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Preparation method of polypeptide raw material aspartic acid beta-tert-butyl ester alpha-methyl ester hydrochloride

A technology of methyl ester hydrochloride and aspartic acid is applied in the preparation of organic compounds, chemical instruments and methods, preparation of cyanide reactions, etc., and can solve the problems of high toxicity of methyl iodide, low yield, long cycle and the like, Achieve the effect of shortening synthesis steps, reducing production cost and high yield

Inactive Publication Date: 2018-12-14
GL BIOCHEM SHANGHAI +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The technical purpose of the present invention is to overcome the complexity in the original process, the cycle is long, the cost is high, and the technical problems such as the high toxicity of methyl iodide used in the literature, the high risk of azidomethane, the poor selectivity of acetic anhydride and the low yield are avoided, and the present invention provides A preparation method of polypeptide raw material aspartic acid β-tert-butyl ester α-methyl ester hydrochloride is proposed. The method is simple and easy to control, has a short reaction cycle and low cost, and is suitable for large-scale production

Method used

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  • Preparation method of polypeptide raw material aspartic acid beta-tert-butyl ester alpha-methyl ester hydrochloride
  • Preparation method of polypeptide raw material aspartic acid beta-tert-butyl ester alpha-methyl ester hydrochloride
  • Preparation method of polypeptide raw material aspartic acid beta-tert-butyl ester alpha-methyl ester hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0020] In the first step, 100KG of raw material aspartic acid is suspended in 400KG of dry tetrahydrofuran, and 60KG of phosphorus oxychloride is added dropwise when the system is 10°C, and the temperature is kept below 15°C throughout the process, and the dropwise addition is completed in about 1 hour. Natural heating reaction, the reaction temperature is controlled between 15-20 ° C, and the reaction time is 12 hours. Centrifuge to obtain aspartic acid internal acid anhydride hydrochloride with a wet weight of 200KG.

[0021] In the second step, 200KG wet weight of aspartic acid anhydride hydrochloride was suspended in 800KG methanol, and reacted at 20°C for 10 hours to obtain aspartic acid α-methyl ester hydrochloride, the system was clear, and the reaction was detected by TLC. , use 70KG triethylamine to slowly adjust the pH value between 7-8, and keep the temperature not higher than 30°C to precipitate the α-methyl aspartic acid ester. After centrifugation and drying, 77...

Embodiment 2

[0026] In the first step, 100 g of raw material aspartic acid is suspended in 400 g of dry tetrahydrofuran, and 60 g of phosphorus oxychloride is added dropwise when the system is at 5°C and the temperature is kept below 15°C throughout the process, and the dropwise addition is completed in about 20 minutes. Natural heating reaction, the reaction temperature is controlled between 20-25 ° C, and the reaction time is 10 hours. Centrifuge to obtain the wet weight of aspartic acid anhydride hydrochloride 195g.

[0027] In the second step, 195g wet weight of aspartic acid anhydride hydrochloride was suspended in 800g methanol, and reacted at 20°C for 10 hours to obtain aspartic acid α-methyl ester hydrochloride, the system was clear, and the reaction was detected by TLC. , use 70g of triethylamine to slowly adjust the pH value between 7-8, and keep the temperature not higher than 30°C, so that aspartic acid α-methyl ester is precipitated. Centrifuge and dry to obtain 78.0 g of asp...

Embodiment 3

[0031] In the first step, 25KG of raw material aspartic acid is suspended in 100KG of dry tetrahydrofuran, and 15KG of phosphorus oxychloride is added dropwise when the system is at 8°C and the temperature is kept below 15°C throughout the process, and the dropwise addition is completed in about 40 minutes. The temperature is naturally raised to react, the temperature is controlled between 18-22° C. during the reaction, and the reaction time is 14 hours. Centrifuge to obtain the wet weight of aspartic acid anhydride hydrochloride 50.5KG.

[0032]In the second step, 50.5KG wet weight of aspartic acid anhydride hydrochloride was suspended in 220KG methanol, and reacted at 20°C for 10 hours to obtain aspartic acid α-methyl ester hydrochloride, the system was clear, and the reaction was detected by TLC At the end, slowly adjust the pH value between 7-8 with 17.5KG triethylamine, and keep the temperature not higher than 30°C to precipitate the α-methyl aspartic acid ester. Centrif...

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Abstract

The invention discloses a preparation method of a polypeptide raw material aspartic acid beta-tert-butyl ester alpha-methyl ester hydrochloride, and mainly solves the technical problems of complex original process, long period, low yield, high cost, high dangerousness and inadaptation for mass production. The preparation method comprises the following steps: firstly, suspending aspartic acid in dry tetrahydrofuran, to prepare aspartic lactonic anhydride hydrochloride under the action of phosphorus oxychloride; secondly, suspending aspartic lactonic anhydride hydrochloride in methanol, carryingout a reaction to obtain aspartic acid alpha-methyl ester hydrochloride, and adjusting the pH value by triethylamine to make aspartic acid alpha-methyl ester separated out; thirdly, suspending aspartic acid alpha-methyl ester in dichloromethane, introducing isobutylene, dropwise adding concentrated sulfuric acid, and carrying out sealed reaction treatment, to obtain an oily substance aspartic acid beta-tert-butyl ester alpha-methyl ester; and fourthly, dissolving the oily substance aspartic acid beta-tert-butyl ester alpha-methyl ester in ethyl ether and dropwise adding ethyl ether-hydrochloric acid gas, to obtain the final product aspartic acid beta-tert-butyl ester alpha-methyl ester hydrochloride.

Description

technical field [0001] The invention relates to a preparation method of polypeptide raw material aspartic acid β-tert-butyl ester α-methyl ester hydrochloride. Background technique [0002] Aspartic acid β-tert-butyl ester α-methyl ester hydrochloride is an important intermediate for synthetic polypeptides, especially liquid-phase synthetic polypeptides. The preparation of aspartic acid β-tert-butyl ester α-methyl ester hydrochloride is especially The general method for the preparation of methyl ester in the process of aspartic acid β-tert-butyl ester α-methyl ester hydrochloride is: 1. Iodomethane method, in the patent VENENUM BIODESIGN LLC; LETOURNEAU, Jeffrey J; COLE, Andrew G; MARINELLI , Brett A; QUINTERO, Jorge G - WO2017 / 214359, 2017, A1 description. 2. Azidomethan method, described in Chemistry of Natural Compounds, 2012, vol. 48, # 2, p. 262 – 266. 3. After dehydration and condensation of acetic anhydride to form an internal acid anhydride, react with methanol to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/24C07C227/02C07C227/18C07D307/66
CPCC07C227/02C07C227/18C07D307/66C07C229/24
Inventor 徐红岩李仲才付等良林国庆孟航李亚军
Owner GL BIOCHEM SHANGHAI
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