CN108203434A - A kind of method of asymmetric synthesis for preparing Solifenacin - Google Patents

A kind of method of asymmetric synthesis for preparing Solifenacin Download PDF

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CN108203434A
CN108203434A CN201611186606.4A CN201611186606A CN108203434A CN 108203434 A CN108203434 A CN 108203434A CN 201611186606 A CN201611186606 A CN 201611186606A CN 108203434 A CN108203434 A CN 108203434A
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CN108203434B (en
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徐明华
蒋涛
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The present invention relates to a kind of method of asymmetric synthesis for preparing Solifenacin.Specifically, the invention discloses a kind of preparation method of Solifenacin, the method under the catalysis of rhodium and chiral sulphur alkene ligand, obtains the key intermediate of high enantioselectivity addition using ortho position substitution aldehyde as raw material；The intermediate obtains Solifenacin through further functional group conversions and cyclization.The method is easy to operate, reaction condition is relatively mild, efficiently highly selective.

Description

A kind of method of asymmetric synthesis for preparing Solifenacin
Technical field
The invention belongs to the preparing technical fields of bulk pharmaceutical chemicals, and in particular, to a kind of the asymmetric of Solifenacin that prepare closes Into method.
Background technology
Overactive bladder (Overactive bladder, OAB) be the common clinical manifestation of urinary dysfunction it One, 2001 Nian9Yue worlds urine control association (ICS) is defined as " the symptom syndrome of low urinary tract function obstacle ", its main feature is that Urgent urination is often accompanied by frequent micturition and enuresis nocturna with or without urge incontinence.OAB incidence is higher at present, according to statistics, 40 years old or more Europe In population, about 1/6 is perplexed by OAB, and U.S.'s OAB incidence has also reached 17%, and what China some areas were carried out Epidemiological survey shows that urinary incontinence incidence is differed for 18%~53%, and the incidence of elderly woman is up to 70%.It is now each There is treatment of a large amount of expenses for OAB in state every year, and in the U.S. in 2000, the expenditure only on this was just 120.2 Hundred million dollars, the 2% of national Health expenditures are accounted for, and many OAB patients generate because of urine urgency-frequency and the urinary incontinence repeatedly The mood of shy embarrassment seriously affects the normal daily life of patient and social activity, therefore, being ground at present about treatment OAB Study carefully as one of hot spot both domestic and external.
Succinic acid Solifenacin (Solifenacin succinate, trade name：Wei Xikang), it is a kind of highly selective courage Alkali energy receptor (M3) retarding agent is developed by Japanese Astellas companies, is listed first in Europe within 2004,2005 by the U.S. FDA approval listings, 2006-2007 log in Japan, and 2009 in the Chinese approval of import.2013-2014 U.S. recipe quantity 3, 873,046, ranking the 38th, 9.12 hundred million dollars of 2013 annual sales amount of the U.S., TOP100 rankings the 49th, rank treatment bladder it is more Dynamic disease first.The medicine for M3 receptors in human bladder, to overactive bladder patient with the urinary incontinence and/or urine Frequently, symptoms of urgency has higher safety and efficacy, and structural formula is：
Solifenacin is the important intermediate for preparing succinic acid Solifenacin, and preparation method mainly has following two kinds：
1) by obtaining optically pure (S) -1 to the fractionation of racemic modification 1-Phenyl-1,2,3,4-tetrahydroisoquinoline, this is The process synthetic method used at present, but cause the significant wastage of other half (R)-configurational isomer；
2) it is synthesized using the asymmetric hydrogenation of transition metal-catalyzed imines 2, document Chang, M.；Li, Wei.； Zhang, X.Angew.Chem.Int.Ed.2011,50,10679 report the not right of Ir/ (S, S)-(f)-binaphane catalysis Claim hydrogenation, but enantioselectivity control is still preferable not to the utmost, ee values are 95%, can't reach the optical purity of chiral drug It is required that in addition, the complex and stability of chiral ligand synthesis used is poor.
Analyze the preparation method of existing Solifenacin it is found that disconnecting route there is one of them (R)-enantiomters Waste is efficiency highest, most practical method using asymmetric catalysis, but the asymmetric catalytic hydrogenation method reported at present It is also to be hoisted in the stereoselectivity control aspect of key intermediate (S) -1.Therefore, the catalysis of development more efficiently, practical Asymmetric method is of great significance.
Invention content
In view of the deficiencies of the prior art, it is an object of the present invention to provide a kind of easy to operate, of low cost, reaction conditions The novel preparation method of mild controllable bladder hyperactivity drug succinic acid Solifenacin precursor Solifenacin.
First aspect present invention provides a kind of preparation method of Solifenacin, including step：
A-1:In atent solvent, formula a compounds and N, N- dimethyl sulfonamide are reacted, so as to form Formulas I Close object；
A:Under transition metal Rh (I) and chiral sulphur alkene ligand L catalysis, in alkaline aqueous solution and the mixture of organic solvent In system, compound of formula I is reacted with organoboron reagent Ph- [B], so as to shape compound of formula II；
The chiral sulphur alkene ligand L has the following structure formula：
Wherein, R3For phenyl, the phenyl of substitution, naphthalene, naphthalene, isopropyl, tertiary butyl or the adamantyl replaced；N=0 Or 1, wherein, the substitution refers to be replaced by substituent group selected from the group below：C1-4 alkyl, halogen, nitro, methoxyl group or N, N- Dimethyl；
B-1:In amine solvent, Formula II compound take off to the reaction of sulfonyl blocking groups, so as to form formula III chemical combination Object；
B-2:In atent solvent, by formula III compound and chloro-formate (R2OC (=O) Cl) reaction, so as to form formula IV compounds；
B-3:In atent solvent, formula IV compound take off to the reaction of hydroxyl protection base, so as to form Formula V chemical combination Object；
C:In atent solvent, in the presence of Mitsunobu reaction reagents, Formula V compound is subjected to ring closure reaction, so as to Form Formula IV compound；
D:In atent solvent, under alkaline condition, Formula IV compound and (R)-(-) -3- quinuclidinols are subjected to transesterification Reaction, so as to form Solifenacin；
In the above formulas, R1For trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon Base or triisopropylsilyl；R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, the substitution refers to by under The substituent group of group is replaced：C1-4 alkyl, halogen, phenyl.
In another preferred example, R2For methyl, ethyl, n-propyl, isopropyl, normal-butyl or benzyl.
In another preferred example, in step A, the molar ratio of the compound of formula I and organoboron reagent is 1:0.33~ 3。
In another preferred example, in step A, the molar ratio of the compound of formula I and organoboron reagent is 1:0.5~2.
In another preferred example, in step A, the organoboron reagent is phenyl boric acid, benzene boric anhydride, phenyl trifluoromethanesulfonate boric acid Potassium, phenyl boric acid pinacol boron ester or tetraphenylboron sodium；And/or the alkaline aqueous solution is potassium hydroxide aqueous solution, potash water Solution or aqueous potassium phosphate solution.
In another preferred example, in step A, the molar ratio of the compound of formula I and organoboron reagent is 1:0.5~2.
In another preferred example, in step A, the transition metal Rh (I) is [Rh (coe)2Cl]2Or [Rh (C2H4)2Cl]2。
In another preferred example, in step A, the organic solvent is selected from the group：Toluene, ortho-xylene, meta-xylene, Paraxylene, 1,2- dichloroethanes, or combination.
In another preferred example, in step A, the temperature of the reaction is 40~100 DEG C.
In another preferred example, in step A, the temperature of the reaction is 40~70 DEG C.
In another preferred example, in step B-1, the amine solvent is selected from the group：N-butylamine, 1,3- propane diamine, second two Amine, or combination.
In another preferred example, in step B-1, the temperature of the reaction for taking off sulfonyl blocking groups is 80~140 DEG C.
In another preferred example, in step B-1, the reaction for taking off sulfonyl blocking groups in microwave or in oil bath into Row.
In another preferred example, in step B-1, the temperature of the reaction for taking off sulfonyl blocking groups for microwave 110~ 125 DEG C or oil bath reflux.
In another preferred example, in step B-2, the chloro-formate is methylchloroformate, ethyl chloroformate, chloro-carbonic acid Propyl ester, isopropyl chlorocarbonate or butyl chlorocarbonate.
In another preferred example, in step B-2, the reaction for taking off hydroxyl protection base is in the effect of tetrabutyl ammonium fluoride Lower progress.
In another preferred example, in step C, the Mitsunobu reaction reagents for diisopropyl azodiformate or The equimolar of diethyl azodiformate and triphenylphosphine ratio (diisopropyl azodiformate or diethyl azodiformate：Three Phenylphosphine) combination.
In another preferred example, in step C, the molar ratio of the Formula V compound and Mitsunobu reaction reagents is 1: 1~5.
In another preferred example, in step C, the Formula V compound (works as Mitsunobu with Mitsunobu reaction reagents When containing many kinds of substance in reaction reagent, the molal quantity of Mitsunobu reaction reagents is with mole of wherein any number of substance herein Number calculate) molar ratio be 1:1~3.
In another preferred example, in step C, the temperature of the ring closure reaction is 20~70 DEG C.
In another preferred example, in step C, the temperature of the ring closure reaction is 20~60 DEG C.
Second aspect of the present invention provides a kind of structure midbody compound as follows：
Wherein,
R is hydrogen, trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or three isopropyls Base silicon substrate；
R ' is hydrogen or phenyl；And R ' be hydrogen when, coupled carbonnitrogen bond be double bond, and R " ' be nothing；Work as R ' for phenyl When；Coupled carbonnitrogen bond is singly-bound, and R " ' is hydrogen；
R " isWherein, R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, The substitution refers to be replaced by substituent group selected from the group below：C1-4 alkyl, halogen, phenyl.
In another preferred example, the midbody compound is following structural formula compound represented：
Wherein, R1For trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or three Isopropyl silicon substrate；R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, the substitution refers to be taken by selected from the group below Replaced for base：C1-4 alkyl, halogen, phenyl.
In another preferred example, R2For methyl, ethyl, n-propyl, isopropyl, normal-butyl or benzyl.
Third aspect present invention provides a kind of chiral sulphur alkene ligand, has the following structure formula：
Wherein, R3For isopropyl orN=0 or 1.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and in below (eg embodiment) specifically It can be combined with each other between each technical characteristic of description, so as to form new or preferred technical solution.As space is limited, herein No longer tire out one by one and state.
Specific embodiment
The present inventor after extensive and in-depth study, has had been surprisingly found that a kind of easy to operate, reaction condition is relatively mild, passes through The new preparation process of the preferable Solifenacin of Ji property.This method eliminates cumbersome chiral resolution step, and it is right to avoid the other half The waste of isomers is reflected, advantageously reduces production cost, there is good prospects for commercial application.On this basis, inventor is complete Into the present invention.
As used herein, " C1-6 alkyl " refers to the alkyl with 1-6 carbon atom of linear chain or branch chain；Such as including first The similar group such as base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, n-pentyl, n-hexyl.
As used herein, " halogen " refers to fluorine, chlorine, bromine, iodine.
Ligand
Ligand used in the present invention is chiral sulphur alkene ligand L, has the following structure formula：
Wherein, R3For phenyl, substituted-phenyl, naphthalene, naphthalene, isopropyl, tertiary butyl or the adamantyl replaced；N=0 or 1, wherein, the substitution refers to be replaced by substituent group selected from the group below：C1-4 alkyl, halogen, nitro, methoxyl group or N, N- bis- Methyl.
In another preferred example, the structural formula of the chiral sulphur alkene ligand L is as follows：
In another preferred example, the chiral sulphur alkene ligand L is R3Chiral sulphur alkene ligand for tertiary butyl.
The preparation method of Solifenacin
The present invention provides a kind of preparation method of new Solifenacin, the method can using ortho position substitution aldimine I as Raw material using chiral sulphur alkene L as ligand, under rhodium (I) catalysis, obtains product II by chiral addition, further passes through a system Key precursor -- the Formula IV compound of Solifenacin is obtained by the reaction in row, so as to which Solifenacin further be made.
The preparation method of the present invention can be as follows：
Wherein, R1For trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or three Isopropyl silicon substrate；R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, the substitution refers to be taken by selected from the group below Replaced for base：C1-4 alkyl, halogen, phenyl.
Specifically, can mainly include the following steps：
A-1:In atent solvent, formula a compounds and N, N- dimethyl sulfonamide are reacted, so as to form Formulas I Close object；
A：Under nitrogen protection, under transition metal rhodium (I) and chiral sulphur alkene ligand L catalysis, in alkaline aqueous solution and have In the mixed solution of solvent, aldimine I is reacted with organoboron reagent, so as to form the addition compound product shown in Formula II；
In this step, the organoboron reagent be phenyl boric acid, benzene boric anhydride, phenyl trifluoromethanesulfonate potassium borate, phenyl boric acid pinacol Boron ester or tetraphenylboron sodium, preferably benzene boric anhydride.Compound of formula I and the molar ratio of organoboron reagent are 1:0.33~3, preferably 1:1.Institute The transition metal rhodium (I) stated is [Rh (coe)2Cl]2Or [Rh (C2H4)2Cl]2, preferably [Rh (coe)2Cl]2.The alkaline water Solution is potassium hydroxide aqueous solution, wet chemical or aqueous potassium phosphate solution, preferably potassium hydroxide aqueous solution.Described is organic Solvent is toluene, ortho-xylene, meta-xylene, paraxylene, 1,2- dichloroethanes, or combination；It is preferred that toluene.Reaction time It is 1~12 hour, preferably 6 hours.Reaction temperature is 40~100 DEG C, preferably 60 DEG C.[Rh(coe)2Cl]2Dosage for 1~ 5mol% (is calculated) by compound of formula I, and preferably 3.3mol% (is calculated) by compound of formula I.The dosage of chiral sulphur alkene ligand for 1~ 5.5mol% (is calculated) by compound of formula I, and preferably 3.3mol% (is calculated) by compound of formula I.
B-1:In amine solvent, Formula II compound take off to the reaction of sulfonyl blocking groups, so as to form formula III chemical combination Object；
In this step, the amine solvent be n-butylamine, 1,3- propane diamine, ethylenediamine, or combination；It is preferred that 1,3- the third two Amine.The temperature of the reaction for taking off sulfonyl blocking groups is 80~140 DEG C, preferably 120 DEG C.Described takes off sulfonyl blocking groups Reaction carried out in microwave or in oil bath.The temperature of the reaction for taking off sulfonyl blocking groups for 110~125 DEG C of microwave or Oil bath flows back.
B-2:In atent solvent, by formula III compound and chloro-formate (R2OC (=O) Cl) reaction, so as to form formula IV compounds；
In this step, the chloro-formate be methylchloroformate, ethyl chloroformate, propyl chlorocarbonate, chloro-carbonic acid isopropyl Ester, butyl chlorocarbonate；It is preferred that ethyl chloroformate.The atent solvent is selected from the group：Dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or combination.
B-3:In atent solvent, formula IV compound take off to the reaction of hydroxyl protection base, so as to form Formula V chemical combination Object；
In this step, the reaction for taking off hydroxyl protection base carries out under the action of tetrabutyl ammonium fluoride.The inertia Solvent is selected from the group：Dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or combination.
C：In atent solvent, in the presence of Mitsunobu reaction reagents, the Formula V compound that is obtained in above-mentioned steps into Row ring closure reaction, so as to form Formula IV compound；
In this step, the Mitsunobu reaction reagents are diisopropyl azodiformate or azoformic acid diethyl Ester is combined with the equimolar ratio of triphenylphosphine, and preferably diisopropyl azodiformate is combined with the equimolar ratio of triphenylphosphine.Formula V Compound and the molar ratio of Mitsunobu reaction reagents are 1:1~5, preferably 1:2.Reaction temperature be 20~70 DEG C, preferably 25 ℃.The atent solvent is selected from the group：Dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or combination.
D：In atent solvent, under alkaline condition, by the Formula IV compound obtained in above-mentioned steps and (R)-(-) -3- Quinuclidinol carries out ester exchange reaction, so as to obtain Solifenacin；
In this step, the alkali is NaH, potassium tert-butoxide, sodium methoxide, sodium ethoxide, or combination；It is preferred that NaH.The ester The temperature of exchange reaction is 80~150 DEG C, preferably 120 DEG C.The atent solvent is selected from the group：Dichloromethane, tetrahydrofuran, first Benzene, ortho-xylene, meta-xylene, paraxylene, DMF, DMSO, or combination；It is preferred that toluene.
Solifenacin made from preparation method of the present invention can be directly used for synthesis Solifenacin succinate.
Intermediate
The present invention also provides the structure for being used to prepare Solifenacin midbody compounds as follows：
Wherein,
R is hydrogen, trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or three isopropyls Base silicon substrate；
R ' is hydrogen or phenyl；And R ' be hydrogen when, coupled carbonnitrogen bond be double bond, and R " ' be nothing；Work as R ' for phenyl When；Coupled carbonnitrogen bond is singly-bound, and R " ' is hydrogen；
R " isWherein, R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, The substitution refers to be replaced by substituent group selected from the group below：C1-4 alkyl, halogen, phenyl.
In another preferred example, the midbody compound is following structural formula compound represented：
Wherein, R1For trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or three Isopropyl silicon substrate；R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, the substitution refers to be taken by selected from the group below Replaced for base：C1-4 alkyl, halogen, phenyl.
In another preferred example, R2For methyl, ethyl, n-propyl, isopropyl, normal-butyl or benzyl.
The present invention provides a kind of preparation method of compound shown in Formulas I, including step：In atent solvent (such as tetrahydrochysene furan Mutter) in, under certain temperature (such as reflux), formula a compounds and N, N- dimethyl sulfonamide are subjected to reaction a period of time (such as 1-36 hours or 5-24 hours), so as to form compound of formula I；
Wherein, R1It is as defined above.
The present invention provides a kind of preparation method of compound shown in Formula II, including step：In transition metal Rh (I) and hand Property the catalysis of sulphur alkene ligand L under, in the mixed system of alkaline aqueous solution and organic solvent, by compound of formula I and organoboron reagent Ph- [B] is reacted, so as to shape compound of formula II；
The chiral sulphur alkene ligand L has the following structure formula：
Wherein, R1、R3It is as defined above.
In this step, the organoboron reagent be phenyl boric acid, benzene boric anhydride, phenyl trifluoromethanesulfonate potassium borate, phenyl boric acid pinacol Boron ester or tetraphenylboron sodium, preferably benzene boric anhydride.Compound of formula I and the molar ratio of organoboron reagent are 1:0.33~3, preferably 1:1.Institute The transition metal rhodium (I) stated is [Rh (coe)2Cl]2Or [Rh (C2H4)2Cl]2, preferably [Rh (coe)2Cl]2.The alkaline water Solution is potassium hydroxide aqueous solution, wet chemical or aqueous potassium phosphate solution, preferably potassium hydroxide aqueous solution.Described is organic Solvent is toluene, ortho-xylene, meta-xylene, paraxylene, 1,2- dichloroethanes, or combination；It is preferred that toluene.Reaction time It is 1~12 hour, preferably 6 hours.Reaction temperature is 40~100 DEG C, preferably 60 DEG C.[Rh(coe)2Cl]2Dosage for 1~ 5mol% (is calculated) by compound of formula I, and preferably 3.3mol% (is calculated) by compound of formula I.The dosage of chiral sulphur alkene ligand for 1~ 5.5mol% (is calculated) by compound of formula I, and preferably 3.3mol% (is calculated) by compound of formula I.
The present invention provides a kind of preparation method of compound shown in formula III, including step：In amine solvent, by Formula II Compound take off the reaction of sulfonyl blocking groups, so as to shape compound of Formula III；
Wherein, R1It is as defined above.
In this step, the amine solvent be n-butylamine, 1,3- propane diamine, ethylenediamine, or combination；It is preferred that 1,3- the third two Amine.The temperature of the reaction for taking off sulfonyl blocking groups is 80~140 DEG C, preferably 120 DEG C.Described takes off sulfonyl blocking groups Reaction carried out in microwave or in oil bath.The temperature of the reaction for taking off sulfonyl blocking groups for 110~125 DEG C of microwave or Oil bath flows back.
The present invention provides a kind of preparation method of compound shown in formula IV, including step：In atent solvent, by formula III compounds are reacted with chloro-formate, so as to shape compound of formula IV；
Wherein, R1、R2It is as defined above.
In this step, the chloro-formate be methylchloroformate, ethyl chloroformate, propyl chlorocarbonate, chloro-carbonic acid isopropyl Ester, butyl chlorocarbonate；It is preferred that ethyl chloroformate.The atent solvent is selected from the group：Dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or combination.
The present invention provides a kind of preparation method of compound shown in Formula V, including step：In atent solvent, by formula IV Compound take off the reaction of hydroxyl protection base, so as to form Formula V compound；
Wherein, R1、R2It is as defined above.
In this step, the reaction for taking off hydroxyl protection base carries out under the action of tetrabutyl ammonium fluoride.The inertia Solvent is selected from the group：Dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or combination.
Main advantages of the present invention include：
The present invention provides a kind of preparation sides of relatively mild, better economy the Solifenacin of easy to operate, reaction condition Method.This method under transition metal rhodium (I) catalysis, using chiral sulphur alkene as ligand, passes through asymmetry using ortho position substitution aldehyde as raw material The cyclisation and transesterification of reaction product obtain drug succinic acid Solifenacin.This method eliminates cumbersome chiral resolution step, The waste of the other half enantiomter is avoided, advantageously reduces production cost, there is certain prospects for commercial application.
With reference to specific implementation, the present invention is further explained.It should be understood that these embodiments be merely to illustrate the present invention and It is not used in and limits the scope of the invention.Test method without specific conditions in the following example, usually according to normal condition, Or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.The present invention is implemented Raw materials used or instrument in example, if not it illustrates, it is commercially available.
Preparation example 1
100mL round-bottomed flasks weigh A (1g, 3.8mmol), add in N, (470mg, 3.8mmol, 1 work as N- dimethyl sulfonamides Amount), the dissolving of 25mL anhydrous tetrahydro furans adds in tetraethyl titanate (1.6mL, 7.6mmol, 2 equivalent), flows back under oil bath (reflux) 12 hours postcoolings are reacted to room temperature, add in saturated salt solution and precipitation, diatomite filtering, ethyl acetate extraction is precipitated It takes, anhydrous sodium sulfate drying, rapid column chromatography obtains 1.22g white solids 1a.
White solid, yield 87%.1H NMR(300MHz,CDCl3)δ9.21(s,1H),8.07(d,J =8.0Hz, 1H), 7.52 (t, J=6.9Hz, 1H), 7.34 (t, J=7.7Hz, 2H), 3.82 (t, J=6.4Hz, 2H), 3.14 (t, J=6.4Hz, 2H), 2.87 (s, 6H), 0.79 (s, 9H), -0.09 (s, 6H)
100mL round-bottomed flasks weigh B (3.6g, 9.2mmol), add in N, N- dimethyl sulfonamides (1.14g, 9.2mmol, 1 Equivalent), the dissolving of 25mL anhydrous tetrahydro furans adds in tetraethyl titanate (3.84mL, 18.32mmol, 2 equivalent), flows back under oil bath (reflux) 12 hours postcoolings are reacted to room temperature, add in saturated salt solution and precipitation, diatomite filtering, ethyl acetate extraction is precipitated It takes, anhydrous sodium sulfate drying, rapid column chromatography obtains 3.52g white solids 1b.
White solid, yield 78%.1H NMR(300MHz,CDCl3)δ9.19(s,1H),8.07 (d, J=7.9Hz, 1H), 7.60-7.28 (m, 13H), 3.87 (t, J=6.2Hz, 2H), 3.23 (t, J=6.2Hz, 2H), 2.77 (s,6H),0.98(s,9H).
Preparation example 2
50mL round-bottomed flasks, add in 218mg compound α, beta-unsaturated aldehyde, 121mg (R)-tertiary fourth sulfenamide, 25mL without Water tetrahydrofuran dissolves, and adds in 0.42mL tetraethyl titanates, be placed under oil bath flow back (reflux) react 6h postcoolings to room temperature, Solid sodium borohydride is added in, 1h is reacted, is slowly added to methanol, until being generated without bubble, saturated salt solution is added in and precipitation is precipitated, Diatomite filters, ethyl acetate extraction, anhydrous sodium sulfate drying, and column chromatography obtains 272mg white solids L1.
White solid, yield 88%.1H NMR(300MHz,CDCl3)δ5.14(s,1H),4.82 (s, 1H), 3.80-3.69 (m, 1H), 3.64 (d, J=7.9Hz, 1H), 3.21 (s, 1H), 2.94 (m, 1H), 1.95 (s, 3H), 1.85 (d, J=6.0Hz, 1H), 1.75-1.60 (m, 5H), 1.49 (s, 5H), 1.25 (s, 9H), 0.94 (d, J=6.0Hz, 1H).
Embodiment 1
Schlenk bottles add in aldimine 1a (148mg, 0.4mmol, l equivalent), and (125mg, 0.4mmol, 1 work as benzene boric anhydride Amount), [Rh (coe)2Cl]2(4.4mg, 3mol%) and chiral branch sulphur alkene ligand L 2 (3.1mg, 3.3mol%), replaces nitrogen, 4mL toluene (toluene), stirring at normal temperature 30min are added in, then potassium hydroxide aqueous solution (1.5M) 0.8mL is added in into system, 60 DEG C reaction 6h.Solvent is spin-dried for, column chromatography (petrol ether/ethyl acetate=5/1) obtains addition compound product 2a (yields (yield): 82%；99%ee).
White solid, yield (yield) 82%, 99%ee. [α]25 D=+24.6 (c 0.71, CHCl3) .1H NMR(300MHz,CDCl3) δ 7.39-7.22 (m, 9H), 5.87 (d, J=6.0Hz, 1H), 5.18 (d, J=6.0Hz, 1H), 3.72 (dd, J=13.9,7.0Hz, 2H), 2.86 (t, J=7.0Hz, 2H), 2.54 (s, 6H), 0.82 (s, 9H), -0.04 (s, 6H).13C NMR(150MHz,CDCl3)δ141.3,139.1,136.9,131.0,128.7,127.8,127.79,127.77, 127.74,126.6,63.8,58.3,37.6,35.6,26.0,18.4,-5.4.HRMS(ESI):C23H36N2O3NaSiS[M+Na ]+:calcd 471.2114,found 471.2119.HPLC:Chiralpak AD-H columns (250mm)；Detection wavelength:224nm； Hexane/isopropyl alcohol=97/3；Flow velocity=0.4mL/min；Retention time:18.6min (main peak), 22.0min.
Embodiment 2
10mL microwave reactions pipe adds in compound 2a (101mg, 0.226mmol, 99%ee), adds 2mL1,3- the third two Amine (1,3-diaminopropane) dissolves, and in 120 DEG C of reaction 30min or oil bath back flow reaction 2h of microwave, is cooled to room temperature, 10mL water, DCM extractions are added in, anhydrous sodium sulfate drying is concentrated to give the product 3a for taking off sulfonyl, direct plunges into next step； Under nitrogen protection, anhydrous methylene chloride 2mL is added in, triethylamine (34.3mg, 0.339mmol, 47 μ L) is added dropwise dropwise under ice-water bath Ethyl chloroformate (27mg, 0.248mmol, 47 μ L) is transferred to normal-temperature reaction 12h, adds in water quenching and goes out, dichloromethane extraction, nothing Water Na2SO4Dry, organic phase is concentrated to give carbamate compounds 4a, then addition 2mL tetrahydrofurans, under ice-water bath dropwise 1M TBAF tetrahydrofuran solutions are added dropwise, are transferred to normal-temperature reaction 12h, post-process, column chromatography (petrol ether/ethyl acetate=1/1), Obtain taking off the product 5a (52mg, three step yields 77%, 99%ee) of TBS protecting groups.
Colourless liquid, yield 77%, 99%ee.1H NMR(300MHz,CDCl3)δ7.31-7.18(m, 9H), 6.26 (d, J=7.3Hz, 1H), 5.67 (d, J=6.4Hz, 1H), 4.22-3.94 (m, 2H), 3.79 (t, J=6.2Hz, 2H), 2.95-2.73 (m, 2H), 2.65 (s, 1H), 1.20 (t, J=6.7Hz, 3H)13C NMR(100MHz,CDCl3)δ 156.1,141.3,140.2,137.2,130.6,128.6,127.8,127.5,127.3,127.0,55.5,35.8, 14.6.HRMS(ESI):C18H21NO3Na[M+Na]+:calcd322.1419,found322.1410.HPLC:Chiralpak AD-H columns (250mm)；Detection wavelength：224nm；Hexane/isopropyl alcohol=90/10；Flow velocity=0.7mL/min；Retention time: 16.3min (main peak), 25.0min.
Embodiment 3
N2Under protection, by compound 5a (42mg, 0.14mmol) and PPh3(73.4mg, 0.28mmol, 2 equivalent) is dissolved in In 1.0mL THF, DIAD (55 μ L, 0.28mmol, 2 equivalent) is slowly added under ice-water bath, turns that reaction 12 hours is stirred at room temperature, it is dense It has contracted after solvent, column chromatography (petrol ether/ethyl acetate=20/1) obtains cyclisation product 6a (28mg, yield 71%, 99%ee).
Colourless liquid, yield 71%, 99%ee.1H NMR(300MHz,CDCl3)δ7.25-7.15 (m, 8H), 7.04 (d, J=6.9Hz, 1H), 6.37 (brs, 1H), 4.22-4.04 (m, 3H), 3.29-3.23 (m, 1H), 2.97- 2.95 (m, 1H), 2.75-2.71 (m, 1H), 1.28 (t, J=6.5Hz, 3H)；LR-MS(ESI):m/z 304.3[M+Na]+ .HPLC:Chiralpak AD-H columns (250mm)；Detection wavelength：224nm；Hexane/isopropyl alcohol=90/10；Flow velocity=0.7mL/ min；Retention time:10.7min, 18.5min (main peak)
Embodiment 4
Schlenk bottles add in aldimine 1b (198mg, 0.4mmol, l equivalent), and (125mg, 0.4mmol, 1 work as benzene boric anhydride Amount), [Rh (coe)2Cl]2(4.4mg, 3mol%) and chiral branch sulphur alkene ligand L 2 (3.1mg, 3.3mol%), replaces nitrogen, 4mL toluene (toluene), stirring at normal temperature 30min are added in, then potassium hydroxide aqueous solution (1.5M) 0.8mL is added in into system, 60 DEG C reaction 6h.Solvent is spin-dried for, column chromatography (petrol ether/ethyl acetate=5/1) obtains addition compound product 2b (yields (yield): 99%；99%ee).
White solid, yield (yield) 99%, 99%ee.1H NMR(300MHz,CDCl3)δ7.55(dd, J=11.5,7.2Hz, 4H), 7.42-7.13 (m, 15H), 5.81 (d, J=6.3Hz, 1H), 4.93 (d, J=6.2Hz, 1H), 3.73 (dd, J=8.7,5.6Hz, 2H), 3.09-2.82 (m, 2H), 2.45 (s, 6H), 1.00 (s, 9H)13C NMR(125MHz, CDCl3)δ140.6,138.6,136.1,135.1,133.2,133.1,130.7,129.12,129.10,128.15,127.18, 127.17,126.2,63.6,57.3,37.0,35.1,26.4,18.7.HPLC:Chiralpak AY-H columns (250mm)；Detection Wavelength：224nm；Hexane/isopropyl alcohol=90/10；Flow velocity=0.7mL/min；Retention time:11.6min (main peak), 17.8min.
Embodiment 5
10mL microwave reactions pipe adds in compound 2b (63mg, 0.134mmol, 99%ee), adds 2mL1,3- propane diamine (1,3-diaminopropane) it dissolves, in 120 DEG C of reaction 30min or oil bath back flow reaction 2h of microwave, is cooled to room temperature, adds Enter 10mL water, DCM extractions, anhydrous sodium sulfate drying is concentrated to give the product 3b for taking off sulfonyl, direct plunges into next step；Nitrogen Under gas shielded, anhydrous methylene chloride 1mL is added in, chloromethane is added dropwise under ice-water bath in triethylamine (20mg, 0.201mmol, 28 μ L) dropwise Sour methyl esters (14mg, 0.148mmol, 12 μ L) is transferred to normal-temperature reaction 12h, adds in water quenching and goes out, and dichloromethane extraction is anhydrous Na2SO4Dry, organic phase is concentrated to give carbamate compounds 4b；2mL tetrahydrofurans are then added in, are dripped dropwise under ice-water bath Add 1M TBAF tetrahydrofuran solutions, be transferred to normal-temperature reaction 12h, post-process, column chromatography (petrol ether/ethyl acetate=3/1) obtains To the product 5b (42mg, three step yields 87%, 99%ee) for taking off TBDPS protecting groups.
Colourless liquid, yield 87%, 99%ee.1H NMR(300MHz,CDCl3)δ7.35- 7.17 (m, 9H), 6.27 (s, 1H), 5.60 (s, 1H), 3.86 (t, J=6.1Hz, 2H), 3.68 (s, 3H), 3.01-2.73 (m, 2H),2.29(s,1H).HPLC:Chiralpak AD-H columns (250mm)；Detection wavelength：224nm；Hexane/isopropyl alcohol=90/ 10；Flow velocity=0.7mL/min；Retention time s:15.4min (main peak), 21.8min.
Embodiment 6
N2Under protection, by compound 5b (14mg, 0.05mmol) and PPh3(39mg, 0.15mmol, 3 equivalent) is dissolved in In 1.0mLTHF, DIAD (30 μ L, 0.15mmol, 3 equivalent) is slowly added under ice-water bath, turns that reaction 12 hours is stirred at room temperature, it is dense It has contracted after solvent, column chromatography (petrol ether/ethyl acetate=30/1) obtains cyclisation product 6b (11mg, 79% yield, 99%ee).
Colourless liquid, 79% yield, 99%ee.1H NMR(300MHz,CDCl3)δ7.24-7.12 (m, 8H), 7.05 (d, J=7.6Hz, 1H), 6.43 (s, 1H), 4.01 (s, 1H), 3.77 (s, 3H), 3.24 (d, J=9.4Hz, 1H),3.07-2.90(m,1H),2.83-2.68(m,1H).LR-MS(ESI):m/z 267[M+Na]+.HPLC:Chiralpak AD-H columns (250mm)；Detection wavelength：224nm；Hexane/isopropyl alcohol=90/10；Flow velocity=0.7mL/min；Retention time s: 13.7min, 22.8min (main peak)
Embodiment 7
At 0 DEG C, added in into dry toluene (toluene) suspension of 60%w/w NaH (36mg, 0.888mmol) (R)-(-) toluene solution of -3- quinuclidinols (35mg, 0.272mmol), after being stirred to react 15 minutes at a temperature of this, adding Close the toluene solution of object 6a (25mg, 0.088mmol).Following reaction mixture is transferred to 120 DEG C of oil bath and reacts 12 hours, divides water Device separates ethyl alcohol.It is cooled to room temperature after reaction, adds in saline solution 50mL, subsequent ethyl acetate extraction, organic layer merges, satisfies And brine It, anhydrous sodium sulfate drying, concentration.Crude product column chromatography (petrol ether/ethyl acetate=30/1), obtains product Colourless liquid (+)-Solifenacin (27mg, yield 85%).
Colourless liquid.1H NMR(400MHz,CDCl3)δ7.26-7.14(m,8H),7.07(d,J =7.1Hz, 1H), 6.32 (s, 1H), 4.83-4.81 (m, 1H), 4.08-3.97 (m, 1H), 3.39-3.22 (m, 2H), 2.88- 2.70(m,7H),2.04(s,1H),1.84-1.82(m,1H),1.72-1.65(m,1H),1.59-1.55(m,1H),1.44- 1.37(m,1H)；13C NMR(100MHz,CDCl3,60℃)δ155.4,143.0,135.7,135.1,129.0,128.6, 128.4,128.2,127.5,127.2,126.3,72.4,58.3,56.1,47.7,46.7,38.9,28.6,25.8,24.8, 20.1.
Embodiment 8
Schlenk bottles add in aldimine 1a (148mg, 0.4mmol, l equivalent), and (125mg, 0.4mmol, 1 work as benzene boric anhydride Amount), [Rh (coe)2Cl]2(4.4mg, 3mol%) and chiral branch sulphur alkene ligand L 1 (3.1mg, 3.3mol%), replaces nitrogen, 4mL toluene (toluene), stirring at normal temperature 30min are added in, then potassium hydroxide aqueous solution (1.5M) 0.8mL is added in into system, 60 DEG C reaction 6h.Solvent is spin-dried for, column chromatography (petrol ether/ethyl acetate=5/1) obtains addition compound product 2a (yields (yield): 85%；99%ee).
White solid, yield (yield) 85%, 99%ee. [α]25 D=+24.6 (c 0.71, CHCl3).1H NMR(300MHz,CDCl3) δ 7.39-7.22 (m, 9H), 5.87 (d, J=6.0Hz, 1H), 5.18 (d, J=6.0Hz, 1H), 3.72 (dd, J=13.9,7.0Hz, 2H), 2.86 (t, J=7.0Hz, 2H), 2.54 (s, 6H), 0.82 (s, 9H), -0.04 (s, 6H).13C NMR(150MHz,CDCl3)δ141.3,139.1,136.9,131.0,128.7,127.8,127.79,127.77, 127.74,126.6,63.8,58.3,37.6,35.6,26.0,18.4,-5.4.HRMS(ESI):C23H36N2O3NaSiS[M+Na ]+:calcd 471.2114,found471.2119.HPLC:Chiralpak AD-H columns (250mm)；Detection wavelength:224nm； Hexane/isopropyl alcohol=97/3；Flow velocity=0.4mL/min；Retention time:18.6min (main peak), 22.0min.
In addition, the experiment proved that, if sulphur alkene ligand chiral in embodiment 1 to be changed to other ligands of the present invention, gained The ee of product (i.e. Formula II compound) is all higher than 85%.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within the model that the application the appended claims are limited It encloses.

Claims (10)

1. a kind of preparation method of Solifenacin, which is characterized in that including step：
A-1:In atent solvent, formula a compounds and N, N- dimethyl sulfonamide are reacted, so as to form compound of formula I；
A:Under transition metal Rh (I) and chiral sulphur alkene ligand L catalysis, in alkaline aqueous solution and the mixed system of organic solvent In, compound of formula I is reacted with organoboron reagent Ph- [B], so as to shape compound of formula II；
The chiral sulphur alkene ligand L has the following structure formula：
Wherein, R3For phenyl, the phenyl of substitution, naphthalene, naphthalene, isopropyl, tertiary butyl or the adamantyl replaced；N=0 or 1, Wherein, the substitution refers to be replaced by substituent group selected from the group below：C1-4 alkyl, halogen, nitro, methoxyl group or N, N- diformazan Base；
B-1:In amine solvent, Formula II compound take off to the reaction of sulfonyl blocking groups, so as to shape compound of Formula III；
B-2:In atent solvent, by formula III compound and chloro-formate (R2OC (=O) Cl) reaction, so as to form formula IV chemical combination Object；
B-3:In atent solvent, formula IV compound take off to the reaction of hydroxyl protection base, so as to form Formula V compound；
C:In atent solvent, in the presence of Mitsunobu reaction reagents, Formula V compound is subjected to ring closure reaction, so as to be formed Formula IV compound；
D:In atent solvent, under alkaline condition, Formula IV compound and (R)-(-) -3- quinuclidinols are subjected to ester exchange reaction, So as to form Solifenacin；
In the above formulas, R1For trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or three Isopropyl silicon substrate；R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, the substitution refers to be taken by selected from the group below Replaced for base：C1-4 alkyl, halogen, phenyl.
2. preparation method as described in claim 1, which is characterized in that in step A, the compound of formula I is tried with organic boron The molar ratio of agent is 1:0.33~3.
3. preparation method as described in claim 1, which is characterized in that in step A, the organoboron reagent for phenyl boric acid, Benzene boric anhydride, phenyl trifluoromethanesulfonate potassium borate, phenyl boric acid pinacol boron ester or tetraphenylboron sodium；And/or the alkaline aqueous solution is hydrogen-oxygen Change aqueous solutions of potassium, wet chemical or aqueous potassium phosphate solution.
4. preparation method as described in claim 1, which is characterized in that in step A, the transition metal Rh (I) is [Rh (coe)2Cl]2Or [Rh (C2H4)2Cl]2。
5. preparation method as described in claim 1, which is characterized in that in step A, the organic solvent is selected from the group：First Benzene, ortho-xylene, meta-xylene, paraxylene, 1,2- dichloroethanes, or combination.
6. preparation method as described in claim 1, which is characterized in that in step B-1, the amine solvent is selected from the group：Just Butylamine, 1,3- propane diamine, ethylenediamine, or combination.
7. preparation method described in claim 1, which is characterized in that in step C, the Mitsunobu reaction reagents are even The equimolar of nitrogen dioctyl phthalate diisopropyl ester or diethyl azodiformate and triphenylphosphine ratio (diisopropyl azodiformate or idol Nitrogen dicarboxylate：Triphenylphosphine) combination.
8. preparation method as described in claim 1, which is characterized in that in step C, the Formula V compound and Mitsunobu The molar ratio of reaction reagent is 1:1~5.
9. a kind of structure midbody compound as follows：
Wherein,
R is hydrogen, trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate or triisopropyl silicon Base；
R ' is hydrogen or phenyl；And R ' be hydrogen when, coupled carbonnitrogen bond be double bond, and R " ' be nothing；When R ' is phenyl；With Its connected carbonnitrogen bond is singly-bound, and R " ' is hydrogen；
R " isWherein, R2For C1-6 alkyl or substituted C1-6 alkyl or phenyls, wherein, it is described Substitution refers to be replaced by substituent group selected from the group below：C1-4 alkyl, halogen, phenyl.
10. a kind of chirality sulphur alkene ligand, has the following structure formula：
Wherein, R3For isopropyl orN=0 or 1.
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