CN109251157A

CN109251157A - (R)-Esomeprazole preparation method

Info

Publication number: CN109251157A
Application number: CN201810586914.9A
Authority: CN
Inventors: 叶雷
Original assignee: Chongqing Runze Pharmaceutical Co Ltd
Current assignee: Chongqing Runze Pharmaceutical Co Ltd
Priority date: 2017-07-13
Filing date: 2018-06-08
Publication date: 2019-01-22

Abstract

The present invention provides the preparation methods of one kind (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters, this method is in such a way that two-phase extracts, first product is extracted from reaction system solvent using water, into water phase, product is entered in ethyl acetate phase from extraction in water again using ethyl acetate again, to purify (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester well in the case where uncrystallizable.(R)-Esomeprazole yield of (the R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters prepared by the present invention through ammonolysis and then purifying preparation is up to 45~50%(in terms of R-4- amino -3-hydroxybutyrate), purity is up to 99.9%, has apparent economy and operability.

Description

(R)-Esomeprazole preparation method

Technical field

The present invention relates to (R)-Esomeprazoles, and in particular to a kind of (R) -4- hydroxyl -2- The preparation method of oxo-1-pyrrolidine ethanamide.

Background technique

(R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide (No. CAS is 68252-28-8) also known as dextrorotation Oxiracetam, the right side Revolve oxiracetam, dextrorotation oxiracetam.Studies have shown that (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide resists insane in calmness There is special biological activity in epilepsy field, and its toxicity is low, and drug safe range is big, is expected to resist as existing high toxicity insane The substitute of epilepsy class drug.(R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters is synthesis (R) -4- hydroxyl -2- oxygen -1- pyrroles The important intermediate of alkyl acetamide.(R) following (R of -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid ester structure₂For C₁-C₆Alkane Base):

(do not find that (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide has calm, anti-epileptic within the long period before Before activity), industry technical staff generally believes that the levo form of 4- hydroxyl -2- oxygen -1- pyrrolidine acetamide is more suitable for developing At nootropics, and d-isomer (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide is handled as impurity, thus to (R) - 4- hydroxyl -2- oxygen -1- pyrrolidine acetamide Study of synthesis method is less.Correspondingly, wherein mesosome (R) -4- hydroxyl -2- oxo - The also rare research of the synthetic method of 1- pyrrolidine acetic acid ester.Chinese patent CN105330582 A discloses one kind (R) -4- hydroxyl - The synthetic method of 2- oxygen -1- pyrrolidine acetamide, this method carry out nitrine using R-4- chloro-3-hydroxybutanoic acid ester as starting material Change reaction, then nitrine restores, and is condensed, then cyclization with halogenated acetic acids ester, obtains (R) -4- hydroxyl -2- oxo -1- pyrroles Alkane acetic acid esters, then ammonolysis obtains (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide.Since the intermediate product of the route is Grease can not be crystallized effectively, and thus the purity of (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters is to final product (R) -4- The influence of hydroxyl -2- oxygen -1- pyrrolidine acetamide yield and purity is with regard to bigger.And it can be generated in reaction process a large amount of organic Impurity and inorganic salts, how in the reaction system to efficiently separate (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester just becomes The important problem of production in practice.

Summary of the invention

In order to solve the problems in the prior art, the purpose of the present invention is to provide one kind (R) -4- hydroxyl -2- oxygen -1- pyrroles Cough up the preparation method of alkane acetic acid esters, (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester purity is high of this method preparation, as medicine Object or chemical intermediate are suitble to the production of downstream product.

Unless otherwise specified, number of the present invention is parts by weight, and the percentage is mass percent.

The object of the present invention is achieved like this:

The preparation method of the present invention (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, which is characterized in that use following road Line is made:

Wherein, R₁For C₁-C₆Alkyl, R₂For C₁-C₆Alkyl.

Lead to (R) -4- hydroxyl -2- oxygen -1- pyrrole for generating a large amount of organic impurities and inorganic salts in above-mentioned reaction system It coughs up alkane acetic acid esters and is difficult to the problem of efficiently separating, inventor have passed through a large amount of experiment, in terms of economy and operability two Considering under, have finally chosen the mode of two-phase extraction, first extracted product from reaction system solvent using water, entered Water phase, then entered product in ethyl acetate phase from extraction in water again using ethyl acetate, so that small polar impurity can stay in In reaction dissolvent phase, big polar impurity and inorganic salts are stayed in water, to purify well in the case where uncrystallizable (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester.

It finds under study for action simultaneously, in above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, and not all R₂For C₁- C₆Arrcostab be suitable for the extraction of above-mentioned two-phase, some ester type compounds are difficult to enter water phase, some esters from reaction dissolvent It is mutually more difficult that compound enters ethyl acetate from water phase.

Preferably, the preparation method of above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, it is characterised in that: R₁For C₁- C₆Alkyl, R₂For isopropyl, n-propyl, isobutyl group, normal-butyl or tert-butyl；Water is added to extract reaction solution after reaction, so Ethyl acetate is added in water phase afterwards to extract again, collects ethyl acetate extracted, is concentrated to get (R) -4- hydroxyl -2- oxygen - 1- pyrrolidine acetic acid ester.

In the above method, R₁For C₁-C₆The preferred R of alkyl₁For methyl, ethyl, isopropyl, n-propyl, normal-butyl, isobutyl Base tert-butyl, cyclopenta or benzyl.

In order to improve the yield of reaction, the preparation method of above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester is special Sign is: reaction dissolvent is butyl acetate, toluene, DMF, one or more of DMSO mixing；Reaction temperature is 55~133 ℃；Reaction time is 2.5~9 hours.

Inventor also found under study for action, when above-mentioned reaction dissolvent is toluene, (R) -4- hydroxyl -2- of two-phase extraction acquisition It is butyl acetate, DMF and DMSO that oxygen -1- pyrrolidine acetic acid ester content, which is significantly higher than reaction dissolvent,；Thus above-mentioned reaction dissolvent is excellent Select toluene.

The preparation method of one kind (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, which is characterized in that use following route It is made:

Wherein, R₁For C₁-C₆Alkyl, R₂For isopropyl, n-propyl, isobutyl group, normal-butyl or tert-butyl；Intermediate compound I is closed Reaction solution is added water to extract by ring after reaction, and ethyl acetate is then added in water phase and extracts again, collects vinegar extracted Acetoacetic ester is concentrated to get (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester；By (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid Ester aminolysis obtains (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide.

Above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester aminolysis is in (R) -4- hydroxyl -2- oxygen -1- pyrrolidines second It is passed through methanol ammonia in acid esters, is reacted at 20~30 DEG C 4~16 hours, it is difficult to understand that target product (R)-is then collected from reaction product La Xitan.

The preferably following route of above-mentioned intermediate compound I is made:

Wherein, R₁For C₁-C₆Alkyl, R₂For C₁-C₆Alkyl, X is halogen；Reaction dissolvent is methanol, ethyl alcohol, dichloromethane The combination of one or more of alkane, ethyl acetate, tetrahydrofuran, acetone, butanone or ethyl butyrate；Catalyst is triethylamine, pyrrole Pyridine or lutidines；Reaction temperature is 5~65 DEG C, and the reaction time is 4.5~10 hours.

The above-mentioned preferred chlorine or bromine of halogen.

Preferably, the molar ratio of above-mentioned intermediate II and halogenated acetic acids ester are as follows: 1:1~3, intermediate II and the catalyst Molar ratio are as follows: 1:2~3.

The preparation method of one kind (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, which is characterized in that use following route It is made:

Wherein, R₁For for methyl, ethyl, isopropyl, n-propyl, normal-butyl, isobutyl group tert-butyl, cyclopenta or benzyl, R₂ For isopropyl, n-propyl, isobutyl group, normal-butyl or tert-butyl；X is bromine；Specific preparation process are as follows:

Intermediate II is reacted under the effect of the catalyst with monobromo-acetic acid ester is made intermediate compound I, and wherein catalyst is three second Amine, pyridine or lutidines, reaction dissolvent are methanol, ethyl alcohol, methylene chloride, ethyl acetate, tetrahydrofuran, acetone, butanone Or the combination of one or more of ethyl butyrate, reaction temperature are 5~65 DEG C, the reaction time is 4.5~10 hours, intermediate II With the molar ratio of monobromo-acetic acid ester are as follows: 1:1~3, the molar ratio of intermediate II and the base catalyst are as follows: 1:2~3；

It is 2.5~9 hours that intermediate compound I, which is 55~133 DEG C of reaction time with temperature in toluene,；It after reaction will reaction Liquid adds water to extract, and ethyl acetate is then added in water phase and extracts again, collects ethyl acetate extracted, is concentrated to get (R)- 4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester.

The preferably following route of above-mentioned intermediate II is made:

First by R-4- amino -3-hydroxybutyrate and 5~20 times of weight R₁- alcohol (such as methanol, ethyl alcohol, normal propyl alcohol, isopropyl The C such as alcohol, cyclopentanol₁-C₆Alcohol) mixing, then be added thionyl chloride reacted 1~5 hour at 0~55 DEG C, R-4- amino -3- The molar ratio of hydroxybutyric acid and thionyl chloride is 1:1~2；The alcoholic solution containing intermediate II is obtained, then from containing intermediate Intermediate II is collected in the alcoholic solution of II.

Specifically, the preparation method of one kind (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, which is characterized in that use Following route is made:

First by R-4- amino -3-hydroxybutyrate and 5~20 times of weight R₁- alcohol (such as methanol, ethyl alcohol, normal propyl alcohol, isopropyl The C such as alcohol, cyclopentanol₁-C₆Alcohol) mixing, then be added thionyl chloride reacted 1~5 hour at 0~55 DEG C, R-4- amino -3- The molar ratio of hydroxybutyric acid and thionyl chloride is 1:1~2；The alcoholic solution containing intermediate II is obtained, then from containing intermediate Intermediate II is collected in the alcoholic solution of II；

(R) -4- hydroxyl -2- oxygen -1- pyrrole is prepared through ammonolysis in above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester Cough up alkyl acetamide；Reaction route is as follows:

Step are as follows:

(1) R-4- amino -3-hydroxybutyrate with contain R₁Alcohol react intermediate compound I, wherein R be made₁For C₁-C₆Alkyl, urge Agent is acylating agent；

(2) intermediate compound I is reacted under base catalysis with halogenated acetic acids ester is made intermediate II, wherein R₂For C₁-C₆Alkyl；

(3) intermediate II ring closure reaction obtains (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester；

(4) (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester aminolysis obtains target product (R) -4- hydroxyl -2- oxygen -1- pyrrole Cough up alkyl acetamide.

Above-mentioned C₁-C₆Alkyl be selected from methyl, ethyl, isopropyl, n-propyl, normal-butyl, isobutyl group tert-butyl, cyclopenta Or benzyl.

Above-mentioned halogenated acetic acids ester is chloracetic acid ester or monobromo-acetic acid ester.

(R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester is 25%~28% with mass percentage concentration at 20~30 DEG C Concentrated ammonia liquor or methanol ammonia gasoloid react 4~16 hours, then from reaction product collect target product (R) -4- hydroxyl -2- Oxygen -1- pyrrolidine acetamide crude product.

Preferably, above-mentioned R₁For methyl, ethyl, isopropyl, n-propyl, normal-butyl, isobutyl group tert-butyl, cyclopenta or benzyl Base, R₂For isopropyl, n-propyl, isobutyl group, normal-butyl or tert-butyl；X is bromine.

Preferably, above-mentioned R₁For methyl, ethyl, isopropyl or n-propyl, R₂For isopropyl, n-propyl, isobutyl group, positive fourth Base or tert-butyl；X is bromine.

Preferably, above-mentioned R₁For ethyl, R₂For normal-butyl；X is bromine.

Preferably, above-mentioned R₁For ethyl, R₂For tert-butyl；X is bromine.

Preferably, above-mentioned R₁For methyl, R₂For normal-butyl；X is bromine.

Preferably, above-mentioned R₁For methyl, R₂For tert-butyl；X is bromine.

Preferably, above-mentioned R₁For methyl, R₂For isopropyl；X is bromine.

Preferably, above-mentioned R₁For methyl, R₂For n-propyl；X is bromine.

Preferably, above-mentioned R₁For ethyl, R₂For isopropyl；X is bromine.

Preferably, above-mentioned R₁For ethyl, R₂For n-propyl；X is bromine.

Above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product purifies with the following method:

Scheme one:

The preparation method of above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, which is characterized in that (R) -4- hydroxyl -2- Oxygen -1- pyrrolidine acetamide crude product is purified using following steps:

(R)-Esomeprazole crude product is dissolved with organic solvent, forms supersaturated solution, Then it crystallizes, filters in -12 DEG C~-21 DEG C of low temperature environment, it is dry, obtain (R) -4- hydroxyl -2- oxo-1-pyrrolidine second Amide crystallization；The organic solvent is in ethyl alcohol, tetrahydrofuran, acetone, methanol, butanone, isoamyl alcohol, acetonitrile, normal propyl alcohol One or more combination.

Preferably, (R) -4- hydroxyl -2- oxo -1- pyrroles is added with the concentration of 5mg/mL-55mg/mL in organic solvent Alkyl acetamide crude product, is stirred continuously, and 35 DEG C~90 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution is sealed It is placed on crystallisation by cooling in -12 DEG C~-21 DEG C of low temperature environment, filters to isolate crystallization, it is dry, obtain (R) -4- hydroxyl -2- Oxo-1-pyrrolidine ethanamide crystallization；The organic solvent be selected from ethyl alcohol, tetrahydrofuran, acetone, methanol, butanone, isoamyl alcohol, The combination of one or more of acetonitrile, normal propyl alcohol.

Preferably -15 DEG C~-20 DEG C of above-mentioned low temperature environment；More preferably -17 DEG C~-19 DEG C.

Specifically, the preparation method of above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, which is characterized in that use Following steps purifying: (R) -4- hydroxyl -2- oxo-1-pyrrolidine is added with the concentration of 5mg/mL-50mg/mL in organic solvent Acetamide crude product, is stirred continuously, and 45 DEG C~75 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution sealing is put The crystallisation by cooling in -17 DEG C~-19 DEG C of low temperature environment is set, crystallization is filtered to isolate, in 65-75 DEG C, relative humidity 0- Dry 4-6h under the conditions of 30%, obtains the crystallization of (R)-Esomeprazole；The organic solvent is selected from The combination of one or more of ethyl alcohol, tetrahydrofuran, acetone, methanol, butanone, isoamyl alcohol, acetonitrile, normal propyl alcohol.

Scheme two:

(R)-Esomeprazole crude product is dissolved in the mixed solvent, filters, filtrate is covered Sealing, stirring；It filters again, filtrate solvent flashing in drier forms crystallization after filtering, collects crystallization, is dried to obtain dextrorotation Oxiracetam crystallization；The mixed solvent is that good solvent is mixed with poor solvent, and wherein good solvent is selected from DMF, dimethyl Acetamide, normal propyl alcohol or n-butanol, poor solvent are selected from methylene chloride, acetone, ethyl acetate, tetrahydrofuran, ether, n-hexane Or petroleum ether；When good solvent is DMF, poor solvent is methylene chloride, acetone, any one in ethyl acetate；When good molten When agent is dimethyl acetamide, poor solvent is tetrahydrofuran, acetone, any one in ethyl acetate；When good solvent is positive When propyl alcohol, poor solvent is tetrahydrofuran, ether, any one in n-hexane；When good solvent is n-butanol, poor solvent For any one in methylene chloride, ether, petroleum ether.

Above-mentioned mixed solvent be DMF (n,N-Dimethylformamide) with it is any one in methylene chloride, acetone, ethyl acetate Kind mixing refers to that mixed solvent can mix for DMF with methylene chloride, or DMF is mixed with acetone, can also be DMF is mixed with ethyl acetate.Similarly, normal propyl alcohol is mixed with any one in tetrahydrofuran, ether, n-hexane, and referring to can Think that normal propyl alcohol is mixed with tetrahydrofuran, or normal propyl alcohol is mixed with ether, can also be mixed for normal propyl alcohol with n-hexane； Dimethyl acetamide is mixed with any one in tetrahydrofuran, acetone, ethyl acetate, refers to dimethyl acetamide and four Hydrogen furans mixing, or dimethyl acetamide is mixed with acetone, or dimethyl acetamide is mixed with ethyl acetate； N-butanol is mixed with any one in methylene chloride, ether, petroleum ether, refers to that n-butanol is mixed with methylene chloride, can also Think that n-butanol is mixed with ether, can also be mixed for n-butanol with petroleum ether.

Preferably, the mass volume ratio of above-mentioned (R)-Esomeprazole crude product and mixed solvent It (g/mL) is 1:2~1:10.

The volume ratio of above-mentioned in the mixed solvent good solvent and poor solvent is 1:1~1:7；It is preferred that 1:2~1:5.

Preferably, it is above-mentioned filtrate is sealed after, mixing time be 3~for 24 hours, mixing speed be 100~150r/min.

It is above-mentioned it is collected by filtration after, at 10-40 DEG C, relative humidity dry 4-6h under conditions of being 55-85%；It is preferred that 25-40 DEG C, relative humidity dry 5-6h under conditions of being 65-85%.

Specifically, the preparation method of above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, which is characterized in that use Following steps purifying: (R)-Esomeprazole crude product is dissolved in the mixed solvent, wherein (R) -4- The mass volume ratio (g/mL) of hydroxy-2-oxo-1-pyrrolidine acetamide and mixed solvent is 1:2~1:10, filtering, by filtrate It seals, with the speed of 100~150r/min stirring 5~for 24 hours, filters again, filtrate stands in drier and waves after filtering Solvent formation crystallization is sent out, crystallization is collected, by the crystallization of collection at 25-40 DEG C, drying 5- under conditions of relative humidity is 65-85% 6h, both；The mixed solvent is that good solvent is mixed with poor solvent, and the volume ratio of good solvent and poor solvent is 1:2 ~1:5, wherein good solvent is selected from DMF, dimethyl acetamide, normal propyl alcohol or n-butanol, and poor solvent is selected from methylene chloride, third Ketone, ethyl acetate, tetrahydrofuran, ether, n-hexane or petroleum ether；When good solvent be DMF when, poor solvent be methylene chloride, Any one in acetone, ethyl acetate；When good solvent is dimethyl acetamide, poor solvent is tetrahydrofuran, acetone, second Any one in acetoacetic ester；When good solvent is normal propyl alcohol, poor solvent is tetrahydrofuran, ether, any in n-hexane It is a kind of；When good solvent is n-butanol, poor solvent is methylene chloride, ether, any one in petroleum ether.

Scheme three:

It is with concentration 20mg/mL-150mg/mL that (R)-Esomeprazole is thick with organic solvent Product dissolution, is made suspension, seals, and is 10-40 DEG C of stirring 20-36h in temperature, and filtrate is stood volatilization crystallization by filtering, Crystal is collected, it is dry, both；The organic solvent is selected from pyridine, isopropanol, methanol, ethyl alcohol, normal propyl alcohol, sec-butyl alcohol, positive fourth Alcohol, isoamyl alcohol, acetonitrile, acetone, butanone, ethylene glycol, tetrahydrofuran.

Preferably, above-mentioned drying be 65-75 DEG C, relative humidity be 0-30% under the conditions of dry 4-6h.

Scheme four:

The first solvent of (R)-Esomeprazole crude product is dissolved, the second solvent is then added Suspension is formed, filtrate is sealed, is stirred continuously in drier by filtering, and solvent flashing forms crystallization, and knot is collected by filtration Crystalline substance is 35-75 DEG C in temperature, and drying 3-8h is both obtained under conditions of relative humidity is 10-40%；First solvent be methanol, Dimethyl acetamide, ethyl alcohol, acetic acid, isopropanol, n-butanol or normal propyl alcohol；Second solvent is petroleum ether, ether, tetrahydro furan It mutters, methylene chloride, acetone, ethyl acetate or n-hexane；When the first solvent be methanol when, the second solvent be petroleum ether, ether or N-hexane；When the first solvent is normal propyl alcohol, the second solvent is ether；When the first solvent is dimethyl acetamide, second is molten Agent is ethyl acetate or ether；When the first solvent is ethyl alcohol, the second solvent is ethyl acetate, petroleum ether or n-hexane；When When one solvent is DMF, the second solvent is methylene chloride, ethyl acetate or ether；When the first solvent is isopropanol, the second solvent For ether or n-hexane；When the first solvent is acetic acid, the second solvent is ether；When the first solvent is n-butanol, second is molten Agent is ether or n-hexane.

Preferably, it is above-mentioned it is collected by filtration after, at 55-75 DEG C, relative humidity dry 4- under conditions of being 15-40% 6h。

The mass volume ratio (g/mL) of above-mentioned (R)-Esomeprazole crude product and the first solvent For 1:1~1:8；The volume ratio of second solvent and the first solvent is 1:1~6:1.

Further, the mass volume ratio of above-mentioned (R)-Esomeprazole crude product and the first solvent It (g/mL) is 1:1~1:5；The volume ratio of second solvent and the first solvent is 1:1~4:1.

The adding manner of above-mentioned second solvent is to be added dropwise, and the dropwise addition is divided to two dropwise addition periods, before 1/2 volume dropwise addition Speed be 300~450mL/min, behind 1/2 volume rate of addition be 100~155mL/min.

Specifically, the preparation method of above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, which is characterized in that (R) - 4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is purified using following steps:

The first solvent of (R)-Esomeprazole crude product is dissolved, wherein (R) -4- hydroxyl - The mass volume ratio (g/mL) of 2- oxo-1-pyrrolidine ethanamide crude product and the first solvent is 1:1~1:8；Then molten in clarification The second solvent is added dropwise in liquid and forms suspension, wherein the volume ratio of the second solvent and the first solvent is 1:1~6:1, and is added dropwise and divides Two dropwise addition periods, before 1/2 volume rate of addition be 320~450mL/min, behind 1/2 volume rate of addition be 100 ~155mL/min；Filtering, filtrate is sealed, is stirred continuously in drier, and mixing speed is 100~150r/min, is waved It sends out solvent and forms crystallization, it is collected by filtration, at 55-75 DEG C, relative humidity dry 4-6h under conditions of being 20-30%, both； First solvent is methanol, dimethyl acetamide, ethyl alcohol, acetic acid, isopropanol, n-butanol or normal propyl alcohol；Second solvent For petroleum ether, ether, tetrahydrofuran, methylene chloride, acetone, ethyl acetate or n-hexane；When the first solvent is methanol, second Solvent is petroleum ether, ether or n-hexane；When the first solvent is normal propyl alcohol, the second solvent is ether；When the first solvent is two When methylacetamide, the second solvent is ethyl acetate or ether；When the first solvent be ethyl alcohol when, the second solvent be ethyl acetate, Petroleum ether or n-hexane；When the first solvent is DMF, the second solvent is methylene chloride, ethyl acetate or ether；When the first solvent When for isopropanol, the second solvent is ether or n-hexane；When the first solvent is acetic acid, the second solvent is ether；When first molten When agent is n-butanol, the second solvent is ether or n-hexane.

Scheme five:

(R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is added in methyl alcohol, supersaturated solution is made；It will obtain Supersaturated solution ethyl alcohol be added form mixed solution, be placed on crystallisation by cooling in 0 DEG C~5 DEG C of low temperature environment, both.

Preferably, (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is added in methyl alcohol, supersaturated solution is made； Ethyl alcohol is added in supersaturated solution and forms mixed solution, the volume ratio of amount and supersaturated solution that ethyl alcohol is added is 1~5:1； Mixed solution is placed on to crystallisation by cooling in 0 DEG C~5 DEG C of low temperature environment, both.

It is further preferred:

(1) (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is added in methyl alcohol, is stirred continuously, is heated to 30 DEG C~100 DEG C of dissolutions, concentration removing part methanol, obtained supersaturated solution；

(2) ethyl alcohol is added in the supersaturated solution that step (1) obtains and forms mixed solution by, and the amount and step of ethyl alcohol is added Suddenly the supersaturated solution volume ratio that (1) obtains is 1~5:1；Mixed solution is placed in 0 DEG C~5 DEG C of low temperature environment cooling Crystallization, both.

Still more preferably, the purifying of above-mentioned (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, (R) -4- hydroxyl -2- Oxygen -1- pyrrolidine acetamide crude product uses following steps:

(1) (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is added in methyl alcohol, is stirred continuously, is heated to 30 DEG C~100 DEG C of dissolutions, active carbon decoloring is added, is filtered, methanol solution is obtained, concentration removes 50%-90% methanol, and satiety is made And solution；

(2) ethyl alcohol is added in the supersaturated solution that step (1) obtains and forms mixed solution by, and the amount and step of ethyl alcohol is added Suddenly the supersaturated solution volume ratio that (1) obtains is 1~5:1；Mixed solution is placed in 0 DEG C~5 DEG C of low temperature environment and is stirred Crystallization, filtering, both.

In purification process of the present invention, stir to be filtered into known in the art for usual manner known in the art Conventional solid-liquid separate mode.

The utility model has the advantages that

The present invention provides the preparation method of one kind (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters, this method passes through The mode of two-phase extraction, is first extracted product using water from reaction system solvent, into water phase, then uses ethyl acetate Product is entered in ethyl acetate phase from extraction in water again, to purify (R) -4- hydroxyl well in the case where uncrystallizable Base -2- oxygen -1- pyrrolidine acetic acid ester.This method raw material is cheap and easy to get, the raw material or solvent being more toxic is not used, to operator Member's safety is good, and does not need large scale equipment, and industrial production compliance is good, produces close to enterprise practical.It prepares through the invention (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters through ammonolysis then purify preparation (R) -4- hydroxyl -2- oxo -1- pyrrole Alkyl acetamide yield is coughed up up to 45~50% (in terms of R-4- amino -3-hydroxybutyrates), purity is up to 99.9%, has apparent Economy and operability.

Embodiment

In order to keep the purpose of the present invention and technical solution clearer, the preferred embodiment of the present invention is carried out below detailed Description.It is noted that following embodiment is served only for that the present invention is further detailed, and should not be understood as to this hair The limitation of bright protection scope.Those skilled in the art's above content according to the present invention make it is some it is nonessential improvement and Adjustment all belongs to the scope of protection of the present invention.The raw materials used in the present invention and reagent are commercial product.

Embodiment 1

- 3 hydroxybutyric acid 14.8kg of R-4- amino is placed in the reaction kettle of 300L, 75kg methanol is added, is cooled to 0-5 DEG C, lower instillation thionyl chloride 14.8kg is stirred, after being added dropwise, 50-55 DEG C is warming up to, stirs one hour.TLC detection has been reacted Entirely.Most of (about 90%) solvent of removing is concentrated under reduced pressure and obtains light yellow oil, as R₁For the intermediate II of methyl.R₁For first The specific structure and nuclear-magnetism of the intermediate II of base are as follows:

1H-NMR(300MHz,DMRO-d6)δ2.0(s,2H),2.06(s,1H)2.53,2.28(m,2H)2.67,2.92 (m,2H),3.67(s,3H)。

Embodiment 2

Intermediate II (R prepared by embodiment 1₁For methyl) grease suction 165kg ethyl acetate dissolution, it is cooled to 5- 10 DEG C, bromoacetic acid N-butyl 27.5kg is added, is slowly dropped into triethylamine 28.2kg, there are a large amount of solids to generate.Insulation reaction 3 is small When, it is to slowly warm up to 20-25 DEG C, the reaction was continued 1 hour.Raw material fully reacting is shown in TLC detection.It filters, the second of solid 20kg Acetoacetic ester top is washed once, and filtrate is transferred in the extraction reaction kettle of 500L and is washed with 40kg × 3 time, combining water layer, water layer EA 40kg is washed once, is incorporated in ethyl acetate phase.Ethyl acetate, which is concentrated under reduced pressure, does to obtain yellow oil, as R₁For methyl, R₂It is positive The intermediate compound I of butyl.R₁For methyl, R₂It is as follows for the intermediate compound I specific structure and nuclear-magnetism of normal-butyl:

1H-NMR(300MHz,DMRO-d6)δ2.0(s,1H),2.06(s,1H)2.28,2.53(m,2H)4.09(m,1H) 2.83,2.58(m,2H),3.67(m,3H),3.51(s,2H),4.08(m,2H)1.57(m,2H)1.33(m,2H)0.96(m, 3H)

Embodiment 3

Intermediate compound I (R prepared by embodiment 2₁For methyl, R₂For the intermediate compound I of normal-butyl.R₁For methyl, R₂Be positive fourth Base) grease is pumped into toluene 200kg dissolution, and collet opens hot water circuit and is warming up to 75-80 DEG C, and insulation reaction 4-5 hour, TLC was supervised Fully reacting is controlled, decompression steams toluene, obtains grease R₂For (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters of normal-butyl Crude product.R₂It is as follows for (the R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters specific structure and nuclear-magnetism of normal-butyl:

1H-NMR(300MHz,DMRO-d6)δ2.06(s,1H)2.51,2.26(m,2H)3.73(m,1H)3.67,3.42 (m,2H),4.16(s,2H),4.08(m,2H),1.57(m,2H),1.33(m,2H),0.96(m,3H)。

Embodiment 4

It is thick that the decompression of embodiment 3 is steamed into grease (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters that toluene obtains Product are cooled to room temperature, and the extraction of water 70kg × 3 time is added, and are merged water phase and are transferred in 500L extractor, the mutually impure barrelling of toluene, Sodium chloride 20kg is added in water phase, the extraction of ethyl acetate 85kg × 4 time is added in stirring and dissolving, and it is dense that merging organic phase is transferred to 500L Contracting tank.It is concentrated under reduced pressure and removes solvent, toluene 17kg band is added water 1 time, collet leads to tap water and is cooled to room temperature, obtains oil after purification Shape object (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters.

Embodiment 5

(R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester (R prepared by above-described embodiment 4₂For normal-butyl) in grease It is pumped into 165kg methanol ammonia (concentration 10%), tank is closed in 25-30 DEG C and is stirred 12-16 hours.TLC monitors fully reacting.It depressurizes dense Contracting removes methanol ammonia gasoloid, and ethyl alcohol 80kg is added, and stirring is cooled to 0-5 DEG C, and a large amount of crystal are precipitated, heat preservation crystallization 10 hours, Filtering, filter cake are washed with 5kg ethyl alcohol top, drain filtrate and obtain (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product 10.4kg. Obtained (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is transferred in 300L bleacher and takes out people's methanol 120kg dissolution, It is warming up to 45-50 DEG C, dissolution of raw material is complete, active carbon 500g stirring is added decoloration 1 hour, is cooled to room temperature, refined filtration is except deactivation Property charcoal, filtrate, which is transferred in 300L crystallizing tank to be concentrated under reduced pressure, removes most of methanol (about 90%), ethyl alcohol 80kg is added while hot, cooling To 0-5 DEG C, stirred crystallization 5 hours, filtering, filter cake washed with 5kg ethyl alcohol top, and 50 DEG C are dried under reduced pressure and obtain within 6 hours (R) -4- hydroxyl - 2- oxygen -1- pyrrolidine acetamide 9.4kg, purity 99.9%.Structure and nuclear magnetic data are as follows:

1H-NMR(300MHz,DMRO-d6)δ2.13(d,1H),2.59(dd,1H),3.71(d,1H),3.89(d,1H), 4.13(d,1H),4.34(m,1H),5.27(R,1H),7.14(R,1H),7.36(R,1H)。

Embodiment 6

Grease (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters crude product prepared by embodiment 3, referring to embodiment 5, (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide is prepared by methanol ammonia, obtains (R) -4- hydroxyl -2- oxygen -1- pyrrolidines Acetamide crude product 10.5kg；Obtained (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is transferred in 300L bleacher and is taken out People's methanol 120kg dissolution, is warming up to 45-50 DEG C, and dissolution of raw material is complete, active carbon 500g stirring is added decoloration 1 hour, is cooled to Room temperature, refined filtration remove active carbon, and filtrate, which is transferred in 300L crystallizing tank to be concentrated under reduced pressure, removes most of methanol (about 90%), while hot plus Enter ethyl alcohol 80kg, is cooled to 0-5 DEG C, stirred crystallization 5 hours, filtering, filter cake was washed with 5kg ethyl alcohol top, and 50 DEG C are dried under reduced pressure 6 hours Obtain (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide 9.3kg, purity 99.3%.

Relative to embodiment 5, embodiment 6 do not carry out (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters purifying and it is direct (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide that ammonolysis obtains, purity are significantly lower than (R) -4- hydroxyl-prepared by embodiment 5 2- oxygen -1- pyrrolidine acetamide, and there are the impurity that multiple contents are greater than 0.1%.According to the regulation of Chinese Pharmacopoeia version in 2015, Impurity of the content greater than 0.1% needs to carry out Structural Identification, and the miscellaneous content of list it is also required to provide toxicology data when higher.Thus originally Invention not only increases the purity of downstream product (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, increases drug safety, Drug research workload is also greatly reduced, is conducive to new drug and innovates.

Embodiment 7

Referring to embodiment 1, -3 hydroxybutyric acid of R-4- amino is placed in reaction kettle, the alcohol of 5~20 times of weight is added (as just The C such as propyl alcohol, isopropanol, cyclopentanol₁-C₆Alcohol) mixing, then be added thionyl chloride reacted 1~5 hour at 0~60 DEG C, R- The molar ratio of 4- amino -3-hydroxybutyrate and thionyl chloride is 1:1~2；Obtain R₁For C₃-C₆Intermediate II, specific structure and Nuclear-magnetism such as the following table 1:

The structure and nuclear-magnetism of 1 intermediate II of table

Embodiment 8

By the intermediate II acetone solution in table 1, it is cooled to 5-10 DEG C, halogenated acetic acids ester is added, is slowly dropped into pyridine, There are a large amount of solids to generate.Insulation reaction 3 hours, it is to slowly warm up to 20-25 DEG C, the reaction was continued 1 hour.TLC detection is shown in that raw material is anti- It should be complete.It filters, solid is washed once with ethyl acetate top, and filtrate water is washed, and water layer is washed once with EA, is incorporated to ethyl acetate phase In.Ethyl acetate, which is concentrated under reduced pressure, does to obtain yellow oil, as intermediate compound I, specific structure and nuclear-magnetism such as the following table 2:

The structure and nuclear-magnetism of 2 intermediate compound I of table

Embodiment 9

Referring to embodiment 3 and 4, the intermediate compound I in table 2 is dissolved with toluene, is reacted 2.5~9 hours at 55~133 DEG C； Add water to extract reaction solution after reaction, ethyl acetate is then added in water phase and extracts again, collects acetic acid extracted Ethyl ester is concentrated to get (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, specific structure and parsing such as the following table 3.

The structure and nuclear-magnetism of table 3 (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester

It is found in preparation process, (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester in table 3, and not all R₂For C₁-C₆ Arrcostab be suitable for the extraction of water of the present invention-ethyl acetate two-phase, such asIt can be from toluene phase It is middle to enter water phase, it can be difficult to entering ethyl acetate phase from water phase；AndIt is difficult to mutually enter water from toluene Phase.

Simultaneously it has also been found that, DMF or DMSO as reaction dissolvent, using water of the present invention-ethyl acetate two-phase effect of extracting compared with Difference；And butyl acetate is extracted as reaction dissolvent using water of the present invention-ethyl acetate two-phase, it is molten that effect of extracting, which is weaker than toluene, Agent.

Embodiment 10

Referring to embodiment 5, (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester prepared by above-described embodiment 9 is 20~30 The concentrated ammonia liquor or methanol ammonia gasoloid for being 25%~28% with mass percentage concentration at DEG C react 4~16 hours, then from reaction Target product (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is collected in product, (R) -4- hydroxyl -2- is made in repurity Oxygen -1- pyrrolidine acetamide.

(R) -4- hydroxyl -2- oxo-1-pyrrolidine acetic acid esters prepared by the present invention first uses in such a way that two-phase extracts Water extracts product from reaction system solvent, into water phase, then using ethyl acetate product extracted from water again into Enter in ethyl acetate phase, to purify (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid well in the case where uncrystallizable Ester prepares (R)-Esomeprazole for ammonolysis, and yield is up to 45~50% (with R-4- amino- 3-hydroxybutyrate meter), purity is up to 99.9%, has apparent economy and operability.

Embodiment 11

The preparation method of the present invention (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, is purified using following steps: being had (R)-Esomeprazole crude product is added with the concentration of 5mg/mL-50mg/mL in solvent, is constantly stirred It mixes, 45 DEG C~75 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution sealing is placed on -17 DEG C~-19 DEG C Low temperature environment in crystallisation by cooling, filter to isolate crystallization, 65-75 DEG C, relative humidity be 0-30% under the conditions of dry 4-6h, Obtain the crystallization of (R)-Esomeprazole；The organic solvent be selected from ethyl alcohol, tetrahydrofuran, acetone, The combination of one or more of methanol, butanone, isoamyl alcohol, acetonitrile, normal propyl alcohol.

Specifically are as follows: (the R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product for preparing embodiment 5 is molten with 10mg/mL For solution in normal propyl alcohol, 32 DEG C of heating, filtering obtains supersaturated solution, and the sealing of this solution is placed on cooling crystallization under -12 DEG C of environment It 25 hours, is separated by filtration, dry 6h or so, obtains colourless sand shaped crystalline substance under the conditions of temperature is 60 DEG C, relative humidity is 35% Body.The colourless sand shaped crystal of preparation is placed on monocrystal silicon sample platform, it is heated to 80 DEG C by 30 DEG C, respectively 35, 45,55,65,75 DEG C of progress powder x-ray diffraction measurements, test result show, the colourless sand shaped crystal of the present invention 30 DEG C- Do not occur crystal phenomenon between 80 DEG C, it is seen that the present invention (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crystallizes high-temperature stability It is good.

Further, referring to the preparation method of embodiment 11, using ethyl alcohol, tetrahydrofuran, acetone, methanol, butanone, isoamyl One of alcohol, acetonitrile are organic solvent, and (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide of preparation crystallizes, 30 DEG C - Do not occur crystal phenomenon between 80 DEG C.

Embodiment 12

(R) preparation method of -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, is purified using following steps: by (R) -4- hydroxyl Base -2- oxo-1-pyrrolidine ethanamide crude product is dissolved in the mixed solvent, wherein (R) -4- hydroxyl -2- oxo-1-pyrrolidine acetyl The mass volume ratio (g/mL) of amine and mixed solvent is 1:2~1:10, and filtering seals filtrate, with 100~150r/min Speed stirring 5~for 24 hours, filter again, after filtering filtrate is stood in drier solvent flashing formed crystallization, collect crystallize, By the crystallization of collection at 25-40 DEG C, relative humidity dry 5-6h under conditions of being 65-85%, both；The mixed solvent is good Solvent is mixed with poor solvent, and the volume ratio of good solvent and poor solvent is 1:2~1:5, wherein good solvent be selected from DMF, Dimethyl acetamide, normal propyl alcohol or n-butanol, poor solvent be selected from methylene chloride, acetone, ethyl acetate, tetrahydrofuran, ether, N-hexane or petroleum ether；When good solvent is DMF, poor solvent is methylene chloride, acetone, any one in ethyl acetate； When good solvent is dimethyl acetamide, poor solvent is tetrahydrofuran, acetone, any one in ethyl acetate；When good molten When agent is normal propyl alcohol, poor solvent is tetrahydrofuran, ether, any one in n-hexane；When good solvent is n-butanol, no Good solvent is methylene chloride, ether, any one in petroleum ether.

Specifically are as follows: (the R)-Esomeprazole crude product for preparing embodiment 5 is with 0.5g/mL Being dissolved in the mixed solvent, (dimethyl acetamide and acetone volume ratio is in 1:5) solution, 40 DEG C of heating for dissolving, filtering will be filtered Liquid seals, and with the speed stirring 20h or so of 100r/min or so, filters again, filtrate stands in drier after filtering Solvent flashing forms crystallization, collects crystallization, and by the crystallization of collection at 30 ± 2 DEG C, relative humidity is dry under conditions of being 70-75% 6h or so obtains colourless sand shaped crystal.The colourless sand shaped crystal of preparation is subjected to dynamic water adsorption analysis (DVS) examination Test, test parameters is as follows: weighing: Ultra digitizes micro- balance SMS Ultra BalanceTM；Flow velocity: N₂, 200sccm, be System control software: DVS-Intrinsic control software ver.1.0.3.1, Data Analysis Software: Isotherm (ISO)analysis suite.Sample 22.4mg, RH=0% are dried, and balance quality to ensure to remove surface adsorption water Point, it is subsequently placed on metal sample pallet, is tested after the dry 2h of 0%RH, temperature is constant at 25 DEG C, controls relative humidity (RH%) variation of the example weight with humidity, combining powder are measured by 0%-90%-0%RH circulation change with 10% gradient X-ray diffraction is characterized to observe influence of the humidity to sample crystal transfer, as a result, it has been found that without significant change.It is prepared by the present invention (R)-Esomeprazole can be stabilized under the conditions of relative humidity is 0-95%, will not be occurred Turn crystalline substance.

Further, referring to the preparation method of embodiment 12, when good solvent is DMF, poor solvent is methylene chloride, third Any one in ketone, ethyl acetate；Or when good solvent is dimethyl acetamide, poor solvent is tetrahydrofuran, acetic acid second Any one in ester；Or when good solvent is normal propyl alcohol, poor solvent is tetrahydrofuran, ether, any one in n-hexane Kind；When good solvent is n-butanol, poor solvent is methylene chloride, ether, any one in petroleum ether；(R) -4- of preparation The crystallization of hydroxyl -2- oxygen -1- pyrrolidine acetamide, can be stabilized under the conditions of relative humidity is 0-95%, will not occur Turn crystalline substance.

Embodiment 13

(R) preparation method of -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, is purified using following steps: using organic solvent (R)-Esomeprazole crude product is dissolved with concentration 20mg/mL-150mg/mL, is sealed, Temperature is 10-40 DEG C of stirring 20-36h, and filtrate is stood volatilization crystallization, collects crystal, be in 65-75 DEG C, relative humidity by filtering Dry 4-6h under the conditions of 0-30%, both；The organic solvent is selected from pyridine, isopropanol, methanol, ethyl alcohol, normal propyl alcohol, Zhong Ding Alcohol, n-butanol, isoamyl alcohol, acetonitrile, acetone, butanone, ethylene glycol, tetrahydrofuran.

Specifically are as follows: use (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product prepared by embodiment 5 with 29mg/mL Tetrahydrofuran stirring and dissolving, seals, and is that the 20-25 DEG C of speed with 200-250r/min stirs 25h in temperature, filters, will Filtrate stands volatilization crystallization, collects crystal, is 70-75 DEG C in temperature, relative humidity dry 4-5h under conditions of being 20-25%, Collect crystallization.(R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crystallization of collection is placed on monocrystal silicon sample platform, by it 80 DEG C are heated to by 30 DEG C, respectively in 35,45,55,65,75 DEG C of progress powder x-ray diffraction measurements, test result is shown, this Invention (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide does not occur crystal phenomenon between 30 DEG C -80 DEG C, it is seen that the present invention (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide high-temperature stability is good.

Further, referring to the preparation method of embodiment 13, using pyridine, isopropanol, methanol, ethyl alcohol, normal propyl alcohol, Zhong Ding One of alcohol, n-butanol, isoamyl alcohol, acetonitrile, acetone, butanone, ethylene glycol are organic solvent, (R) -4- hydroxyl -2- of preparation The crystallization of oxygen -1- pyrrolidine acetamide, does not occur crystal phenomenon between 30 DEG C -80 DEG C.

Embodiment 14

(R) preparation method of -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide purifies (R) -4- hydroxyl-using following steps 2- oxygen -1- pyrrolidine acetamide crude product: the first solvent of (R)-Esomeprazole crude product is dissolved, Wherein the mass volume ratio (g/mL) of (R)-Esomeprazole crude product and the first solvent is 1:1~1: 8；Then the second solvent is added dropwise in clear solution and forms suspension, wherein the volume ratio of the second solvent and the first solvent is 1:1 ~6:1, and be added dropwise be divided to two dropwise addition periods, before 1/2 volume rate of addition be 320~450mL/min, behind 1/2 volume Rate of addition be 100~155mL/min；Filtering, filtrate is sealed, is stirred continuously in drier, mixing speed is 100~150r/min, solvent flashing forms crystallization, collected by filtration, and at 55-75 DEG C, relative humidity is the condition of 20-30% Lower dry 4-6h, both；First solvent is methanol, dimethyl acetamide, ethyl alcohol, acetic acid, isopropanol, n-butanol or positive third Alcohol；Second solvent is petroleum ether, ether, tetrahydrofuran, methylene chloride, acetone, ethyl acetate or n-hexane；When first molten When agent is methanol, the second solvent is petroleum ether, ether or n-hexane；When the first solvent is normal propyl alcohol, the second solvent is ether； When the first solvent is dimethyl acetamide, the second solvent is ethyl acetate or ether；When the first solvent is ethyl alcohol, second is molten Agent is ethyl acetate, petroleum ether or n-hexane；When the first solvent is DMF, the second solvent is methylene chloride, ethyl acetate or second Ether；When the first solvent is isopropanol, the second solvent is ether or n-hexane；When the first solvent is acetic acid, the second solvent is Ether；When the first solvent is n-butanol, the second solvent is ether or n-hexane.

Specifically are as follows: (the R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product for preparing embodiment 5 is with quality volume It is that 1:3 dissolves in methyl alcohol than (g/mL), 40 DEG C of heating, filtering obtains clear solution, petroleum ether is then added dropwise in clear solution Formed suspension, wherein the volume ratio of petroleum ether and methanol be 6:1, and be added dropwise be divided to two dropwise addition periods, before 1/2 volume drop Acceleration is 380mL/min, behind 1/2 volume rate of addition be 125mL/min；Filtering, filtrate is sealed, in drying It being stirred continuously in device, mixing speed 130r/min, solvent flashing forms crystallization, and it is collected by filtration, at 70 DEG C, relative humidity Dry 4h, both obtains crystal under conditions of being 25%.Using pharmacopeia annex XIXC in 2015, " bulk pharmaceutical chemicals and drug preparation stability were tried Test guideline " in the regulation in relation to bulk pharmaceutical chemicals accelerated test, investigate the crystal stability of preparation.Specially in climatic chamber In, it at 40 ° ± 2 DEG C of temperature, is carried out under conditions of relative humidity 75% ± 5%, (R) -4- hydroxyl -2- oxygen of discovery preparation after 2h Generation -1- pyrrolidine acetamide crystal is unchanged；(the R)-Esomeprazole crystal prepared after 10d without Variation；(the R)-Esomeprazole crystal prepared after 15d is still unchanged.It can be seen that preparation (R)-Esomeprazole crystal at 40 ° ± 2 DEG C of temperature, the condition of relative humidity 75% ± 5% Under can be stabilized, will not occur turn crystalline substance.

Further, referring to the preparation method of embodiment 14, when the first solvent is methanol, dimethyl acetamide, ethyl alcohol, vinegar Acid, isopropanol, n-butanol or normal propyl alcohol；Second solvent is petroleum ether, ether, tetrahydrofuran, methylene chloride, acetone, acetic acid second Ester or n-hexane；Or when the first solvent is methanol, the second solvent is petroleum ether, ether or n-hexane；Or when the first solvent is When normal propyl alcohol, the second solvent is ether；Or when the first solvent is dimethyl acetamide, the second solvent is ethyl acetate or second Ether；Or when the first solvent is ethyl alcohol, the second solvent is ethyl acetate, petroleum ether or n-hexane；Or when the first solvent is DMF When, the second solvent is methylene chloride, ethyl acetate or ether；Or when the first solvent be isopropanol when, the second solvent be ether or N-hexane；Or when the first solvent is acetic acid, the second solvent is ether；Or when the first solvent is n-butanol, the second solvent is When ether or n-hexane, (R)-Esomeprazole crystal of preparation is at 40 ° ± 2 DEG C of temperature, relatively It can be stabilized under conditions of humidity 75% ± 5%, will not occur to turn crystalline substance.

Claims

1. the preparation method of one kind (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, which is characterized in that use following route system :

Wherein, R₁For C₁-C₆Alkyl, R₂For isopropyl, n-propyl, isobutyl group, normal-butyl or tert-butyl；It after reaction will be anti- It answers liquid that water is added to extract, ethyl acetate is then added in water phase and extracts again, collects ethyl acetate extracted, is concentrated to get (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester.

2. method as described in claim 1, it is characterised in that: R₁For C₁-C₆Alkyl be selected from methyl, ethyl, isopropyl, positive third Base, normal-butyl, isobutyl group tert-butyl, cyclopenta or benzyl.

3. method as claimed in claim 1 or 2, it is characterised in that: reaction dissolvent is butyl acetate, toluene, in DMF, DMSO One or more mixing；Reaction temperature is 55~133 DEG C；Reaction time is 2.5~9 hours.

4. method as claimed in claim 3, it is characterised in that: reaction dissolvent is toluene.

5. such as any one of claim 1-4 the method, it is characterised in that: the intermediate compound I is made with following route:

Wherein, R₁For C₁-C₆Alkyl, R₂For C₁-C₆Alkyl, X is halogen；Reaction dissolvent be methanol, ethyl alcohol, methylene chloride, The combination of one or more of ethyl acetate, tetrahydrofuran, acetone, butanone or ethyl butyrate；Catalyst be triethylamine, pyridine or Lutidines；Reaction temperature is 5~65 DEG C, and the reaction time is 4.5~10 hours.

6. method as claimed in claim 5, it is characterised in that: the halogen is chlorine or bromine.

7. such as claim 5 or 6 the methods, it is characterised in that: the molar ratio of the intermediate II and halogenated acetic acids ester are as follows: 1: 1~3, the molar ratio of intermediate II and the catalyst are as follows: 1:2~3.

8. such as any one of claim 5-8 the method, it is characterised in that: the intermediate II is made using following route:

First by R-4- amino -3-hydroxybutyrate and 5~20 times of weight R₁Then thionyl chloride is added at 0~55 DEG C in -ol mixing The molar ratio of lower reaction 1~5 hour, R-4- amino -3-hydroxybutyrate and thionyl chloride is 1:1~2；Acquisition contains intermediate II Alcoholic solution, intermediate II is then collected from the alcoholic solution containing intermediate II.

9. the preparation method of one kind (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester, which is characterized in that use following route system :

Wherein, R₁For for methyl, ethyl, isopropyl, n-propyl, normal-butyl, isobutyl group tert-butyl, cyclopenta or benzyl, R₂It is different Propyl, n-propyl, isobutyl group, normal-butyl or tert-butyl；X is bromine；Specific preparation process are as follows:

Intermediate II is reacted under the effect of the catalyst with monobromo-acetic acid ester is made intermediate compound I, and wherein catalyst is triethylamine, pyrrole Pyridine or lutidines, reaction dissolvent are methanol, ethyl alcohol, methylene chloride, ethyl acetate, tetrahydrofuran, acetone, butanone or butyric acid The combination of one or more of ethyl ester, reaction temperature are 5~65 DEG C, and the reaction time is 4.5~10 hours, intermediate II and bromo The molar ratio of acetic acid esters are as follows: 1:1~3, the molar ratio of intermediate II and the base catalyst are as follows: 1:2~3；Intermediate compound I is in toluene In be 55~133 DEG C of reaction time with temperature be 2.5~9 hours；Water is added to extract reaction solution after reaction, then in water phase Middle addition ethyl acetate extracts again, collects ethyl acetate extracted, is concentrated to get (R) -4- hydroxyl -2- oxygen -1- pyrrolidines Acetic acid esters.

10. the preparation method of one kind (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide, which is characterized in that use following route system :

Step are as follows:

(1) R-4- amino -3-hydroxybutyrate with contain R₁Alcohol react intermediate II, wherein R be made₁For C₁-C₆Alkyl, catalyst For acylating agent；

(2) intermediate II is reacted under base catalysis with halogenated acetic acids ester is made intermediate compound I, wherein R₂For C₁-C₆Alkyl；

(3) intermediate compound I ring closure reaction obtains (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester；

(4) (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetic acid ester aminolysis obtains target product (R) -4- hydroxyl -2- oxygen -1- pyrrolidines Acetamide.

11. the method as described in right will go 10, it is characterised in that: the C₁-C₆Alkyl be selected from methyl, ethyl, isopropyl, N-propyl, normal-butyl, isobutyl group tert-butyl, cyclopenta or benzyl.

12. method as described in claim 10 or 11, it is characterised in that: the step (1) is first by R-4- amino -3- hydroxyl The R of butyric acid and 5~20 times of weight₁- alcohol (such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, cyclopentanol C₁-C₆Alcohol) mixing, so Thionyl chloride is added afterwards to react 1~5 hour at 0~55 DEG C, the molar ratio of R-4- amino -3-hydroxybutyrate and thionyl chloride is 1:1~2；The alcoholic solution containing intermediate II is obtained, intermediate II is then collected from the alcoholic solution containing intermediate II.

13. method as described in claim 10 or 11, it is characterised in that: the step (2) is intermediate II and monobromo-acetic acid Ester reacts under the effect of the catalyst is made intermediate compound I, and wherein catalyst is triethylamine, pyridine or lutidines, reacts molten Agent is one or more of methanol, ethyl alcohol, methylene chloride, ethyl acetate, tetrahydrofuran, acetone, butanone or ethyl butyrate group It closes, reaction temperature is 5~65 DEG C, and the reaction time is 4.5~10 hours, the molar ratio of intermediate II and monobromo-acetic acid ester are as follows: 1:1 ~3, the molar ratio of intermediate II and the base catalyst are as follows: 1:2~3.

14. such as the described in any item methods of claim 10-13, it is characterised in that: the step (3) is intermediate compound I in toluene In be 55~133 DEG C of reaction time with temperature be 2.5~9 hours；Water is added to extract reaction solution after reaction, then in water phase Middle addition ethyl acetate extracts again, collects ethyl acetate extracted, is concentrated to get (R) -4- hydroxyl -2- oxygen -1- pyrrolidines Acetic acid esters.

15. such as the described in any item methods of claim 10-14, it is characterised in that: the step (4) is by (R) -4- hydroxyl - The concentrated ammonia liquor or methanol ammonia that 2- oxygen -1- pyrrolidine acetic acid ester is 25%~28% with mass percentage concentration at 20~30 DEG C are molten Liquid reacts 4~16 hours, and target product (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide is then collected from reaction product.

16. such as the described in any item methods of claim 10-15, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product is purified using following steps: by (R)-Esomeprazole crude product organic solvent Dissolution forms supersaturated solution, then crystallizes in -12 DEG C~-21 DEG C of low temperature environment, filters, dry, obtains (R) -4- hydroxyl The crystallization of base -2- oxo-1-pyrrolidine ethanamide；The organic solvent is selected from ethyl alcohol, tetrahydrofuran, acetone, methanol, butanone, different The combination of one or more of amylalcohol, acetonitrile, normal propyl alcohol.

17. the method described in claim 16, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide is thick Product use following steps to purify: (R) -4- hydroxyl -2- oxo -1- is added with the concentration of 5mg/mL-55mg/mL in organic solvent Pyrrolidine acetamide crude product, is stirred continuously, and 35 DEG C~90 DEG C heating for dissolving, filtering forms supersaturated solution；By supersaturated solution Sealing is placed on crystallisation by cooling in -12 DEG C~-21 DEG C of low temperature environment, filters to isolate crystallization, dry, obtains (R) -4- hydroxyl The crystallization of base -2- oxo-1-pyrrolidine ethanamide；The organic solvent is selected from ethyl alcohol, tetrahydrofuran, acetone, methanol, butanone, different The combination of one or more of amylalcohol, acetonitrile, normal propyl alcohol.

18. the method as described in claim 16 or 17, which is characterized in that preferably -15 DEG C~-20 DEG C of the low temperature environment；More It is preferred that -17 DEG C~-19 DEG C.

19. such as the described in any item methods of claim 16-18, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product uses following steps to purify: (R) -4- hydroxyl is added with the concentration of 5mg/mL-50mg/mL in organic solvent Base -2- oxo-1-pyrrolidine ethanamide crude product, is stirred continuously, and 45 DEG C~75 DEG C heating for dissolving, filtering forms supersaturated solution； Supersaturated solution sealing is placed on crystallisation by cooling in -17 DEG C~-19 DEG C of low temperature environment, crystallization is filtered to isolate, in 65-75 DEG C, relative humidity be 0-30% under the conditions of dry 4-6h, obtain the crystallization of (R)-Esomeprazole；Institute It states organic solvent and is selected from one or more of ethyl alcohol, tetrahydrofuran, acetone, methanol, butanone, isoamyl alcohol, acetonitrile, normal propyl alcohol group It closes.

20. such as the described in any item methods of claim 10-15, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product is purified using following steps: it is molten that (R)-Esomeprazole crude product is dissolved in mixing In agent, filtering seals filtrate, stirs；It filtering again, filtrate solvent flashing in drier forms crystallization after filtering, Crystallization is collected, the crystallization of dextrorotation Oxiracetam is dried to obtain；The mixed solvent mixes for good solvent with poor solvent, wherein Good solvent be selected from DMF, dimethyl acetamide, normal propyl alcohol or n-butanol, poor solvent be selected from methylene chloride, acetone, ethyl acetate, Tetrahydrofuran, ether, n-hexane or petroleum ether；When good solvent is DMF, poor solvent is methylene chloride, acetone, ethyl acetate In any one；When good solvent is dimethyl acetamide, poor solvent is tetrahydrofuran, acetone, appointing in ethyl acetate It anticipates one kind；When good solvent is normal propyl alcohol, poor solvent is tetrahydrofuran, ether, any one in n-hexane；Work as good solvent When for n-butanol, poor solvent is methylene chloride, ether, any one in petroleum ether.

21. method as claimed in claim 20, it is characterised in that: (the R)-Esomeprazole The mass volume ratio (g/mL) of crude product and mixed solvent is 1:2~1:10.

22. the method as described in claim 20 or 21, which is characterized in that the in the mixed solvent good solvent and poor solvent Volume ratio is 1:1~1:7；It is preferred that 1:2~1:5.

23. such as the described in any item methods of claim 20-22, it is characterised in that: after sealing filtrate, mixing time is 3~for 24 hours, mixing speed is 100~150r/min.

24. such as the described in any item methods of claim 20-23, it is characterised in that: after collected by filtration, at 10-40 DEG C, phase Dry 4-6h under conditions of being 55-85% to humidity；It is preferred that 25-40 DEG C, relative humidity dry 5- under conditions of being 65-85% 6h。

25. such as the described in any item methods of claim 20-24, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product is purified using following steps: it is molten that (R)-Esomeprazole crude product is dissolved in mixing In agent, wherein the mass volume ratio (g/mL) of (R)-Esomeprazole crude product and mixed solvent is 1: 2~1:10, filtering, filtrate is sealed, and with the speed of 100~150r/min stirring 5~for 24 hours, is filtered, is filtered again after filtering Liquid stands solvent flashing in drier and forms crystallization, collects crystallization, by the crystallization of collection at 25-40 DEG C, relative humidity 65- Dry 5-6h under conditions of 85%, both；The mixed solvent be good solvent mixed with poor solvent, good solvent with it is bad The volume ratio of solvent is 1:2~1:5, and wherein good solvent is selected from DMF, dimethyl acetamide, normal propyl alcohol or n-butanol, poor solvent Selected from methylene chloride, acetone, ethyl acetate, tetrahydrofuran, ether, n-hexane or petroleum ether；It is bad when good solvent is DMF Solvent is methylene chloride, acetone, any one in ethyl acetate；When good solvent is dimethyl acetamide, poor solvent is Tetrahydrofuran, acetone, any one in ethyl acetate；When good solvent is normal propyl alcohol, poor solvent is tetrahydrofuran, second Any one in ether, n-hexane；When good solvent is n-butanol, poor solvent is methylene chloride, ether, appointing in petroleum ether It anticipates one kind.

26. such as the described in any item methods of claim 10-15, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product uses following steps to purify: with organic solvent with concentration 20mg/mL-150mg/mL by (R) -4- hydroxyl -2- The dissolution of oxo-1-pyrrolidine ethanamide crude product, is made suspension, seals, and is 10-40 DEG C of stirring 20-36h, mistake in temperature Filtrate is stood volatilization crystallization, collects crystal by filter, dry, both；The organic solvent is selected from pyridine, isopropanol, methanol, second Alcohol, normal propyl alcohol, sec-butyl alcohol, n-butanol, isoamyl alcohol, acetonitrile, acetone, butanone, ethylene glycol, tetrahydrofuran.

27. method as claimed in claim 26, which is characterized in that the drying is in 65-75 DEG C, relative humidity 0-30% Under the conditions of dry 4-6h.

28. such as the described in any item methods of claim 10-15, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product is purified using following steps: by the first solvent of (R)-Esomeprazole crude product Then dissolution is added the second solvent and forms suspension, filtrate is sealed, is stirred continuously in drier by filtering, is volatilized molten Dosage form is collected by filtration at crystallization, is 35-75 DEG C in temperature, and dry 3-8h had been both under conditions of being 10-40% for relative humidity ?；First solvent is methanol, dimethyl acetamide, ethyl alcohol, acetic acid, isopropanol, n-butanol or normal propyl alcohol；Described second is molten Agent is petroleum ether, ether, tetrahydrofuran, methylene chloride, acetone, ethyl acetate or n-hexane；When the first solvent is methanol, the Two solvents are petroleum ether, ether or n-hexane；When the first solvent is normal propyl alcohol, the second solvent is ether；When the first solvent is When dimethyl acetamide, the second solvent is ethyl acetate or ether；When the first solvent is ethyl alcohol, the second solvent is acetic acid second Ester, petroleum ether or n-hexane；When the first solvent is DMF, the second solvent is methylene chloride, ethyl acetate or ether；When first When solvent is isopropanol, the second solvent is ether or n-hexane；When the first solvent is acetic acid, the second solvent is ether；When When one solvent is n-butanol, the second solvent is ether or n-hexane.

29. method as claimed in claim 28, it is characterised in that: after collected by filtration, at 55-75 DEG C, relative humidity is Dry 4-6h under conditions of 15-40%.

30. the method as described in claim 28 or 29, it is characterised in that: (the R) -4- hydroxyl -2- oxo-1-pyrrolidine second The mass volume ratio (g/mL) of crude amide and the first solvent is 1:1~1:8；The volume ratio of second solvent and the first solvent For 1:1~6:1.

31. such as the described in any item methods of claim 28-30, it is characterised in that: (the R) -4- hydroxyl -2- oxo -1- pyrrole The mass volume ratio (g/mL) for coughing up alkyl acetamide crude product and the first solvent is 1:1~1:5；Second solvent and the first solvent Volume ratio is 1:1~4:1.

32. such as the described in any item methods of claim 28-31, it is characterised in that: the adding manner of second solvent is drop Add, the dropwise addition is divided to two dropwise addition periods, before the rate of addition of 1/2 volume be 300~450mL/min, behind 1/2 volume Rate of addition is 100~155mL/min.

33. such as the described in any item methods of claim 28-32, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product is purified using following steps: by the first solvent of (R)-Esomeprazole crude product Dissolution, wherein the mass volume ratio (g/mL) of (R)-Esomeprazole and the first solvent for 1:1~ 1:8；Then the second solvent is added dropwise in clear solution and forms suspension, wherein the volume ratio of the second solvent and the first solvent is 1: 1~6:1, and be added dropwise be divided to two dropwise addition periods, before 1/2 volume rate of addition be 320~450mL/min, behind 1/2 volume Rate of addition be 100~155mL/min；Filtering, filtrate is sealed, is stirred continuously in drier, mixing speed is 100~150r/min, solvent flashing forms crystallization, collected by filtration, and at 55-75 DEG C, relative humidity is the condition of 20-30% Lower dry 4-6h, both；First solvent is methanol, dimethyl acetamide, ethyl alcohol, acetic acid, isopropanol, n-butanol or positive third Alcohol；Second solvent is petroleum ether, ether, tetrahydrofuran, methylene chloride, acetone, ethyl acetate or n-hexane；When first molten When agent is methanol, the second solvent is petroleum ether, ether or n-hexane；When the first solvent is normal propyl alcohol, the second solvent is ether； When the first solvent is dimethyl acetamide, the second solvent is ethyl acetate or ether；When the first solvent is ethyl alcohol, second is molten Agent is ethyl acetate, petroleum ether or n-hexane；When the first solvent is DMF, the second solvent is methylene chloride, ethyl acetate or second Ether；When the first solvent is isopropanol, the second solvent is ether or n-hexane；When the first solvent is acetic acid, the second solvent is Ether；When the first solvent is n-butanol, the second solvent is ether or n-hexane.

34. such as the described in any item methods of claim 10-15, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product is purified using following steps: (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is added in methyl alcohol, Supersaturated solution is made；Ethyl alcohol is added in obtained supersaturated solution and forms mixed solution, is placed on 0 DEG C~5 DEG C of low temperature ring Crystallisation by cooling in border, both.

35. method as claimed in claim 34, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide is thick Product are purified using following steps: (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product being added in methyl alcohol, supersaturation is made Solution；In supersaturated solution be added ethyl alcohol formed mixed solution, be added ethyl alcohol amount and supersaturated solution volume ratio be 1~ 5:1；Mixed solution is placed on to crystallisation by cooling in 0 DEG C~5 DEG C of low temperature environment, both.

36. the method as described in claim 34 or 35, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrrolidines acetyl Amine crude product is purified using following steps: (1) (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide crude product is added in methyl alcohol, no Disconnected stirring is heated to 30 DEG C~100 DEG C dissolutions, and concentration removes part methanol, and supersaturated solution is made；(2) is obtained in step (1) To supersaturated solution in ethyl alcohol be added form mixed solution, the amount of ethyl alcohol is added and supersaturated solution body that step (1) obtains Product is than being 1~5:1；Mixed solution is placed on to crystallisation by cooling in 0 DEG C~5 DEG C of low temperature environment, both.

37. such as the described in any item methods of claim 34-36, which is characterized in that (the R) -4- hydroxyl -2- oxygen -1- pyrroles Alkyl acetamide crude product is purified using following steps: (1) it is thick that (R) -4- hydroxyl -2- oxygen -1- pyrrolidine acetamide is added in methyl alcohol Product are stirred continuously, and are heated to 30 DEG C~100 DEG C dissolutions, are added active carbon decoloring, filter, and methanol solution is obtained, and concentration removes Supersaturated solution is made in 50%-90% methanol；(2) ethyl alcohol is added in the supersaturated solution that step (1) obtains and forms mixing by Solution, is added the amount of ethyl alcohol and supersaturated solution volume ratio that step (1) obtains is 1~5:1；Mixed solution is placed on 0 DEG C Stirred crystallization in~5 DEG C of low temperature environment, filtering, both.