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New method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane

A technology of tert-butoxycarbonylamino and diphenyl, which is applied in the field of medicine and chemical industry, can solve the problems of complex operation, difficult synthesis, harsh reaction conditions, etc., achieve high chemical purity and optical purity, reduce the number and types of solvents, and react The effect of easily controlled conditions

Active Publication Date: 2013-06-19
JINAN ASIA PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method involves nearly 30 kinds of solvent reagents, etc.; the process is cumbersome and the number of solvent reagents is large, which may easily cause the following problems: (1) The operation is complicated and dangerous; (2) The solvent reagents and intermediates are difficult to recycle, and there are many three wastes ; (3) There are many intermediates, all of which need to be purified, resulting in increased manufacturing costs and lower overall yields; (4) The synthesis is extremely difficult, the reaction conditions are harsh, and the process is unstable; (5) NaBH 4 The price is expensive and the dosage is large, resulting in high product cost

Method used

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  • New method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane
  • New method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] In a dry 200L reactor, pump 75L of isopropanol, add 4.8kg of KBH under stirring 4 , lower the temperature to -5~-10°C; and slowly add 20kg of methanesulfonic acid dropwise therein, maintain the temperature at -5~-10°C, and continue to keep stirring for 30min after dropping; then, slowly dropwise add 13.7 15L of isopropanol solution of kg RT-1, keep the temperature below 10°C; after dropping, keep stirring at 5-10°C for 12h; Continue to stir for 30 minutes after the amide drops, then slowly add 4.6kg of KBH in portions 4 , moved to room temperature reaction after adding, about 3 hours; to the end of the reaction; after the reaction was completed, 20kg of water was added dropwise to quench the reaction, and the solid was basically dissolved; then 19.2kg of K was added 2 CO 3 , adjust the pH value to 9-10 to obtain a solution of RT-2 for later use.

Embodiment 2

[0035] In the RT-2 solution prepared in Example 1, add dropwise 7L of 8.6Kg (BOC) 2 The isopropanol solution of O was dripped in 20 minutes; the reaction was kept at 10-20°C, and the reaction was completed in about 4-8 hours; then 2Kg of activated carbon was added to it, heated to 50°C and stirred for 30 minutes, then filtered; 3 solution.

Embodiment 3

[0037] Pump the RT-3 solution prepared in Example 2 into a 200L autoclave, and add 1.4Kg of Pd / C (10%), and then clean the pipeline with a small amount of isopropanol; replace with nitrogen 3 times, and then replaced with hydrogen 3 times, reacted at 1.0-1.5MPa, 70-75°C for 6h, until no more hydrogen was absorbed; cooled to 20-25°C, filtered, washed with 20L isopropanol, and the filtrate was Crude BDH solution.

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Abstract

The invention discloses a new method for industrial production of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert-butyloxycarbonylamino-1,6-diphenyl hexane (BDH), belonging to the technical fields of pharmaceuticals and chemicals. The BDH is synthesized by a one-pot method by using 5-amino-2-dibenzylamino-1,6-diphenyl-4-en-3-one as the raw material. In the production method, the reaction is easy to control;the post treatment is easy; the single solvent is easy to recycle so that few three wastes are generated; the yield of the product is high; the single-batch production time is greatly shortened; and the production efficiency is improved.

Description

technical field [0001] The invention relates to a new method for industrial production of (2S, 3S, 5S)-2-amino-3-hydroxy-5-tert-butoxycarbonylamino-1,6-diphenylhexane, which belongs to the technical field of medicine and chemical industry. Background technique [0002] (2S,3S,5S)-2-amino-3-hydroxy-5-tert-butoxycarbonylamino-1,6-diphenylhexane, referred to as BDH, is a synthetic antiviral drug lopinavir, The important intermediates of ritonavir (ritonavir) etc., its structural formula is as follows. [0003] [0004] Since lopinavir / ritonavir is a protease inhibitor used in the treatment of AIDS (HIV), it accounts for more than 50% of the market share of protease inhibitors for the treatment of HIV virus infection; and lopinavir / ritonavir has Listed abroad, its efficacy and safety have been fully affirmed. Therefore, it is of great significance to develop this product in our country. [0005] Lu Ming et al reported a preparation of (2S,3S,5S)-2-amino-3-hydroxyl-5-tert f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/20C07C269/06C07C269/08
Inventor 彭立增
Owner JINAN ASIA PHARMA TECH