Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam

Abstract

The invention belongs to the field of the preparation of chiral drug intermediates and particularly relates to a method for synthesizing a intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam. The method is characterized by taking 2-bromobutyric acid as a starting raw material and comprising the steps of: firstly, preparing a 2-bromobutyric amide intermediate, reacting the 2-bromobutyric amide intermediate to generate DL-2-aminobutyrylamide, and finally, splitting and salifying the DL-2-aminobutyrylamide to synthesize the L-2-aminobutyrylamide hydrochloride. Compared with the traditional synthesis method, the method has the advantages of mild reaction conditions, low cost, higher yield, greatly improved process safety, cheap and easily-obtained raw materials, simple unit operations and low requirements on equipment and is suitable for industrial large-scale production, amidation reaction is carried out at normal temperature and normal pressure, and the reaction is easy to control.

Description

technical field [0001] The invention belongs to the field of preparation of chiral drug intermediates, in particular to a method for synthesizing L-2-aminobutyramide hydrochloride, an intermediate of chiral drug levetiracetam. Background technique [0002] The preparation method of chiral drug levetiracetam has been reported in the literature, such as EP1566376, CN1015541B and CN1583721A have introduced the synthesis of the compound respectively, the main route has, the first is starting raw material with L-2-aminobutyric acid, through Esterification, ammonolysis, cyclization or cyclization, esterification, and then ammonolysis to obtain the target product. Although this route has few steps, the starting material L-2-aminobutyric acid is expensive and the cost is higher. The second is to use n-propionaldehyde as the starting material to prepare the target compound through six steps of Streck reaction, hydrolysis, resolution, esterification, ammonolysis and cyclization. This...

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Problems solved by technology

Although the route has few steps, the starting material L-2-aminobutyric acid is expensive and the cost is higher

The second is to use n-propionaldehyde as the starting material to prepare the target compound through six steps of Streck reaction, hydrolysis, resolution, esterification, ammonolysis and cyclization. This method has long reaction steps and the yield is only 4.7%. , CN1583721A improved this route, using iso-n-propanal and sodium cyanide as starting materials, and prepared the target compound through four steps of Streck reaction, hydrolysis, resolution and cyclization. With this method, the yield of the product It has been improved, but this method uses the highly toxic compound sodium cyanide, which has higher requirements on the safety of operators, the treatment of three wastes and environmental protection

2-Bromobutyric acid undergoes ammoniation reaction with ammonia water to generate 2-aminobutyric acid. Since the ammonium bromide and 2-aminobutyric acid are difficult to separate, it needs to be refined, and the reaction yield is low, about 70% molar yield

In addition, in the reaction of ammonolysis, first generate 2-aminobutyric acid methyl ester by 2-aminobutyric acid, and then react with ammonia gas to obtain mixed 2-aminobutyramide, the reaction rate is slow, and the ammonia reaction is 24 hours, sometimes Ammonia gas generates pressure, which requires high equipment and affects process safety

Therefore this route exists the defect that yield is low, and process safety is poor

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