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Preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide

A pyrrolidine acetamide, -4- technology, applied in the direction of organic chemistry, etc., can solve the problems of increased impurity content, unfavorable industrial production, high enantiomer content, etc.

Active Publication Date: 2016-02-17
CHONGQING RUNZE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the current synthesis route of dexoxiracetam, the high-purity target compound is basically obtained by column chromatography or ion exchange resin, which is not conducive to industrial production
Moreover, a strong alkaline environment is required during the synthesis process, which easily destroys dextro-oxiracetam and increases the impurity content; The content of enantiomers is relatively high, which does not meet the needs of clinical and testing

Method used

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  • Preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide
  • Preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide
  • Preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] A kind of synthetic method of (R)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, it is carried out as follows,

[0067] (1) Preparation of Intermediate I:

[0068] Take 50g of the raw material R-methyl 4-chloro-3-hydroxybutyrate, put it into a single-necked bottle, add 50ml of DMF, stir, cool in an ice-water bath, add 50g of sodium azide, keep the temperature not exceeding 40°C, after the addition The temperature was raised to 60°C. After 2 hours of reaction, the reaction was stopped to obtain a yellow solution. Add 100 ml of water, extract with 100 ml of ethyl acetate, concentrate to remove ethyl acetate, and obtain Intermediate I as a yellow oil. After nuclear magnetic detection, the intermediate I is: 1H-NMR (300MHz, CDCl3): δ1.42-1.73 (m, 2H) 2.76-2.67 (ABsystem, m, 2H,), 3.31-3.23 (ABsystem, m, 2H) , 3.75(s, 3H), 4.40(m, 1H), 3.70(s, 1H). Intermediate I is: R1 is methyl.

[0069] (2) Preparation of Intermediate II

[0070] The intermediate I obtained in step (2) w...

Embodiment 2

[0080] A kind of synthetic method of (R)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, it is carried out as follows,

[0081] (1) Preparation of Intermediate I:

[0082]Weigh 50kg of methyl R-4-chloro-3-hydroxybutyrate, add it to a 500L azidation reaction kettle, add 50L of DMF, stir evenly, cool the jacket in an ice-water bath, add 50Kg of sodium azide, and keep the temperature constant When the temperature exceeds 40°C, the ice water in the jacket is pressed out, and the jacket is passed through hot water to raise the internal temperature to 60°C. After 2 hours of reaction, the reaction was stopped to obtain a yellow solution. Add 100 L of water to the kettle, extract with 100 L of ethyl acetate, separate and discard the water phase, concentrate the organic phase to remove ethyl acetate, and obtain Intermediate I as a yellow oil. After nuclear magnetic detection, the intermediate I is: 1H-NMR (300MHz, CDCl3): δ1.42-1.73 (m, 2H) 2.76-2.67 (ABsystem, m, 2H,), 3.31-3.23 (ABsystem,...

Embodiment 3

[0094] 1, a kind of synthetic method of (R)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, as follows:

[0095] (1) Stir R-4-chloro-3-hydroxybutyric acid ethyl ester with 18 times the weight of DMSO and 1 times the weight of sodium azide, and react with azidation at 60°C for about 5 hours. The raw materials are basically The reaction is complete, stop the reaction, directly concentrate to remove the solvent, and solidify at low temperature to obtain intermediate I; meanwhile, the above solvents also use DMF, n-propanol, isopropanol, n-butanol, tert-butanol, toluene or cyclopentanol, etc. Preparation of intermediate I, and finally by nuclear magnetic detection, the prepared intermediate I is: 1H-NMR (300MHz, CDCl3): δ1.42-1.73 (m, 5H) 2.76-2.67 (ABsystem, m, 2H,), 3.31-3.23 (ABsystem, m, 2H), 4.40 (m, 1H), 3.70 (s, 1H).

[0096] (2) With the intermediate I obtained from step (1), in 15 weight times of ethanol of R-4-chloro-3-hydroxybutyrate ethyl ester, add 0.5 times of weight of 10...

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Abstract

The invention provides a preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide. The preparation method comprises the following steps: (1) with R-4-chloro-3-hydroxy butyrate as an initial raw material, subjecting the initial raw material and an azido reaction agent to an azido reaction so as to obtain an intermediate I; (2) subjecting the intermediate I to a reduction reaction so as to obtain an intermediate II; (3) subjecting the intermediate II and halogenated acetate to a condensation reaction so as to obtain an intermediate III; (4) subjecting the intermediate III to a ring closure reaction so as to obtain an intermediate IV; and (5) subjecting the intermediate IV to an aminolysis reaction so as to obtain (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide. The preparation method can prepare a (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide product with ideal yield of at least more than 38%, and a novel synthetic route is opened up for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide.

Description

technical field [0001] The present invention relates to (R)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, in particular to a preparation method of (R)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide. Background technique [0002] Oxiracetam is a nootropic drug synthesized for the first time in 1974 by the Italian Skeleton Bichem Company. It is a derivative of hydroxyaminobutyric acid (GABOB), which can promote learning, enhance memory, and protect the center of damaged nerve cells. Nervous system drugs. (R)-4-Hydroxy-2-oxo-1-pyrrolidineacetamide is the dextrorotary form of oxiracetam. It has been reported that the activity of the levorotatory form of oxiracetam is higher than that of the dextrorotary form, but the dextrorotary form There is still a strong effect of promoting learning, enhancing memory, and protecting the central nervous system of damaged nerve cells, and has an important market in the application of levoxiracetam's reference substance. [0003] In the current synthesis...

Claims

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Application Information

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IPC IPC(8): C07D207/273
Inventor 谢玲玲袁华杰代丽萍叶雷
Owner CHONGQING RUNZE PHARM CO LTD
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