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Novel preparation method of L-alanine isopropyl ester hydrochloride

A technology of isopropyl alanine and hydrochloride, which is applied in the preparation of organic compounds, chemical instruments and methods, and cyanide reaction preparation, etc., can solve the problems of high cost of waste treatment, ineffective separation, and increased difficulty in operation, etc. problem, to achieve the effect of reducing consumption, sufficient supply and improving utilization rate

Inactive Publication Date: 2017-03-22
ZHEJIANG GENEBEST PHARMA
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0003] As the key intermediate of sofosbuvir, L-alanine isopropyl ester hydrochloride has relatively mature synthetic methods at present. Generally, thionyl chloride is used to acyl chloride alanine and then react with isopropanol, but This method needs to use a large amount of thionyl chloride and isopropanol, generally needs more than 4 times the amount of thionyl chloride and isopropanol of 8 times the amount, after the reaction is finished, the two cannot be effectively separated after mixing, so it will It causes a lot of waste of raw materials. At the same time, as a strong irritating and corrosive raw material, thionyl chloride is used in large quantities, which also increases the difficulty of operation. The cost of three wastes treatment is high, and there is also a large loss of equipment.

Method used

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  • Novel preparation method of L-alanine isopropyl ester hydrochloride
  • Novel preparation method of L-alanine isopropyl ester hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] A. Preparation of 4-methyl-2,5-diketooxazolidine (Ⅱ)

[0022] Add L-alanine (89g, 1.0mol), 1,2-dichloroethane (890g) into the reactor, stir well and then add solid phosgene (148g, 0.5mol) in batches under necessary cooling measures ), keep the temperature of the mixture not exceeding 60°C during the addition process, remove the cooling device after the addition, and keep the temperature at 60±5°C for 12 hours. Finally, add n-hexane (445g), stir for 1 hour, and collect the precipitated white or off-white solid by filtration, which is the crude product of 4-methyl-2,5-diketooxazolidine (II). After drying, 101.3g was obtained. The yield About 88.1%. The content detected by HPLC is greater than 95%, and the product can be directly used in the next reaction without further purification. After purification by sampling column chromatography, the detection spectrum data are as follows:

[0023] 1H NMR (CDCl3, 500MHz) δ: 1.53 (3H, d), 4.58-4.62 (H, m). FAB-MS (m / z): 116 (M+...

Embodiment 2

[0028] Other steps are the same as in Example 1, except that the preparation method of 4-methyl-2,5-diketooxazolidine (II) in step A is as follows:

[0029] Add L-alanine (89g, 1.0mol), 1,2-dichloroethane (180g) into the reactor, stir well and then add solid phosgene (99g, 0.33mol) in batches under necessary cooling measures ), keep the temperature of the mixture not exceeding 60°C during the addition process, remove the cooling device after the addition, and keep the temperature at 60±5°C for 6 hours. Finally, add n-hexane (445g), stir for 1 hour, and collect the precipitated white or off-white solid by filtration, which is the crude product of 4-methyl-2,5-diketooxazolidine (II). After drying, 83.5g was obtained. The yield About 72.6%. The content detected by HPLC is greater than 95%, and the product can be directly used in the next reaction without further purification. After purification by sampling column chromatography, the detection spectrum data are as follows:

[0...

Embodiment 3

[0032] Other steps are the same as in Example 1, except that the preparation method of 4-methyl-2,5-diketooxazolidine (II) in step A is as follows:

[0033] Add L-alanine (89g, 1.0mol), 1,2-dichloroethane (550g) into the reactor, stir well and then add solid phosgene (120g, 0.4mol) in batches under necessary cooling measures ), keep the temperature of the mixture not exceeding 60°C during the addition process, remove the cooling device after the addition, and keep the temperature at 60±5°C for 9 hours. Finally, add n-hexane (445g), stir for 1 hour, and collect the precipitated white or off-white solid by filtration, which is the crude product of 4-methyl-2,5-diketooxazolidine (II). After drying, 95.8g was obtained. The yield About 83.3%. The content detected by HPLC is greater than 95%, and the product can be directly used in the next reaction without further purification. After purification by sampling column chromatography, the detection spectrum data are as follows:

[0...

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Abstract

The invention provides a novel preparation method of L-alanine isopropyl ester hydrochloride, and relates to a preparation method of an intermediate of a new drug sofosbuvir for treating chronic hepatitis. The method sequentially comprises the following steps that L-alanine is adopted as a raw material to react with triphosgene for ring closure, after ring opening is conducted through isopropanol under the acidic condition, salt formation is conducted, and the product L-alanine isopropyl ester hydrochloride is obtained. According to the novel preparation method, a brand-new synthetic route is provided, the adopted raw material is wide and sufficient in source, the cost is low, the reaction conditions are mild, the processes are simple, all the reactions are conventionally operated, the condition that a large quantity of high-irritation raw materials such as thionyl chloride are used is avoided, and a good industrial prospect is achieved.

Description

technical field [0001] The invention relates to a preparation method of L-alanine isopropyl ester hydrochloride, and a preparation method of a new drug sofosbuvir intermediate for treating chronic hepatitis C. Background technique [0002] Since the 1990s, my country's economy has developed rapidly, and people's living standards have also been significantly improved, and the incidence of various diseases has also increased year by year. Sofosbuvir is a new drug for the treatment of chronic hepatitis C. The drug is the first to safely and effectively treat certain types of hepatitis C without the need for interferon. Clinical trials have confirmed that for hepatitis C 1 and 4, the overall sustained virological response rate (SVR) of the drug combined with peginterferon and ribavirin is as high as 90%. Since its listing, it has been widely used and achieved good clinical results. [0003] As the key intermediate of sofosbuvir, L-alanine isopropyl ester hydrochloride has relat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/12C07C229/08
CPCC07C227/12C07D263/44
Inventor 宋苗根金国平骆裕晨孙杭炬
Owner ZHEJIANG GENEBEST PHARMA
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