CN102633705A - Method for preparing oxiracetam - Google Patents
Method for preparing oxiracetam Download PDFInfo
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- CN102633705A CN102633705A CN201210090934XA CN201210090934A CN102633705A CN 102633705 A CN102633705 A CN 102633705A CN 201210090934X A CN201210090934X A CN 201210090934XA CN 201210090934 A CN201210090934 A CN 201210090934A CN 102633705 A CN102633705 A CN 102633705A
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Abstract
The invention discloses a method for preparing oxiracetam. The method comprises the following step of carrying out catalytic hydrogenation by taking 4-chloro-acetylacetic ester as a raw material under the action of certain temperature, certain pressure and a catalyst to obtain 4-cholor-3-hydroxyl butyrate. According to the method, three wastes can be avoided, the environmental pollution can be avoided, the raw material 4-chloro-acetylacetic ester is low in price and easy to obtain, the yield is high, and a product can be almost quantitatively obtained. A microwave reaction method is used in the step of preparing the oxiracetam by cyclization, so that the unnecessary loss of heat energy can be reduced, the reaction yield and the reaction rate are improved, and the product is easy to separate and purify.
Description
Technical field
The present invention relates to a kind of method for preparing oxiracetam, belong to the medicinal chemicals preparing technical field.
Background technology
Oxiracetam, its chemical name is the 4-hydroxy pyrrolidone-2-acetamine, chemical structural formula is shown below:
Being brain metabolism improving medicine of new generation, is pyrrolidinone compounds (ring GABOB) verivate, and the piracetam analogue all has good efficacy to cerebro-vascular diseases, brain injury, brain tumor (postoperative), intracranial infection, dementia, brain degenerative disease etc.Oxiracetam was produced the listing in Europe early than 1987 by Italian ISFS.S.P.A company, at present in 40 the countries and regions list marketings in the whole world.The study on the synthesis of relevant oxiracetam has a large amount of reports for many years.Patent US5276164; US4118396; JP9026267; The CN101121688 report is a starting raw material with the ketene dimer, obtain oxiracetam through different routes, but the ubiquitous problem of this method is that reactions step is longer, and yield is lower.In recent years the more technology of bibliographical information be with 3-hydroxyl-4-halo butanoic acid derivative be raw material directly and G-NH2 prepared in reaction oxiracetam, like patent JP03181458; JP62286964; US4686296; WO2005115978, though this technology step is brief, raw materials used market value is higher, and reaction yield is lower, finished product needs the chromatographic column purifying, is unfavorable for suitability for industrialized production.
Summary of the invention
The objective of the invention is, solve existing oxiracetam preparing method's shortcoming, a kind of environmental protection is provided, step is shorter, and yield is high, is beneficial to the method for preparing oxiracetam of suitability for industrialized production.
The said method for preparing oxiracetam of the present invention is to be starting raw material with 4-chloracetyl acetic ester, and it has following structure formation:
R is methyl or ethyl in the following formula.
Concrete synthetic route chemical equation is following:
Concrete, the method for preparing oxiracetam of the present invention may further comprise the steps:
(1) is raw material with 4-chloracetyl acetic ester, 4-chloracetyl acetic ester and metal catalyst are put into autoclave, make solvent with alcohols; Add an amount of achirality phosphine part, controlled temperature 50-100 ℃, use earlier pressure to be the nitrogen replacement of 5atm three times; Use pressure to be the hydrogen exchange of 5atm three times again, carry out hydrogenation then, required hydrogen pressure is 10-100atm; React to hydrogen pressure and no longer reduce, obtain 4-chloro-3-butyric ester;
(2) the 4-chloro-3-butyric ester that step (1) is obtained adds an amount of mineral alkali and glycyl amide hydrochloride, carries out cyclization and obtains the product oxiracetam.
Step (2) reaction process can adopt conventional heating reflux reaction, and control reaction temperature 50-120 ℃, time 20-40 hour;
Step (2) reaction process can also be carried out the microwave catalysis reaction, and microwave power is controlled between 100-400 watt, and the reaction times is 10-100 minute.
Extraction solvent behind step (2) heating reflux reaction solvent or the microwave reaction is ethanol, methyl alcohol, Virahol, n-propyl alcohol, propyl carbinol, the trimethyl carbinol, N; Dinethylformamide, 1; 4-dioxane, THF, MTBE, water, wherein a kind of.
The present invention, raw material 4-chloracetyl acetic ester is 4-chloroacetyl acetacetic ester or 4-chloro methyl acetoacetate in the step (1).
The present invention, solvent is ethanol or methyl alcohol in the step (1).
The present invention, metal catalyst is palladium chloride, Trichlororhodium, ruthenium trichloride in the step (1), wherein a kind of; The mol ratio of substrate 4-chloracetyl acetic ester and catalyzer is (5000: 1)-(20000: 1).
The present invention, achirality phosphine part is a DIOP (chemical name: pseudoallyl-2,3-dihydroxyl-1 in the step (1); Two [(2-p-methoxy-phenyl) phenyl phosphorus] ethane), BINAP (chemical name: 1,1 '-dinaphthalene-2,2 '-two diphenyl phosphines), SEGPHOS (chemical name: 5 the two diphenylphosphine butane of 4-), DIPAMP (chemical name:; Two (diphenylphosphine)-4 of 5-; 4-two-1,3-piperonyl cyclonene, wherein a kind of; The mol ratio of substrate 4-chloracetyl acetic ester and part is (5000: 1)-(20000: 1).
The present invention, the mineral alkali that adds in the step (2) is salt of wormwood, yellow soda ash, Strontium carbonate powder, saleratus, sodium hydrogencarbonate, Pottasium Hydroxide, sodium hydroxide, calcium hydroxide, wherein a kind of; The mol ratio of substrate 4-chloro-3-butyric ester and mineral alkali is (1: 1)-(1: 5).
The present invention, the mol ratio of substrate 4-chloro-3-butyric ester and glycyl amide hydrochloride is (1: 1)-(1: 5) in the step (2).
The beneficial effect that the present invention obtains is following:
The present invention is a raw material with 4-chloracetyl acetic ester; Method with shortening; Under certain temperature, pressure, catalyst action, obtain 4-chloro-3-butyric ester, this method does not have the three wastes, environmentally safe; And raw material 4-chloracetyl acetic ester is cheap and easy to get, and yield is higher almost can quantitatively to obtain product.And traditional method is to prepare 4-chloro-3-butyric ester with Peng Qinghuana or potassium borohydride reduction 4-chloracetyl acetic ester, and this method can produce a large amount of waste residue and waste liquid on producing, and environmental disruption is bigger, and yield is low, the higher suitability for industrialized production that is unfavorable for of cost.The present invention has used the method for microwave reaction in cyclization prepares the step of oxiracetam, the heating means that microwave method is more traditional have a lot of remarkable advantages.Distinctive self the deep layer heat characteristic of microwave replaces traditional synthetic thermal convection conduction pattern, reduces unnecessary heat energy loss; Microwave condition can increase the collision frequency and the effective collision probability of molecule, thereby improves reaction yield; Microwave reaction speed is fast, general 10-100 minute; In the microwave reaction not with an organic solvent, the non-environmental-pollution problem.
Embodiment
Following specific embodiment is used to explain the present invention, but these embodiment only limit to explain the object of the invention, and does not limit scope of the present invention in any form.
Embodiment 1
Get 49.38g (300mmol) 4-chloroacetyl acetacetic ester and 100ml alcoholic acid mixed solution is poured in the 200ml single port bottle, under reduced pressure use ultrasonic degas.Take by weighing the Palladous chloride of 10.64mg (0.06mmol) and the DIOP part of 29.9mg (0.06mmol) rapidly with microbalance, then under nitrogen protection with it and outgased substrate and solvent join in the 500ml autoclave.Under the room temperature, go out the air in the autoclave, and then, charge into hydrogen to reacting required pressure with hydrogen exchange three times with nitrogen replacement.Be allowed to condition under the temperature of setting and react the regular hour, no longer change stopped reaction to pressure.Logical recirculated water cooling kettle temperature is to room temperature; Carefully discharge hydrogen, take out reactor drum, on Rotary Evaporators, steam solvent; At last with oil pump underpressure distillation and collect 80-85 ℃ cut under 15 mmhg; Get product 4-chloro-ethyl 3-hydroxybutanoate 49g, yield 99.2%, gc content 97.8%.
Under the room temperature, in being furnished with the 500ml four-hole bottle of stirring, reflux exchanger, TM, add the 250ml absolute ethyl alcohol and make solvent, the glycyl amide hydrochloride of 22.1g (200mmol), 21.2g (200mmol) soda ash light stir 1h (white opacity shape system) and add 33.3g (200mmol) 4-chloro-ethyl 3-hydroxybutanoate then rapidly; Heat temperature raising is to refluxing, and refluxes and spends the night after (reaction times is about 16h) question response finishes, and the heat filter is with 50ml absolute ethanol washing filter cake; Merging filtrate, concentrating under reduced pressure ethanol gets the orange red oily matter of 38.2g; Add the stirring of 100ml water and make its dissolving, water is used dichloromethane extraction, 2 * 40ml; Separatory, water revolve steam the orange red sticking oil of 15g, add 100ml methyl alcohol; Add 3g gac and 3g silica gel reflux then and stir 30min, heat is considered, and the filtrating room temperature is placed and spent the night; Suction filtration gets 8g white crystals body, and yield is 25.0%, m.p.=165-167 ℃.
Embodiment 2
Get the mixed solution of 45.18g (300mmol) 4-chloro methyl acetoacetate and 100ml methyl alcohol and pour in the 200ml single port bottle, under reduced pressure use ultrasonic degas.Take by weighing the Palladous chloride of 10.64mg (0.06mmol) and the DIOP part of 29.9mg (0.06mmol) rapidly with microbalance, then under nitrogen protection with it and outgased substrate and solvent join in the 500ml autoclave.Under the room temperature, go out the air in the autoclave, and then, charge into hydrogen to reacting required pressure with hydrogen exchange three times with nitrogen replacement.Be allowed to condition under the temperature of setting and react the regular hour, no longer change stopped reaction to pressure.Logical recirculated water cooling kettle temperature is to room temperature; Carefully discharge hydrogen, take out reactor drum, on Rotary Evaporators, steam solvent; At last with oil pump underpressure distillation and collect 78-82 ℃ cut under 15 mmhg; Get product 4-chloro-3-beta-hydroxymethyl butyrate 42g, yield 93.2%, gc content 98.8%.
Under the room temperature, in being furnished with the 500ml four-hole bottle of stirring, reflux exchanger, TM, add 250mlDMF and make solvent, the glycyl amide hydrochloride of 22.1g (200mmol), 21.2g (200mmol) soda ash light stir 1h (white opacity shape system) and add 30.5g (200mmol) 4-chloro-3-beta-hydroxymethyl butyrate then rapidly; Heat temperature raising is to refluxing, and refluxes and spends the night after (reaction times is about 16h) question response finishes, and the heat filter is with 50ml dry DMF washing leaching cake; Merging filtrate, concentrating under reduced pressure gets the orange red oily matter of 37.6g; Add the stirring of 100ml water and make its dissolving, water is used dichloromethane extraction, 2 * 40ml; Separatory, water revolve steam the orange red sticking oil of 15g, add 100ml methyl alcohol; Add 3g gac and 3g silica gel reflux then and stir 30min, heat is considered, and the filtrating room temperature is placed and spent the night; Suction filtration gets 22g white crystals body, and yield is 70.0%, m.p.=165-167 ℃.
Embodiment 3
Get the mixed solution of 49.38g (300mmol) 4-chloroacetyl acetacetic ester and 100ml methyl alcohol and pour in the 200ml single port bottle, under reduced pressure use ultrasonic degas.Take by weighing the Trichlororhodium of 12.56mg (0.06mmol) and the DIPAMP part of 27.51mg (0.06mmol) rapidly with microbalance, then under nitrogen protection with it and outgased substrate and solvent join in the 500ml autoclave.Under the room temperature, go out the air in the autoclave, and then, charge into hydrogen to reacting required pressure with hydrogen exchange three times with nitrogen replacement.Be allowed to condition under the temperature of setting and react the regular hour, no longer change stopped reaction to pressure.Logical recirculated water cooling kettle temperature is to room temperature; Carefully discharge hydrogen, take out reactor drum, on Rotary Evaporators, steam solvent; At last with oil pump underpressure distillation and collect 89-91 ℃ cut under 6 mmhg; Get product 4-chloro-ethyl 3-hydroxybutanoate 47g, yield 95%, gc content 98.8%.
Under the room temperature, in being furnished with the 500ml four-hole bottle of stirring, reflux exchanger, TM, add the 250ml absolute ethyl alcohol and make solvent, the glycyl amide hydrochloride of 21.2g (200mmol) soda ash light and 22.1g (200mmol) is heated to backflow; Slowly drip 33.3g (200mmol) 4-chloro-ethyl 3-hydroxybutanoate then, finish for about 10 hours, add the back backflow and spend the night (reaction times is about 20h), after question response finishes; The heat filter is with 50ml absolute ethanol washing filter cake, merging filtrate, concentrating under reduced pressure ethanol; Get the orange red oily matter of 38g, add the stirring of 100ml water and make its dissolving, water is used dichloromethane extraction, 2 * 40ml; Separatory, water revolve steam the orange red sticking oil of 19g, add 100ml methyl alcohol; Add 3g gac and 3g silica gel reflux then and stir 30min, heat is considered, and the filtrating room temperature is placed and spent the night; Suction filtration gets 12g white crystals body, and yield is 37.5%, m.p.=165-167 ℃.
Embodiment 4
Get the mixed solution of 49.38g (300mmol) 4-chloroacetyl acetacetic ester and 100ml methyl alcohol and pour in the 200ml single port bottle, under reduced pressure use ultrasonic degas.Take by weighing the ruthenium trichloride of 12.45mg (0.06mmol) and the SEGPHOS part of 36.6mg (0.06mmol) rapidly with microbalance, then under nitrogen protection with it and outgased substrate and solvent join in the 500ml autoclave.Under the room temperature, go out the air in the autoclave, and then, charge into hydrogen to reacting required pressure with hydrogen exchange three times with nitrogen replacement.Be allowed to condition under the temperature of setting and react the regular hour, no longer change stopped reaction to pressure.Logical recirculated water cooling kettle temperature is to room temperature; Carefully discharge hydrogen, take out reactor drum, on Rotary Evaporators, steam solvent; At last with oil pump underpressure distillation and collect 89-91 ℃ cut under 6 mmhg; Get product 4-chloro-ethyl 3-hydroxybutanoate 48g, yield 97%, gc content 98.9%.
Under the room temperature, in being furnished with the 500ml four-hole bottle of stirring, reflux exchanger, TM, add the 250ml absolute ethyl alcohol and make solvent, 21.2g (200mmol) soda ash light is heated to backflow; Glycyl amide hydrochloride and 33.3g (200mmol) 4-chloro-ethyl 3-hydroxybutanoate with 22.1g (200mmol) is divided into 10 parts then, adds in each 1 hour aly (to be to add 2.21g glycyl amide hydrochloride and 3.33g 4-chloro-ethyl 3-hydroxybutanoate in per 1 hour, to add the back backflow and spend the night (reaction times is about 20h), after question response finishes; The heat filter is with 50ml absolute ethanol washing filter cake, merging filtrate, concentrating under reduced pressure ethanol; Get the orange red oily matter of 38g, add the stirring of 100ml water and make its dissolving, water is used dichloromethane extraction, 2 * 40ml; Separatory, water revolve steam the orange red sticking oil of 19g, add 100ml methyl alcohol; Add 3g gac and 3g silica gel reflux then and stir 30min, heat is considered, and the filtrating room temperature is placed and spent the night; Suction filtration gets 16g white crystals body, and yield is 50.0%, m.p.=165-167 ℃.
Embodiment 5
Get the mixed solution of 49.38g (300mmol) 4-chloroacetyl acetacetic ester and 100ml methyl alcohol and pour in the 200ml single port bottle, under reduced pressure use ultrasonic degas.Take by weighing the ruthenium trichloride of 12.45mg (0.06mmol) and the BINAP part of 37.3mg (0.06mmol) rapidly with microbalance, then under nitrogen protection with it and outgased substrate and solvent join in the 500ml autoclave.Under the room temperature, go out the air in the autoclave, and then, charge into hydrogen to reacting required pressure with hydrogen exchange three times with nitrogen replacement.Be allowed to condition under the temperature of setting and react the regular hour, no longer change stopped reaction to pressure.Logical recirculated water cooling kettle temperature is to room temperature; Carefully discharge hydrogen, take out reactor drum, on Rotary Evaporators, steam solvent; At last with oil pump underpressure distillation and collect 89-91 ℃ cut under 6 mmhg; Get product 4-chloro-ethyl 3-hydroxybutanoate 47g, yield 96%, gc content 99.2%.
With 21.2g (200mmol) soda ash light, the glycyl amide hydrochloride of 22.1g (200mmol) and 33.3g (200mmol) 4-chloro-ethyl 3-hydroxybutanoate are put into 250ml single port bottle, place it in then on the glass round platform in the microwave reactor, pass the small sircle hole at microwave reactor top in order to prolong; Dock with reaction flask in the microwave reactor through two mouthfuls of Glass tubings, 200 watts of reaction power are set, after 30 minutes reaction times, stop heating; The cooling back added the 100ml absolute ethyl alcohol and stirring 10 minutes in flask, suction filtration is with 50ml absolute ethanol washing filter cake, merging filtrate; Concentrating under reduced pressure ethanol gets the orange red oily matter of 36g, adds the stirring of 100ml water and makes its dissolving, and water is used dichloromethane extraction; 2 * 40ml, separatory, water revolve steam the orange red sticking oil of 29g, add 100ml methyl alcohol; Add 3g gac and 3g silica gel reflux then and stir 30min, heat is considered, and the filtrating room temperature is placed and spent the night; Suction filtration gets 22g white crystals body, and yield is 68.7%, m.p.=165-167 ℃.
Embodiment 6
Get the mixed solution of 45.18g (300mmol) 4-chloro methyl acetoacetate and 100ml methyl alcohol and pour in the 200ml single port bottle, under reduced pressure use ultrasonic degas.Take by weighing the ruthenium trichloride of 12.45mg (0.06mmol) and the BINAP part of 37.3mg (0.06mmol) rapidly with microbalance, then under nitrogen protection with it and outgased substrate and solvent join in the 500ml autoclave.Under the room temperature, go out the air in the autoclave, and then, charge into hydrogen to reacting required pressure with hydrogen exchange three times with nitrogen replacement.Be allowed to condition under the temperature of setting and react the regular hour, no longer change stopped reaction to pressure.Logical recirculated water cooling kettle temperature is to room temperature; Carefully discharge hydrogen, take out reactor drum, on Rotary Evaporators, steam solvent; At last with oil pump underpressure distillation and collect 78-82 ℃ cut under 15 mmhg; Get product 4-chloro-3-beta-hydroxymethyl butyrate 43g, yield 94.5%, gc content 98.6%.
With 21.2g (200mmol) soda ash light, the glycyl amide hydrochloride of 22.1g (200mmol) and 30.5g (200mmol) 4-chloro-3-beta-hydroxymethyl butyrate are put into 250ml single port bottle, place it in then on the glass round platform in the microwave reactor, pass the small sircle hole at microwave reactor top in order to prolong; Dock with reaction flask in the microwave reactor through two mouthfuls of Glass tubings, 200 watts of reaction power are set, after 30 minutes reaction times, stop heating; The cooling back adds the 100ml anhydrous methanol in flask stirred 10 minutes, and suction filtration is with 50ml anhydrous methanol washing leaching cake, merging filtrate; Concentrating under reduced pressure methyl alcohol gets the orange red oily matter of 38g, adds the stirring of 100ml water and makes its dissolving, and water is used dichloromethane extraction; 2 * 40ml, separatory, water revolve steam the orange red sticking oil of 32g, add 100ml methyl alcohol; Add 3g gac and 3g silica gel reflux then and stir 30min, heat is considered, and the filtrating room temperature is placed and spent the night; Suction filtration gets 28g white crystals body, and yield is 89.4%, m.p.=165-167 ℃.
Claims (8)
1. method for preparing oxiracetam is characterized in that may further comprise the steps:
(1) is raw material with 4-chloracetyl acetic ester, 4-chloracetyl acetic ester and metal catalyst put into autoclave, alcoholic solvent; Add an amount of achirality phosphine part, controlled temperature 50-100 ℃, use earlier pressure to be the nitrogen replacement of 5atm three times; Use pressure to be the hydrogen exchange of 5atm three times again, carry out hydrogenation then, required hydrogen pressure is 10-100atm; React to hydrogen pressure and no longer reduce, obtain 4-chloro-3-butyric ester;
(2) the 4-chloro-3-butyric ester that step (1) is obtained adds an amount of mineral alkali and glycyl amide hydrochloride, carries out cyclization and obtains the product oxiracetam.
2. method according to claim 1 is characterized in that: raw material 4-chloracetyl acetic ester is 4-chloroacetyl acetacetic ester or 4-chloro methyl acetoacetate, has following structure formation:
R is methyl or ethyl in the formula.
3. method according to claim 1 and 2 is characterized in that metal catalyst is palladium chloride, Trichlororhodium, ruthenium trichloride in the step (1), wherein a kind of, and the mol ratio of substrate 4-chloracetyl acetic ester and catalyzer is (5000: 1)-(20000: 1).
4. method according to claim 1 and 2 is characterized in that achirality phosphine part is DIOP, DIPAMP, BINAP, SEGPHOS in the step (1), wherein a kind of; The mol ratio of substrate 4-chloracetyl acetic ester and achirality phosphine part is (5000: 1)-(20000: 1).
5. method according to claim 1 and 2; It is characterized in that the mineral alkali that adds in the step (2) is: salt of wormwood, yellow soda ash, Strontium carbonate powder, saleratus, sodium hydrogencarbonate, Pottasium Hydroxide, sodium hydroxide, calcium hydroxide; Wherein a kind of, the mol ratio of substrate 4-chloro-3-butyric ester and mineral alkali is (1: 1)-(1: 5).
6. method according to claim 1 and 2; It is characterized in that step (2) reaction process carries out conventional heating reflux reaction, control reaction temperature 50-120 ℃, time 20-40 hour; Reaction solvent is ethanol, methyl alcohol, Virahol, n-propyl alcohol, propyl carbinol, the trimethyl carbinol, N; Dinethylformamide, 1,4-dioxane, THF, MTBE, water, wherein a kind of.
7. method according to claim 1 and 2; It is characterized in that step (2) reaction process carries out microwave catalysis reaction, microwave power is controlled between 100-400 watt, and the reaction times is 10-100 minute; Extraction solvent behind the microwave reaction is ethanol, methyl alcohol, Virahol, n-propyl alcohol, propyl carbinol, the trimethyl carbinol, N; Dinethylformamide, 1,4-dioxane, THF, MTBE, water, wherein a kind of.
8. method according to claim 1 and 2 is characterized in that the mol ratio of middle substrate 4-chloro-3-butyric ester of step (2) and glycyl amide hydrochloride is (1: 1)-(1: 5).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993079A (en) * | 2012-12-17 | 2013-03-27 | 苏州浩波科技股份有限公司 | Preparation method of chiral 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN103145557A (en) * | 2013-03-27 | 2013-06-12 | 石家庄手性化学有限公司 | Preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity |
| CN107021898A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of method that ball-milling method prepares levo-oxiracetam crystal formation II |
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| CN1899695A (en) * | 2005-07-21 | 2007-01-24 | 中国科学院大连化学物理研究所 | Method for using palladium homogeneous system in enantioselective catalysis of ketone hydride |
| CN101898993A (en) * | 2009-05-28 | 2010-12-01 | 狄渊 | Preparation method of 4-hydroxyl ketopyrrolidine-2-acetamide |
| CN102134212A (en) * | 2010-01-27 | 2011-07-27 | 重庆圣华曦药业股份有限公司 | Preparation method of Oxiracetam |
| WO2011141160A1 (en) * | 2010-05-11 | 2011-11-17 | Lonza Ltd | A process for the hydrogenation of ketoesters |
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- 2012-03-31 CN CN201210090934XA patent/CN102633705A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1899695A (en) * | 2005-07-21 | 2007-01-24 | 中国科学院大连化学物理研究所 | Method for using palladium homogeneous system in enantioselective catalysis of ketone hydride |
| CN101898993A (en) * | 2009-05-28 | 2010-12-01 | 狄渊 | Preparation method of 4-hydroxyl ketopyrrolidine-2-acetamide |
| CN102134212A (en) * | 2010-01-27 | 2011-07-27 | 重庆圣华曦药业股份有限公司 | Preparation method of Oxiracetam |
| WO2011141160A1 (en) * | 2010-05-11 | 2011-11-17 | Lonza Ltd | A process for the hydrogenation of ketoesters |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993079A (en) * | 2012-12-17 | 2013-03-27 | 苏州浩波科技股份有限公司 | Preparation method of chiral 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN103145557A (en) * | 2013-03-27 | 2013-06-12 | 石家庄手性化学有限公司 | Preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity |
| CN103145557B (en) * | 2013-03-27 | 2015-06-03 | 石家庄手性化学有限公司 | Preparation method of S-4-chlorine-3-hydroxy butyric acid ethyl ester with optical purity |
| CN107021898A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | A kind of method that ball-milling method prepares levo-oxiracetam crystal formation II |
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Application publication date: 20120815 |