CN102603606A - Preparation method of (S)-oxiracetam - Google Patents
Preparation method of (S)-oxiracetam Download PDFInfo
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- CN102603606A CN102603606A CN2011100245217A CN201110024521A CN102603606A CN 102603606 A CN102603606 A CN 102603606A CN 2011100245217 A CN2011100245217 A CN 2011100245217A CN 201110024521 A CN201110024521 A CN 201110024521A CN 102603606 A CN102603606 A CN 102603606A
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- water
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- ester hydrochloride
- ethyl ester
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- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 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 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 63
- 239000000047 product Substances 0.000 claims abstract description 61
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims abstract description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000003513 alkali Substances 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 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 abstract description 15
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 13
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000001953 recrystallisation Methods 0.000 claims abstract description 12
- 238000005406 washing Methods 0.000 claims abstract description 11
- 238000000746 purification Methods 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 28
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 20
- 230000001476 alcoholic effect Effects 0.000 claims description 19
- 239000012141 concentrate Substances 0.000 claims description 19
- 230000002378 acidificating effect Effects 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 125000002091 cationic group Chemical group 0.000 claims description 16
- 239000011347 resin Substances 0.000 claims description 16
- 229920005989 resin Polymers 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 14
- 235000017550 sodium carbonate Nutrition 0.000 claims description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- 239000003957 anion exchange resin Substances 0.000 claims description 11
- 239000013078 crystal Substances 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 238000004090 dissolution Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 150000004703 alkoxides Chemical class 0.000 claims description 7
- 239000000284 extract Substances 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 229960001227 oxiracetam Drugs 0.000 description 16
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 5
- 238000006386 neutralization reaction Methods 0.000 description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 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
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 150000003440 styrenes Chemical class 0.000 description 2
- 229910052715 tantalum Inorganic materials 0.000 description 2
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 2
- FUDDLSHBRSNCBV-VKHMYHEASA-N (4s)-4-hydroxyoxolan-2-one Chemical compound O[C@@H]1COC(=O)C1 FUDDLSHBRSNCBV-VKHMYHEASA-N 0.000 description 1
- 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
- FWIBCWKHNZBDLS-UHFFFAOYSA-N 3-hydroxyoxolan-2-one Chemical compound OC1CCOC1=O FWIBCWKHNZBDLS-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
- 239000004593 Epoxy Substances 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960002298 aminohydroxybutyric acid Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 239000002026 chloroform extract 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
- YQGDEPYYFWUPGO-UHFFFAOYSA-N gamma-amino-beta-hydroxybutyric acid Chemical compound [NH3+]CC(O)CC([O-])=O YQGDEPYYFWUPGO-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- DWAWYEUJUWLESO-UHFFFAOYSA-N trichloromethylsilane Chemical compound [SiH3]C(Cl)(Cl)Cl DWAWYEUJUWLESO-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of (S)-oxiracetam. The preparation method is characterized by comprising the following steps of: taking glycine ethyl ester hydrochloride and ethyl-(S)-4-halo-3-hydroxy-butanoate as raw materials, reacting in an alcohol solvent under alkaline conditions, filtering, washing with an inorganic alcohol, concentrating, extracting, performing water phase concentration, and introducing concentrated ammonia water to react so as to get a crude product of the (S)-oxiracetam; and performing purification treatment on the crude product, wherein the glycine ethyl ester hydrochloride is firstly mixed with an alkali and the alcohol solvent, the ethyl-(S)-4-halo-3-hydroxy-butanoate raw material is further dripped into the mixture, and the alkali is added in a plurality of times for controlling the pH value of the reaction at 9-9.5; and the purification treatment of the crude product comprises ion exchange resin treatment and recrystallization treatment by adopting water and acetone in the weight ratio of 1:(5-15) as solvents. The yield of the (S)-oxiracetam prepared by the preparation method disclosed by the invention is as high as 35%, and the HPLC (high-performance liquid chromatography) purity of the prepared (S)-oxiracetam product is above 99.4%; and simultaneously, the preparation method has the advantages of mild reaction conditions, short cycle and simplicity in operation, and is conductive to industrialized large-scale production.
Description
Technical field
The present invention relates to the preparation of oxiracetam, be specifically related to the preparation method of (S)-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.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 ((S)-4-hydroxyl-2-oxo-N-pyrrolidine acetamide), USP 4,824; 966,4,843,166 and 5; 276,164 disclose oxiracetam and intermediates preparation thereof, and 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 oxiracetam through the two key reduction of hydrogenation; Therefore, this method has the shortcoming that is not suitable for the pure oxiracetam of preparation optically-active, and in addition, the preparation yield of 4-(C1-C2)-alkoxyl group-3-pyrroline-2-one-1-base-acetate (C1-C4)-alkyl ester is low.The open 2000-9456 of Korean Patent discloses the method for preparing pure (the s)-oxiracetam of optically-active; In the method; At first from synthetic (s)-3 of pure (the s)-3-of optically-active hydroxybutyrolactone, 4-epoxy butyrates is as the midbody under the aqueous conditions, then; Under aqueous conditions with G-NH2 with this midbody compound amidation, follow cyclisation; In industry, has advantage aspect yield and the purity though as if this technology compared with above-mentioned method; But its shortcoming be because (s)-purity of 3-hydroxybutyrolactone is low to cause producing a lot of impurity; And prepare highly purified (s)-3-hydroxybutyrolactone and can't reach; Therefore, this method does not obtain having the oxiracetam that is suitable for the required purity of medicinal application.
Summary of the invention
The object of the present invention is to provide a kind of yield height, high (the S)-oxiracetam preparation method who is suitable for the required purity of medicinal application of purity.
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 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 alcoholic solvent with alkali earlier, and dripping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate raw material and gradation adding alkali more therein is 9-9.5 with the pH that controls reaction; Said purification process to bullion comprises that carrying out ion exchange resin treatment is that 1: 5～15 water is that solvent carries out the recrystallization processing with acetone with adopting weight part ratio.
The contriver finds that in R&D process the adding mode 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 feed way 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.
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 3-5 hour under 60-67 ℃, pH9-10 that said glycine ethyl ester hydrochloride mixes with alkali, alcoholic solvent earlier; Further preferably, under 60-63 ℃, pH9.5, stirred 3 hours.
In order further to make glycine ethyl ester hydrochloride dissociate into glycine ethyl ester; Above-mentioned alkali 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 7-10 a times of alkali weight, further is preferably 8 times.
Be beneficial to the stable environment of product in order in reaction process, to form; At glycine ethyl ester hydrochloride and alkali with after alcoholic solvent mixes; It is that branch 3-5 time (preferred 3 times) adding alkali is 9-9.5 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 3 hours, is 60-68 ℃ of reaction 26-30 hour at system temperature.
In order further to improve yield and purity, the present invention (S)-4-halogen-3-hydroxyl-ethyl n-butyrate preferably adopts (S)-4-chloro-3-hydroxyl-ethyl n-butyrate; The usage ratio of each material of the present invention is preferably glycine ethyl ester hydrochloride with molar ratio computing: (S)-and 4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.3～1.6; Further be preferably glycine ethyl ester hydrochloride: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.5.
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.
More particularly; The preparation of the present invention (S)-oxiracetam bullion be glycine ethyl ester hydrochloride earlier with alkali, alcoholic solvent in stirring 3-5 hour down of 60-67 ℃, pH9-10; 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 7-10 doubly; Dividing then and adding alkali 3-5 time is 9-9.5 with pH in the hierarchy of control; Drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate simultaneously; The dropping time is 3 hours; At system temperature is 60-68 ℃ of reaction 26-30 hour, wherein glycine ethyl ester hydrochloride with (S)-mol ratio of 4-halogen-3-hydroxyl-ethyl n-butyrate is 1: 1.3-1.6; 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 adds strong aqua after concentrating again, and reaction made (S)-oxiracetam bullion in 4～6 hours under 28～30 ℃.
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 3 hours down of 60-63 ℃, pH9.5; Wherein alkali preferably adopts yellow soda ash; Alcoholic solvent preferably adopts 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 8 times of alkali weight; Dividing then and adding alkali 3 times is 9-9.5 with pH in the hierarchy of control; Drip (S)-4-chloro-3-hydroxyl-ethyl n-butyrate simultaneously; The dropping time is 3 hours; At system temperature is 63-65 ℃ of reaction 26-28 hour, wherein glycine ethyl ester hydrochloride with (S)-mol ratio of 4-chloro-3-hydroxyl-ethyl n-butyrate is 1: 1.5; 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 26% ammoniacal liquor, 28～30 ℃ of reactions 4～6 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 carries out above-mentioned recrystallization to be handled; Said thick product is used water dissolution, wherein thick product: water=1 gram: 1.3 milliliters.
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: 13 milliliters.
In order to improve the purity of the finished product, recrystallization process of the present invention carries out under-10～10 ℃.
In order further to improve the purity of the finished product of the present invention, recrystallization process of the present invention be with dissolving crude product in water, under-2～3 ℃, be added dropwise to acetone, stir 2～8h, obtain crystallized product; The weight part of said bullion and water is 1: 0.3～0.5, and the weight part ratio of water and acetone is 1: 5～10; More preferably, under 0～3 ℃, be added dropwise to acetone, stir 3～4h, obtain crystallized product; The weight part of said bullion and water is 1: 0.4, and the weight part ratio of water and acetone is 1: 7.
Purification process of the present invention further was preferably before crystallisation process, and the bullion that makes is made with extra care earlier, specifically was that 2～8 times the ethanol that adds above-mentioned bullion weight stirs, and leached, and made refined products; Or/and after above-mentioned recrystallization process, carry out recrystallize (secondary crystal).For above-mentioned crystallisation process is distinguished, the recrystallize here is called secondary crystal, and above-mentioned recrystallization process is called primary crystallization.
Secondary crystal of the present invention is that above-mentioned primary crystallization product is water-soluble, under-10～-5 ℃, is added dropwise to acetone, stirs 0.5～3h, obtains the secondary crystal product; The weight part ratio of said primary crystallization product and water is 1: 0.6～0.8, and the weight part ratio of water and acetone is 1: 12～15.
In order further to improve the purity of final product, refinement treatment of the present invention is that the ethanol that adds 6 times of its weight in the bullion after concentrating through ion exchange resin treatment stirs, and leaches, and makes refined products; Primary crystallization of the present invention is with water-soluble through bullion refining or that pass through after ion exchange resin treatment concentrates, under 0 ℃, is added dropwise to acetone, stirs 3h, obtains crystallized product, and the weight part of said bullion and water is 1: 0.4, and the weight part ratio of water and acetone is 1: 7; Secondary crystal of the present invention is that the primary crystallization product is water-soluble, under-6 ℃, is added dropwise to acetone, stirs 1h, obtains the secondary crystal product, and the weight part ratio of said primary crystallization product and water is 1: 0.7, and the weight part ratio of water and acetone is 1: 13.
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 has also played very positive effect simultaneously.The yield height of (the S)-oxiracetam of the present invention preparation can be up to 35%, and (the S)-oxiracetam product HPLC purity that makes can be up to more than 99.4%, and gentle, cycle of reaction conditions shortly, simple to operate is beneficial to commercial scale prodn simultaneously.
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.Adopt acetone and water as the solvent in the crystallisation process; Effectively reduce foreign matter content, significantly improved the quality of the finished product; The most of organic solvent toxicity that uses among the present invention 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 9.5 times to mix in 3 hours with glycine ethyl ester hydrochloride 139.6g and sodium hydrogencarbonate 84.0, absolute ethyl alcohol 1344ml at 60～63 ℃, pH; The pH of dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate 250.0g, 3 addings of branch sodium hydrogencarbonate 84.0g control reaction systems is 9.5, reacted 26～28 hours down at 63～65 ℃ again, and the time of said dropping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is 3 hours; Wherein the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2, and the absolute ethyl alcohol consumption is 8 times of alkali weight, glycine ethyl ester hydrochloride with (S)-mol ratio of 4-chloro-3-hydroxyl-ethyl n-butyrate is 1: 1.5;
(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 26% strong aqua 28～30 ℃ down reaction made (S)-oxiracetam bullion in 4～6 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; Said bullion: water=1 gram: 1.3 milliliters, said thick product: said strongly acidic cationic exchange resin=1 gram: 13 milliliters;
(b) ethanol that adds 6 times of its weight in the bullion after concentrating through ion exchange resin treatment stirs, and leaches, and makes refined products; Will be water-soluble through the bullion after refined products concentrates, under 0 ℃, be added dropwise to acetone, stir 3h, obtain crystallized product, the weight part of said bullion and water is 1: 0.4, the weight part ratio of water and acetone is 1: 7; Described crystallized product is water-soluble, under-6 ℃, be added dropwise to acetone, stir 1h, obtain the secondary crystal product, the weight part ratio of said primary crystallization product and water is 1: 0.7, the weight part ratio of water and acetone is 1: 13.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.50%, 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 9～10 times to mix in 3～5 hours with glycine ethyl ester hydrochloride and alkali, alcoholic solvent at 60～67 ℃, pH, drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate, gradation again and add alkali to control the pH of reaction system be that 9-9.5 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 strongly acidic cationic exchange resin, then through strongly basic anion exchange resin neutralization and collection solution, concentrated;
(b) adopt ethanol to carry out refinement treatment above-mentioned bullion after concentrating through ion exchange resin then, the ethanol that adds 2 times of bullion weight stirs, leaches, and makes refined products; Carry out crystallization treatment then, will be water-soluble through the bullion after refining, under-2 ℃, be added dropwise to acetone, stir 1h, obtain crystallized product, the weight part of said bullion and water is 1: 0.6, the weight part ratio of water and acetone is 1: 14.
The HPLC purity of (the S)-Aura west tantalum product that finally makes reaches 99.3%, and yield reaches 34%.
Embodiment 3
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) be to stir for 9 times to mix in 5 hours with glycine ethyl ester hydrochloride and sodium hydrogencarbonate, absolute ethyl alcohol at 60～63 ℃, pH, drip (S)-4-halogen-3-hydroxyl-ethyl n-butyrate, gradation again and add sodium hydrogencarbonate and control the pH of reaction system and 9.5 fully react; Wherein the mol ratio of glycine ethyl ester hydrochloride and sodium hydrogencarbonate is 1: 2, and the absolute ethyl alcohol consumption is 7～10 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; Said bullion: water=1 gram: 1 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 12 milliliters;
(b) then above-mentioned bullion after concentrating through ion exchange resin is carried out recrystallization and handle, bullion is water-soluble, under 2 ℃, be added dropwise to acetone; Stir 5h; Obtain crystallized product, the weight part of said bullion and water is 1: 0.7, and the weight part ratio of water and acetone is 1: 15.
The HPLC purity of (the S)-4-hydroxyl that finally makes-2-oxo-N-pyrrolidine acetamide product reaches 98.8%, and yield is up to 34%.
Embodiment 4
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) be to stir for 9～10 times to mix in 2～4 hours with glycine ethyl ester hydrochloride and yellow soda ash, anhydrous methanol at 65～67 ℃, pH; The pH of dropping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate, 3～5 addings of branch yellow soda ash control reaction systems is 9-9.5, reacted 26-28 hour down at 65～68 ℃ again, and the time of said dropping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is 2 hours; Wherein the mol ratio of glycine ethyl ester hydrochloride and yellow soda ash is 1: 1, and the anhydrous methanol consumption is 7～10 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; Said bullion: water=1 gram: 0.8 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 7 milliliters;
(b) then above-mentioned bullion after concentrating through ion exchange resin is carried out recrystallization and handle, bullion is water-soluble, be added dropwise to acetone, stir and obtain crystallized product, the weight part ratio of said water and acetone is 1: 8.
The HPLC purity of (the S)-Aura west tantalum product that finally makes reaches 99.20%, and yield reaches 34.5%.
Embodiment 5
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 9-9.5 fully reacts;
(b) filter then, with inorganic alkoxide thorough washing filtrating, concentrate, enriched material is water-soluble, adds that chloroform 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 strongly acidic cationic exchange resin, then through strongly basic anion exchange resin neutralization and collection solution, concentrated;
(b) then above-mentioned bullion after concentrating through ion exchange resin is carried out primary crystallization and handle, bullion is water-soluble, be added dropwise to acetone, stirring, obtain crystallized product, the weight part ratio of said bullion and water is 1: 0.5, the weight part ratio of water and acetone is 1: 10; Carry out secondary crystal at last and handle, the primary crystallization product is water-soluble, be added dropwise to acetone and stir, obtain the secondary crystal product, the weight part ratio of water and acetone is 1: 12 in the said secondary crystal.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.2%, and yield is 33%.
Embodiment 6～10:
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%～99.6%, and yield reaches 28%～35%.
Claims (10)
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 alcoholic solvent with alkali earlier, and dripping (S)-4-halogen-3-hydroxyl-ethyl n-butyrate raw material and gradation adding alkali more therein is 9-9.5 with the pH that controls reaction; Said purification process to bullion comprises that carrying out ion exchange resin treatment is that 1: 5～15 water is that solvent carries out the recrystallization processing with acetone with adopting weight part ratio.
2. preparation method as claimed in claim 1 is characterized in that: it is stirring 3-5 hour under 60-67 ℃, pH9-10 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 7-10 doubly.
4. preparation method as claimed in claim 3 is characterized in that: it is stirring 4 hours under 60-63 ℃, pH9.5 that said glycine ethyl ester hydrochloride mixes with alkali, alcoholic solvent earlier; The consumption of said absolute ethyl alcohol is 8 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 3-5 adding of branch alkali is 9-9.5 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 3 hours, is 60-68 ℃ of reaction 26-30 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: 1.3～1.6.
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 3 hours down of 60-63 ℃, pH9.5; 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 8 times of alkali weight; Dividing then and adding alkali 3 times is 9-9.5 with pH in the hierarchy of control; Drip (S)-4-chloro-3-hydroxyl-ethyl n-butyrate simultaneously; The dropping time is 3 hours; At system temperature is 63-65 ℃ of reaction 26-30 hour, wherein glycine ethyl ester hydrochloride with (S)-mol ratio of 4-chloro-3-hydroxyl-ethyl n-butyrate is 1: 1.5; 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 26% ammoniacal liquor, 28～30 ℃ of reactions 4～6 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 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 described recrystallization to be handled; Said thick product is used water dissolution, wherein thick product: water=1 gram: 1.3 milliliters.
9. preparation method as claimed in claim 8 is characterized in that: said strongly acidic cationic exchange resin is the 732# strongly acidic cationic exchange resin; Said strongly basic anion exchange resin is the 711# strongly basic anion exchange resin; The consumption of said strongly acidic cationic exchange resin is: said thick product: said strongly acidic cationic exchange resin=1 gram: 13 milliliters.
10. preparation method as claimed in claim 8; It is characterized in that: it is in water with dissolving crude product that said recrystallization is handled; Under-2～3 ℃, be added dropwise to acetone, stir 2～8h, obtain the primary crystallization product; The weight part of said bullion and water is 1: 0.3～0.5, and the weight part ratio of water and acetone is 1: 5～10; Carry out the crystallization second time again; Said primary crystallization product is water-soluble, under-10～-5 ℃, be added dropwise to acetone, stir 0.5～3h; Obtain the secondary crystal product; Said that the primary crystallization product is water-soluble, the weight part ratio of its crystallized product and water is 1: 0.6～0.8, and the weight part ratio of water and acetone is 1: 12～15.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| 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 of (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
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2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| 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 of (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
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