CN102603597B - Preparation method of (S)-oxiracetam - Google Patents
Preparation method of (S)-oxiracetam Download PDFInfo
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- CN102603597B CN102603597B CN201110023874.5A CN201110023874A CN102603597B CN 102603597 B CN102603597 B CN 102603597B CN 201110023874 A CN201110023874 A CN 201110023874A CN 102603597 B CN102603597 B CN 102603597B
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- oxiracetam
- ethyl ester
- exchange resin
- alkali
- ester hydrochloride
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- IHLAQQPQKRMGSS-BYPYZUCNSA-N 2-[(4s)-4-hydroxy-2-oxopyrrolidin-1-yl]acetamide Chemical compound NC(=O)CN1C[C@@H](O)CC1=O IHLAQQPQKRMGSS-BYPYZUCNSA-N 0.000 title abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 39
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000003513 alkali Substances 0.000 claims abstract description 30
- 239000012043 crude product Substances 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000012047 saturated solution Substances 0.000 claims abstract description 18
- 238000000746 purification Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 4
- 239000000047 product Substances 0.000 claims description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- 239000003729 cation exchange resin Substances 0.000 claims description 16
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- 230000001476 alcoholic effect Effects 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 239000003957 anion exchange resin Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012141 concentrate Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000006386 neutralization reaction Methods 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 6
- 238000009792 diffusion process Methods 0.000 claims description 6
- 239000003456 ion exchange resin Substances 0.000 claims description 6
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 229960004756 ethanol Drugs 0.000 claims description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 12
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005406 washing Methods 0.000 abstract description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 abstract 3
- 238000002156 mixing Methods 0.000 abstract 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 229960001227 oxiracetam Drugs 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 150000004703 alkoxides Chemical class 0.000 description 5
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 5
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 3
- IHLAQQPQKRMGSS-SCSAIBSYSA-N 2-[(4r)-4-hydroxy-2-oxopyrrolidin-1-yl]acetamide Chemical compound NC(=O)CN1C[C@H](O)CC1=O IHLAQQPQKRMGSS-SCSAIBSYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960002298 aminohydroxybutyric acid Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- QVPLPSZGHFSYEQ-UHFFFAOYSA-N 2-amino-2-hydroxybutanoic acid Chemical compound CCC(N)(O)C(O)=O QVPLPSZGHFSYEQ-UHFFFAOYSA-N 0.000 description 1
- FUDDLSHBRSNCBV-UHFFFAOYSA-N 4-hydroxyoxolan-2-one Chemical compound OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- YQGDEPYYFWUPGO-UHFFFAOYSA-N gamma-amino-beta-hydroxybutyric acid Chemical compound [NH3+]CC(O)CC([O-])=O YQGDEPYYFWUPGO-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Abstract
A preparation method of (S)-oxiracetam comprises the steps of conducting a reaction of a glycine ethyl ester hydrochloride with (S)-4-halgen-3-hydroxy-ethyl butyrate in an alcohol solvent under an alkaline condition, wherein the glycine ethyl ester hydrochloride and the (S)-4-halgen-3-hydroxy-ethyl butyrate are adopted as raw materials, filtering, washing with an inorganic alcohol, concentrating, then extracting, conducting water-phase concentration, introducing stronger ammonia water for a reaction so as to prepare a crude product of (S)-oxiracetam, and purifying the crude product; and mixing the glycine ethyl ester hydrochloride with alkali and the alcohol solvent firstly, then dropping the (S)-4-halgen-3-hydroxy-ethyl butyrate raw material in the mixture, and adding the alkali in times so as to control the pH value in the reaction to be 8-9. Purification treatment comprises the steps that the crude product of (S)-oxiracetam is dissolved in a benign solvent, a saturated solution is prepared at the room temperature, and then the saturated solution is dispersed in a closed environment by a poor solvent. The HPLC (high-performance liquid chromatography) purity of the prepared (S)-oxiracetam reaches up to more than 99.0%, the yield is high and reaches up to 33%, the reaction condition is moderate, the operation is simple, and the industrialized scale production is facilitated.
Description
Technical field
The present invention relates to prepare the method for oxiracetam, be specifically related to the method for a kind of preparation (S)-oxiracetam, belong to the field of chemical synthesis.
Background technology
Oxiracetam (oxiracetam), be by Italian SmithKline Bi Qiemu company in 1974 synthetic nootropics first, this medicine went on the market in Italy in 1987, the raceme that oxiracetam is comprised of two kinds of isomer (S)-oxiracetam ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam).Report about oxiracetam, disclosing it is a kind of synthetic hydroxy-amino-butyric acid (GABOB) cyclic derivatives, can promote ATP in brain, promote vagusstoff to synthesize and strengthen the conduction of nervous excitation, to the antidromicity due to anoxic is forgetful, there is an improved action, can hypermnesis, improve learning capacity, be one of active drug of the illnesss such as treatment dementia of the Alzheimer type (AD), vascular dementia (VD).
Report about synthetic (S)-oxiracetam; United States Patent (USP) 4; 797; 496 and the method for preparing oxyracetam that discloses of WO 93/06826; in the document, disclosed method comprises from chiral beta-hydroxy butyrolactone acquisition chirality alkyl 3; 4-epoxy butyric ester; make products therefrom react and make products therefrom carry out N deprotection with the G-NH2 of N protection; then through cyclisation, obtain the pure oxyracetam of optically-active; the step of the method is relatively less; but due to chirality alkyl 3,4-epoxy butyric ester synthesis yield is extremely low and cause the method cost high.US Patent No. 4173569 has been addressed the synthetic method of another kind of (s)-oxiracetam: (s)-GABOB is starting raw material, through sillylation reagent protection hydroxyl, product after cyclization reacts with halogenated acetic acids ethyl ester, reaction product is through Deprotection, ammonia solution, finally obtains target compound; This kind of preparation method is not suitable for commercial scale production, and using protecting group to carry out protection to hydroxyl can increase reactions steps, wastes raw material, consuming time longer, increases cost, and total recovery is reduced.
Summary of the invention
The object of the present invention is to provide that a kind of yield is high, purity is high, be suitable for the preparation method of required (the S)-oxiracetam of medicinal application.
The present invention seeks to be achieved through the following technical solutions:
A kind of preparation method of (S)-oxiracetam, it is characterized in that: adopting glycine ethyl ester hydrochloride is that raw material reacts under alcoholic solvent and alkaline condition with (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, filter, through washing, concentrate again with inorganic alkoxide, through extraction, separation, pass into the purification process that strong aqua reaction makes (S)-oxiracetam crude product and crude product; Described glycine ethyl ester hydrochloride is first to mix with alcoholic solvent with alkali, then dropping (S)-4-halogen-3-hydroxy-butyric acid ethyl ester raw material and gradation therein to add alkali to take the pH that control reacts be 8-9; The described purification process to crude product comprises carries out ion exchange resin treatment and (S)-oxiracetam crude product is dissolved in its optimum solvent, and at room temperature makes saturated solution, then under closed environment, with its poor solvent, spreads.
Contriver finds that in R&D process the addition sequence of raw material is worthy of careful study very much, due to the unsettled characteristic of glycine ethyl ester, therefore raw material is to adopt glycine ethyl ester hydrochloride but be in fact that glycine ethyl ester is participating in reaction, thereby and order of addition(of ingredients) is determining whether glycine ethyl ester hydrochloride can dissociate into fully the height that glycine ethyl ester is determining reaction product yield in reaction; Simultaneously, reaction product (S)-oxiracetam has under highly basic condition easily destroyed characteristic, and reaction is to require to carry out under alkaline condition, alkali is again indispensable reaction raw materials simultaneously, therefore in the reaction that has product to produce, adds the mode of alkali and condition to have special being particular about.
In order to improve the yield of final product, the present invention, after above-mentioned extraction, water concentrate, also carries out column chromatography for separation, then passes into strong aqua preparation (S)-oxiracetam.
In order to make glycine ethyl ester hydrochloride raw material of the present invention fully dissociate into glycine ethyl ester, be beneficial to the carrying out of reaction, the yield of raising the finished product, it is to stir 1-3 hour under 68-73 ℃, pH8-9 that described glycine ethyl ester hydrochloride first mixes with alkali, alcoholic solvent, further preferably, under 68-70 ℃, pH8.7, stir 2 hours.
In order further to make glycine ethyl ester hydrochloride dissociate into glycine ethyl ester, alkali of the present invention preferably adopts sodium carbonate or sodium bicarbonate, alcoholic solvent preferably adopts dehydrated alcohol, wherein the mol ratio of glycine ethyl ester hydrochloride and sodium carbonate is 1: 1, or the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, the consumption of dehydrated alcohol is 5-8 times of alkali weight, more preferably 6 times.
In order to form and to be beneficial to the stable environment of product in reaction process, after glycine ethyl ester hydrochloride mixes with alkali, alcoholic solvent, it is that minute 2-4 time (preferably 2 times) to add alkali to take pH in the hierarchy of control be 8-9 that gradation adds alkali, drip (S)-4-halogen-3-hydroxy-butyric acid ethyl ester simultaneously, time for adding is 2.5 hours, at system temperature, is 60-65 ℃ of reaction 22-26 hour.
The present invention (S)-4-halogen-3-hydroxy-butyric acid ethyl ester preferably adopts (S)-4-chloro-3-hydroxyl-ethyl butyrate; (S) consumption of-4-halogen-3-hydroxy-butyric acid ethyl ester is preferably glycine ethyl ester hydrochloride: (S)-4-halogen-3-hydroxy-butyric acid ethyl ester=1mol: 0.8-1.3mol.
More particularly, the preparation of the present invention (S)-oxiracetam crude product is that glycine ethyl ester hydrochloride first stirs 1-3 hour with alkali, alcoholic solvent under 68-73 ℃, pH8-9, wherein alkali preferably adopts sodium carbonate or sodium bicarbonate, alcoholic solvent preferably adopts dehydrated alcohol, the mol ratio of glycine ethyl ester hydrochloride and sodium carbonate is 1: 1, or the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, the consumption of dehydrated alcohol be alkali weight 5-8 doubly; Then divide that to add for 2-4 time alkali to take pH in the hierarchy of control be 8-9, drip (S)-4-halogen-3-hydroxy-butyric acid ethyl ester simultaneously, time for adding is 2.5 hours, at system temperature, be 60-65 ℃ of reaction 22-26 hour, wherein glycine ethyl ester hydrochloride is 1 with the mol ratio of (S)-4-halogen-3-hydroxy-butyric acid ethyl ester: 0.8-1.3; Filter, filtrate is fully washed, concentrated with methyl alcohol or ethanol, enriched material is soluble in water, then adds the chloroform of 4 times of filtrate weight to extract, and after water is concentrated, column chromatography for separation obtains (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethyl acetate; Finally add again strong aqua, at 23～26 ℃, react 5～7 hours.
In order further to improve the yield of the present invention's preparation (S)-oxiracetam, the preparation of the present invention (S)-oxiracetam crude product is that glycine ethyl ester hydrochloride first stirs 2 hours under 68-70 ℃, pH8.7 with alkali, alcoholic solvent, wherein alkali preferably adopts sodium bicarbonate, alcoholic solvent preferably adopts dehydrated alcohol, the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, and the consumption of dehydrated alcohol is 6 times of alkali weight; Then divide that to add for 2 times alkali to take pH in the hierarchy of control be 8.5-9, drip (S)-4-chloro-3-hydroxyl-ethyl butyrate simultaneously, time for adding is 2.5 hours, at system temperature, be 62-64 ℃ of reaction 24-25 hour, wherein glycine ethyl ester hydrochloride is 1: 1.1 with the mol ratio of (S)-4-chloro-3-hydroxyl-ethyl butyrate; Filter, filtrate is fully washed, concentrated with methyl alcohol or ethanol, enriched material is soluble in water, then adds the chloroform of 4 times of filtrate weight to extract, and after water is concentrated, column chromatography for separation obtains (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethyl acetate; The last mass percentage concentration that adds is again 23% ammoniacal liquor, reacts 5～7 hours at 23～26 ℃.
The purification process of the thick product of the present invention is that thick product is also collected with passing through storng-acid cation exchange resin after water dissolution, then passes through in strongly basic anion exchange resin and the solution of collection, and the pH value that makes the solution of described collection completes while being neutral; Then the thick product after the solution of neutralization being collected concentrates is dissolved in its optimum solvent, and at room temperature makes saturated solution, then under closed environment, with its poor solvent, spreads.
In order to improve exchange capacity, exchange velocity, storng-acid cation exchange resin of the present invention is preferably 732# storng-acid cation exchange resin; Strongly basic anion exchange resin of the present invention is preferably 711# strongly basic anion exchange resin.
In order further to improve the present invention (S)-oxiracetam product yield and purity, in purification process process of the present invention, the consumption of described storng-acid cation exchange resin is: described thick product: described storng-acid cation exchange resin=1 gram: 8 milliliters.
The optimum solvent of the present invention refer to (S)-oxiracetam within it solubleness be greater than 10 grams/100 grams solvents, poor solvent refer to (S)-oxiracetam within it solubleness at 1 gram/solvent below 100 grams, for optimum dissolving (easily broad dose) and the definition of poor solvent (slightly soluble or indissoluble solvent), be that those skilled in the art all know.
For (the S)-oxiracetam purity that makes to make is higher, the optimum solvent of the present invention is preferably dehydrated alcohol or propyl carbinol; Poor solvent of the present invention is preferably anhydrous diethyl ether, sherwood oil or normal hexane; Wherein agents useful for same all can be analytical pure or chemical purity rank.
For (S)-oxiracetam purity of further making to make is higher, crystallisate is more stable, the consumption of poor solvent of the present invention be (S)-oxiracetam saturated solution volume 6-9 doubly, preferable amount is 8 times.
The present invention adopts the temperature of poor solvent diffusion to be preferably 24-28 ℃, is preferably 3-6 days diffusion time.
Specifically, purification process of the present invention is with also collecting by 732# storng-acid cation exchange resin after water dissolution by thick product, pass through again in 711# strongly basic anion exchange resin and the solution of collecting, the pH value that makes the solution of described collection completes while being neutral, the described laggard row ion exchange resin treatment of water dissolution for thick product, thick product wherein: water=1 gram: 0.7 milliliter, described thick product: described 732# storng-acid cation exchange resin=1 gram: 8 milliliters; Then the thick product after the solution of neutralization being collected concentrates is dissolved in dehydrated alcohol or propyl carbinol, at 22 ℃, stir and make saturated solution, under closed environment, with the anhydrous diethyl ether of 8 times of amounts of described saturated solution volume, at 26 ℃, spread 5 days, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The present invention has following beneficial effect:
1, the main raw material that the present invention uses is (S)-4-halogen-ethyl 3-hydroxybutanoate and glycine ethyl ester hydrochloride, is commercial goods, the cheap and easy to get and environmental protection, pollution-free of raw material; Meanwhile, the present invention first glycine ethyl ester hydrochloride carries out described free processing, has effectively reduced the consumption of material in reaction, has reduced cost, the yield of reaction is also played a positive role simultaneously.The yield height of (S)-oxiracetam prepared by the present invention can be up to 33%, and reaction conditions is gentle, the cycle shortly, simple to operate is beneficial to commercial scale production, and (the S)-oxiracetam product HPLC purity simultaneously making reaches more than 99.0%.
2, the present invention has adopted ion exchange resin treatment in purifying the finished product (S)-oxiracetam; compare with available technology adopting silica gel column chromatography method; although treatment effect is suitable; but ion exchange resin can repeatedly be regenerated and reuse on the one hand, has reduced cost; ion exchange resin is to carry out wash-out with pure water on the other hand; avoided with an organic solvent, pollution-free, simultaneously preferably for the large production of large-scale industrial.The present invention selects optimum dissolution with solvents, the poor solvent method of diffusion of suitable (S)-oxiracetam, effectively reduce foreign matter content, significantly improved the quality of the finished product, and the majority of organic solvent toxicity of using is little, it is low to pollute, the water using in last handling process is pollution-free avirulent especially, so the present invention is not only suitable for suitability for industrialized production, also meet national requirements for environmental protection.
Embodiment
Below by embodiment, the present invention is specifically described; be necessary to be pointed out that at this following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the 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
A preparation method for (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) by glycine ethyl ester hydrochloride 139.6g and sodium bicarbonate 84.0g, dehydrated alcohol 1008ml, at 70 ℃, pH, be that 8.7 times stirrings mix for 2 hours, drip (S)-4-chloro-3-hydroxyl-ethyl butyrate 183.3g again, divide the pH that adds for 2 times sodium bicarbonate 84.0g to control reaction system to be 9, at 62～64 ℃, to react 24～25 hours, the time of described dropping (S)-4-halogen-3-hydroxy-butyric acid ethyl ester is 2.5 hours; Wherein the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, and dehydrated alcohol consumption is 6 times of alkali weight, and glycine ethyl ester hydrochloride is 1: 1.1 with the mol ratio of (S)-4-chloro-3-hydroxyl-ethyl butyrate;
(b) then filter, with the abundant wash filtrate of inorganic alkoxide, concentrated, enriched material is water-soluble, then add the chloroform of 4 times of filtrate weight to extract, water is concentrated, column chromatography for separation; Finally adding mass percentage concentration is that 23% strong aqua reacts and within 5～7 hours, makes (S)-oxiracetam crude product at 23～26 ℃.
2, the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by 732# storng-acid cation exchange resin, then by 711# strongly basic anion exchange resin, neutralize and collect solution, concentrated;
(b) the thick product after the solution of then neutralization being collected concentrates is dissolved in propyl carbinol, at 22 ℃, stir and make saturated solution, under closed environment, with the normal hexane of 8 times of volumes of described saturated solution, at 26 ℃, spread 5 days, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The HPLC purity of (the S)-oxiracetam product finally making reaches 99.30%, and yield reaches 35%.
Embodiment 2
A preparation method for (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) by glycine ethyl ester hydrochloride and alkali, alcoholic solvent, at 68～73 ℃, pH, be that 8～9 times stirrings mix for 1～3 hour, then to drip the pH that (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, gradation add alkali to control reaction system be that 8-9 fully reacts;
(b) then filter, with the abundant wash filtrate of inorganic alkoxide, concentrated, enriched material is water-soluble, then add the methylene dichloride of 5 times of filtrate weight to extract, water is concentrated; Finally add strong aqua reaction to make (S)-oxiracetam crude product.
2, the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by 732# storng-acid cation exchange resin, then by 711# strongly basic anion exchange resin, neutralize and collect solution, concentrated; Described crude product: water=1 gram: 0.8 milliliter, described thick product: described storng-acid cation exchange resin=1 gram: 12 milliliters;
(b) the thick product after the solution of then neutralization being collected concentrates is dissolved in propyl carbinol, at 22 ℃, stir and make saturated solution, under closed environment, with the sherwood oil of 7 times of amounts of described saturated solution volume, at 25 ℃, spread 3 days, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The HPLC purity of (the S)-oxiracetam product finally making reaches 99.1%, and yield reaches 30%.
Embodiment 3
A preparation method for (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) by glycine ethyl ester hydrochloride and sodium bicarbonate, anhydrous methanol, at 68～73 ℃, pH, be that 8 times stirrings mix for 3 hours, then drip pH that (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, gradation add sodium bicarbonate to control reaction system and 8.8 fully react; Wherein the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, and dehydrated alcohol consumption is 5～8 times of alkali weight;
(b) then filter, with the abundant wash filtrate of inorganic alkoxide, concentrated, enriched material is water-soluble, then add that ethyl acetate extracts, water concentrated, separated; Finally add strong aqua reaction to make (S)-oxiracetam crude product;
2, the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by 001 * 7 strongly acidic styrene type cation exchange resin, then by 201 * 7 basicity styrene series anion exchange resins, neutralize and collect solution, concentrated;
(b) the thick product after the solution then neutralization collected is concentrated is dissolved in propyl carbinol, at room temperature stir and make saturated solution, under closed environment with normal hexane diffusion, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The HPLC purity of (the S)-oxiracetam product finally making reaches 98.5%, and yield is up to 33%.
Embodiment 4
A preparation method for (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) glycine ethyl ester hydrochloride is mixed with alkali, alcoholic solvent, then to drip the pH that (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, gradation add alkali to control reaction system be that 8-9 fully reacts;
(b) then filter, with the abundant wash filtrate of inorganic alkoxide, concentrated, enriched material is water-soluble, then adds that ethyl acetate extracts, water concentrated; Finally add strong aqua reaction to make (S)-oxiracetam crude product.
2, the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by 732# storng-acid cation exchange resin, then by 711# strongly basic anion exchange resin, neutralize and collect solution, concentrated; Described crude product: water=1 gram: 0.7 milliliter, described thick product: described storng-acid cation exchange resin=1 gram: 8 milliliters;
(b) the thick product after the solution of then neutralization being collected concentrates is dissolved in dehydrated alcohol, at 20 ℃, stir and make saturated solution, under closed environment, with the anhydrous diethyl ether of 6 times of amounts of described saturated solution volume, at 24 ℃, spread 6 days, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The HPLC purity of (the S)-oxiracetam product finally making reaches 99.05%, and yield is 28%.
Embodiment 5～9:
A preparation method for (S)-oxiracetam, is undertaken by following material and processing parameter, and all the other are with embodiment 1.
The HPLC purity of (S)-oxiracetam product that above embodiment finally makes reaches 98.5%～99.2%, and yield reaches 28%～34%.
Claims (2)
1. the preparation method of a (S)-Olaxiracetam, it is characterized in that: adopt glycine ethyl ester hydrochloride first to stir 2 hours under 68-70 ℃, pH8.7 with alkali, alcoholic solvent, wherein alkali is sodium carbonate, alcoholic solvent is dehydrated alcohol, the mol ratio of glycine ethyl ester hydrochloride and sodium carbonate is 1:1, and the consumption of dehydrated alcohol is 6 times of alkali weight; Then divide that to add for 2 times alkali to take pH in the hierarchy of control be 8.5-9, drip ATS-4 simultaneously, time for adding is 2.5 hours, at system temperature, be 62-64 ℃ of reaction 24-25 hour, wherein the mol ratio of glycine ethyl ester hydrochloride and ATS-4 is 1:1.1; Filter, filter residue is fully washed, concentrated with ethanol, enriched material is soluble in water, then adds the chloroform of 4 times of filtrate weight to extract, and after water is concentrated, column chromatography for separation obtains (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethyl acetate; The last mass percentage concentration that adds is again 23% ammoniacal liquor, reacts the purification process that makes (S)-Olaxiracetam crude product and crude product for 5～7 hours at 23～26 ℃;
The purification process of described thick product is first thick product also to be collected with passing through storng-acid cation exchange resin after water dissolution, pass through again in strongly basic anion exchange resin and the solution of collecting, the pH value that makes the solution of described collection completes while being neutral, then the thick product after the solution of neutralization being collected concentrates is dissolved in its optimum solvent, and at room temperature make saturated solution, then under closed environment, with its poor solvent, spread;
Described optimum solvent is dehydrated alcohol or propyl carbinol; Described poor solvent is anhydrous diethyl ether, sherwood oil or normal hexane; The consumption of described poor solvent is 6-9 times of (S)-Olaxiracetam saturated solution volume; The temperature of described employing poor solvent diffusion is 24-28 ℃, and be 3-6 days diffusion time.
2. the method for claim 1, it is characterized in that: described purification process is with also collecting by 732# storng-acid cation exchange resin after water dissolution by thick product, pass through again in 711# strongly basic anion exchange resin and the solution of collecting, the pH value that makes the solution of described collection completes while being neutral, the described laggard row ion exchange resin treatment of water dissolution for thick product, thick product wherein: water=1 gram: 0.7 milliliter, described thick product: described 732# storng-acid cation exchange resin=1 gram: 8 milliliters; Then the thick product after the solution of neutralization being collected concentrates is dissolved in dehydrated alcohol or propyl carbinol, at 22 ℃, stir and make saturated solution, under closed environment, with the anhydrous diethyl ether of 8 times of amounts of described saturated solution volume, at 26 ℃, spread 5 days, by the crystal of separating out after filtration, the dry (S)-Olaxiracetam product that obtains.
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| CN106631961A (en) * | 2013-06-19 | 2017-05-10 | 成都百途医药科技有限公司 | Synthetic method of oxiracetam |
| CN103554000B (en) * | 2013-11-06 | 2015-03-11 | 重庆润泽医药有限公司 | (S)-oxiracetam crystal form III, and preparation method and application thereof |
| CN107021911A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of method for preparing levo-oxiracetam crystal formation II |
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| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| CN101914052A (en) * | 2010-08-02 | 2010-12-15 | 胡建荣 | Oxiracetam compound and new method thereof |
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| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| CN101914052A (en) * | 2010-08-02 | 2010-12-15 | 胡建荣 | Oxiracetam compound and new method thereof |
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