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A kind of resolution method of (s)-(+)-2-aminobutanamide hydrochloride

A technology of aminobutyramide and hydrochloride, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of carboxylic acid amide optical isomers, can solve the problem of low resolution yield, and achieve simple and efficient operation of each step. The effect of reducing environmental pollution and reducing production costs

Active Publication Date: 2021-12-21
宁波赜军医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The invention provides a method for resolving (S)-(+)-2-aminobutanamide hydrochloride, which solves the problem of low resolution yield of existing (S)-(+)-2-aminobutanamide , the total recovery rate can be greatly improved after multiple splits, and the optical purity is high

Method used

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  • A kind of resolution method of (s)-(+)-2-aminobutanamide hydrochloride
  • A kind of resolution method of (s)-(+)-2-aminobutanamide hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Embodiment 1 The preparation of optically pure (S)-(+)-2 aminobutanamide hydrochloride

[0031] Take by weighing (S)-(+)-2-aminobutyramide resolution mother liquor 5kg, its main component is the L-tartrate of (R)-(-)-2-aminobutanamide, and resolution solvent methanol, through Quantitatively it contains about 250 g of (R)-(-)-2-aminobutyramide.

[0032] Most of the methanol was removed under reduced pressure distillation at 60°C, 1.5kg of water was added, and ammonia gas was introduced to saturation, then 7.89g of salicylaldehyde was added, heated to 90°C, and reacted for about 8 hours. Stop heating, cool to room temperature, concentrate under reduced pressure to remove ammonia water, adjust the pH to about 7 with 2mol / L hydrochloric acid, add about 2.5L of methanol, cool to 15°C, a large amount of white solid precipitates, filter, and drain to obtain pure The product (S)-(+)-2-aminobutyramide tartrate is about 302g, and its optical purity is >99%.

[0033] Add about 3...

Embodiment 2

[0034] Embodiment 2 Preparation of optically pure (S)-(+)-2 aminobutyramide hydrochloride

[0035] Take (S)-(+)-2-aminobutyramide and resolve 3.5kg of mother liquor, its main components are (R)-(-)-2-aminobutanamide, L-tartaric acid, and resolution solvent methanol, after Quantitatively it contains about 175 g of (R)-(-)-2-aminobutyramide.

[0036] Remove most of the methanol under reduced pressure distillation at 60°C, add 1.0kg of water, add triethylamine until the pH of the system reaches 8.5, then add 2.17g of n-butyraldehyde, heat to 80°C, and react for about 6 hours. Stop heating, cool to room temperature, concentrate under reduced pressure to remove excess triethylamine, adjust the pH to about 7 with 2mol / L hydrochloric acid, add about 2L of methanol, cool to 15°C, a large amount of white solid precipitates, filter, and drain , to obtain about 200 g of pure (S)-(+)-2-aminobutyramide tartrate.

[0037] Add about 200g of the above pure (S)-(+)-2-aminobutyramide tartrate...

Embodiment 3

[0038] Embodiment 3 Preparation of optically pure (S)-(+)-2 aminobutanamide hydrochloride

[0039] Weigh 5kg of (S)-(+)-2-aminobutanamide resolution mother liquor, its main components are (R)-(-)-2-aminobutanamide, L-tartaric acid, and resolution solvent ethanol, after quantitative It contains about 250 g of (R)-(-)-2-aminobutanamide.

[0040] Remove most of the methanol under reduced pressure distillation at 60°C, add 1.5kg of water, 482g of triethylenediamine, and 7.89g of salicylaldehyde, heat to 85°C, and react for about 5 hours. Stop heating, cool to room temperature, concentrate under reduced pressure to remove part of the water, adjust the pH to about 7 with 1mol / L hydrochloric acid, add about 2.5L of methanol, cool to 15°C, a large amount of white solid precipitates, filter, and drain to obtain The pure product (S)-(+)-2-aminobutyramide tartrate is about 298g, and its optical purity is >99%.

[0041] Add about 298g of the above pure (S)-(+)-2-aminobutyramide tartrate t...

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Abstract

The invention discloses a resolution method of (S)-(+)-2-aminobutyramide hydrochloride, 1. The method comprises: using 2-aminobutanamide and L-tartaric acid in a molar ratio of 2:1 to resolve The mother liquor that divides is raw material, remove solvent, add water, weak base and aromatic aldehyde or / and aliphatic aldehyde, the mass ratio of (R)-(+)-2-aminobutanamide in aromatic aldehyde or / and aliphatic aldehyde and mother liquor 0.01~0.05:1, heat reaction; use hydrochloric acid to adjust the pH to neutral, add methanol or ethanol, cool and crystallize to obtain (S)-(+)-2-aminobutyramide tartrate, add methanol or ethanol, pass Add ammonia gas or add sodium hydroxide solution, stir to remove solids, remove the solvent from the remaining liquid, adjust the pH with methanolic hydrochloric acid or ethanol hydrochloric acid, and precipitate solids to obtain (S)-(+)-2-aminobutyramide hydrochloride Salt. The method of the invention can greatly improve the total recovery rate of multiple splits, and has high optical purity.

Description

technical field [0001] The invention relates to chiral resolution of aminobutyramide hydrochloride, in particular to a resolution method for (S)-(+)-2-aminobutanamide hydrochloride. Background technique [0002] The preparation method of the anti-epileptic drug levetiracetam has been disclosed in relevant patents, such as EP1566376, CN1015541B, CN 583721A and CN101130504B all introduce the synthesis of the drug, and there are two main routes: [0003] (1) Using chiral L-2-aminobutyric acid as a starting material, undergoing esterification, ammonolysis, and cyclization routes; [0004] (2) Using n-propionaldehyde as the starting material, the target product was obtained through Streck reaction, hydrolysis, resolution, esterification, ammonolysis and cyclization. [0005] The above-mentioned route (1) starts with chiral raw materials, which is very expensive and the cost is quite high. Although the route (2) has two more steps than the route (1), it is cheap and has a high yi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/20C07C237/06C07B57/00
CPCC07B57/00C07C231/20C07C237/06
Inventor 郑新华范思雨王红芳王奕凌何显明
Owner 宁波赜军医药科技有限公司
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