Synthesis method of N-acetyl-L-cysteine

Abstract

The invention discloses a synthesis method of N-acetyl-L-cysteine, which belongs to the field of amino acid manufacture, and comprises the following steps of: dissociating commercially available industrial L-cysteine hydrochloride monohydrate serving as a starting material by using sodium hydroxide to obtain L-cysteine sodium salt, acylating with acetic anhydride to obtain N-acetyl-L-cysteine sodium salt, and finally, adjusting the acid with hydrochloric acid to obtain an N-acetyl-L-cysteine crude product, and refining the crude product with pure water to obtain an N-acetyl-L-cysteine finished product. According to the synthesis method disclosed by the invention, the material ratio and reaction conditions are optimized, on the basis of reducing the cost of the raw materials, the conversion rate is increased to 97% or above, the generation of related impurities is greatly reduced, the post-treatment operation steps are optimized, the efficiency is improved, and the reaction molar yield is increased to 80% or above under the condition that the product quality is not influenced.

Description

technical field [0001] The invention belongs to the field of amino acid synthesis, and in particular relates to a synthesis method of N-acetyl-L-cysteine. Background technique [0002] N-acetyl-L-cysteine ​​exerts a strong mucolytic effect by decomposing mucin complexes and nucleic acids, changing purulent components in sputum and other mucus and mucus secretions from thick to thin. Dyspnea caused by sticky sputum obstruction, such as difficulty in expectoration after surgery, acute and chronic bronchitis, bronchiectasis, tuberculosis, pneumonia, emphysema, etc. It can be used for the detoxification of acetaminophen poisoning, and its structure is as follows: [0003] [0004] Currently reported synthesis methods mainly use L-cysteine ​​hydrochloride monohydrate as a raw material and acetic anhydride as an acylating reagent: for example, Chinese patents CN103102295A, CN104844488A, CN109096161A, etc. [0005] Among them, CN103102295A discloses a production method of N-ac...

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Problems solved by technology

[0005] Among them, CN103102295A discloses a production method of N-acetyl-L-cysteine, which comprises L-cysteine ​​hydrochloride monohydrate and acetic anhydride at a pressure of 0.4MPa and a temperature of 125-135°C Carry out acylation reaction, this method requires high to production equipment, energy consumption is big, and excessive acetic anhydride also can cause impurity D to increase greatly simultaneously, thereby reduces reaction yield

[0006] CN104844488A discloses a production method of N-acetyl-L-cysteine, which has the following disadvantages: 1) no inert gas protection is used when dissociating L-cysteine ​​hydrochloride monohydrate, which will lead to The substrate is oxidized to generate impurity A; 2) When the temperature is high when acetic anhydride is added dropwise, it will lead to the formation of peracetyl impurity D; 3) Concentrating the reaction solution at a lower pH value will lead to a significant increase in related impurities

The yield of this method is the mass yield, and the molar yield is less than 60%. It may be that the yield is too low due to too many related impurities.

[0007] CN109096161A discloses a production method of N-acetyl-L-cysteine, which uses L-cysteine ​​hydrochloride as a starting material, and reacts with acetic anhydride to obtain N-acetyl-L-cysteine Cystine, this method is basically consistent with CN104844488A, its yield is the mass yield, the molar yield is 62%~74%, and this method recovers the crude product twice from the mother liquor and then merges and refines with the crude product for the first time, which is not Comply with pharmaceutical GMP production standards, making this method unusable for pharmaceutical GMP production

[0008] That is, the existing process has problems such as difficult control of side reactions, large fluctuations in impurity content, cumbersome actual production operations, and high energy consumption. Therefore, it is necessary to develop a N-acetyl-L -The industrial synthesis route of cysteine ​​is of great significance

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