CN102134212B - Preparation method of Oxiracetam - Google Patents
Preparation method of Oxiracetam Download PDFInfo
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- CN102134212B CN102134212B CN201010101601A CN201010101601A CN102134212B CN 102134212 B CN102134212 B CN 102134212B CN 201010101601 A CN201010101601 A CN 201010101601A CN 201010101601 A CN201010101601 A CN 201010101601A CN 102134212 B CN102134212 B CN 102134212B
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Abstract
The invention relates to a preparation method of Oxiracetam, which takes 4-chlorine acetoacetic ester (1) as raw material, and prepared by the following synthetic route. The preparation method is simple and convenient, and has short route, low raw material, higher product yield, low cost and good purity.
Description
Technical field
The present invention relates to a kind of preparation method of oxiracetam.
Background technology
Oxiracetam; Chemical name is 4-hydroxyl-2-OXo-1-pyrrolidine ethanamide; Structure is a kind of nootropics suc as formula shown in (VI), the clinical senile dementia that can be used for; Incomplete, the memory disorder of brain function that diseases such as many infraction dementias and neurosis, cerebral trauma, encephalitis cause is particularly to preventing and treating the evident in efficacy of senile dementia.This compound is more synthetic in 1974 than Qie Mu company by Italian SmithKline first, and the compound method of having reported at present has: JP62026267, EP223328; The compound method of bibliographical informations such as JP3181458 is a starting raw material with the ketene dimer, warp and chlorine reaction; After making 4-chloracetyl Acetyl Chloride 98Min.; Obtain the 4-chloroacetyl acetacetic ester with ethyl esterification again, prepare 4-chloro-ethyl 3-hydroxybutanoate with sodium borohydride reduction then, last and G-NH2 cyclization obtains oxiracetam (VI).This synthetic route is short, but ring-closure reaction step yield is low, and production cost is higher.Its synthetic route is:
The compound method of US4118396 report; Be to be starting raw material,, obtain 2-(4-hydroxyl-3-ethoxycarbonyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE through the sodium ethylate catalyzed cyclization again with 2-ethoxycarbonyl Acetyl Chloride 98Min. acidylate with the iminodiacetic acid (salt) acetoacetic ester; Hydrolysis decarboxylation obtains 2-(2 then; 4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE obtains 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE with sodium borohydride reduction again, and last ammonia is separated and obtained oxiracetam (VI).The shortcoming of this method is that synthetic route is long, and midbody must be through purified, complex operation, and total recovery is low.Its synthetic route is:
Patent DE2758937; The compound method of bibliographical informations such as DE2759033; Being to be starting raw material by 4-amino-3-hydroxybutyric acid, is condensation/protective material with the hexamethyldisilazane, makes the trimethyl silicon based oxygen base of 4--2-oxo-pyrrolidine; Obtain 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE with the METHYL BROMOACETATE condensation again, last ammonia is separated and is obtained oxiracetam (VI).Starting raw material in this compound method is not easy to obtain, and has increased protection and deprotection steps, and yield is reduced.Its synthetic route is following:
Notification number is that the Chinese patent reported method of CN1268611C is to be starting raw material with the 4-chloroacetyl acetacetic ester; Make 4-azido-methyl aceto acetate with the sodiumazide condensation; Reduction makes 4-amino-3-hydroxybutyric acid; After cyclization makes 4-hydroxyl-2-Pyrrolidone again, obtain 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE with the ethyl chloroacetate condensation, last ammonia is separated and is obtained oxiracetam (VI).The raw material sodiumazide price of using in this compound method is higher, explosive; Without the protection hydroxyl protection, unavoidably will produce O-hydrocarbonylation by product when midbody 4-hydroxyl-2-Pyrrolidone and ethyl chloroacetate condensation, the impurity that follow-up ammonolysis reaction produces can get in the finished product, influences the oxiracetam quality.Its synthetic route is following:
Summary of the invention
To above-mentioned situation, it is a kind of more easy that the present invention will provide, and the even more ideal oxiracetam preparation method of effect.
Oxiracetam preparation method of the present invention is to be starting raw material with 4-chloracetyl acetic ester (I), is undertaken by following mode:
1 ' starting raw material 4-chloracetyl acetic ester (I) separated with ammoniacal liquor ammonia obtain 4-chloracetyl ethanamide (II),
2 ' 4-chloracetyl ethanamide (II) cyclization under the alkaline condition of pH 7-12 becomes tetramethyleneimine-2,4-diketone (III),
3 ' tetramethyleneimine-2,4-diketone (III) obtains 2-(2,4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) with chloracetate or bromacetate condensation,
4 ' with the 4-ketone group reduction of 2-(2,4-dioxo tetramethyleneimine-1-yl) acetic ester (IV), obtain 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) acetic ester (V),
The reduction of 5 ' 4-ketone group becomes 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) acetic ester (V) and obtains oxiracetam (VI) through ammonolysis reaction, and the preparation route is following:
In the formula: X is Cl or Br; R, R
1Be respectively identical or different C
1-4Alkyl wherein all is preferably methyl or ethyl, helps improving speed of response.
Above-mentioned preparing method's reaction conditions is comparatively gentle.For example: said the 1st ' step ammonolysis reaction in the above-mentioned preparation process; Can adopt the domestic method of carrying out ammonolysis reaction at present with ammoniacal liquor; Wherein used ammonia concn also has no special requirements, but test-results shows, is that the strong aqua of 25%～28w% serves as preferred to adopt concentration.Ammonolysis reaction generally can both carry out under-10 ℃～20 ℃ temperature condition smoothly, serves as preferred with 0 ℃～10 ℃ temperature of reaction wherein.Reaction temperature is spent low, can prolong the reaction times undoubtedly; And when being appreciated that by the constructional feature of raw material (I) and product (II) temperature of reaction is too high, be prone to that hydrolysis takes place and/or ammonia is separated side reactions such as dechlorination.
Basic reaction conditions in the above-mentioned preparation process in said the 2nd ' step reaction; Generally can select by the formed alkali reaction environment of mineral alkali commonly used such as alkali-metal oxyhydroxide such as potassium, sodium or carbonate; Particularly preferably be alkaline condition, but be not limited only to this in the pH8 that forms by alkaline carbonate～10.Test shows, can increase by product under the strong excessively alkaline condition, influences tetramethyleneimine-2, the yield of 4-diketone (III).Because the too high easy generation polymerization side reactions of temperature, therefore be lower than 120 ℃ with boiling point, be preferably the alcohol that is lower than 100 ℃ or ketone as the reaction medium solvent, like C such as methyl alcohol commonly used, ethanol, propyl alcohol, Virahol, propyl carbinols
1-4The low-boiling point alcohol kind solvent, acetone, C such as butanone
1-3The lower boiling ketones solvent, or in the acetonitrile dielectric solvent, this step reaction can be carried out smoothly, but is not limited only to this.Reaction solvent wherein serves as preferred with methyl alcohol, ethanol etc., except that conveniently be easy to get with cheap, also more be prone to be used, and tetramethyleneimine-2 with corresponding mineral alkali, the yield of 4-diketone (III) is also higher.This step is reflected at room temperature can carry out and accomplish to the temperature condition that refluxes smoothly, and temperature is different, and the reaction times is different.
The condensation reaction in said the 3rd ' step generally can select strongly alkaline compounds such as sodium Metal 99.5, sodium alkoxide or sodium hydride as condensing agent in the preparation process.The test-results demonstration, because the unsafe factor in the sodium Metal 99.5 use is more, sodium alkoxide can react with the ethyl chloroacetate of one of condensation raw material and produce the etherificate by product, therefore, aspect security and minimizing by product, sodium hydride is more preferred condensing agent.At toluene, benzene, inert solvents such as YLENE, or N, dinethylformamide, in the acetonitrile isopolarity aprotic solvent, this is reflected at room temperature and to the wide temperature range that refluxes, can carries out smoothly and accomplish.
Above-mentioned the 4th ' step is with 2-(2; 4-dioxo tetramethyleneimine-1-yl) the 4-carbonyl reduction in the acetic ester (IV) is 4-OH; It is reduction reaction the most conventional in the chemical reaction; The reductive agent that can select to use is a lot, is the metallic reducing agents such as palladium, platinum etc. at body like alkali-metal hydroborates such as POTASSIUM BOROHYDRIDE 97MIN commonly used, Peng Qinghuana, lithium aluminum hydride, with carbon.Take all factors into consideration from the aspects such as simplicity of the security used, price, preparation, wherein to use alkali-metal hydroborates such as POTASSIUM BOROHYDRIDE 97MIN, Peng Qinghuana the most preferred as reductive agent.Test-results shows, this step is reflected in-20 ℃～30 ℃ temperature condition commonly used of broad and can carries out smoothly.For more helping the carrying out of reduction reaction, avoid the loss property consumption of high reaction activity reductive agent, this step reaction is further carried out under protection of inert gas such as nitrogen being better.
Because product oxiracetam (VI) has bigger water-soluble; So last ammonolysis reaction in the above-mentioned preparation process; Oxiracetam (VI) there is the mode that feeds ammonia in the low boiling point organic solvents such as methyl alcohol than low-solubility, ethanol carry out to preferably to be employed in; Can help simplifying reacted separation post-processing operation, also help avoiding the loss of product, improve product yield.This step ammonolysis reaction can carry out under-10 ℃～30 ℃ broad temperature condition commonly used.
Test-results shows, among the above-mentioned preparation method of the present invention, and by tetramethyleneimine-2,4-diketone (III) elder generation and chloracetate
Restore after (or bromacetate) condensation; Can avoid by product to the protection and/or the O-hydrocarbonylation of hydroxyl, can make synthetic route shorter and the operation more easy, and because of cost of material cheap; Total recovery is higher; Preparation cost is low, good product purity, the suitable especially oxiracetam raw material of using as injection.
Below embodiment through embodiment, foregoing of the present invention is remake further detailed description.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment
The preparation of embodiment 1:4-chloracetyl ethanamide (II)
Method 1: to being cooled to 0-5 ℃ of concentration is to drip 4-chloro methyl acetoacetate (I) 20kg among the 25-28w% strong aqua 100L, drips off and continues stirring reaction 2 hours, filters; With the cold water washing filter cake that is lower than 10 ℃; Drying obtains 4-chloracetyl ethanamide (II) 13.6kg, yield 75.6%.
Method 2: to being cooled to 0-5 ℃ of concentration is to drip 4-chloroacetyl acetacetic ester (I) 20kg among the 25-28w% strong aqua 100L, drips off and continues stirring reaction 2 hours, filters; With the cold water washing filter cake that is lower than 10 ℃; Drying obtains 4-chloracetyl ethanamide (II) 11.9kg, yield 72.1%.
Embodiment 2: tetramethyleneimine-2, the preparation of 4-diketone (III)
Method 1: with 4-chloracetyl ethanamide (II) 13kg, with methyl alcohol 104L, salt of wormwood 19.9kg mixes, pH9-10, temperature rising reflux 12 hours.Filtered while hot, filtrating was cooled to 0-5 ℃ of crystallization 4 hours.Filter, use methanol wash, drying obtains tetramethyleneimine-2,4-diketone (III) 5.9kg, yield 62.1%, fusing point 120-122 ℃.
Method 2: with 4-chloracetyl ethanamide (II) 13kg, with ethanol 104L, salt of wormwood 19.9kg mixes, pH9-10, and 8 hours filtered while hot of temperature rising reflux, filtrating was cooled to 0-5 ℃ of crystallization 4 hours.Filter, use washing with alcohol, drying obtains tetramethyleneimine-2,4-diketone (III) 6.1kg, yield 64.2%, fusing point 120.5-122 ℃.
Method 3: with 4-chloracetyl ethanamide (II) 13kg, with acetone 130L, salt of wormwood 19.9kg mixes, pH9-10, and 12 hours filtered while hot of temperature rising reflux, filtrating was cooled to 0-5 ℃ of crystallization 4 hours.Filter, use washing with acetone, drying obtains tetramethyleneimine-2,4-diketone (III) 5.6kg, yield 59.6%, fusing point 119-121 ℃.
Method 4: with 4-chloracetyl ethanamide (II) 13kg, with acetonitrile 130L, salt of wormwood 19.9kg mixes, pH9-10, and 8 hours filtered while hot of temperature rising reflux, filtrating was cooled to 0-5 ℃ of crystallization 6 hours.Filter, use the acetonitrile washing leaching cake, drying obtains tetramethyleneimine-2,4-diketone (III) 5.4kg, yield 56.8%, fusing point 119-122 ℃.
Method 5: get 4-chloracetyl ethanamide (II) 13kg, ethanol 104L, salt of wormwood 19.9kg, pH9-10,50-60 ℃ was reacted 24 hours, filtered while hot, filtrating was cooled to 0-5 ℃ of crystallization 4 hours.Filter, use washing with alcohol, drying obtains tetramethyleneimine-2,4-diketone (III) 5.8kg, yield 61.1%, fusing point 120-122 ℃.
Method 6: get 4-chloracetyl ethanamide (II) 13kg, ethanol 104L, yellow soda ash 15.3kg, pH8-9,8 hours filtered while hot of temperature rising reflux, filtrating was cooled to 0-5 ℃ of crystallization 4 hours.Filter, use washing with alcohol, drying obtains tetramethyleneimine-2,4-diketone (III) 5.9kg, yield 62.1%, fusing point 120-122 ℃.
Method 7: get 4-chloracetyl ethanamide (II) 13kg, ethanol 104L, sodium hydroxide 5.8kg, pH11-12,8 hours filtered while hot of temperature rising reflux, filtrating is cooled to 0-5 ℃, crystallization 4 hours.Filter, use washing with alcohol, drying obtains tetramethyleneimine-2,4-diketone (III) 3.8kg, 40%, fusing point 114-119 ℃.
The preparation of embodiment 3:2-(2,4-dioxo tetramethyleneimine-1-yl) acetic ester (IV)
Method 1: sodium hydride 60%2.5kg is suspended in toluene 60L, slowly adds tetramethyleneimine-2,4-diketone (III) 6kg, stirring at room reaction 1 hour; Room temperature drips ethyl chloroacetate 8.2kg again, drips off to be warming up to 50-60 ℃ of reaction 8 hours, is cooled to room temperature, adds entry 20L washing toluene layer; Repeat 1 time, tell toluene layer, drying is filtered; Concentrate and obtain 2-(2,4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 8.9kg, yield 79.5%, fusing point 88-91 ℃.
Method 2: sodium hydride 60%2.5kg is suspended in toluene 60L, slowly adds tetramethyleneimine-2,4-diketone (III) 6kg, stirring at room reaction 1 hour; Room temperature drips methyl chloroacetate 7.2kg again, drips off to be warming up to 50-60 ℃ of reaction 8 hours, is cooled to room temperature, adds entry 20L washing toluene layer; Repeat 1 time, tell toluene layer, drying is filtered; Concentrate and obtain 2-(2,4-dioxo tetramethyleneimine-1-yl) methyl acetate (IV) 7.9kg, yield 76.0%.
Method 3: sodium hydride 60%2.5kg is suspended in toluene 60L, slowly adds tetramethyleneimine-2,4-diketone (III) 6kg, stirring at room reaction 1 hour; Room temperature drips ethyl chloroacetate 8.2kg again, drips off and is warming up to back flow reaction 4 hours, is cooled to room temperature, adds entry 20L washing toluene layer; Repeat 1 time, tell toluene layer, drying is filtered; Concentrate and obtain 2-(2,4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 8.6kg, yield 76.8%, fusing point 88-91 ℃.
Method 4: sodium hydride 60%2.5kg is suspended in toluene 60L, slowly adds tetramethyleneimine-2,4-diketone (III) 6kg, stirring at room reaction 1 hour; Room temperature dripping bromine ETHYLE ACETATE 11.1kg drips off and is warming up to 50-60 ℃ of reaction 6 hours again, is cooled to room temperature, adds entry 20L washing toluene layer; Repeat 1 time, tell toluene layer, drying; Filter, concentrate and obtain 2-(2,4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 9.2kg.Yield 82.1%, fusing point 89-91 ℃.
Method 5: 60%2.5kg is suspended in N with sodium hydride, and dinethylformamide 30L slowly adds tetramethyleneimine-2,4-diketone (III) 6kg; Stirring at room reaction 1 hour, room temperature drips ethyl chloroacetate 8.2kg again, drips off to be warming up to 50-60 ℃ of reaction 8 hours, is cooled to room temperature; Impouring water 100L extracts water layer with ETHYLE ACETATE 50L, repeats combined ethyl acetate 3 times; With saturated brine 30L washing 1 time, tell ETHYLE ACETATE, drying is filtered; Concentrate and obtain 2-(2,4-dioxo tetramethyleneimine-1 base) ETHYLE ACETATE (IV) 8.5kg, yield 75.9%, fusing point 88-92 ℃.
Method 6: sodium ethylate 4.3kg is suspended in toluene 60L, slowly adds tetramethyleneimine-2,4-diketone (III) 6kg, stirring at room reaction 1 hour; Room temperature drips ethyl chloroacetate 8.2kg again, drips off to be warming up to 50-60 ℃ of reaction 12 hours, is cooled to room temperature, adds entry 20L washing toluene layer; Repeat 1 time, tell toluene layer, drying is filtered; Concentrate and obtain 2-(2,4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 8.1kg, yield 72.3%, fusing point 82-87 ℃.
Method 7: sodium Metal 99.5 1.5kg is dropped among the toluene 60L, is heated to backflow, treat that sodium Metal 99.5 melts after, be cooled to room temperature under stirring fast; In the sodium sand that makes, drip tetramethyleneimine-2,4-diketone (III) 6kg drips off stirring at room reaction 1 hour, and room temperature drips ethyl chloroacetate 8.2kg again; Drip off and be warming up to 50-60 ℃ of reaction 8 hours, be cooled to room temperature, add entry 20L washing toluene layer, repeat 1 time; Tell toluene layer, drying is filtered, and concentrates and obtains 2-(2; 4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 9.3kg, yield 83.0%, fusing point 88-91 ℃.
The preparation of embodiment 4:2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) acetic ester (V)
Method 1: with 2-(2; 4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 9kg uses the 45L dissolve with methanol, and 10～20 ℃ of gradation add Peng Qinghuana 1.8kg, insulation reaction 3 hours; Drip 10% Hydrogen chloride and regulate the pH value to neutral; Filter, filtrating concentrating obtains 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE (V) oily matter 8.9kg, yield 97.8%.
Method 2: with 2-(2; 4-dioxo tetramethyleneimine-1-yl) methyl acetate (IV) 7.6kg uses the 38L dissolve with methanol, and 10～20 ℃ of gradation add Peng Qinghuana 1.6kg, insulation reaction 3 hours; Drip 10% Hydrogen chloride and regulate the pH value to neutral; Filter, filtrating concentrating obtains 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) methyl acetate (V) oily matter 7.6kg, and yield is near theoretical amount.
Method 3: with 2-(2; 4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 9kg is dissolved in methyl alcohol 45L, and-5～5 ℃ of gradation add Peng Qinghuana 1.8kg, insulation reaction 3 hours; Drip 10% Hydrogen chloride and regulate the pH value to neutral; Filter, filtrating concentrating obtains 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE (V) oily matter 9kg, and yield is near theoretical amount.
Method 4: with 2-(2; 4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 9kg is dissolved in methyl alcohol 45L, and gradation adds POTASSIUM BOROHYDRIDE 97MIN 2.6kg, and 10～20 ℃ were reacted 3 hours; Drip 10% Hydrogen chloride and regulate pH value to neutral; Filter, concentrate and obtain 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE (V) oily matter 8.9kg, yield 97.8%.
Method 5: 2-(2,4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 9kg is dissolved in THF 45L, and gradation adds lithium aluminum hydride 1.8kg; Temperature rising reflux reaction 3 hours is cooled to 0～5 ℃, slowly drips water 1.7kg and decomposes remaining lithium aluminum hydride; Drip off behind the water stirring at room half a hour; Filter, concentrate and obtain 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE (V) oily matter 8.3kg, yield 91.2%.
Method 6: with 2-(2; 4-dioxo tetramethyleneimine-1-yl) ETHYLE ACETATE (IV) 9kg is dissolved among the methyl alcohol 45L, adds 5%Pd/C 1.6kg, under the 5atm pressure; 50～60 ℃ of hydrogenations 3 hours; The emptying after-filtration reclaims catalyzer, and filtrating concentrating obtains 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE (V) 9kg, and yield is near theoretical amount.
Embodiment 5: the preparation of oxiracetam (VI)
Method 1: 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE (V) 9kg is dissolved in methyl alcohol 90L; 0 ℃ feeds ammonia to saturated, and 0-5 ℃ was stirred 5 hours, is warming up to 20-25 ℃ of reaction 1 hour; The pressure reducing and steaming solvent obtains oxiracetam (VI) bullion; Obtain refined prod 5.1kg with acetone recrystallization, yield 67.1%, fusing point 167-169 ℃
Method 2: 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE (V) 9kg is dissolved in methyl alcohol 90L; 20～25 ℃ feed ammonia to saturated; 20-25 ℃ was stirred 4 hours, and the pressure reducing and steaming solvent obtains oxiracetam (VI) bullion, obtains refined prod 4.9kg with acetone recrystallization; Yield 64.5%, fusing point 166-168 ℃
Method 3: 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) methyl acetate (V) 7.6kg is dissolved in methyl alcohol 76L; 0 ℃ feeds ammonia to saturated, and 0-5 ℃ was stirred 5 hours, is warming up to 20-25 ℃ of reaction 1 hour; The pressure reducing and steaming solvent obtains oxiracetam (VI) bullion; Obtain refined prod 4.5kg with acetone recrystallization, yield 65.2%, fusing point 167-169 ℃.
Claims (10)
1. the preparation method of oxiracetam is characterized in that being undertaken by following mode:
1 ', be raw material with 4-chloracetyl acetic ester (I), separate with ammoniacal liquor ammonia and obtain 4-chloracetyl ethanamide (II),
2 ', 4-chloracetyl ethanamide (1I) cyclization under the alkaline condition of pH 8-12 becomes tetramethyleneimine-2,4-diketone (III),
3 ', tetramethyleneimine-2,4-diketone (III) and chloracetate or bromacetate condensation obtain 2-(2,4-dioxo tetramethyleneimine-1-yl) acetic ester (IV),
4 ', the reduction of the 4-ketone group of 2-(2,4-dioxo tetramethyleneimine-1-yl) acetic ester (IV) is obtained 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) acetic ester (V),
5 ', 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) acetic ester (V) obtains oxiracetam (IV) through ammonolysis reaction, the preparation route is following:
In the formula: R, R
1Be respectively identical or different C
1-4Alkyl, X are Cl or Br.
2. preparation method as claimed in claim 1 is characterized in that the used ammoniacal liquor of said the 1st ' step ammonolysis reaction is the strong aqua of concentration 25%～28w%.
3. according to claim 1 or claim 2 preparation method is characterized in that said the 1st ' step ammonolysis reaction carries out under-10 ℃～20 ℃ temperature.
4. preparation method as claimed in claim 3 is characterized in that said temperature of reaction is 0 ℃～I0 ℃.
5. preparation method as claimed in claim 1 is characterized in that in the alkaline condition that is had formed pH 8～10 by alkaline carbonate, carrying out in said the 2nd ' step reaction.
6. like claim 1 or 5 described preparing methods, it is characterized in that said the 2nd ' step is reflected at and be lower than 120 ℃ alcohol or ketone with boiling point, or acetonitrile is to carry out in the reaction medium.
7. preparation method as claimed in claim 1, the condensation reaction that it is characterized in that said the 3rd ' step is with sodium Metal 99.5, and sodium alkoxide or sodium hydride are to carry out under the condition of condensing agent.
8. preparation method as claimed in claim 7 is characterized in that said condensing agent is a sodium hydride.
9. preparation method as claimed in claim 1 is characterized in that said the 4th ' step reduction reaction is a reductive agent with alkali-metal hydroborate.
10. preparation method as claimed in claim 1 is characterized in that the ammonolysis reaction in said the 5th ' step carries out with the mode that feeds ammonia.
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| CN102924357A (en) * | 2011-08-09 | 2013-02-13 | 重庆圣华曦药业股份有限公司 | Preparation method for oxiracetam intermediate |
| CN102633705A (en) * | 2012-03-31 | 2012-08-15 | 石家庄利康医药科技有限公司 | Method for preparing oxiracetam |
| CN103342673B (en) * | 2013-07-31 | 2015-11-18 | 石药集团欧意药业有限公司 | A kind of Oxiracetam crystal form and preparation method thereof |
| CN103588695B (en) * | 2013-11-25 | 2015-08-05 | 石药集团欧意药业有限公司 | Oxiracetam compound of a kind of crystallized form and preparation method thereof |
| CN104725294B (en) * | 2015-03-25 | 2018-05-29 | 浙江工业大学 | A kind of new synthetic method of Oxiracetam key intermediate 2- (2,4- dioxo pyrrolidin -1- bases) ethyl acetate |
| CN105820102A (en) * | 2016-05-10 | 2016-08-03 | 武汉工程大学 | Oxiracetam synthesis technology |
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| CN1513836A (en) * | 2002-06-22 | 2004-07-21 | 张家港浩波化学品有限公司 | Method of preparing 4-hydroxy pyrrolidone-2-acetamine |
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| CN1513836A (en) * | 2002-06-22 | 2004-07-21 | 张家港浩波化学品有限公司 | Method of preparing 4-hydroxy pyrrolidone-2-acetamine |
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Application publication date: 20110727 Assignee: CHONGQING CHANGJIE PHARMACEUTICAL Co.,Ltd. Assignor: CHONGQING SHENGHUAXI PHARMACEUTICAL Co.,Ltd. Contract record no.: X2021980002704 Denomination of invention: Preparation of oxiracetam Granted publication date: 20121024 License type: Exclusive License Record date: 20210416 |