35 results about "1-pyrrolidineacetamide" patented technology

A preparation method of (s)-4-hydroxy-2-oxo-1-pyrrolidineacetamide. The preparation method comprises the following steps of crude product preparation and crystallization, wherein the step of crystallization adopts acetone and water as solvents. Levo-oxiracetam prepared through the preparation method has high purity above 99.3 wt% and low impurity content of 0 to 0.5 wt%. The preparation method has the advantages that a material addition mode adopted by the preparation method realizes that frequency of addition of an inorganic base is reduced; operation is simple; and the preparation method is in favor of industrialized production.

The invention belongs to the field of pharmaceutical chemicals and particularly relates to an oxiracetam synthesis technology, ethyl acetoacetate and glycine are taken as the raw materials, the ethyl acetoacetate is changed into 4-halogeneated ethyl acetoacetate by halogenation reaction, the 4-halogeneated ethyl acetoacetate and glycine ester formed by the glycine are cyclized to form 2,4-dioxo-1-pyrrolidine acetate, and 4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained after hydrolysis and aminolysis. According to the oxiracetam synthesis technology, the related raw materials are easy to obtain, and the synthesis technology is simple and has good industrial values.

An (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide racemate referred to as (S)-oxiracetam crystal form II has a diffraction peak at a diffraction angle 2θ of 10.669, 13.25, 13.847, 14.198, 16.729, 17.934, 18.746, 18.816, 20.273, 20.413, 21.431, 21.617, 21.663, 23.38, 24.324, 24.415, 26.069, 26.107, 27.901, 28.621, 28.925, 29.449, 29.484, 31.702, 36.516, 37.685, or 39.721 degrees. The purity of the (S)-oxiracetam crystal form II can be up to 98.5%, and the (S)-oxiracetam crystal form II has the advantages of simple preparation method, mild control condition, low production cost, and the produced oxiracetam hydrate crystal form II has a high purity (the oxiracetam hydrate crystal form having a purity of 8%˜98.5% can be prepared by a crude levo-oxiracetam having a purity of 92%, and thus having a good reproducibility in production.

A process provided for the preparation of the (S)- and (R)- alpha- ethyl-2-oxo-1-pyrrolidineacetamide of formula:(1) from (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid of formula:(2) comprising: i) combining the (RS)-2 with a chiral base (resolving agent) in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-2 and chiral base; ii) regenerating (S)- or (R)-2 from the crystallized diastereomeric salt by treating with a suitable acid or acidic ion-exchange resin; iii) optionally regenerating (R)- or (S)-2 or their mixture (predominantly one enantiomer) from the crystallization mother liquor by treating with a suitable acid or acidic ion-exchange resin; iv) optionally epimerizing (RS)-2 by treating (R)- or (S)-2 or their mixture (predominantly one enantiomer) of step iii with an acid anhydride; V) optionally converting (RS)-2 of step iv into enantiomerically enriched (S)- or (R)-2 through steps i and ii; vi) formation of the mixed anhydride by reacting (R)- or (S)-2 with an alkyl or aryl sulfonyl halogen compound RSO2X in the presence of a suitable base; and vii) reacting the mixed anhydride with ammonia; wherein R represents C 1 to C 15 alkyl or aryl groups such as methyl, ethyl, p-toluenyl, 2,4,6-trimethylbenzyl, 2,4,6-trichloribenzyl, and X represents a halogen atom such as F, Cl and Br atoms.

The invention belongs to the field of medicine synthesis, and particularly relates to an oxiracetam derivative and a method for preparing (S)-4-hydroxy-2-oxo-1-pyrrolidinyl acetamide from the derivative. The derivative is prepared from racemate oxiracetam and phthalic anhydride under the existence of pyridine and then reacts with a resolving agent of (S) type chiral amine to obtain solid, and the solid is acidified and extracted and then hydrolyzed under the alkaline condition to obtain (S)-4-hydroxy-2-oxo-1-pyrrolidinyl acetamide. The method is high in yield, good in product purity and suitable for the large-scale industrial preparation method.

A preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide comprises allowing reaction of ethyl glycinate hydrochloride and ethyl (S)-4-halo-3-hydroxybutyrate in alcohol solvent and alkaline conditions, filtering, washing, concentrating, extracting, separating, introducing ammonia water to obtain a crude product, and purifying the crude product, wherein the ethyl glycinate hydrochloride is dissociated by using diethyl ether and ammonia gas to obtain ethyl glycinate; the alcohol solvent is anhydrous methanol or anhydrous ethanol; and the alkaline condition is provided by sodium carbonate or sodium bicarbonate. The method adopts ethyl (S)-4-halo-3-hydroxybutyrate and ethyl glycinate hydrochloride as main raw materials, which has the characteristics of cheap and easily-accessible raw material, environment friendliness and no pollution; and the method firstly carries out dissociation on the ethyl glycinate hydrochloride, which effectively reduces the material consumption in reaction and lowers the cost, and simultaneously plays a positive role in the reaction yield. The method has the characteristics of low preparation cost, high yield up to 36% and mild reaction conditions, and is suitable for industrial production. The prepared (S)-oxiracetam product has high performance liquid chromatography (HPLC) purity up to above 98.5%.

The present invention relates to a method for treating a patient having suffered from severe aphasia associated with cerebrovascular accident chronic stage for at least three years, wherein said treatment consists essentially of administering a composition comprising 2-oxo-1-pyrrolidineacetamide as an active ingredient and a pharmaceutically acceptable carrier.

The invention relates to a stable preparation for injection by taking S-oxiracetam as active ingredient. The preparation is a composition for injection, and is formed by the S-oxiracetam or salts thereof serving as active ingredient and pharmaceutically acceptable auxiliary material. To restrain the racemization of the S-oxiracetam, when the powder injection with the active ingredient is prepared, and only the pH value of the S-oxiracetam medicament solution ranges from 4.5 to 7.0, the pH value is between 5.4 to 6.6 preferably, so that the S-oxiracetam medicament solution can be produced, and the final freeze-dried product has acceptable long stability; and moreover, when injection is produced, a rotary steam sterilization method needs to be adopted, terminal rotating sterilization is performed for 15 to 45 minutes under the temperature of 121 DEG C, and the terminal rotating sterilization is performed for 15 to 20 minutes preferably, so that the S-oxiracetam injection with high purity can be obtained and has acceptable long stability.

The invention discloses a sustained-release capsule with (S)-4-hydroxyl-2-oxo-1-pyrrolidine acetamide. The sustained-release capsule is prepared by the following raw materials and auxiliary materials in parts by weight: 1 part of (S)-4-hydroxyl-2-oxo-1-pyrrolidine acetamide, 1.1-1.6 parts of lactose, 1.8-2.5 parts of hydroxypropyl methyl cellulose K4M, 0.7-1.1 parts of carnauba wax, 0.03-0.07 part of stearyl alcohol, 0.02-0.08 part of magnesium stearate, 0.5-1.1 parts of calcium hydrophosphate, 1.0-1.7 parts of micro-powder silica gel and 3.2-4.7 parts of alcohol solution with the concentration of 50%-70%. The sustained-release capsule disclosed by the invention has the advantages that the particle fluidity is good, the repose angles of the particles are less than 37 degrees, the release speed is slow, and the release period is 12 hours, therefore, compared with the traditional preparation, the taking times can be reduced and the sustained-release capsule only needs to be taken once a day; simultaneously, the stability is good, the capsule cannot be adhered in the storage process, and the shelf life can reach 24 months.

The invention provides (S)-4-hydroxyl-2-oxo-1-pyrrolidine acetamide for injection, which is prepared from the following raw and auxiliary materials: 65-85% of (S)-4-hydroxyl-2-oxo-1-pyrrolidine acetamide, 8-25% of propylene glycol, 5-25% of lecithin and 1-5% of benzyl alcohol. The pH value of the (S)-4-hydroxyl-2-oxo-1-pyrrolidine acetamide injection during sterilization is basically not changed, and the product has good stability, is free of crystallization during storage, has long effective period which can reach more than 18 months, is low in impurities during effective period with total impurity being lower than 0.36%, can reduce pain during injection to patients and has good patient compliance.

An (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide having a good stability is prepared from, by weight, 1 part of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, 0.6-1.1 parts of L-cysteine, 0.7-1.3 parts of mannitol, 0.5-1.1 parts of microcrystalline cellulose, 0.9-1.5 parts of carboxymethylcellulose sodium, 0.5-1.0 part of lactose, 0.13-0.18 part of talcum powder, 1.3-1.8 parts of polyethylene glycol 4000, 1.0-1.5 parts of hydroxypropyl methylcellulose, 1-5 parts of sucrose, 0.3-0.9 part of ethyl maltol, 1.0-1.5 parts of honey and 10-16 parts of ethanol with the volume fraction being 55-70%. The (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide granule prepared in the invention has the advantages of small impurity increasing amount being only 0.03% in the preparation process, no adhesion to a screen and easiness in granulation during granulation, small quantity of powder layers, uniform particle size, good fluidity, realization of the Xiuzi angle being less than 37 DEG and the loading difference being less than 5%, good stability during storage, no moisture absorption caking, long shelf life reaching up to 24 months, and good mouthfeel, and can be received by most patients.

The invention relates to a preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide. The preparation method comprises 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, washing with an inorganic alcohol, concentrating, extracting, separating, and introducing ammonia water to get a crude product of the (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide; and performing purification treatment on the crude product, wherein the glycine ethyl ester hydrochloride firstly needs to adopt ethyl ether and ammonia gas to dissociate so as to get glycine ethyl ester. The main raw materials adopted in the preparation method disclosed by the invention are the ethyl-(S)-4-halo-3-hydroxy-butanoate and the glycine ethyl ester hydrochloride, and the raw materials are low in price, easy to obtain, environment-friendly and pollution-free; and according to the preparation method disclosed by the invention, dissociation treatment is firstly performed on the glycine ethyl ester hydrochloride, thus the using quantity of the materials in the reaction is effectively reduced, the cost is lowered, and a positive role is simultaneously played for the reaction yield. (S)-oxiracetam prepared by the preparation method disclosed by the invention has low cost, high yield which is as high as 36% and mild reaction conditions, and is conductive to industrialized large-scale production, and the HPLC (high-performance liquid chromatography) purity of the prepared (S)-oxiracetam product is above 98.5%.

The invention relates to a preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide. The preparation method comprises 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, washing with an inorganic alcohol, concentrating, extracting, separating, and introducing ammonia water to get a crude product of the (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide; and performing purification treatment on the crude product, wherein the glycine ethyl ester hydrochloride firstly needs to adopt ethyl ether and ammonia gas to dissociate so as to get glycine ethyl ester. The main raw materials adopted in the preparation method disclosed by the invention are the ethyl-(S)-4-halo-3-hydroxy-butanoate and the glycine ethyl ester hydrochloride, and the raw materials are low in price, easy to obtain, environment-friendly and pollution-free; and according to the preparation method disclosed by the invention, dissociation treatment is firstly performed on the glycine ethyl ester hydrochloride, thus the using quantity of the materials in the reaction is effectively reduced, the cost is lowered, and a positive role is simultaneously played for the reaction yield. (S)-oxiracetam prepared by the preparation method disclosed by the invention has low cost, high yield which is as high as 36% and mild reaction conditions, and is conductive to industrialized large-scale production, and the HPLC (high-performance liquid chromatography) purity of the prepared (S)-oxiracetam product is above 98.5%.

An (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide granule is prepared from, by weight, 1 part of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, 0.7-1.3 parts of L-cysteine, 1.0-1.5 parts of mannitol, 0.7-1.2 parts of microcrystalline cellulose, 0.9-1.5 parts of carboxymethylcellulose sodium, 0.7-1.3 parts of lactose, 0.13-0.18 part of magnesium stearate, 0.6-1.1 parts of polyethylene glycol 4000, 0.9-1.7 parts of hydroxypropyl methylcellulose, 0.8-1.3 part of low-substituted hydroxypropyl cellulose, 0.06-0.11 part of polysorbate 80, 0.5-1.2 parts of honey and 8-13 parts of an ethanol solution with the volume fraction being 50-70%. The (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide prepared in the invention has the advantages of small impurity increasing amount only being 0.03%, no adhesion to a screen and easy granulation during granulation, fast dissolution speed, short complete-dissolution time not exceeding 30 s, good stability during storage, no moisture absorbing caking, and long shelf life reaching up to 24 months.