CN102603607A - Preparation method of (R)-oxiracetam - Google Patents
Preparation method of (R)-oxiracetam Download PDFInfo
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Abstract
A preparation method of (R)-oxiracetam comprises the following steps: taking glycine ethyl ester hydrochloride and (R)-4-halo-3-hydroxyl-ethyl butyrate as raw materials to react in an alcohol solvent under an alkali condition, washing with inorganic alcohol, concentrating, extracting and separating, introducing ammonia water to prepare a crude product of oxiracetam, and purifying the crude product, wherein glycine ethyl ester hydrochloride is firstly dissociated by diethyl ether and ammonia into glycine ethyl ester. According to the invention, the main raw materials are (R)-4-halo-3-hydroxyl-ethyl butyrate and glycine ethyl ester hydrochloride, and are cheap, easily accessible, environment-friendly and pollution-free; and the glycine ethyl ester hydrochloride is firstly dissociated, so that the use amount of the materials in the reaction is effectively reduced, the cost is reduced and the yield of the reaction is improved. The prepared (R)-oxiracetam is low in cost, high in yield which can reach 33%, and mild in reaction condition which is beneficial for industrial production in large scale. The HPLC (high performance liquid chromatography) purity of the prepared (R)-oxiracetam product reaches more than 98.5%.
Description
Technical field
The present invention relates to the preparation of oxiracetam, be specifically related to a kind of preparation method of (R)-oxiracetam.
Background technology
Oxiracetam (oxiracetam); Be by Italian SmithKline than Qie Mu company in 1974 synthetic nootropics first; This medicine in 1987 in Italy listing, oxiracetam by two kinds of isomer (S)-oxiracetam ((S)-oxiracetam) with (R)-oxiracetam (raceme of (R)-oxiracetam) form.(R)-and oxiracetam is a single enantiomer of oxiracetam, chemistry is by name: (R)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide.The nootropics oxiracetam is a kind of synthetic hydroxy-amino-butyric acid (GABOB) verivate, and it is that a kind of can the promotion learnt, memory, the medicine for central nervous system of protection injured nerve cell.
Authorize the USP 4,124,594,4,173,569 and 4,629 of I.S.F.Spa, 797 disclose a kind of method for preparing the pure oxyracetam of optically-active.Disclosed method comprises and makes the reaction of optically-active pure (s)-γ amino-beta--hydroxybutyric acid and silylating reagent with the protection hydroxyl in these patents, make products therefrom in the presence of acid acceptor and wherein Hal represent the formula Hal (CH of halogen atom
2C00R) aliphatic acid halogen compounds reaction obtains the pure oxyracetam of optically-active through cyclisation and hydrolysis then.Though this method provides optically-active pure oxyracetam, its shortcoming is: expensive raw materials, step is many, yield is low, and expensive.Authorize the USP 4,824,966,4,843,166 and 5,276 of Lonza Ltd, 164 disclose oxyracetam and intermediates preparation thereof.Disclosed method comprises and makes 4-(C in these patents
1-C
2)-alkoxyl group-3-pyrroline-2-one-1-base-acetate (C
1-C
4)-alkyl ester and trichloromethyl silane reaction are carried out hydrogenation and amidation to products therefrom then with the protection hydroxyl.According to this method, obtain racemize oxyracetam through the two key reduction of hydrogenation.Therefore, this method has the shortcoming that is not suitable for the pure oxyracetam of preparation optically-active.In addition, the preparation yield of 4-(C1-C2)-alkoxyl group-3-pyrroline-2-one-1-base-acetate (C1-C4)-alkyl ester is low.But do not see also that up till now relevant bibliographical information crosses the preparation method of (R)-oxiracetam.
Summary of the invention
The object of the present invention is to provide the preparation method of (R)-oxiracetam that a kind of cost is low, yield is high.
The present invention seeks to realize through following technical scheme:
(R)-preparation method of oxiracetam; It is characterized in that: adopt glycine ethyl ester hydrochloride with (R)-4-halogen-3-hydroxyl-ethyl n-butyrate is that raw material reacts under alcoholic solvent and alkaline condition; Through filtering; With inorganic alkoxide washing, concentrated, concentrate through extraction, water again, feed the purification process that ammoniacal liquor makes (R)-oxiracetam bullion and bullion; Said glycine ethyl ester hydrochloride will adopt ether to dissociate into glycine ethyl ester with ammonia earlier.
In order further to improve the yield of the present invention (R)-oxiracetam, also carry out column chromatography for separation through extraction, water after concentrating above-mentioned, feed ammoniacal liquor preparation (R)-oxiracetam bullion again.
For the consumption that reduces reaction raw materials in the reaction process of the present invention, reduce cost; Simultaneously that glycine ethyl ester hydrochloride is free more fully to improve yield and to be beneficial to purification process; The present invention preferably adds glycine ethyl ester hydrochloride in the ether the free of glycine ethyl ester hydrochloride, feeds ammonia more at low temperatures.
In the free treating processes of the present invention to glycine ethyl ester hydrochloride; Obtain glycine ethyl ester in order further to dissociate fully; Its temperature that feeds ammonia is 2 ℃～-5 ℃; Further be preferably-3 ℃～-5 ℃, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia relation is 1mol: 1100～1300ml: 1.2～1.7mol.
Specifically; The present invention is that glycine ethyl ester hydrochloride is added in the anhydrous diethyl ether to the free processing of glycine ethyl ester hydrochloride; Ice-cold to-3 ℃～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia concerns to be 1mol: 1250ml: 1.5mol.
In order to make reactant and product be easy to dissolve and react the convenient processing after accomplishing that alcoholic solvent of the present invention is preferably anhydrous methanol or absolute ethyl alcohol.
The present invention (R)-4-halogen-3-hydroxyl-ethyl n-butyrate preferably adopts (R)-4-chloro-3-hydroxyl-ethyl n-butyrate; The alkali that the present invention adds preferably adopts yellow soda ash or sodium hydrogencarbonate.
In order further to improve yield and to be more conducive to purification process; The usage ratio of each material of the present invention is preferably glycine ethyl ester with molar ratio computing: sodium hydrogencarbonate: (R)-and 4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1～1.5: 1.2～1.8; The consumption of said absolute ethyl alcohol is 3～7 times of sodium hydrogencarbonate, in weight part; Further be preferably glycine ethyl ester: sodium hydrogencarbonate: (R)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.4: 1.6, the consumption of absolute ethyl alcohol is 4 times of sodium hydrogencarbonate.
More particularly, the preparation of the present invention (R)-oxiracetam bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether, and is ice-cold to-4 ℃～-5 ℃, feeds ammonia, and concentrated glycine ethyl ester filters, will filtrate; Add absolute ethyl alcohol then, sodium hydrogencarbonate be added dropwise to (R)-4-chloro-3-hydroxyl-ethyl n-butyrate, the time of said dropping (R)-4-chloro-3-hydroxyl-ethyl n-butyrate is 3～3.5 hours, control pH be 8～9, temperature of reaction is 65～75 ℃, reacts 20～30 hours; Filter, will filtrate with methyl alcohol or ethanol thorough washing, concentrate, enriched material is soluble in water, and the chloroform that adds 4 times of filtrating weight again extracts, and water concentrates; Add strong aqua at last again, reacted 4～7 hours down at 25～32 ℃; Said glycine ethyl ester: sodium hydrogencarbonate: (R)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1～1.5: 1.2～1.8, the consumption of said absolute ethyl alcohol is 3～7 times of sodium hydrogencarbonate weight.
In order further to improve the yield of the present invention's preparation (R)-oxiracetam; The preparation of the present invention (R)-oxiracetam bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether; Ice-cold to-4 ℃～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia concerns to be 1mol: 1250ml: 1.5mol; Add absolute ethyl alcohol then, sodium hydrogencarbonate and described (the R)-4-chloro-3-hydroxyl-ethyl n-butyrate of dropping dripped 3 hours, and control pH is 8.5, and temperature of reaction is 75 ℃, reacts 28 hours; Filter, filtrate, concentrate with the ethanol thorough washing, the chloroform that adds 4 times of filtrating weight again extracts, water concentrates column chromatography for separation; Add mass percentage concentration at last and be 28% strong aqua, 30 ℃ of reactions 5 hours down; Said glycine ethyl ester: sodium hydrogencarbonate: (R)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.4: 1.6, with molar ratio computing, the consumption of absolute ethyl alcohol is 4 times of sodium hydrogencarbonate weight; The add-on of said 28% strong aqua is 4-8 a times of above-mentioned post separated product weight.
The thick purification of product of the present invention be with thick product with water dissolution after through strongly acidic cationic exchange resin and collect, again through in the strongly basic anion exchange resin with the solution of collecting, make pH value completion when neutral of the solution of said collection; Thick product after the solution concentration of collecting that will neutralize then carries out recrystallization to be handled.
In order to improve exchange capacity, exchange velocity, strongly acidic cationic exchange resin of the present invention is preferably the 732# strongly acidic cationic exchange resin; Strongly basic anion exchange resin of the present invention is preferably the 711# strongly basic anion exchange resin.
It is to adopt ethanol to carry out the recrystallization processing first time that recrystallization of the present invention is handled, and adopts the mixed solvent of methanol/acetone to carry out the recrystallization processing second time.
In order further to improve the present invention (R)-oxiracetam product gas purity; In the purification process process of the present invention; The aqueous solution of said thick product is pressed thick product: water=1 gram: 1.2 milliliters, the consumption of said strongly acidic cationic exchange resin is: said thick product: said strongly acidic cationic exchange resin=1 gram: 13 milliliters; The consumption that said use ethanol carries out recrystallization processing for the first time is: the thick product after said the concentrating: ethanol=1 gram: 1.5 milliliters; The consumption of said second time of recrystallization in handling is: the thick product behind the recrystallization for the first time: methyl alcohol=1 gram: 2 milliliters, wherein the volume ratio of methyl alcohol and acetone is 1: 2 in the mixed solvent of methanol/acetone.
The present invention has following beneficial effect:
1, the main raw material of the present invention's use is (R)-4-halogen-ethyl 3-hydroxybutanoate and glycine ethyl ester hydrochloride, is the commercial goods, the cheap and easy to get and environmental protection, pollution-free of raw material; Simultaneously, the present invention at first carries out described free processing with glycine ethyl ester hydrochloride, has effectively reduced the consumption of material in the reaction, has reduced cost, and the yield to reaction has also played positive effect simultaneously.The cost of (the R)-oxiracetam of the present invention's preparation is low, yield can be up to 33%, and reaction conditions is gentle, the cycle is short, simple to operate, is beneficial to commercial scale prodn, and (the R)-oxiracetam product HPLC purity that makes simultaneously reaches more than 98.5%.
2, the present invention has adopted ion exchange resin treatment in purifying the finished product (R)-oxiracetam, compares with the available technology adopting silica gel column chromatography method, though treatment effect is suitable; But the on the one hand ion exchange resin repeated use of can repeatedly regenerating has reduced cost; Ion exchange resin is to use pure water to come wash-out on the other hand; Avoided with an organic solvent, pollution-free, simultaneously preferablyly be used for the big production of large-scale industrial.The most of organic solvent toxicity that uses among the present invention is little, pollution is low, and it is avirulent that the water that uses in the last handling process is pollution-free especially, so the present invention not only is suitable for suitability for industrialized production, also meets national requirements for environmental protection.
Embodiment
Through embodiment the present invention is carried out concrete description below; Be necessary to be pointed out that at this following examples only are used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present invention, the person skilled in the art in this field can make some nonessential improvement and adjustment to the present invention according to the invention described above content.
Embodiment 1
(R)-and the preparation method of oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) glycine ethyl ester hydrochloride 139.6g is joined among the anhydrous diethyl ether 1250ml; Ice-cold extremely-4 ℃ of feeding ammonia 25.5g make glycine ethyl ester hydrochloride dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: anhydrous diethyl ether: ammonia is 1mol: 1250ml: 1.5mol;
(b) in above-mentioned product, add absolute ethyl alcohol 470ml, sodium hydrogencarbonate 117.6g, dropping (R)-4-chloro-3-hydroxyl-ethyl n-butyrate 266.6g, the said dropping time is 3 hours, is 75 ℃ in pH8.5, temperature and reacts 28 hours down;
(c) filter, filtrate, concentrate with the ethanol thorough washing, enriched material is water-soluble, and the chloroform that adds 4.5 times of filtrating weight again extracts, water concentrates column chromatography for separation; Add mass percentage concentration at last and be 28% ammoniacal liquor, 30 ℃ down reaction made (R)-oxiracetam bullion in 5 hours, wherein the consumption of 28% ammoniacal liquor is 6 times of column chromatography for separation product weight;
Glycine ethyl ester wherein: sodium hydrogencarbonate: (R)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.4: 1.6, with molar ratio computing, the consumption of absolute ethyl alcohol is 4 times of sodium hydrogencarbonate weight;
2, the purifying of bullion:
(a) with the above-mentioned bullion that makes of water dissolution, through the 732# strongly acidic cationic exchange resin, then through neutralization of 711# strongly basic anion exchange resin and collection solution, concentrated; Said bullion: water=1 gram: 1.2 milliliters, said thick product: said strongly acidic cationic exchange resin=1 gram: 13 milliliters;
(b) adopt ethanol to carry out first time recrystallization above-mentioned bullion after concentrating through ion exchange resin then and handle, adopt the mixed solvent of methanol/acetone to carry out the recrystallization processing second time and make (R)-oxiracetam product; Said through spissated thick product behind the ion exchange resin: ethanol=1 gram: 1.5 milliliters; Thick product behind the said first time recrystallization: methyl alcohol=1 gram: 2 milliliters, wherein the volume ratio of methyl alcohol and acetone is 1: 2 in the mixed solvent of methanol/acetone.
The HPLC purity of (the R)-oxiracetam product that finally makes reaches 99.5%, and yield is up to 33%.
Embodiment 2
(R)-and the preparation method of oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) glycine ethyl ester hydrochloride is joined in the anhydrous diethyl ether, ice-cold extremely-4 ℃ of feeding ammonias make glycine ethyl ester hydrochloride dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: anhydrous diethyl ether: ammonia is 1mol: 1300ml: 1.2mol;
(b) in above-mentioned product, add anhydrous methanol, yellow soda ash, (R)-4-iodo-3-hydroxyl-ethyl n-butyrate are 65 ℃ in pH8, temperature and reacted 20 hours down;
(c) filter, filtrate, concentrate with the ethanol thorough washing, enriched material is water-soluble, and the ETHYLE ACETATE that adds 5 times of filtrating weight again extracts, water concentrates column chromatography for separation; Add mass percentage concentration at last and be 27% ammoniacal liquor, 25 ℃ down reaction made (R)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide bullion in 7 hours, wherein the consumption of 27% ammoniacal liquor is 8 times of column chromatography for separation product weight; Glycine ethyl ester wherein: yellow soda ash: (R)-4-iodo-3-hydroxyl-ethyl n-butyrate=1: 1.5: 1.8, with molar ratio computing, the consumption of anhydrous methanol is 7 times of yellow soda ash weight;
2, the purifying of bullion:
(a) with the above-mentioned bullion that makes of water dissolution, through 001 * 7 strongly acidic styrene type cation exchange resin, then through neutralization of 201 * 7 basicity styrene series anion exchange resins and collection solution, concentrated; Said bullion: water=1 gram: 0.6 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 10 milliliters;
(b) adopt ethanol to carry out first time recrystallization above-mentioned bullion after concentrating through ion exchange resin then and handle, adopt the mixed solvent of methanol/acetone to carry out the recrystallization processing second time and make (R)-oxiracetam product; Said through spissated thick product behind the ion exchange resin: ethanol=1 gram: 1.5 milliliters; Thick product behind the said first time recrystallization: methyl alcohol=1 gram: 1 milliliter, wherein the volume ratio of methyl alcohol and acetone is 1: 2 in the mixed solvent of methanol/acetone.
The HPLC purity of (the R)-oxiracetam product that finally makes reaches 99.2%, and yield reaches 28%.
Embodiment 3
(R)-and the preparation method of oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) glycine ethyl ester hydrochloride is suspended in the CP ether, feeds ammonia then and make glycine ethyl ester hydrochloride dissociate into glycine ethyl ester;
(b) in above-mentioned product, add absolute ethyl alcohol, sodium hydrogencarbonate, dropping (R)-4-bromo-3-hydroxyl-ethyl n-butyrate, the said dropping time is 3.5 hours, is 70 ℃ in pH9, temperature and reacts 20～26 hours down;
(c) filter then, with ethanol thorough washing filtrating, concentrated, enriched material is water-soluble, and the chloroform that adds 4 times of filtrating weight again extracts, water concentrates; Add mass percentage concentration at last and be 26% ammoniacal liquor, 28 ℃ down reaction made (R)-oxiracetam bullion in 6 hours;
Glycine ethyl ester wherein: sodium hydrogencarbonate: (R)-4-bromo--3-hydroxyl-ethyl n-butyrate=1: 1: 1.2, with molar ratio computing, the consumption of absolute ethyl alcohol is 3 times of sodium hydrogencarbonate weight;
2, the purifying of bullion:
(a) with the above-mentioned bullion that makes of water dissolution, through the 732# strongly acidic cationic exchange resin, then through neutralization of 711# strongly basic anion exchange resin and collection solution, concentrated; Said bullion: water=1 gram: 0.6 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 10 milliliters;
(b) adopt ethanol to carry out first time recrystallization above-mentioned bullion after concentrating through ion exchange resin then and handle, adopt the mixed solvent of methanol/acetone to carry out the recrystallization processing second time and make (R)-oxiracetam product; Said through spissated thick product behind the ion exchange resin: ethanol=1 gram: 1.5 milliliters; Thick product behind the said first time recrystallization: methyl alcohol=1 gram: 2 milliliters, wherein the volume ratio of methyl alcohol and acetone is 1: 3 in the mixed solvent of methanol/acetone.
The HPLC purity of (the R)-oxiracetam product that finally makes reaches 99.3%, and yield is up to 26%.
Embodiment 4～8:
A kind of preparation method of (R)-oxiracetam is undertaken by following material and processing parameter, and all the other are with embodiment 1.
The HPLC purity of (R)-oxiracetam product that above embodiment finally makes reaches more than 98.5%～99.26%, and yield reaches 28%～33%.
Claims (10)
1. the preparation method of (R)-oxiracetam; It is characterized in that: adopt glycine ethyl ester hydrochloride with (R)-4-halogen-3-hydroxyl-ethyl n-butyrate is that raw material reacts under alcoholic solvent and alkaline condition; Through filtering, concentrating, feed the purification process that ammoniacal liquor makes (R)-oxiracetam bullion and bullion with inorganic alkoxide washing, the extraction of concentrated warp again, water; Said glycine ethyl ester hydrochloride will adopt ether to dissociate into glycine ethyl ester with ammonia earlier.
2. preparation method as claimed in claim 1 is characterized in that: said is that glycine ethyl ester hydrochloride is added in the ether to the free of glycine ethyl ester hydrochloride, feeds ammonia more at low temperatures; The temperature of said feeding ammonia is 2～-5 ℃, and the usage ratio relation of said glycine ethyl ester hydrochloride, ether and ammonia is 1mol: 1100～1300ml: 1.2～1.7mol.
3. according to claim 1 or claim 2 preparation method; It is characterized in that: said free processing to glycine ethyl ester hydrochloride is that glycine ethyl ester hydrochloride is added in the anhydrous diethyl ether; Ice-cold to-3～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, anhydrous diethyl ether and ammonia concerns to be 1mol: 1250ml: 1.5mol.
4. preparation method as claimed in claim 3 is characterized in that: said alcoholic solvent is anhydrous methanol or absolute ethyl alcohol.
5. preparation method as claimed in claim 4 is characterized in that: said (R)-4-halogen-3-hydroxyl-ethyl n-butyrate is (R)-4-chloro-3-hydroxyl-ethyl n-butyrate; The alkali of said adding is yellow soda ash or sodium hydrogencarbonate.
6. preparation method as claimed in claim 5; It is characterized in that: the usage ratio of said each material is glycine ethyl ester with the molar ratio computing: sodium hydrogencarbonate: (R)-and 4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1～1.5: 1.2～1.8; The consumption of said absolute ethyl alcohol is 3～7 times of sodium hydrogencarbonate, in weight part.
7. preparation method as claimed in claim 6; It is characterized in that: the usage ratio of said each material is glycine ethyl ester with the molar ratio computing: sodium hydrogencarbonate: (R)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.4: 1.6; The consumption of absolute ethyl alcohol is 4 times of sodium hydrogencarbonate, in weight part.
8. preparation method as claimed in claim 1; It is characterized in that: the preparation of said (R)-oxiracetam bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether; Ice-cold to-4 ℃～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia concerns to be 1mol: 1100～1300ml: 1.2～1.7mol; Add absolute ethyl alcohol then, sodium hydrogencarbonate and dropping (R)-4-chloro-3-hydroxyl-ethyl n-butyrate, the time of said dropping (R)-4-chloro-3-hydroxyl-ethyl n-butyrate is 3～3.5 hours, and control pH is 8～9, and temperature of reaction is 65～75 ℃, reacts 20～30 hours; Filter, will filtrate with methyl alcohol or ethanol thorough washing, concentrate, enriched material is soluble in water, and the chloroform that adds 4 times of filtrating weight again extracts, and water concentrates the back column chromatography for separation and gets (R)-4-hydroxyl-2-OXo-1-pyrrolidine ETHYLE ACETATE; Add strong aqua at last again, reacted 4～7 hours down at 25～32 ℃; Said glycine ethyl ester: sodium hydrogencarbonate: (R)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1～1.5: 1.2～1.8, the consumption of said absolute ethyl alcohol is 3～7 times of sodium hydrogencarbonate weight; The add-on of said 28% strong aqua is 4-8 a times of said column chromatography for separation product weight.
9. like claim 5 or 8 described preparing methods; It is characterized in that: said thick purification of product be with thick product with water dissolution after through strongly acidic cationic exchange resin and collect; Pass through in the strongly basic anion exchange resin again and the solution of collecting, completion when the pH value that makes the solution of said collection is neutral; Thick product after the solution concentration of collecting that will neutralize then carries out recrystallization to be handled.
10. preparation method as claimed in claim 9 is characterized in that: said strongly acidic cationic exchange resin is the 732# strongly acidic cationic exchange resin, and said strongly basic anion exchange resin is the 711# strongly basic anion exchange resin; It is to adopt ethanol to carry out the recrystallization processing first time that said recrystallization is handled, and adopts the mixed solvent of methanol/acetone to carry out the recrystallization processing second time; The aqueous solution of said thick product is pressed thick product: water=1 gram: 1.2 milliliters, the consumption of said strongly acidic cationic exchange resin is: said thick product: said strongly acidic cationic exchange resin=1 gram: 13 milliliters; The consumption that said use ethanol carries out recrystallization processing for the first time is: the thick product after said the concentrating: ethanol=1 gram: 1.5 milliliters; The consumption of said second time of recrystallization in handling is: the thick product behind the recrystallization for the first time: methyl alcohol=1 gram: 2 milliliters, wherein the volume ratio of methyl alcohol and acetone is 1: 2 in the mixed solvent of methanol/acetone.
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