A kind of preparation method of N-methoxycarbonyl-l-tert-leucine

A technology of tertiary leucine and tertiary leucine amine salt, which is applied in the field of medicine and chemical industry, can solve the problems of high cost, unsuitable large-scale industrial production of MOC-L-tertiary leucine, and difficulties in the separation and extraction of L-tertiary leucine and other problems, to achieve the effect of low cost, high product purity, simple and reasonable process

Active Publication Date: 2016-06-01
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, this route uses L-tert-leucine as a chiral raw material, and the separation and extraction of L-tert-leucine is difficult and costly, which is not suitable for large-scale industrial production of MOC-L-tert-leucine

Method used

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  • A kind of preparation method of N-methoxycarbonyl-l-tert-leucine
  • A kind of preparation method of N-methoxycarbonyl-l-tert-leucine

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Add 765 g of ethyl acetate into a 1000 ml reaction flask, add 100 g of N-methoxycarbonyl-tert-leucine while stirring, and heat to 50-60°C. Stir to completely dissolve, add 66.7g of D-α-phenylethylamine, after the dropwise addition, keep warm for 10 minutes, cool down until the material precipitates, keep warm for 1 hour, then cool down to 0-5°C, keep warm for 1 hour, and filter with suction to get the wet product .

[0049] Add 240g of the above wet product into a 2000ml bottle, add 750g of water, stir to dissolve, and cool to 0-10°C. Add alkaline water dropwise to adjust the pH to about 11, extract with 1200ml of toluene, wash the toluene layer with 300g of water once, recover D-α-phenylethylamine from the toluene layer, pump 500g of ethyl acetate into the water layer, cool to 0-5°C, Use hydrochloric acid to adjust PH=1 to 3, control the temperature not to exceed 10°C, separate layers, add 100g of anhydrous magnesium sulfate to the organic layer and dry for 2 hours, f...

Embodiment 2

[0051] Add 765g of acetone into a 1000ml reaction flask, add 100g of N-methoxycarbonyl-tert-leucine while stirring, and heat to 40-45°C. Stir to completely dissolve, add 66.7kg of D-α-phenylethylamine, after the dropwise addition, keep warm for 10 minutes, cool until the material precipitates and keep warm for 1 hour, then cool down to -5°C to 0°C, keep warm for 1 hour, and filter with suction to get Wet product.

[0052] Add 120g of the above wet product into a 1000ml bottle, add 400g of water, stir to dissolve, and cool to 0-10°C. Add liquid alkali water dropwise to adjust the pH to about 11, extract with 600ml toluene, wash the toluene layer with 150g water once, recover D-α-phenylethylamine from the toluene layer, pump 300g ethyl acetate into the water layer, cool to 0-5°C, Use hydrochloric acid to adjust PH=1 to 3, control the temperature not to exceed 10°C, separate layers, add 50g of anhydrous magnesium sulfate to the organic layer and dry for 2 hours, filter with suct...

Embodiment 3

[0054] Add 600 g of isopropanol and 50 g of water into a 1000 ml reaction flask, add 100 g of N-methoxycarbonyl-tert-leucine while stirring, and heat to 45-50°C. Stir to completely dissolve, add 66.7kg of D-α-phenylethylamine, after the dropwise addition, keep warm for 10 minutes, cool until the material precipitates and keep warm for 1 hour, then cool down to -5°C to 0°C, keep warm for 1 hour, and filter with suction to get Wet product.

[0055] Add 60g of the above wet product into a 500ml bottle, add 200g of water, stir to dissolve, and cool to 0-10°C. Add liquid alkali water dropwise to adjust the pH to about 11, extract with 300ml toluene, wash the toluene layer with 80g water once, recover D-α-phenylethylamine from the toluene layer, pump 200g ethyl acetate into the water layer, cool to 0-5°C, Use hydrochloric acid to adjust PH=1 to 3, control the temperature not to exceed 10°C, separate layers, add 20g of anhydrous magnesium sulfate to the organic layer and dry for 2 h...

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Abstract

The invention relates to a preparation method of MOC-L-tertiary leucine, in particular to a method for splitting 2-methoxy group acylamino-3, 3-dimethyl butyric acid to prepare the MOC-L-tertiary leucine. Two kinds of diastereoisomer amine salt of the 2-methoxy group acylamino-3, 3-dimethyl butyric acid are formed through the 2-methoxy group acylamino-3, 3-dimethyl butyric acid and a resolving agent amine compound, MOC-L-tertiary leucine amine salt is obtained through separation, and the MOC-L-tertiary leucine is obtained by utilizing of the free acid MOC-L-tertiary leucine amine salt. The preparation method is low in cost, simple and reasonable in technique, high in product purity and suitable for industrial production of the MOC-L-tertiary leucine.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a preparation method of N-methoxycarbonyl-L-tert-leucine. Background technique [0002] N-methoxycarbonyl-L-tert-leucine, also known as MOC-L-tert-leucine, CAS number 162537-11-3, English name (S)-N-(METHOXYCARBONYL)-TERT-LEUCINE, the structure is as follows shown in the formula, [0003] . [0004] MOC-L-tert-leucine is a very important intermediate in pharmaceutical and chemical industry, widely used, and can be used as a key intermediate in the synthesis of many types of drugs. [0005] Example 46 of patent US5849911 (applied date: April 9, 1997) applied by Swiss Novartis first disclosed atazanavir and its preparation method, which included a MOC-L-tert-leucine as shown in the following formula Preparation method of atazanavir with acid as intermediate. Subsequently, WO2010146119, WO2008065490, US20090270499, WO2009130534, CN101391978, US7829720 a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/04
Inventor 车大庆邬卫国徐明东
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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