CN102603597A - Preparation method of (S)-oxiracetam - Google Patents
Preparation method of (S)-oxiracetam Download PDFInfo
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- CN102603597A CN102603597A CN2011100238745A CN201110023874A CN102603597A CN 102603597 A CN102603597 A CN 102603597A CN 2011100238745 A CN2011100238745 A CN 2011100238745A CN 201110023874 A CN201110023874 A CN 201110023874A CN 102603597 A CN102603597 A CN 102603597A
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- Prior art keywords
- alkali
- oxiracetam
- ester hydrochloride
- ethyl ester
- exchange resin
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- 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 claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 47
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000003513 alkali Substances 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000012047 saturated solution Substances 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000000746 purification Methods 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 44
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 20
- 230000001476 alcoholic effect Effects 0.000 claims description 19
- 230000002378 acidificating effect Effects 0.000 claims description 18
- 125000002091 cationic group Chemical group 0.000 claims description 17
- 239000011347 resin Substances 0.000 claims description 17
- 229920005989 resin Polymers 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 239000012141 concentrate Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 14
- 239000003957 anion exchange resin Substances 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 11
- 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
- 238000009792 diffusion process Methods 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 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 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- 239000000284 extract Substances 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 150000004703 alkoxides Chemical class 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 238000001035 drying 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 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
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 abstract 3
- 239000012043 crude product Substances 0.000 abstract 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 229960001227 oxiracetam Drugs 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 6
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000006386 neutralization reaction Methods 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-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
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960002298 aminohydroxybutyric acid Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001875 compounds Chemical class 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
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- YQGDEPYYFWUPGO-UHFFFAOYSA-N gamma-amino-beta-hydroxybutyric acid Chemical compound [NH3+]CC(O)CC([O-])=O YQGDEPYYFWUPGO-UHFFFAOYSA-N 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
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 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
- 239000004615 ingredient Substances 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 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
- 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 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.Report about oxiracetam; Disclosing it is a kind of synthetic hydroxy-amino-butyric acid (GABOB) cyclic derivatives, can promote ATP in the brain, promotes vagusstoff to synthesize and strengthen the conduction of nervous excitation; To the antidromicity due to the anoxic is forgetful improved action arranged; Can hypermnesis, improve learning capacity, be one of active drug of treatment DAT (AD), vascular dementia illnesss such as (VD).
About the report of synthetic (S)-oxiracetam, USP 4,797; 496 methods that prepare oxyracetam that disclose with WO 93/06826; Disclosed method comprises from chiral beta-hydroxy GBL acquisition chirality alkyl 3 in the document, and 4-epoxy butyric ester makes the G-NH2 reaction of products therefrom and N protection and makes products therefrom carry out the N deprotection; Obtain the pure oxyracetam of optically-active through cyclisation then; The step of this method is less relatively, but because chirality alkyl 3, and 4-epoxy butyric ester synthesis yield is extremely low and cause this method cost high.U.S. Pat 4173569 has been addressed the compound method of another kind of (s)-oxiracetam: (s)-and GABOB is a starting raw material; Through sillylation reagent protection hydroxyl; Product after the cyclization and the reaction of halogenated acetic acids ethyl ester; Reaction product is through the deprotection base, and ammonia is separated, and obtains target compound at last; This kind preparation method is not suitable for commercial scale prodn, and using the protection base that hydroxyl is protected can increase reactions step, 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 the preparation method that a kind of yield is high, purity is high, be suitable for required (the S)-oxiracetam of medicinal application.
The present invention seeks to realize through following technical scheme:
A kind of preparation method of (S)-oxiracetam; It is characterized in that: adopt glycine ethyl ester hydrochloride with (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is that raw material react under alcoholic solvent and alkaline condition, filter, through with the inorganic alkoxide washing, concentrate again and react the purification process that makes (S)-oxiracetam bullion and bullion through extraction, separation feeding strong aqua; Said glycine ethyl ester hydrochloride is to mix with alcoholic solvent with alkali earlier, and dripping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate raw material and gradation adding alkali more therein is 8-9 with the pH that controls reaction; Said purification process to bullion comprises carries out ion exchange resin treatment and (S)-oxiracetam bullion is dissolved in its optimum solvent, and at room temperature processes saturated solution, then under closed environment with its poor solvent diffusion.
The contriver finds that in R&D process the addition sequence of raw material is worthy of careful study very much; Because the unsettled characteristic of glycine ethyl ester; Therefore raw material is to adopt glycine ethyl ester hydrochloride but come down to glycine ethyl ester participating in reaction, thereby and order of addition(of ingredients) is determining whether glycine ethyl ester hydrochloride can dissociate into the height that glycine ethyl ester is determining the reaction product yield fully in reaction; Simultaneously; Reaction product (S)-oxiracetam has easy ruined characteristic under the highly basic condition; And reaction is to require under alkaline condition, to carry out, and alkali is again indispensable reaction raw materials simultaneously, and the mode and the condition that therefore in the reaction that product production is arranged, add alkali have special being particular about.
In order to improve the yield of final product, the present invention also carries out column chromatography for separation after above-mentioned extraction, water concentrate, and feeds strong aqua preparation (S)-oxiracetam again.
Be beneficial to the carrying out that reacts, the yield that improves the finished product in order to make glycine ethyl ester hydrochloride raw material of the present invention fully dissociate into glycine ethyl ester; It is stirring 1-3 hour under 68-73 ℃, pH8-9 that said glycine ethyl ester hydrochloride mixes with alkali, alcoholic solvent earlier; Further preferably, under 68-70 ℃, pH8.7, stirred 2 hours.
In order further to make glycine ethyl ester hydrochloride dissociate into glycine ethyl ester; Alkali of the present invention preferably adopts yellow soda ash or sodium hydrogencarbonate; Alcoholic solvent preferably adopts absolute ethyl alcohol, and wherein the mol ratio of glycine ethyl ester hydrochloride and yellow soda ash is 1: 1, or the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2; The consumption of absolute ethyl alcohol is 5-8 a times of alkali weight, further is preferably 6 times.
Be beneficial to the stable environment of product in order in reaction process, to form; At glycine ethyl ester hydrochloride with after alkali, alcoholic solvent mix; It is that branch 2-4 time (preferred 2 times) adding alkali is 8-9 with pH in the hierarchy of control that gradation adds alkali; Drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate simultaneously, the dropping time is 2.5 hours, is 60-65 ℃ of reaction 22-26 hour at system temperature.
The present invention (S)-4-halogen-3-hydroxyl-ethyl n-butyrate preferably adopts (S)-4-chloro-3-hydroxyl-ethyl n-butyrate; (S)-consumption of 4-halogen-3-hydroxyl-ethyl n-butyrate is preferably glycine ethyl ester hydrochloride: (S)-4-halogen-3-hydroxyl-ethyl n-butyrate=1mol: 0.8-1.3mol.
More particularly; The preparation of the present invention (S)-oxiracetam bullion be glycine ethyl ester hydrochloride earlier with alkali, alcoholic solvent in stirring 1-3 hour down of 68-73 ℃, pH8-9; Wherein alkali preferably adopts yellow soda ash or sodium hydrogencarbonate, and alcoholic solvent preferably adopts absolute ethyl alcohol, and the mol ratio of glycine ethyl ester hydrochloride and yellow soda ash is 1: 1; Or the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2, the consumption of absolute ethyl alcohol be alkali weight 5-8 doubly; Dividing then and adding alkali 2-4 time is 8-9 with pH in the hierarchy of control; Drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate simultaneously; The dropping time is 2.5 hours; At system temperature is 60-65 ℃ of reaction 22-26 hour, wherein glycine ethyl ester hydrochloride with (S)-mol ratio of 4-halogen-3-hydroxyl-ethyl n-butyrate is 1: 0.8-1.3; 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 (S)-4-hydroxyl-2-OXo-1-pyrrolidine ETHYLE ACETATE; Add strong aqua at last again, reacted 5～7 hours down at 23～26 ℃.
In order further to improve the yield of the present invention's preparation (S)-oxiracetam; The preparation of the present invention (S)-oxiracetam bullion be glycine ethyl ester hydrochloride earlier with alkali, alcoholic solvent in the stirring 2 hours down of 68-70 ℃, pH8.7; Wherein alkali preferably adopts sodium hydrogencarbonate; Alcoholic solvent preferably adopts absolute ethyl alcohol, and the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2, and the consumption of absolute ethyl alcohol is 6 times of alkali weight; Dividing then and adding alkali 2 times is 8.5-9 with pH in the hierarchy of control; Drip (S)-4-chloro-3-hydroxyl-ethyl n-butyrate simultaneously; The dropping time is 2.5 hours; At system temperature is 62-64 ℃ of reaction 24-25 hour, wherein glycine ethyl ester hydrochloride with (S)-mol ratio of 4-chloro-3-hydroxyl-ethyl n-butyrate is 1: 1.1; 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 (S)-4-hydroxyl-2-OXo-1-pyrrolidine ETHYLE ACETATE; The last mass percentage concentration that adds again is 23% ammoniacal liquor, 23～26 ℃ of reactions 5～7 hours down.
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 is dissolved in its optimum solvent, and at room temperature processes saturated solution, under closed environment, spreads with its poor solvent then.
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.
In order further to improve the present invention (S)-oxiracetam product yield and purity, in the purification process process of the present invention, the consumption of said strongly acidic cationic exchange resin is: said thick product: said strongly acidic cationic exchange resin=1 gram: 8 milliliters.
The optimum solvent of the present invention be meant (S)-oxiracetam within it solubleness greater than 10 the gram/100 the gram solvents; Poor solvent is meant (the S)-oxiracetam solvent of solubleness below 1 gram/100 grams within it, is that those skilled in the art all know for the optimum dissolving (being prone to broad dose) and the definition of poor solvent (slightly soluble or indissoluble solvent).
In order to make (the S)-oxiracetam purity that makes higher, the optimum solvent of the present invention is preferably absolute ethyl 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.
(the S)-oxiracetam purity that makes is higher, crystallisate is more stable in order further to make, and the consumption of poor solvent of the present invention is 6-9 a times of (S)-oxiracetam saturated solution volume, and 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 be with thick product with water dissolution after through the 732# strongly acidic cationic exchange resin and collect; Pass through in the 711# 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, said thick product is with the laggard capable ion exchange resin treatment of water dissolution; Wherein thick product: water=1 gram: 0.7 milliliter, said thick product: said 732# strongly acidic cationic exchange resin=1 gram: 8 milliliters; Thick product after the solution concentration of collecting that will neutralize then is dissolved in absolute ethyl alcohol or propyl carbinol; Under 22 ℃, stir and process saturated solution; Anhydrous diethyl ether with 8 times of amounts of said saturated solution volume under closed environment spread 5 days down at 26 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
The present invention has following beneficial effect:
1, the main raw material of the present invention's use is (S)-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 glycine ethyl ester hydrochloride carries out described free processing, has effectively reduced the consumption of material in the reaction, has reduced cost, and the yield to reaction also plays a positive role simultaneously.The yield height of (the S)-oxiracetam of the present invention preparation can be up to 33%, and reaction conditions is gentle, the cycle shortly, simple to operate is beneficial to commercial scale prodn, and (the S)-oxiracetam product HPLC purity that makes simultaneously reaches more than 99.0%.
2, the present invention has adopted ion exchange resin treatment in purifying the finished product (S)-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 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 most of organic solvent toxicity that uses is little, pollution is low; 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
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) be to stir for 8.7 times to mix in 2 hours with glycine ethyl ester hydrochloride 139.6g and sodium hydrogencarbonate 84.0g, absolute ethyl alcohol 1008ml at 70 ℃, pH; The pH of dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate 183.3g, 2 addings of branch sodium hydrogencarbonate 84.0g control reaction systems is 9, reacted 24～25 hours down at 62～64 ℃ again, and the time of said dropping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is 2.5 hours; Wherein the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2, and the absolute ethyl alcohol consumption is 6 times of alkali weight, glycine ethyl ester hydrochloride with (S)-mol ratio of 4-chloro-3-hydroxyl-ethyl n-butyrate is 1: 1.1;
(b) filter then, with inorganic alkoxide thorough washing filtrating, concentrated, enriched material is water-soluble, and 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 23% strong aqua 23～26 ℃ down reaction made (S)-oxiracetam bullion in 5～7 hours.
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;
The thick product that (b) will neutralize then after the solution concentration of collecting is dissolved in propyl carbinol; Under 22 ℃, stir and process saturated solution; Normal hexane with 8 times of volumes of said saturated solution under closed environment spread 5 days down at 26 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.30%, and yield reaches 35%.
Embodiment 2
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) be to stir for 8～9 times to mix in 1～3 hour with glycine ethyl ester hydrochloride and alkali, alcoholic solvent at 68～73 ℃, pH, drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate, gradation again and add alkali to control the pH of reaction system be that 8-9 fully reacts;
(b) filter then, with inorganic alkoxide thorough washing filtrating, concentrated, enriched material is water-soluble, and the methylene dichloride that adds 5 times of filtrating weight again extracts, water concentrates; Add the strong aqua reaction at last and make (S)-oxiracetam bullion.
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: 0.8 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 12 milliliters;
The thick product that (b) will neutralize then after the solution concentration of collecting is dissolved in propyl carbinol; Under 22 ℃, stir and process saturated solution; Sherwood oil with 7 times of amounts of said saturated solution volume under closed environment spread 3 days down at 25 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.1%, and yield reaches 30%.
Embodiment 3
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) be to stir for 8 times to mix in 3 hours with glycine ethyl ester hydrochloride and sodium hydrogencarbonate, anhydrous methanol at 68～73 ℃, pH, drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate, gradation again and add sodium hydrogencarbonate and control the pH of reaction system and 8.8 fully react; Wherein the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2, and the absolute ethyl alcohol consumption is 5～8 times of alkali weight;
(b) filter then, with inorganic alkoxide thorough washing filtrating, concentrate, enriched material is water-soluble, adds that ETHYLE ACETATE extracts, water concentrates, separation again; Add the strong aqua reaction at last and make (S)-oxiracetam bullion;
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;
The thick product that (b) will neutralize then after the solution concentration of collecting is dissolved in propyl carbinol, at room temperature stir and process saturated solution, under closed environment with the normal hexane diffusion, with the crystal of separating out through filter, drying obtains (S)-oxiracetam product.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 98.5%, and yield is up to 33%.
Embodiment 4
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) glycine ethyl ester hydrochloride is mixed with alkali, alcoholic solvent, the pH that drips (S)-4-halogen-3-hydroxyl-ethyl n-butyrate, gradation adding alkali control reaction system again is that 8-9 fully reacts;
(b) filter then, with inorganic alkoxide thorough washing filtrating, concentrate, enriched material is water-soluble, adds that ETHYLE ACETATE extracts, water concentrated again; Add the strong aqua reaction at last and make (S)-oxiracetam bullion.
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: 0.7 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 8 milliliters;
The thick product that (b) will neutralize then after the solution concentration of collecting is dissolved in absolute ethyl alcohol; Under 20 ℃, stir and process saturated solution; Anhydrous diethyl ether with 6 times of amounts of said saturated solution volume under closed environment spread 6 days down at 24 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.05%, and yield is 28%.
Embodiment 5～9:
A kind of preparation method of (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 (11)
1. the preparation method of (S)-oxiracetam; It is characterized in that: adopt glycine ethyl ester hydrochloride with (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is that raw material reacts under alcoholic solvent and alkaline condition; Filter, concentrate through extraction, water through washing, concentrate again with inorganic alkoxide, the reaction of feeding strong aqua makes the purification process of (S)-oxiracetam bullion and bullion; Said glycine ethyl ester hydrochloride is to mix with alkali, alcoholic solvent earlier, and dripping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate raw material and gradation adding alkali more therein is 8-9 with the pH that controls reaction; Said purification process comprises (S)-oxiracetam bullion is dissolved in its optimum solvent, and at room temperature processes saturated solution, then under closed environment with its poor solvent diffusion.
2. preparation method as claimed in claim 1 is characterized in that: it is stirring 1-3 hour under 68-73 ℃, pH8-9 that said glycine ethyl ester hydrochloride mixes with alkali, alcoholic solvent earlier.
3. preparation method as claimed in claim 2; It is characterized in that: said alkali is yellow soda ash or sodium hydrogencarbonate; Alcoholic solvent is an absolute ethyl alcohol; Wherein the mol ratio of glycine ethyl ester hydrochloride and yellow soda ash is 1: 1, or the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2, the consumption of absolute ethyl alcohol be alkali weight 5-8 doubly.
4. preparation method as claimed in claim 3 is characterized in that: it is stirring 2 hours under 68-70 ℃, pH8.7 that said glycine ethyl ester hydrochloride mixes with alkali, alcoholic solvent earlier; The consumption of said absolute ethyl alcohol is 6 times of alkali weight.
5. like claim 2 or 4 described preparing methods; It is characterized in that: at glycine ethyl ester hydrochloride and alkali with after alcoholic solvent mixes; It is that 2-4 adding of branch alkali is 8-9 with pH in the hierarchy of control that gradation adds alkali; Drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate simultaneously, the dropping time is 2.5 hours, is 60-65 ℃ of reaction 22-26 hour at system temperature.
6. preparation method as claimed in claim 5 is characterized in that: said (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is (S)-4-chloro-3-hydroxyl-ethyl n-butyrate; Said glycine ethyl ester hydrochloride with (S)-mol ratio of 4-chloro-3-hydroxyl-ethyl n-butyrate is 1: 0.8～1.3.
7. preparation method as claimed in claim 1; It is characterized in that: the preparation of said (S)-oxiracetam bullion be glycine ethyl ester hydrochloride earlier with alkali, alcoholic solvent in the stirring 2 hours down of 68-70 ℃, pH8.7; Wherein alkali is yellow soda ash; Alcoholic solvent is an absolute ethyl alcohol, and the mol ratio of glycine ethyl ester hydrochloride and yellow soda ash is 1: 1, and the consumption of absolute ethyl alcohol is 6 times of alkali weight; Dividing then and adding alkali 2 times is 8.5-9 with pH in the hierarchy of control; Drip (S)-4-chloro-3-hydroxyl-ethyl n-butyrate simultaneously; The dropping time is 2.5 hours; At system temperature is 62-64 ℃ of reaction 24-25 hour, wherein glycine ethyl ester hydrochloride with (S)-mol ratio of 4-chloro-3-hydroxyl-ethyl n-butyrate is 1: 1.1; Filter, will filtrate with the 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 (S)-4-hydroxyl-2-OXo-1-pyrrolidine ETHYLE ACETATE; The last mass percentage concentration that adds again is 23% ammoniacal liquor, 23～26 ℃ of reactions 5～7 hours down.
8. like claim 1,2,3,4 or 7 described preparing methods; It is characterized in that: said thick purification of product be earlier 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; When being neutral, the pH value that makes the solution of said collection accomplishes; Thick product after the solution concentration of collecting that will neutralize then is dissolved in its optimum solvent, and at room temperature processes saturated solution, under closed environment, spreads with its poor solvent then; 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.
9. method as claimed in claim 8 is characterized in that: said optimum solvent is absolute ethyl alcohol or propyl carbinol; Said poor solvent is anhydrous diethyl ether, sherwood oil or normal hexane.
10. method as claimed in claim 9 is characterized in that: the consumption of said poor solvent is 6-9 times of (S)-oxiracetam saturated solution volume; The temperature of said employing poor solvent diffusion is 24-28 ℃, and be 3-6 days diffusion time.
11. method as claimed in claim 8; It is characterized in that: said purification process be with thick product with water dissolution after through the 732# strongly acidic cationic exchange resin and collect; Pass through in the 711# strongly basic anion exchange resin again and the solution of collecting; When being neutral, the pH value that makes the solution of said collection accomplishes; Said thick product is with the laggard capable ion exchange resin treatment of water dissolution, and wherein thick product: water=1 gram: 0.7 milliliter, said thick product: said 732# strongly acidic cationic exchange resin=1 restrains: 8 milliliters; Thick product after the solution concentration of collecting that will neutralize then is dissolved in absolute ethyl alcohol or propyl carbinol; Under 22 ℃, stir and process saturated solution; Anhydrous diethyl ether with 8 times of amounts of said saturated solution volume under closed environment spread 5 days down at 26 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
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| WO2013159285A1 (en) * | 2012-04-24 | 2013-10-31 | 重庆润泽医疗器械有限公司 | Method for preparing (s)-oxiracetam |
| CN103554000A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | (S)-oxiracetam crystal form III, and preparation method and application thereof |
| CN104230777A (en) * | 2013-06-19 | 2014-12-24 | 成都百途医药科技有限公司 | Synthetic method of oxiracetam |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013159285A1 (en) * | 2012-04-24 | 2013-10-31 | 重庆润泽医疗器械有限公司 | Method for preparing (s)-oxiracetam |
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| 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 |
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| 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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