；R3Can be
It is monosubstituted or polysubstituted, work as R3For it is polysubstituted when, substituent can be with identical or different；
In substituent Ia, n is that 0~2, p is that 0~2, q is that 1~2, X and Y is independently each carbon, oxygen or nitrogen；When n is 0
When, X is carbon, and when p is 0, Y is carbon.
Substituent Ia is preferably following any substituent：
In the present invention, described Tamao-Fleming oxidation reactions are the classical name reactions of this area, the above method and
Condition can be the conventional method and condition of the such Tamao-Fleming oxidation reactions in this area, for example, may be referred to document
(Fleming,I；Barbero,A；Walter,D；Chem Rev, 1997,97,2063-2192) and its quote pertinent literature in
Method carry out.
For above-mentioned Tamao-Fleming oxidation reactions, particularly preferred following methods and condition in the present invention：
Described Tamao-Fleming oxidation reactions preferably comprise the steps of：
In solvent, in the presence of alkali and fluorination reagent, compound 2 and oxidant are subjected to Tamao-Fleming oxidations
Reaction.
Wherein, described preferred solvents for one in water, methanol, tetrahydrofuran, ethanol and DMF
Kind is a variety of.Described solvent and the volume mass of described compound 2 are more preferably than preferably 1mL/g~300mL/g
3mL/g~100mL/g.Described alkali is preferably triethylamine, diisopropylethylamine (Hunig base), saleratus, carbonic acid
One or more in hydrogen sodium and caesium bicarbonate.Described alkali and the molar ratio of described compound 2 be preferably 0.5~
30, more preferably 0.8~15.Described oxidant is preferably hydrogen peroxide, Peracetic acid, tert-Butanol peroxide, m-chloro peroxide benzene
In formic acid, chlorine, bromine, iodine, N- dichloro-succinic acids Asia acid amides, N- bromosuccinic acids Asia acid amides and N- iodo succinic acid Asia acid amides
One or more.Described hydrogen peroxide is the aqueous solution of hydrogen peroxide；The concentration of described hydrogen peroxide is preferably quality hundred
Divide ratio 1%~60%.Described oxidant and the molar ratio of described compound 2 are preferably 0.8~30, and more preferably 1
~20.Described fluorination reagent is preferably one kind or more in sodium fluoride, cesium fluoride, potassium fluoride, hydrogen fluoride and boron trifluoride
Kind.Described fluorination reagent and the molar ratio of described compound 2 are preferably 0.8~30, and more preferably 1~10.It is described
Tamao-Fleming oxidation reactions time can by detection to reaction no longer progress untill.Described Tamao-Fleming
The temperature of oxidation reaction is preferably -20 DEG C~120 DEG C, more preferably 0~80 DEG C.
In the present invention, for the structural formula of described Entecavir under different acid-base conditions, there may also be as follows
Dynamic isomer：
, can be conventional by this area after the Entecavir for being made as shown in Equation 1 by above-mentioned preparation method in the present invention
Post processing mode, such as add water to be heated at 60 DEG C~100 DEG C, filter (such as being filtered with diatomite), by filtrate crystallisation by cooling,
It can obtain as follows with the entecavir compound of the crystallization water, its structure：
Present invention also offers the preparation method of described compound 11, it comprises the following steps：In organic solvent, it is sour
Under the conditions of existing, compound 12 and hydroxy protecting agent are carried out to the reaction of upper hydroxyl protecting group, obtain compound 11；
Wherein R2、R10And P1Definition be the same as those described above.Each reaction condition and institute in the method for above-mentioned prepare compound 11
State identical.
Present invention also offers compound 2, compound 3, compound 4, compound 5, compound 6, compound 8, compound
9th, compound 10 or compound 11；
Wherein, the definition of each substituent is same as above.
Heretofore described " alkyl " means the saturated aliphatic hydrocarbons of side chain or straight chain, such as " C1~C3Alkyl "
Refer to containing the side chain that carbon number is 1,2 or 3 or the saturated aliphatic hydrocarbons of straight chain, such as methyl, ethyl, n-propyl or isopropyl
Base.
Described " alkoxy " mean alkyl be connected with oxygen atom after generation group, i.e., " RO- ", R is alkyl, such as
“C1~C3Alkoxy " refer to containing carbon number be 1,2 or 3 alkyl be connected with oxygen atom after generation group, such as methoxyl group,
Ethyoxyl, positive propoxy or isopropoxy.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and it is each preferably to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
Room temperature in the present invention refers to environment temperature, is 10 DEG C~35 DEG C.
The positive effect of the present invention is：The preparation method raw material of the present invention is cheap and easy to get, and reaction condition is gentle, instead
High conversion rate is answered, post-processing operation is easy, and product yield is high, and purity is good, and Atom economy is good, environment-friendly, and production cost is low,
It is suitable for industrialized production.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
Embodiment 1
Embodiment 1-1 is in (the R of compound 21For) (30.1g, 86.5mmol) water (6500mL) solution in add
Saleratus (260g, 2600mmol), potassium fluoride (100g, 1720mmol).Obtained mixed liquor slowly adds under 70 degrees Celsius
Enter 30% hydrogen peroxide (550g, 4320mmol).Mixed liquor after being added dropwise adds after being incubated and stirring 3 hours under 70 degrees Celsius
Enter acetic acid (1150mL), and continue 70 degrees Celsius of insulation and stir 30 minutes.Mixed liquor is slow cooling to 5 after diatomite filters
Degree Celsius.The powdered crystal for being collected by filtration to obtain is scattered in 2500mL distilled water again after 5 degrees Celsius are distilled water washing
In, it is heated to 95 degrees Celsius and is allowed to be completely dissolved.Obtained clear liquid is slow cooling to 5 degrees Celsius.Obtained powder is collected by filtration
Shape crystal simultaneously dries as required target compound 121.3g, yield 89%.
1H NMR(400MHz,DMSO-d6):δ10.57(br s,1H)7.69(s,1H)6.41(br s,2H)5.36(m,
1H)5.12(m,1H)4.89(s,1H)4.83(m,1H)4.58(m,1H)4.22(m,1H)3.55(m,2H)2.52(m,1H)2.21
(m,1H)2.04(m,1H)
13C NMR(100MHz,DMSO-d6):δ156.8,153.4,151.4,151.2,135.9,116.2,109.2,
70.3,62.9,55.0,54.0,39.2
ESI-MS：278.1[M+H]+。
Embodiment 1-2~embodiment 1-4, specific experiment condition and product knot is prepared according to embodiment 1-1 identicals method
Structure appraising datum is shown in Table 1.
The embodiment 1-2 of table 1 to embodiment 1-4 (in addition to table conditional, other conditions are with embodiment 1-1)
Embodiment 2
Embodiment 2-1
Compound 3-1 (R2ForP2For benzyl) in dichloromethane (82mL) solution of (82.0g, 165mmol) plus
Enter the concentrated sulfuric acid (8.2ml, 98%).Obtained brown liquid is slowly dropped into potassium hydroxide after being stirred 2 hours under 25 degrees Celsius
In the aqueous solution (2M, 1.6L).Obtained mixed liquor adds acetic acid regulation pH=6~7 after being evaporated organic solvent.It is collected by filtration to obtain
Solid and to dry be required target compound 2-1 (R1For) 50g, yield 87%.
1H NMR(400MHz,CDCl3):δ7.64(s,1H),5.30(s,2H),5.16-5.10(m,1H),3.88-3.72
(m,2H),3.56-3.46(m,1H),2.52-2.38(m,1H),2.17-1.92(m,2H),1.90-1.75(m,1H),1.73-
1.54(m,4H),1.00-0.70(m,4H)；
13C NMR(100MHz,CD3OD):δ159.4,155.2,153.9,153.1,129.1,117.4,112.1,63.2,
59.7,44.1,30.1,19.5,17.1,8.6,
ESI-MS：348.1[M+H]+。
Embodiment 2-2~embodiment 2-8, specific experiment condition and product knot is prepared according to embodiment 2-1 identicals method
Structure appraising datum is shown in Table 2.
The embodiment 2-2 of table 2 to embodiment 2-8 (in addition to table conditional, other conditions are with embodiment 2-1)
Embodiment 3
Embodiment 3-1
2,6- di-tert-butyl-4-methy phenols (100g, 454mmol) add compound after melting completely at 80 degrees celsius
4-1(R2ForP2For benzyl, R6For hydrogen atom, R7For methyl) in aceticanhydride (390mL) solution of (65g, 94mmol),
And add glacial acetic acid (40mL).Obtained mixed liquor cools to 50 degrees Celsius after stirring at 80 degrees celsius 8 hours, and adds first
The aqueous solution (6N, 390mL) of alcohol (780mL) and hydrochloric acid.Obtained mixed liquor cools to after stirring 72 hours at 50 c
25 degrees Celsius.N-hexane extraction (300mL × 2) is added in obtained mixed liquor.First alcohol and water mixed phase is mutually evaporated organic solvent
The aqueous solution (3N) the regulation pH=7 of potassium hydroxide is added afterwards.It is required mesh that obtained white solid, which is collected by filtration, and dries
Mark compound 3-1 (R2ForP2For benzyl) 38g, yield 82%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.64(s,1H),7.55-7.26(m,8H),5.30(s,
2H),5.16-5.10(m,1H),4.38(s,2H),3.72-3.62(m,2H),3.56-3.46(m,1H),2.72-2.58(m,
1H),2.17-1.92(m,2H),1.90-1.75(m,1H),1.73-1.54(m,4H),1.00-0.70(m,2H)；
13C NMR(100MHz,CD3OD):δ168.2,159.4,155.2,153.9,153.1,150.1,139.6,
138.6,133.8,129.5,129.0,128.8,128.6,122.6,117.4,112.1,74.3,73.6,59.7,45.5,
34.6,20.8,19.1,7.9；
ESI-MS：499.2[M+H]+。
Embodiment 3-2~embodiment 3-8, specific experiment condition and product knot is prepared according to embodiment 3-1 identicals method
Structure appraising datum is shown in Table 3.
The embodiment 3-2 of table 3 to embodiment 3-8 (in addition to table conditional, other conditions are with embodiment 3-1)
Embodiment 4
Embodiment 4-1
Compound 5-1 (R2ForP2For benzyl, R6For hydrogen atom) dichloromethane of (45g, 72.3mmol)
Diethoxy methanol ethyl ester (12mL, 75mmol) is added in (450mL) solution.Obtained reaction solution adds pair under 0 degree Celsius
Toluenesulfonic acid (4.5g, 0.0261mol).It is molten that the reaction solution adds saturated sodium bicarbonate water after being stirred 12 hours under 25 degrees Celsius
Liquid (100mL).After organic phase that stratification obtains is dried over sodium sulfate, it is institute to be evaporated the white solid that organic solvent obtains
Target compound 4-1 (the R needed2ForP2For benzyl, R6For hydrogen atom, R7For methyl) 48g, yield 96%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.55-7.19(m,14H),5.55(s,2H),4.83(s,
2H),4.39-4.31(m,3H),3.72-3.52(m,2H),3.35-3.21(m,2H),2.88-2.72(m,1H),2.27-2.16
(m,2H),2.01(s,3H),1.75-1.44(m,5H),1.13-0.85(m,2H)；
13C NMR(100MHz,CD3OD):δ170.3,168.2,161.6,158.4,154.3,150.1,139.6,
137.4,135.3,133.8,128.7,128.6,128.6,128.3,128.3,128.2,128.2,122.6,117.8,
116.2,82.1,73.7,69.0,68.7,67.6,60.4,46.7,27.8,21.0,20.3,11.4,6.4
ESI-MS：693.3[M+H]+。
Embodiment 4-2~embodiment 4-8, specific experiment condition and product knot is prepared according to embodiment 4-1 identicals method
Structure appraising datum is shown in Table 4.
The embodiment 4-2 of table 4 to embodiment 4-8 (in addition to table conditional, other conditions are with embodiment 4-1)
Embodiment 5
Embodiment 5-1
Compound 6-1 (R2ForP2For benzyl, R6For hydrogen atom) (130g, 341mmol), N, N- dimethyl methyls
Acid amides 1300mL, add O-6- benzyl guanines (90.4g, 375mmol) and lithium hydroxide (8.18g, 341mmol).Obtain
After suspended liquid stirs 12 hours under 95 degrees Celsius, 200mL is concentrated to through being evaporated under reduced pressure.The concentrate is slowly dropped to
In 1000mL saturated solution of sodium bicarbonate.Be collected by filtration the solid of generation and with distillation water washing after dry.The solid is dissolved in second
Filtered after acetoacetic ester (200mL) by 200g silica gel, silica gel further elutes by 1000mL ethyl acetate.Merge all filter out
Ethyl acetate phase and be evaporated organic solvent.Obtained white solid is required target compound 5-1 (R2For
P2For benzyl, R6For hydrogen atom) 180g, yield 85%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.55-7.19(m,14H),5.55(s,2H),5.00(s,
1H),4.83(s,2H),4.74-4.64(m,1H),4.33(d,2H),4.26-4.17(m,1H),3.55-3.37(m,2H),
3.35-3.21(m,2H),2.88-2.72(m,1H),2.27-2.16(m,2H),1.75-1.44(m,5H),1.13-0.85(m,
2H)；
13C NMR(100MHz,CD3OD):δ168.2,161.6,158.4,154.3,150.1,139.6,137.4,
135.3,133.8,128.7,128.6,128.6,128.3,128.3,128.2,128.2,122.6,116.2,82.2,73.7,
69.0,68.4,65.3,62.9,48.7,20.3,20.2,11.4,6.1
ESI-MS：623.3[M+H]+。
Embodiment 5-2~embodiment 5-8, specific experiment condition and product knot is prepared according to embodiment 5-1 identicals method
Structure appraising datum is shown in Table 5.
The embodiment 5-2 of table 5 to embodiment 5-8 (in addition to table conditional, other conditions are with embodiment 5-1)
Embodiment 6
Embodiment 6-1
Tetraisopropoxy titanium (64mL, 223mmol) is added in 2100mL dichloromethane and is cooled to subzero 30 degrees Celsius.
Compound 8-1 (R are added inside the solution2ForP2For benzyl) (409g, 1.12mol) and (2S, 3S)-tartaric acid
Diisopropyl ester (62g, 265mmol).Obtained mixed liquor is slowly added to anhydrous peroxide after being stirred 1 hour under subzero 30 degrees Celsius
The tert-butyl alcohol (2.5M toluene solution, 500mL).Keep reaction temperature at subzero 20~30 degrees Celsius after 3 hours, delay in reaction solution
It is slow to add sodium thiosulfate (2M, 350mL).Rear reaction solution is added dropwise slowly to be warming up to 25 degrees Celsius and pass through diatomite mistake
Filter.Obtained filtrate aqueous phase isolated after stratification merges institute after dichloromethane extracts (1000mL × 2)
Some dichloromethane.The organic phase of merging is washed step by step further across saturated ammonium chloride (500mL) and saturated aqueous common salt (200mL)
Dried after washing through sodium peroxydisulfate.It is required target compound intermediate 6-1 (R to be evaporated the white powder that organic solvent obtains2
ForP2For benzyl) 380g, yield 89%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.55-7.26(m,8H),4.43(s,2H),3.72(s,
1H),3.47(s,1H),3.33-3.27(m,2H),3.05(d,1H),2.66(t,1H),2.38-2.26(m,1H),1.91-
1.85(m,2H),1.73-1.54(m,4H),1.00-0.70(m,2H)；
13C NMR(100MHz,CD3OD):δ168.2,150.1,138.6,133.8,129.5,129.0,128.8,
128.6,122.6,81.7,73.8,73.3,61.8,61.2,43.1,21.8,20.8,7.2,-1.3；
ESI-MS：382.2[M+H]+。
Embodiment 6-2~embodiment 6-8, specific experiment condition and product knot is prepared according to embodiment 6-1 identicals method
Structure appraising datum is shown in Table 6.
The embodiment 6-2 of table 6 to embodiment 6-8 (in addition to table conditional, other conditions are with embodiment 6-1)
Embodiment 7
Embodiment 7-1
Compound 9-1 (R2ForP1ForP2For benzyl) 123g (0.28mol) is dissolved in 600mL ethanol
In, and add p-methyl benzenesulfonic acid 6g (0.0348mol).Obtained reaction solution cools to 0 after being stirred 12 hours under 25 degrees Celsius
Degree Celsius, and add 100mL saturated sodium bicarbonate aqueous solutions.Obtained mixed liquor uses t-butyl methyl ether (200mL after being evaporated methanol
× 3) extract.Merge organic phase and dried through sodium peroxydisulfate.It is required mesh to be evaporated the white powder obtained after organic solvent
Mark compound intermediate 8-1 (R2ForP2For benzyl) 90g, yield 88%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.55-7.26(m,8H),5.57(s,1H),4.43(s,
2H),4.18-4.00(m,2H),3.33-3.27(m,2H),3.16(t,1H),2.98-2.86(m,1H),2.53-2.39(m,
1H),2.33-2.20(m,1H),1.73-1.54(m,4H),1.00-0.70(m,2H)；
13C NMR(100MHz,CD3OD):δ168.2,150.1,139.6,138.6,133.8129.5,129.0,128.8,
128.6,126.1,122.6,78.3,73.9,61.5,47.1,30.2,28.6,10.5,7.5；
ESI-MS：366.2[M+H]+。
Embodiment 7-2~embodiment 7-8, specific experiment condition and product knot is prepared according to embodiment 7-1 identicals method
Structure appraising datum is shown in Table 7.
The embodiment 7-2 of table 7 to embodiment 7-8 (in addition to table conditional, other conditions are with embodiment 7-1)
Embodiment 8
Embodiment 8-1
Compound 10-1 (R2ForP1For) 134g (0.39mol) is dissolved in 2000mLDMF (N, N- bis-
NMF) in, addition sodium hydrogen (sodium hydride being scattered in mineral oil of weight/mass percentage composition 60%, 18.7g,
0.47mol), cool to 0 degree Celsius and benzyl bromine 55.2mL (0.2241mol) is added dropwise.5 degrees Celsius are kept below after dripping off to react
Night.It is slowly added to 2000mL and reaction is quenched.Obtained mixed liquor through 2000mL × 2 ethyl acetate extraction, the ethyl acetate of merging
It is mutually dried over sodium sulfate after washing (1000mL × 2) and saturated aqueous common salt (1000mL) washing, it is evaporated what organic solvent obtained
Dark red oil is required target compound intermediate 9-1 (R2ForP1ForP2For benzyl)
157g, yield 92%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.55-7.26(m,8H),5.57(s,1H),4.43(s,
2H),4.02-3.84(m,2H),3.33-3.27(m,2H),3.20-3.15(m,4H),2.98-2.86(m,1H),2.53-2.39
(m,1H),2.33-2.20(m,1H),1.73-1.54(m,4H),1.31(s,6H),1.00-0.70(m,2H)；
13C NMR(100MHz,CD3OD):δ168.2,150.1,142.2,138.6,133.8129.5,129.0,128.8,
128.6,122.6,119.5,100.2,78.3,73.9,66.1,48.5,42.8,28.6,24.5,20.8,10.5,7.5；
ESI-MS：438.2[M+H]+。
Embodiment 8-2~embodiment 8-8, specific experiment condition and product knot is prepared according to embodiment 8-1 identicals method
Structure appraising datum is shown in Table 8.
The embodiment 8-2 of table 8 to embodiment 8-8 (in addition to table conditional, other conditions are with embodiment 8-1)
Embodiment 9
Embodiment 9-1
Compound 11-1 (R2ForR10For methyl, P1For) 155g (0.41mol) is dissolved in 2800mL toluene
In, 5 degrees Celsius of lower diisobutyl aluminium hydrides (2M toluene solution, 1L) are maintained, are reacted 2 hours under 5 degree, sodium acid carbonate saturation
It is slowly dropped under solution 1500mL stirrings, obtained mixed liquor split-phase after diatomite filters.Aqueous phase extracts (700mL with toluene
× 3) obtained all toluene phases, are merged, it is required target chemical combination to be evaporated the pale yellow oily liquid that organic solvent obtains
Thing intermediate 10-1 (R2ForR10For methyl, P1For) 122g, yield 86%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.55-7.26(m,3H),5.78(s,1H),4.15-4.05
(m,1H),3.84-3.75(m,1H),3.68-3.55(m,1H),3.42-3.31(m,2H),3.25-3.09(m,4H),2.85-
2.71(m,1H),2.59-2.42(m,1H),2.32-2.17(m,1H),1.83-1.54(m,4H),1.31(s,6H),1.15-
0.81(m,2H)；
13C NMR(100MHz,CD3OD):δ168.2,150.1,142.2,133.8,128.6,122.6,119.5,
100.2,66.1,64.9,48.5,45.0,28.7,24.5,20.8,11.1,7.3；
ESI-MS：348.2[M+H]+。
Embodiment 9-2~embodiment 9-8, specific experiment condition and product knot is prepared according to embodiment 9-1 identicals method
Structure appraising datum is shown in Table 9.
The embodiment 9-2 of table 9 to embodiment 9-8 (in addition to table conditional, other conditions are with embodiment 9-1)
Embodiment 10
Embodiment 10-1, wherein R2ForR10For methyl
Compound 12-1 (R2ForR10For methyl) 109g (0.358mol) is dissolved in 1200mL toluene, adds
4.4g (0.0256mol) p-methyl benzenesulfonic acid, 2- methoxyl group propylene 257g (3.564mol) are added dropwise after being cooled to 0 degree Celsius.Temperature control
Below 5 degrees Celsius, stirring reaction 3 hours.Saturated solution of sodium bicarbonate 1000mL is added, aqueous phase is through toluene (400mL after split-phase
× 2) extract.The toluene of merging mutually washs through saturated nacl aqueous solution, and it is required mesh to be evaporated toluene and obtain weak yellow liquid
Mark compound intermediate 11-1 (R2ForR10For methyl, P1For) 128g, yield 95%.
1H NMR(400MHz,CDCl3):δ8.68(d,1H),7.55-7.26(m,3H),5.78(s,1H),3.92(s,
2H),3.61(s,3H),3.51-3.42(m,1H),3.15(s,3H),2.69-2.55(m,1H),2.39-2.24(m,1H),
2.13-2.00(m,1H),1.83-1.54(m,4H),1.31(s,6H),1.15-0.81(m,2H)；
13C NMR(100MHz,CD3OD):δ170.1,168.2,150.1,133.8,128.6,126.1,122.6,
120.1,100.2,64.3,52.4,48.5,47.1,28.1,24.5,20.8,10.2,6.9；
ESI-MS：376.2[M+H]+。
Embodiment 10-2~embodiment 10-8, specific experiment condition and product is prepared according to embodiment 10-1 identicals method
Structural Identification data are shown in Table 10.
The embodiment 10-2 of table 10 to embodiment 10-8 (in addition to table conditional, other conditions are with embodiment 10-1)
Embodiment 11
Raw material in the embodiment series is the equal amount of mixture of following two structures：
Embodiment 11-1
R2=R10For methyl.
2600 milliliters of isopropanols are dissolved in compound 13-1 (520g, 1.80mol), and add (1R, 2R) -2- amino -1-
(4- nitrobenzophenones) propane -1,3- glycol (cas:716-61-0) (212g, 1.0mol).Obtained mixed solution is at 70 degrees Celsius
Lower stirring is slow cooling to 25 degrees Celsius after 2 hours.Obtained solid is collected by filtration and is dissolved in 1200 ml methanols simultaneously after drying
It is slowly added to the concentrated sulfuric acid (98%, 120mL).Obtained mixed liquor is stirred at room temperature 12 and was as a child slowly added to sodium hydroxide water
Solution (3M, 3000mL).Obtained mixed liquor passes through n-hexane extraction (2000mL × 2).Organic phase is obtained by extraction through sodium sulphate
Organic solvent is evaporated after drying, obtained pale yellow oily liquid is required target compound 12-1 (223g, yield
82%).
1H-NMR(400MHz,CD3OD)δ8.68(d,1H),7.60-7.35(m,3H),5.59(s,1H),4.20(s,2H),
3.67(s,3H),3.18(d,1H),2.64(m,1H),2.49-2.47(m,1H),2.27-2.23(m,1H),1.85-1.45(m,
4H),1.05-1.25(m,2H)；
13C-NMR(400MHz,CD3OD)δ174.6,167.9,149.4,133.8,131.0,128.2,122.8,123.5,
66.3,52.3,44.4,29.0,21.6,17.3,16.5；
ESI-MS：304.1[M+H]+。
Embodiment 11-2~embodiment 11-18, specific experiment condition and production is prepared according to embodiment 11-1 identicals method
Thing Structural Identification data are shown in Table 11.
The embodiment 11-2 to 11-18 of table 11 (in addition to table conditional, other conditions are with embodiment 11-1)
Embodiment 12
In the embodiment series, raw material is the equal amount of mixture of following two structures：
Product is the equal amount of mixture of following two structures：
Embodiment 12-1
R2=
2600 milliliters of ethanol are dissolved in the compound 14-1 (505g, 1.76mol) as shown in above formula and add boron hydrogen in batches
Change sodium (66.9g, 1.76mol).Obtained mixture is stirred at room temperature 3 and as a child cooled to 0 degree Celsius, and adds 500 millis
Rise saturated ammonium chloride solution.Mixed liquor adds ethyl acetate extraction (2000mL × 3) after being evaporated organic solvent.The organic phase of merging
Dried again through sodium peroxydisulfate after saturated common salt water washing (1000mL), it is institute to be evaporated the faint yellow solid that organic phase obtains
The target compound 13-1 (482g, yield 95%) needed.
1H-NMR(400MHz,CD3OD)δ8.68(d,1H),7.60-7.35(m,3H),5.59(s,1H),4.20(s,2H),
3.28(d,1H),2.49-2.47(m,1H),2.34(s,1H),2.27-2.23(m,2H),1.85-1.45(m,4H),1.05-
1.25(m,2H)；
13C-NMR(400MHz,CD3OD)δ182.7,167.9,149.4,133.8,131.0,128.2,123.5,122.8,
66.3,46.9,29.0,21.6,17.0,16.5；
ESI-MS：290.1[M+H]+。
Embodiment 12-2~embodiment 12-18, specific experiment condition and production is prepared according to embodiment 12-1 identicals method
Thing Structural Identification data are shown in Table 12.
The embodiment 12-2 to 12-18 of table 12 (in addition to table conditional, other conditions are with embodiment 12-1)
Embodiment 13
In the embodiment series, raw material is the equal amount of mixture of following two structures：
Product is the equal amount of mixture of following two structures：
Embodiment 13-1
R2=
2600 milliliters of ethanol are dissolved at 0 degree Celsius in the starting material compound 15-1 (723g, 2.52mol) as shown in above formula
Lower addition sodium carbonate (534g, 5.04mol).Obtained mixture filters after being stirred at room temperature 3 hours.Obtained filtrate adds
Watery hydrochloric acid (3M, 850mL), mixed liquor add ethyl acetate mashing (2000mL × 3) after being evaporated organic solvent.The organic phase of merging
Dried again through sodium peroxydisulfate after saturated common salt water washing (1000mL), it is institute to be evaporated the faint yellow solid that organic phase obtains
The target compound 14-1 (706g, yield 98%) needed.
1H-NMR(400MHz,CD3OD)δ9.68(s.1H),8.68(d,1H),7.60-7.35(m,3H),6.55(s,1H),
3.28(d,1H),2.49-2.47(m,1H),2.27-2.23(m,2H),1.85-1.45(m,4H),1.05-1.25(m,2H)；
13C-NMR(400MHz,CD3OD)δ192.9,182.7,167.9,156.7,149.4,133.8,129.2,128.2,
122.8,43.2,28.5,21.6,16.5,16.4；
ESI-MS：288.1[M+H]+。
Embodiment 13-2~embodiment 13-18, specific experiment condition and production is prepared according to embodiment 13-1 identicals method
Thing Structural Identification data are shown in Table 13.
The embodiment 13-2 to 13-18 of table 13 (in addition to table conditional, other conditions are with embodiment 13-1)
Embodiment 14
Product is the equal amount of mixture of following two compounds in the series embodiment.
Embodiment 14-1
R2=
In the tert-butyl alcohol (982g) and water (1960g) of the starting material compound 16-1 (491g, 1.52mol) as shown in above formula
Triethylamine 706g is instilled in mixed solution under 25 degrees Celsius.Drip off rear reaction solution be warming up to 85 degree allow its flow back, heat about 60 points
0 is down to after clock.Organic solvent mixed liquor is evaporated to be kept for 0~5 degree Celsius and be slowly added to concentrated hydrochloric acid (37%) regulation pH~6.It is mixed
Liquid is closed by ethyl acetate extraction (2600mL X 3).The organic phase of merging is dried by saturated common salt water washing, with sodium sulphate
And it is required target compound 15-1 (327g, yield 75%) to be evaporated the buff oily liquids that organic solvent obtains.
1H-NMR(400MHz,CD3OD)δ9.72(s.1H),8.68(d,1H),7.60-7.35(m,3H),6.00(s,1H),
5.59(s,1H),3.46(d,1H),3.08(m,1H),2.60(d,1H),1.85-1.45(m,4H),1.05-1.25(m,2H)；
13C-NMR(400MHz,CD3OD)δ201.5,183.1,167.9,149.4,134.2,133.8,129.1,128.2,
122.8,57.5,34.3,21.7,19.1,16.5；
ESI-MS：288.1[M+H]+。
Embodiment 14-2~embodiment 14-18, specific experiment condition and production is prepared according to embodiment 14-1 identicals method
Thing Structural Identification data are shown in Table 14.
The embodiment 14-2 to 14-18 of table 14 (in addition to table conditional, other conditions are with embodiment 14-1)
Embodiment 15
Embodiment 15-1
R2=
It is dissolved in 1800ml n-hexanes, cools in the starting material compound 17-1 254g (1.19mol) as shown in above formula
To 0 degree Celsius, add dichloroacetyl chloride (390.5g, 2.65mol), maintain 5~10 degrees Celsius under be added dropwise triethylamine (535g,
5.30mol), the mixed liquor after dripping off stirs 14 hours under 25 degrees Celsius.Water (1500ml) is added in reaction mixture.Stand
Isolated aqueous phase is extracted with n-hexane (500ml X 3).The organic phase of merging is with saturated common salt water washing and through sodium sulphate
It is required target compound 16-1 (378g, yield 98%) that organic solvent is evaporated after drying and obtains buff oily liquids.
1H-NMR(400MHz,CD3OD)δ8.68(d,1H),7.60-7.35(m,3H),6.00(s,1H),5.59(s,1H),
4.08(d,1H),3.68-3.57(m,1H),2.74(s,1H),1.85-1.45(m,4H),1.05-1.25(m,2H)；
13C-NMR(400MHz,CD3OD)δ183.1,167.9,149.4,138.0,133.8,129.2,128.2,122.8,
88.3,70.1,34.0,21.7,19.1,16.5；
ESI-MS：324.1[M+H]+。
Embodiment 15-2~embodiment 15-18, specific experiment condition and production is prepared according to embodiment 15-1 identicals method
Thing Structural Identification data are shown in Table 15.
The embodiment 15-2 to 15-18 of table 15 (in addition to table conditional, other conditions are with embodiment 15-1)
Embodiment 16
Example 16-1
R2=
Sodium cyclopentadiene (165g, 1.87mol) is dissolved in 1650ml tetrahydrofurans, is cooled under nitrogen protection subzero
50 degrees Celsius, it is added dropwise small in subzero 45 degrees Celsius reactions about 3 in initiation material (271g, the 1.48mol) as shown in above formula, temperature control
When.1000ml water quenchings are added after the completion of reaction to go out reaction.Evaporate remaining mixed liquor n-hexane after tetrahydrofuran (1500ml ×
3) extract.The organic phase of merging uses 0.5M hydrochloric acid (0.5M, 500mL) and saturated common salt water washing, organic phase sodium sulphate successively
Dry, filtering, it is required target compound 17-1 (299g, yield to be spin-dried for organic solvent and obtain oily bronzing liquid
95%).
1H-NMR(400MHz,CD3OD)δ8.68(d,1H),7.60-7.35(m,3H),6.62-6.52(m,4H),3.61
(s,1H),1.85-1.45(m,4H),1.05-1.25(m,2H)；
13C-NMR(400MHz,CD3OD)δ167.9,149.4,133.8,133.0,132.0,128.2,122.8,21.7,
19.1,16.5；
ESI-MS：214.1[M+H]+
Embodiment 16-2~embodiment 16-18, specific experiment condition and production is prepared according to embodiment 16-1 identicals method
Thing Structural Identification data are shown in Table 16.
The embodiment 16-2 to 16-18 of table 16 (in addition to table conditional, other conditions are with example 16-1)
Embodiment 17R2X is synthesized
R2- Cl synthesis has detailed description in documents below and document cited in them：
Russian Journal of General Chemistry 2006,76,1261
Chemische Berichte 1915,48,1238
Journal of Organometallic Chemistry 1975,86,197
Journal of the American Chemical Society 1946,68,485
Journal of the American Chemical Society 2010,132,8270
Its general principle can be represented by formula illustrated below：
Wherein R-21 is corresponding aromatic ring yl lithium compound.Wherein W1、W2Respectively independent-MgBr or-MgCl.
Embodiment 17-1
R2=
Synthetic method one
Step 1：Subzero 40 are kept to arrive in 2- chloropyridines (1.15Kg, 10.2mol) tetrahydrofuran (4600mL) solution
Subzero 50 degrees Celsius are added dropwise butyl lithium (2.5M hexane solutions, 4200mL).Reaction solution after being added dropwise slowly is warming up to 25
Degree Celsius and at such a temperature stir 2 hours.Obtained brownish red reaction solution addition is pre-chilled to subzero 50 degrees Celsius of four chlorinations
In tetrahydrofuran (6800mL) solution of silicon (1.7Kg, 10mol).Control rate of addition keeps system subzero 40 to subzero 50 to take the photograph
Family name's degree.The mixed liquor obtained after being added dropwise be slowly warming up to 25 degrees Celsius and at such a temperature stir 12 hours after in blanket of nitrogen
Enclose the solid for pushing and filtering out generation.Filtrate be pre-chilled to subzero 50 degrees Celsius it is standby.
Step 2：1,3- dibromopropanes (2.2Kg, 10.9mol) are slowly added into suspension 264g magnesium chips (11mol) in stirring
Tetrahydrofuran (17.6L) in.Rate of addition is controlled to keep reaction temperature at subzero 40~50 degrees Celsius.It is incubated after being added dropwise
Subzero 50 degrees Celsius are pre-chilled in the mixed liquor that subzero 40~50 degrees Celsius obtained after 2 hours, and adds and is prepared by 2- chloropyridines
Reaction mixture.Rate of addition is controlled to keep reaction temperature at subzero 40~50 degrees Celsius.Slowly it is warming up to after being added dropwise
60 degrees Celsius and stir 3 hours.Concentration of reaction solution is evaporated under reduced pressure to addition n-hexane (20L) after 20 liters.It is filtered to remove generation
Solid.It is required target compound intermediate (1.16Kg, 62%) that distillation under pressure, which obtains colourless liquid, after filtrate concentration.
Embodiment 17-1
Synthetic method two
Step 1：1,3- dibromopropanes (2.2Kg, 10.9mol) are slowly added into suspension 264g magnesium chips (11mol) in stirring
Tetrahydrofuran (17.6L) in.Rate of addition is controlled to keep reaction temperature at subzero 40~50 degrees Celsius.It is incubated after being added dropwise
Subzero 50 degrees Celsius are pre-chilled in the mixed liquor that subzero 40~50 degrees Celsius obtained after 2 hours.Tetrachloro is added dropwise in the reaction solution
SiClx (1.7Kg, 10mol).Rate of addition is controlled to keep reaction temperature at subzero 40~50 degrees Celsius.Slowly risen after being added dropwise
Temperature cools to 60 degrees Celsius and after stirring 3 hours is pre-chilled to subzero 50 degrees Celsius.
Step 2：Subzero 40 are kept to arrive in 2- chloropyridines (1.15Kg, 10.2mol) tetrahydrofuran (4600mL) solution
Subzero 50 degrees Celsius are added dropwise butyl lithium (2.5M hexane solutions, 4200mL).Reaction solution after being added dropwise slowly is warming up to 25
Degree Celsius and at such a temperature stir 2 hours.Obtained brownish red reaction solution is pre-chilled to subzero 50 degrees Celsius, and is slowly added into
Step 1 is prepared in reaction solution.Rate of addition is controlled to keep reaction temperature at subzero 40~50 degrees Celsius.Obtained after being added dropwise
Mixed liquor be slowly warming up to 25 degrees Celsius and stir 12 hours at such a temperature after, pressure distillation and concentration reaction solution to after 20 liters plus
Enter n-hexane (20L).It is filtered to remove the solid of generation.It is required target that distillation under pressure, which obtains colourless liquid, after filtrate concentration
Compound intermediate (1.53Kg, 82%).
R2=
1H-NMR(400MHz,CDCl3)δ8.68(d,1H),7.60-7.35(m,3H),1.85-1.45(m,4H),1.05-
1.25(m,2H)；
13C-NMR(400MHz,CDCl3)167.9,149.4,133.8,128.2,122.8,17.6,12.5
Embodiment 17-2~embodiment 17-18, specific experiment condition and production is prepared according to embodiment 17-1 identicals method
Thing Structural Identification data are shown in Table 17.
The embodiment 17-2 to 17-18 of table 17 (in addition to table conditional, method one or method of the other conditions with example 17-1
Two)
Claims (12)
- A kind of 1. preparation method of entecavir midbodies compound 10, it is characterised in that：Comprise the following steps：In organic solvent In, in the presence of reducing agent, ester type compound 11 is subjected to reduction reaction, obtains compound 10；Wherein, R2ForR21For unsubstituted pyridine radicals or unsubstituted C6Aryl；P1ForWherein R8For hydrogen；R9For C1~C6Straight or branched alkyl；R10For C1~C4Straight chained alkyl；Described reducing agent is diisobutyl aluminium hydride, lithium aluminium hydride reduction, red aluminum or sodium borohydride, when reducing agent is sodium borohydride When, the reaction is carried out in the presence of lithium chloride and/or lithium bromide.
- 2. the preparation method of entecavir midbodies compound 10 as claimed in claim 1, it is characterised in that：Described R21For Following any substituent：
- 3. the preparation method of entecavir midbodies compound 10 as claimed in claim 1, it is characterised in that：As described P1Described in R9For C1~C6Straight or branched alkyl when, described C1~C6Straight or branched alkyl For methyl, ethyl or propyl group；As described R10For C1~C4Straight chained alkyl when, described C1~C4Straight chained alkyl be methyl.
- 4. the preparation method of the entecavir midbodies compound 10 as described in any one of claims 1 to 3, it is characterised in that： Described organic solvent be dichloromethane, toluene, 1,2- dichloroethanes, tetrahydrofuran and one kind in 2- methyltetrahydrofurans or It is a variety of；The mole of described reducing agent is 1~5 times of the mole of described compound 11；The temperature of described reduction reaction Spend for -78 DEG C~100 DEG C.
- 5. the preparation method of entecavir midbodies compound 10 as claimed in claim 4, it is characterised in that：Described reduction The molar ratio of agent and described compound 11 is 1.1~3；When reducing agent is sodium borohydride, described reduction reaction is in chlorine Carried out in the presence of change lithium and/or lithium bromide, described lithium chloride and/or lithium bromide and the molar ratio of described compound 11 For 0.1~2；The temperature of described reduction reaction is -20 DEG C~40 DEG C.
- 6. the preparation method of the entecavir midbodies compound 10 as described in any one of Claims 1 to 5, it is characterised in that： Described compound 11 is prepared by following methods, the method for preparing described compound 11 comprises the following steps：Organic molten In agent, under the conditions of acid is existing, compound 12 and hydroxy protecting agent are carried out to the reaction of upper hydroxyl protecting group, obtain compound 11；According still further to the preparation method prepare compound 10 described in any one of Claims 1 to 5；Wherein, R2Definition it is as claimed in claim 1 or 2, R10Definition as described in claim 1 or 3, P1Definition such as right It is required that described in 1 or 3.
- 7. the preparation method of entecavir midbodies compound 10 as claimed in claim 6, it is characterised in that：Described in preparation Compound 11 method in, described hydroxy protecting agent isWherein R8For hydrogen；R9For C1~C6Straight chain or branch Alkyl group.
- 8. the preparation method of entecavir midbodies compound 10 as claimed in claim 7, it is characterised in that：Described in preparation Compound 11 method in,As the R described in described hydroxy protecting agent9For C1~C6Straight or branched alkyl when, described C1~C6Straight chain Or branched alkyl is methyl, ethyl or propyl group.
- 9. the preparation method of entecavir midbodies compound 10 as claimed in claim 6, it is characterised in that：Preparing chemical combination In the method for thing 11, described organic solvent is one kind or more in aromatic hydrocarbon solvent, halogenated hydrocarbon solvent and alkane solvents Kind；Described acid is organic acid；The described sour and molar ratio of described compound 12 is 0.01~10；Described hydroxyl is protected The molar ratio for protecting reagent and described compound 12 is 1~100；The temperature of the reaction of described upper hydroxyl protecting group is -20 DEG C~100 DEG C.
- 10. the preparation method of entecavir midbodies compound 10 as claimed in claim 9, it is characterised in that：In preparationization In the method for compound 11, described aromatic hydrocarbon solvent is toluene；Described halogenated hydrocarbon solvent is dichloromethane and/or two chloroethenes Alkane；Described alkane solvents are the one or more in n-hexane, pentane, petroleum ether and normal heptane；Described organic acid For p-methyl benzenesulfonic acid；The described sour and molar ratio of described compound 12 is 0.01~1；Described hydroxy protecting agent with The molar ratio of described compound 12 is 1~20；The temperature of the reaction of described upper hydroxyl protecting group is -20 DEG C~40 DEG C.
- 11. a kind of preparation method of entecavir midbodies compound 11, it is characterised in that comprise the following steps：In organic solvent In, under the conditions of acid is existing, compound 12 and hydroxy protecting agent are carried out to the reaction of upper hydroxyl protecting group, obtain compound 11 ；Wherein, R2Definition it is as claimed in claim 1 or 2, R10Definition as described in claim 1 or 3, P1Definition such as right It is required that described in 1 or 3；Reaction condition is as described in any one of claim 6~10.
- 12. a kind of compound as shown in Equation 11,Wherein, R2Definition as described in any one of claim 1 or 2, R10Definition as described in claim 1 or 3, P1Definition As described in claim 1 or 3.
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| CN102596956A (en) * | 2009-10-12 | 2012-07-18 | 韩美控股株式会社 | Novel method for preparing entecavir and intermediate used therein |
| CN102952156A (en) * | 2011-08-29 | 2013-03-06 | 南京工业大学 | Anti-hepatitis B drug entecavir intermediate and synthesis thereof |
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| CN1747959A (en) * | 2002-12-11 | 2006-03-15 | 布里斯托尔-迈尔斯斯奎布公司 | Preparation of antiviral drug [1S-(1α, 3α, 4β)]-2-amino-1, 9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6 H-purin-6-one method |
| CN102596956A (en) * | 2009-10-12 | 2012-07-18 | 韩美控股株式会社 | Novel method for preparing entecavir and intermediate used therein |
| CN102952156A (en) * | 2011-08-29 | 2013-03-06 | 南京工业大学 | Anti-hepatitis B drug entecavir intermediate and synthesis thereof |
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Address after: 314213 north of zhaquan Road, dushangang Town, Pinghu City, Jiaxing City, Zhejiang Province (room 248, building 3, pingshangang district development and construction management committee, Pinghu City) Patentee after: Zhejiang Xingyue Pharmaceutical Technology Co.,Ltd. Address before: 314213 north of zhaquan Road, dushangang Town, Pinghu City, Jiaxing City, Zhejiang Province (room 248, building 3, pingshangang district development and construction management committee, Pinghu City) Patentee before: HSING PHARMACEUTICALS Co.,Ltd. |