Synthesis method of N-acetyl-L-cysteine

A technology of cysteine ​​and synthesis method, applied in the field of amino acid synthesis, which can solve the problems of large fluctuations in impurity content, difficult control of side reactions, high energy consumption, etc., achieve high molar yield, and avoid the effect of thermal decomposition

Active Publication Date: 2021-10-01
ZHEJIANG JINHUA CONBA BIO PHARM CO LTD
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  • Abstract
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  • Application Information

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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

Method used

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  • Synthesis method of N-acetyl-L-cysteine
  • Synthesis method of N-acetyl-L-cysteine
  • Synthesis method of N-acetyl-L-cysteine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Put 150kg of L-cysteine ​​hydrochloride monohydrate into the reaction kettle, then pump in 300kg of pure water, protect it with nitrogen, stir and cool down to -5°C; add 256kg of 40% sodium hydroxide solution, drop it, and keep it warm for -5 Stir at ℃ for 30 minutes; add 90 kg of acetic anhydride dropwise, after dropping, keep warm at -5°C and stir for 30 minutes; rise to an internal temperature of 90°C and react for 4 hours, then concentrate under reduced pressure to dryness; add 150 kg of pure water, add 247 kg of 9N hydrochloric acid dropwise, and finish dropping Cool down to -5°C to crystallize for 3 hours; filter and dry to obtain 124.3 kg of crude N-acetyl-L-cysteine;

[0044] Put 124.3kg of crude N-acetyl-L-cysteine ​​into the reaction kettle, then pump in 124kg of pure water, protect it with nitrogen, heat up to 90°C to dissolve, then drop to -5°C for crystallization for 3 hours; filter and dry to obtain N-acetyl-L-cysteine ​​refined product 111.9kg.

Embodiment 2

[0046] Put 600kg of L-cysteine ​​hydrochloride monohydrate into the reaction kettle, then pump in 1200kg of pure water, protect it with nitrogen, stir and cool down to 5°C; add 2732kg of 15% sodium hydroxide solution, drop it, keep it warm at 5°C and stir 5min; add 340kg of acetic anhydride dropwise, keep warm at 5°C and stir for 5min; rise to an internal temperature of 70°C for 1 hour, then concentrate to dryness under reduced pressure; add 600kg of pure water, dropwise add 1460kg of 6N hydrochloric acid, drop the temperature to 5 ℃ for 1 hour; filter and dry to obtain 499.8kg of crude N-acetyl-L-cysteine;

[0047] Put 499.8kg of crude N-acetyl-L-cysteine ​​into the reaction kettle, then pump in 500kg of pure water, protect it with nitrogen, heat up to 70°C to dissolve, then drop to 5°C for crystallization for 1 hour; filter and dry to obtain N - Acetyl-L-cysteine ​​refined product 449.9kg.

Embodiment 3

[0049] Put 500kg of L-cysteine ​​hydrochloride monohydrate into the reaction kettle, then pump in 1000kg of pure water, protect it with nitrogen, stir and cool down to 10°C; add 1140kg of 30% sodium hydroxide solution, drop it, keep it warm at 10°C and stir 20min; add 300kg of acetic anhydride dropwise, after dropping, keep warm at 10°C and stir for 20min; rise to an internal temperature of 80°C for 3 hours, then concentrate to dryness under reduced pressure; add 500kg of pure water, dropwise add 2446kg of 3N hydrochloric acid, drop the temperature to 10°C ℃ crystallization for 2 hours; filter and dry to obtain 418.6 kg of crude N-acetyl-L-cysteine;

[0050] Put 418.6kg of crude N-acetyl-L-cysteine ​​into the reaction kettle, then pump in 420kg of pure water, protect it with nitrogen, heat up to 50°C to dissolve, then drop to 10°C for crystallization for 2 hours; filter and dry to obtain N - Acetyl-L-cysteine ​​refined product 376.7kg.

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C319/12C07C323/59
CPCC07C319/12C07C323/58C07C323/59
Inventor 余斌陆纪宏金鑫金岩倪牡丹廖玉华
Owner ZHEJIANG JINHUA CONBA BIO PHARM CO LTD
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