CN101723871B - Method for preparing 4-hydroxy pyrrolidone-2-acetamide - Google Patents
Method for preparing 4-hydroxy pyrrolidone-2-acetamide Download PDFInfo
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- CN101723871B CN101723871B CN2009102289693A CN200910228969A CN101723871B CN 101723871 B CN101723871 B CN 101723871B CN 2009102289693 A CN2009102289693 A CN 2009102289693A CN 200910228969 A CN200910228969 A CN 200910228969A CN 101723871 B CN101723871 B CN 101723871B
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- acetamine
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- hydroxy pyrrolidone
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Abstract
The invention relates to a method for preparing 4-hydroxy pyrrolidone-2-acetamide, comprising the steps of: (1) under nitrogen protection, sequentially adding glycinamide hydrochloride, solvent and alkali into a reactor of a stirring device, leading the molar ratio between the glycinamide hydrochloride and the alkali to be 1:1-2.6, and ensuring the quantity of the solvent to be 3-6 times of the glycinamide hydrochloride; then adding phase transferring agent with the mass being 0.5-10% of the glycinamide hydrochloride, and reacting for 0.5h at the room temperature; (2) dripping 3-hydroxy-4-chlorobutyric acid derivative with the molar weight being equal to the glycinamide hydrochloride into the reaction liquid within 0.5-3h; heating for backflow reaction for 1-70h; and finally, refining to obtain the 4-hydroxy pyrrolidone-2-acetamide. The method solves the problems of more by-products and difficult purification in the prior art, leads the yield of the target product 4-hydroxy pyrrolidone-2-acetamide to be correspondingly increased, and omits the treatment process of ion exchange resin for the reaction liquid.
Description
Technical field
The invention belongs to the synthetic field of bulk drug, be specially the slightly method of alkane ketone-2-ethanamide of a kind of 4-of preparation hydroxyl pyrrole.
Background technology
The 4-hydroxy pyrrolidone-2-acetamine is commonly called as oxiracetam, English name Oxiracetam, and the trade(brand)name oxyracetam is the brain metabolism improving medicine, belongs to the annular derivant of gamma amino butyric acid.Can promote that ATP and vagusstoff are synthetic in the brain, have anti-physical factor, the injury of brain function due to the chemical factor and promote the effect of brain intracellular metabolite.To the antidromicity due to the anoxic is forgetful improved action arranged.Can hypermnesis, improve learning capacity.
The 4-hydroxy pyrrolidone-2-acetamine is in 1977, by Italian I.S.F. company synthetic [US4118396] first, listing in 1984.For many years, there are a large amount of preparing methods to report appearance about it.Addressed the preparation method of 4-hydroxy pyrrolidone-2-acetamine among U.S. Pat 48244861 and the US4868313; They set out with 3-hydroxyl-4-halo butanoic acid derivative, prepare the purpose product through chemical reaction processes such as hydroxyl protection, cyclization, deprotection base, ammonifications.But this method prepares the 4-hydroxy pyrrolidone-2-acetamine has shortcomings such as cost height, complex process and reaction yield are low, so be inappropriate for suitability for industrialized production.Among U.S. Pat 4686296 and the European patent EP 0223328A1, proposing with butyric ester and glycyl amide hydrochloride is starting raw material, one-step synthesis purpose product (yield 35%), but need to use Amberlite type resin isolation, trivial operations in the last handling process.Among the Japanese Patent JP62026267, propose with 3-hydroxyl-4-halo butanoic acid derivative directly and G-NH2 react and prepare purpose product 4-hydroxy pyrrolidone-2-acetamine.But in this method, long reaction time, aftertreatment complicacy and yield are lower, therefore also are inappropriate for industrialized production.
Addressed the preparation method of 4-hydroxy pyrrolidone-2-acetamine among Chinese patent CN1948258 and the CN101121688; They are starting raw material with the ketene dimer; Obtain the purpose product via different step respectively, but all have the problem that reactions step is complicated, overall yield of reaction is low in two kinds of methods.Among the Chinese patent CN1513836A, proposing with 4-halo acetoacetate derivative is starting raw material, obtains the purpose product through hydrogenation, cyclization, replacement and ammonification, total recovery 47.6%.Used the trinitride with explosion hazard in this method, in ammonifying process, need use liquefied ammonia and reaction under condition of high voltage in addition, operation easier is bigger.Chinese patent CN101367757A is a raw material with 4-halogen-3-butyric ester, and reaction obtains purpose product, yield 24% under polar solvent and alkaline condition.This method only obtains the 4-hydroxy pyrrolidone-2-acetamine by single step reaction; Reactions step is simple; But the product by product is more, and post-reaction treatment need be used strongly acidic styrene type cation exchange resin reaction solution is handled, thereby so aftertreatment is complicated causes yield lower.
Summary of the invention
The object of the invention is more, the difficult problem of purifying of by product in the synthetic 4-hydroxy pyrrolidone-2-acetamine method of raw material for being directed against with 4-halogen-3-butyric ester; A kind of method of the 4-of preparation hydroxy pyrrolidone-2-acetamine is provided; This method is added a kind of consisting of phase-transferring agent in reaction process, can obviously improve the yield of purpose product 4-hydroxy pyrrolidone-2-acetamine.
Reaction scheme of the present invention is following:
2H
2NCH
2CONH
2·HCl+Na
2CO
3→2H
2NCH
2CONH
2+2NaCl+H
2O+CO
2
2CH
2ClCHOHCH
2COOCH
3+2H
2NCH
2CONH
2+Na
2CO
3
Technical scheme of the present invention is:
A kind of method for preparing the 4-hydroxy pyrrolidone-2-acetamine may further comprise the steps:
(1), under the nitrogen protection; In the reactor drum that whipping appts is housed, add sweet amine amide hydrochloride, solvent and alkali successively; Its proportioning is the sweet amine amide hydrochloride of mol ratio: alkali=1: 1～2.6; Quantity of solvent is 3～6 times of sweet amine amide hydrochloride quality, adds 0.5%～10% consisting of phase-transferring agent of glycyl amide hydrochloride quality again, reacts 0.5h under the room temperature then;
(2), in 0.5～3h, drip 3-hydroxyl-4-chloro-butyric acid verivate in the reaction solution upward with sweet amine amide hydrochloride equimolar amount; Be warming up to back flow reaction 1～70h then, after recrystallization filter; Washing, oven dry obtains product 4-hydroxy pyrrolidone-2-acetamine.
The described consisting of phase-transferring agent of step (1) is anhydrous sorbitol laurate (Span-20); Anhydrous sorbitol cetylate (Span-40); Span60 (Span-60); Witconol AL 69-66 (Span-85); Polyoxyethylene sorbitan laurate (Tween-20); Polyoxyethylene sorbitan stearate (Tween-60); Nonyl pheno [8] ether (NP-8); Nonyl pheno [12] ether (NP-12); Nonyl pheno [30] ether (NP-30); Nonyl pheno [40] ether (NP-40); X 2073; Varion CDG-K; The octadecyl dimethyl betaine; Trimethyllaurylammonium bromide or octadecyl trimethylammonium bromide.
The described solvent of step (1) is N, dinethylformamide, methyl-sulphoxide etc.; Or ester compound, ETHYLE ACETATE, butylacetate etc.; Or ether compound, like diglyme; Or ketone compounds, acetone etc.; Or nitrile compounds, acetonitrile etc.; Or alcohol compound, methyl alcohol, ethanol, Virahol etc.; Or aromatic compounds, benzene, toluene etc.; Or the mixture of above material, be preferably ethanol.
The described alkali of step (1) is sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium ethylate or sodium tert-butoxide.
The described 3-hydroxyl of step (2)-4-chloro-butyric acid verivate is 3-hydroxyl-4-chloro-butyric acid methyl esters or 3-hydroxyl-4-neoprene acid ethyl ester.
Beneficial effect of the present invention does; The consisting of phase-transferring agent that only need add sweet amine amide hydrochloride quality 0.5%～10% can obviously improve 4-hydroxy pyrrolidone-2-acetamine yield; 4-hydroxy pyrrolidone-2-acetamine yield is 52.8% when using Tween-20 to do consisting of phase-transferring agent, relatively can improve 9.5 percentage points when not using consisting of phase-transferring agent.And the adding of consisting of phase-transferring agent can reduce the generation of by product in the reaction process, thereby can obtain pure article with the method for recrystallization, has avoided the treating processes of spent ion exchange resin to reaction solution.
Embodiment
Embodiment 1 (Comparative Examples that does not promptly add consisting of phase-transferring agent),
Under the nitrogen protection, in mechanical stirring 250ml four-hole bottle is housed, add sweet amine amide hydrochloride 16.6g (0.15mol), absolute ethyl alcohol 100ml and soda ash light 40.0g (0.38mol) react 0.5h under the room temperature.(content 98% 0.15mol), dripped complete in 40 minutes then in reaction solution, to drip 4-chloro-3-beta-hydroxymethyl butyrate 23.3g.Pick up counting reaction times 20h after being warming up to backflow then.
Behind the reaction 20h, decompress filter while hot, filter cake is used absolute ethanol washing.Get filtrating, underpressure distillation steams solvent.Evaporate to dryness gets the brown thick liquid, and it is dissolved in the 50ml water, the above-mentioned aqueous solution is passed through also to collect behind the strongly acidic styrene type cation exchange resin, again with the aqueous solution that obtains with collection in the strong-basicity styrene series anion exchange resin.Concentrate the brown thick liquid, add 25ml absolute ethyl alcohol recrystallization.Separate out solid, decompress filter, filter cake is used absolute ethanol washing, the gained filter cake, dry 4h in 80 ℃ of baking ovens gets product 10.3g (yield 43.3%).
Embodiment 2,
Under the nitrogen protection, in mechanical stirring 250ml four-hole bottle is housed, add sweet amine amide hydrochloride 16.6g (0.15mol), absolute ethyl alcohol 100ml and soda ash light 40.0g (0.38mol) add Tween-200.50g, react 0.5h under the room temperature.(content 98% 0.15mol), dripped complete in 40 minutes then to drip 4-chloro-3-beta-hydroxymethyl butyrate 23.3g.Pick up counting reaction times 20h after being warming up to backflow then.
Behind the reaction 20h, decompress filter while hot, filter cake is used absolute ethanol washing.Get filtrating, underpressure distillation steams solvent.Evaporate to dryness gets the brown thick liquid, adds 25ml absolute ethyl alcohol recrystallization.Separate out solid, decompress filter, filter cake is used absolute ethanol washing, the gained filter cake, dry 4h in 80 ℃ of baking ovens gets product 12.5g (yield 52.8%).
Product is detected by nucleus magnetic hydrogen spectrum, proves target product.HNMR(DMSO)δ：2.34(2H)，3.42(2H)，3.84(2H)，4.33(1H)，5.21(1H)，7.12(1H)，7.31(1H)。
Embodiment 3,
Under the nitrogen protection, in mechanical stirring 250ml four-hole bottle is housed, add sweet amine amide hydrochloride 16.6g (0.15mol), methyl alcohol 100ml and soda ash light 21.2g (0.20mol) add Tween-200.50g, at room temperature react 0.5h.(content 98% 0.15mol), dripped complete in 40 minutes then to drip 4-chloro-3-beta-hydroxymethyl butyrate 23.3g.Pick up counting reaction times 20h after being warming up to backflow then.
Behind the reaction 20h, decompress filter while hot, filter cake is used methanol wash.Get filtrating, underpressure distillation steams solvent.Evaporate to dryness gets the brown thick liquid, adds 25ml absolute ethyl alcohol recrystallization.Separate out solid, decompress filter, filter cake is used absolute ethanol washing, the gained filter cake, dry 4h in 80 ℃ of baking ovens gets product 11.7g (yield 49.3%).
Embodiment 4,
Under the nitrogen protection, in mechanical stirring 250ml four-hole bottle is housed, add sweet amine amide hydrochloride 16.6g (0.15mol), toluene 100ml and soda ash light 40.0g (0.38mol) add Tween-20 0.50g, at room temperature react 0.5h.(content 98% 0.15mol), dripped complete in 40 minutes then to drip 4-chloro-3-beta-hydroxymethyl butyrate 23.3g.Pick up counting reaction times 20h after being warming up to 80 ℃ then.
Behind the reaction 20h, decompress filter while hot, filter cake is used toluene wash.Get filtrating, underpressure distillation steams solvent.Evaporate to dryness gets the brown thick liquid, adds 25ml absolute ethyl alcohol recrystallization.Separate out solid, decompress filter, filter cake is used absolute ethanol washing, the gained filter cake, dry 4h in 80 ℃ of baking ovens gets product 11.3g (yield 47.5%).
Embodiment 5,
Under the nitrogen protection, in mechanical stirring 250ml four-hole bottle is housed, add sweet amine amide hydrochloride 16.6g (0.15mol), absolute ethyl alcohol 100ml and Anhydrous potassium carbonate 41.5g (0.30mol) add Tween-200.50g, at room temperature stir 0.5h.(content 98% 0.15mol), dripped complete in 40 minutes then to drip 4-chloro-3-beta-hydroxymethyl butyrate 23.3g.Pick up counting reaction times 20h after being warming up to backflow then.
Behind the reaction 20h, decompress filter while hot, filter cake is used absolute ethanol washing.Get filtrating, underpressure distillation steams solvent.Evaporate to dryness gets the brown thick liquid, adds 25ml absolute ethyl alcohol recrystallization.Separate out solid, decompress filter, filter cake is used absolute ethanol washing, the gained filter cake, dry 4h in 80 ℃ of baking ovens gets product 11.6g (yield 49.1%).
Embodiment 6-19,
Adopt different consisting of phase-transferring agent and different additions, other steps are as shown in table 1 with the reaction result that embodiment 2 obtains.
Can be known by embodiment 6-19, use consisting of phase-transferring agent, its product yield is basically more than 45%, and do not use consisting of phase-transferring agent to compare yield to be improved; And because the interpolation consisting of phase-transferring agent can improve reaction pair purpose product selectivity, thereby make the purge process of product simple.Therefore use preparation method that consisting of phase-transferring agent improves the 4-hydroxy pyrrolidone-2-acetamine and have the advantages that product yield height, product are easy to purifying.
Table 1: the yield of different phase-transfer catalysts and 4-hydroxy pyrrolidone-2-acetamine among the embodiment 6-19
| Embodiment number | Consisting of phase-transferring agent | Consisting of phase-transferring agent addition (g) | 4-hydroxy pyrrolidone-2-acetamine yield (%) |
| 6 | Tween-60 | 0.09 | 46.9 |
| 7 | Span-20 | 0.20 | 46.5 |
| 8 | Span-40 | 0.40 | 45.2 |
| 9 | Span-60 | 0.70 | 45.1 |
| 10 | Span-85 | 0.50 | 45.4 |
| 11 | NP-8 | 0.90 | 48.1 |
| 12 | NP-12 | 1.10 | 47.2 |
| 13 | NP-30 | 0.50 | 46.7 |
| 14 | NP-40 | 0.50 | 47.4 |
| 15 | X 2073 | 1.60 | 48.5 |
| 16 | Varion CDG-K | 0.70 | 48.5 |
| 17 | The octadecyl dimethyl betaine | 1.66 | 49.1 |
| 18 | Trimethyllaurylammonium bromide | 0.10 | 45.0 |
| 19 | The octadecyl trimethylammonium bromide | 0.20 | 46.2 |
Claims (5)
1. method for preparing the 4-hydroxy pyrrolidone-2-acetamine is characterized by and may further comprise the steps:
(1), under the nitrogen protection; In the reactor drum that whipping appts is housed, add sweet amine amide hydrochloride, solvent and alkali successively; Its proportioning is the sweet amine amide hydrochloride of mol ratio: alkali=1: 1～2.6; Quantity of solvent is 3～6 times of sweet amine amide hydrochloride quality, adds 0.5%～10% consisting of phase-transferring agent of glycyl amide hydrochloride quality again, reacts 0.5h under the room temperature then;
(2), in 0.5～3h, drip 3-hydroxyl-4-chloro-butyric acid verivate in the reaction solution upward with sweet amine amide hydrochloride equimolar amount; Be warming up to back flow reaction 1～70h then, after recrystallization filter; Washing, oven dry obtains product 4-hydroxy pyrrolidone-2-acetamine;
Described consisting of phase-transferring agent is the anhydrous sorbitol laurate; The anhydrous sorbitol cetylate; Span60; Witconol AL 69-66; The polyoxyethylene sorbitan laurate; The polyoxyethylene sorbitan stearate; Nonyl pheno [8] ether; Nonyl pheno [12] ether; Nonyl pheno [30] ether; Nonyl pheno [40] ether; X 2073; Varion CDG-K; The octadecyl dimethyl betaine; Trimethyllaurylammonium bromide or octadecyl trimethylammonium bromide.
2. the method for preparing the 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1; It is characterized by the described solvent of step (1) is N; Dinethylformamide, the mixture of one or more materials in methyl-sulphoxide, ETHYLE ACETATE, butylacetate, diglyme, acetone, acetonitrile, methyl alcohol, ethanol, Virahol, benzene, the toluene.
3. the method for preparing the 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized by the described solvent of step (1) is ethanol.
4. the method for preparing the 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized by the described alkali of step (1) is sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium ethylate or sodium tert-butoxide.
5. the method for preparing the 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized by the described 3-hydroxyl of step (2)-4-chloro-butyric acid verivate is 3-hydroxyl-4-chloro-butyric acid methyl esters or 3-hydroxyl-4-neoprene acid ethyl ester.
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| CN102718691A (en) * | 2012-07-20 | 2012-10-10 | 上海现代哈森（商丘）药业有限公司 | Novel piracetam synthetic method |
| CN105820101B (en) * | 2015-01-04 | 2018-12-18 | 哈尔滨三联药业股份有限公司 | A kind of preparation method of the pure 1- of optically-active (carbamoyl) methyl -4- hydroxy-2-pyrrolidinone |
| CN110003075A (en) * | 2019-05-21 | 2019-07-12 | 重庆医药高等专科学校 | A kind of preparation method of 2- (4- hydroxyl -2- oxo-1-pyrrolidine base) acetamide |
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