68567-97-5

The invention relates to the field, organic synthesis and medicine technology. In particular, the invention provides a method for preparing 2 - (4 -hydroxy -2 - oxo -1 - pyrrolidinyl) acetamide, which uses methyl 4 - chloroacetoacetate as a starting material, condenses, crystallizes and crystallizes after carbonyl reduction to obtain a target product, and the total yield is approximately unitz 90% is left and right. The method optimizes the reaction steps by improving the synthesis route, namely the 2 - (4 - hydroxyl -2 - oxo -1 - pyrrolidinyl) acetamide, and shortens the production cycle, and shortens the production cycle. The production cost, as well as the emission. The method is cheap and easy to obtain, simple and convenient to operate, low in impurities, high in yield, and particularly suitable for industrial production. (by machine translation)

The invention belongs to the technical field of drug synthesis, in particular to a preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide. The 4-hydroxy-2-oxo-1-pyrrolidine acetamide is produced by intramolecular dehydration of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid to obtain lactone which is then reacted with ammonia water. The preparation method of the 4-hydroxy-2-oxo-1-pyrrolidine acetamide has the advantages of short reaction period, mild conditions, low production cost, high product yield, good quality and the like, so that the method is suitable for industrial large-scale production.

The invention discloses a synthetic method for an anti-senile dementia drug of oxiracetam (I), and mainly provides a novel synthetic route. The method comprises the following steps of reacting a compound (when R is -Me and NO2) shown as a formula (V) with glycinamide hydrochloride of a compound shown as a formula (VI) under an alkaline condition to obtain a compound (wherein R is -Me and NO2) shown as a formula (IV); reacting the compound (wherein R is -Me and NO2) shown as the formula (IV) with ethyl 4-chloro-3-hydroxybutyrate of a compound shown as a formula (III) to obtain a compound (wherein R is -Me and NO2) shown as a formula (II); then removing protection groups under an acidic condition and intramolecularly cyclizing to obtain a compound shown as the formula (I) of 4-hydroxy-2-oxo-1-pyrrolidine acetamide, the compound (I) being oxiracetam. According to the synthetic route, raw materials and reagents have low toxicity, low cost and easy availability. The synthetic route is simple to operate, has relatively high yield and is suitable for industrial production.

The invention provides an oxiracetam intermediate as well as a preparation method and application thereof. The oxiracetam intermediate is a solid or a crystalline solid, low in preparation cost, and easy to purify and store, and can be used for efficiently preparing oxiracetam. The structural formula is as shown in the specifications.

The invention relates to a synthesis method of (S)-oxiracetam. The method comprises the following steps: (1) carrying out an esterification reaction on alcohol and S-4-amino-3-hydroxybutyrate taken as a starting material to obtain an intermediate I; (2) enabling the intermediate I and halogenated acetic ester to be subjected to a condensation reaction to obtain an intermediate II; (3) carrying out a ring closing reaction on the intermediate II to obtain an intermediate III; and (4) carrying out an ammonolysis reaction on the intermediate III to obtain the target product (S)-oxiracetam. After the synthesis route of the oxiracetam is adopted, the (S)-oxiracetam with more ideal yield of 20% or more is at least obtained; and therefore, a new oxiracetam synthesis route is opened up.

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 oxiracetam preparation method comprises the following steps: (a) azidation reaction of 4-chloro-3-hydroxybutyrate as a starting material and an azidation reagent to obtain an give intermediate I; (2) reduction reaction of the intermediate I to obtain an intermediate II; (2) condensation reaction of the intermediate II and a halogenated acetic acid ester to obtain an intermediate III; (3) ring closing reaction of the intermediate III to obtain an intermediate IV; and (4) aminolysis reaction of the intermediate IV to obtain desired product oxiracetam. The desired product oxiracetam with an ideal yield of at least more than 38% can be obtained, and a new oxiracetam synthetic route is opened up.

A crystal form I of the racemate of 4-hydroxy-2-oxo-1-pyrrolidine acetamide is prepared by the following steps: dissolving crude racemate of 4-hydroxy-2-oxo-1-pyrrolidine acetamide in a small molecular alcohol solvent to reach supersaturation; heating and stirring overnight at 38-42°C to obtain an suspended sediment; filtering and drying to obtain a crystal. The crystal form I of the racemate of 4-hydroxy-2-oxo-1-pyrrolidine acetamide in the present invention has a high purity which can reach 99.5%.

Process for the production of 4-hydroxy-2-oxoyrrolidin-1-yl-acetamide, a cerebrally active pharmaceutical agent. A 4-halo-3-alkoxy-butenoic acid ester is reacted with glycine to new intermediate products of the formula: STR1 There is further by acid hydrolysis of the alkoxy group, subsequent hydrogenation, esterification of the carboxyl function and finally conversion to the end product by reaction with ammonia.

The enantioselective synthesis of oxiracetam has been accomplished from readily available optically active D(+) and L(-) malic acids. the key step of the described method involves the selective reduction of a chiral cyclic diimide; in this way, both enantiomers of 4-hydroxy-2-oxopyrrolidine-N-acetamides were prepared.

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Process for preparing pyrrolidinone derivatives of (1) STR1 in which R is hydrogen, alkyl or acyl characterized in that a compound of (2) STR2 wherein R1 is hydrogen and R2 is benzyl or substituted benzyl, or R1 and R2 can together form a group STR3 where R4 and R5 are independently hydrogen, alkyl, phenyl or optionally substituted aryl or together are 1,4-butylene or 1,5-pentylene; R3 is hydrogen or straight or branched alkyl of 1 to 4 carbon atoms; and X is alkyl subjected to N-deprotection and the deprotected intermediate is cyclized intramolecularly. The deprotected intermediates can be isolated as acid-addition salts.

A process for producing oxiracetam (4-hydroxy-2-oxo-1-pyrrolidineacetamide) useful as an agent for improving brain metabolism, under mild conditions and in a single process is provided, this process comprises reacting glycinamide with a butyric acid ester expressed by the formula STR1 wherein A represents a halogen atom or an epoxy group, B represents hydroxyl group, but when A is an epoxy group, A and B together form an epoxy group, and R represents an alkyl group.

Preparation of compounds of the formula: STR1 wherein n is 1, 2 or 3, R1 and R2, which may be the same or different, are hydrogen or alkyl containing 1 to 3 carbon atoms and the asterisk indicates the center of asymmetry of the molecule, and compounds of the formula STR2 wherein R" is a saturated or unsaturated aliphatic hydrocarbon containing 1 to 6 carbon atoms, R3 is hydrogen or acyl containing 1 to 7 carbon atoms and the asterisk indicates the center of asymmetry of the molecule. The compounds produced by the present invention improve learning memory and display a protecting effect against the E.E.G. consequence of an overdose of barbiturates and against the reduced performance following brain damage (e.g. cerebral edema).

Pyrrolidine derivatives of the formula STR1 are prepared from γ-amino-β-hydroxybutyric acid which, after reaction with a silylating agent, is reacted, in the presence of an acid acceptor, with a halogen derivative of an ester of an aliphatic acid and then cyclized to give the corresponding N-alkoxy-carbonylalkyl derivative which is converted into the corresponding amide by treatment with ammonia or with a mono- or di-substituted amine. The compounds produced by the present invention improve learning memory and display a protecting effect against the E.E.G. consequence of an overdose of barbituates and against the reduced performance following brain damage (e.g. cerebral edema).

Pyrrolidin-2-one derivatives of the formula: STR1 wherein R represents hydrogen, an acyl radical containing from 2 to 7 carbon atoms, a saturated or unsaturated alkyl, containing from 1 to 6 carbon atoms, aralkyl, cycloalkyl or aromatic, R1 and R2 may be the same or different and represent hydrogen, a saturated or unsaturated alkyl radical, containing from 1 to 3 carbon atoms, cycloalkyl radical or R1 and R2, together with the adjacent nitrogen atom, may form an heterocyclic ring optionally containing an additional heteroatom selected from the group consisting of oxygen and nitrogen, n represents an integer from 0 to 2 inclusive, and the process for their preparation are described.

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