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Synthetic method of oxiracetam

A synthetic method and compound technology, applied in the field of medicine, can solve the problems of yield and finished product quality, salt is not easy to remove, etc., and achieve the effect of reducing production cost, simple operation, and suitable for industrial production

Active Publication Date: 2013-10-16
广安凯特制药有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the starting material, the total yield of this route can reach 22.5%, but the salt remaining in the target product is not easy to remove. In addition, side reactions such as hydrolysis accompanied by the reduction reaction also affect the yield and the quality of the finished product.

Method used

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  • Synthetic method of oxiracetam
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  • Synthetic method of oxiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (1) Add 100 g of diketene and 500 g of dichloromethane into the reaction flask, and control the temperature at 20-30° C. Slowly add 476g of bromine dropwise, maintaining the temperature at 20-30°C. After the drop is complete, the reaction solution is stirred for 6 hours. The water pump decompresses and recovers dichloromethane until no obvious liquid evaporates (control temperature ≤ 30°C).

[0042] (2) Control the temperature of 4-bromo-3-oxobutyryl bromide obtained in the above step (1) at 20-30° C., add 45 g of methanol dropwise to the residual liquid, and after the addition is complete, the reaction liquid is stirred for 30 minutes. Control temperature ≤ 50°C, -0.08MPa, evaporate methanol to dryness under reduced pressure to obtain 204g of methyl 4-bromo-3-oxobutanoate, two-step yield 87.9%.

[0043] (3) Put 200g of methyl 4-bromo-3-oxobutanoate and 400g of methanol into a 2000ml reaction bottle, cool down to 15-17°C, control the temperature at 15-20°C, slowly add ...

Embodiment 2

[0046] (1) Add 420 g of diketene and 2730 g of dichloromethane into the reaction flask, and control the temperature at 20-30° C. Slowly add bromine 1490g dropwise, maintain the temperature at 20-30°C, pass through for about 8 hours, and stir the reaction solution for 1 hour. The water pump decompresses and recovers dichloromethane until no obvious liquid evaporates (control temperature ≤ 30°C). The steps for preparing oxiracetam refined product from 4-bromo-3-oxobutyryl bromide are the same as (2), (3) and (4) in Example 1, and the total yield is 49.2%. ( 1 H-NMR (D 2 O) δ2.82 (1H, dd, J = 17.8Hz), 2.34 (1H, dd, 17.8Hz), 4.58 (1H, d, J = 6.0Hz), 3.45 (1H, d, J = 11.4Hz), 3.84(1H,dd,J=11.4Hz), 3.93(1H,d,J=16.0Hz), 4.06(1H,d,J=16.0Hz)

Embodiment 3

[0048] (1) (2) (3) the synthesis steps are all with example 1.

[0049] (4) Add 73g of glycinamide hydrochloride, 500g of anhydrous methanol, and 41g of sodium hydroxide into the reaction flask, heat up to reflux, and slowly add 100g of methyl 4-bromo-3-hydroxybutyrate dropwise (about 1.0 hour dropwise), after the dropwise addition, continue the reflux reaction for 24.0 hours, after the reaction, filter while hot, and wash the filter cake once with 100g hot methanol. Methanol was distilled off under reduced pressure to obtain a solid viscous substance, and 400 g of methanol was added, stirred and crystallized to obtain crude oxiracetam. Add the crude product to 400°C of methanol and raise the temperature to about 50°C, add 10 g of activated carbon to keep it warm for decolorization, and cool down to crystallize to obtain 53 g of refined oxiracetam with a yield of 66.1%.

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Abstract

The invention discloses a synthetic method of oxiracetam. The synthetic method is characterized in that acety ketene is used as a raw material, and four steps of bromination, esterification, reduction and ring closure are carried out to obtain the oxiracetam. The synthetic method provided by the invention has the advantages of easy operation, high safety, environmental protection, cheap and easily available raw materials, mild reaction conditions, high yield and substantially reduced product cost, thereby being more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing oxiracetam. Background technique [0002] Oxiracetam, English name Oxiracetam, chemical name 4-hydroxy-2-oxo-1-pyrrolidineacetamide, molecular formula C 6 h 10 N 2 o 3 (158.16); is a nootropic drug acting on the cholinergic reticular structure of the brain stem. It was first synthesized by the Italian ISF company in 1974. It was first listed in Italy as Neuromet in 1987, and listed in Portugal as Neupan in 1991. [0003] Oxiracetam has been widely used since it was launched in China in 1998. Currently, there are capsules, injections (small water injections) and other varieties. There are many synthetic routes of oxiracetam crude drug, resulting in large differences in its yield and quality. [0004] Chinese patent application CN1513836A discloses a preparation process of oxiracetam, which uses 4-haloacetoacetic acid derivatives as start...

Claims

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Application Information

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IPC IPC(8): C07D207/273
Inventor 周旭东游红全王廷圣
Owner 广安凯特制药有限公司
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