Preparation method of Sacubitril intermediate

An intermediate and weight ratio technology, applied in the field of compound preparation, can solve the problems of difficult to obtain intermediates, cumbersome routes, large amount of auxiliary reagents, etc., and achieve the effects of short method steps, increased reaction yield, and mild reaction conditions

Active Publication Date: 2019-08-30
甘肃皓天医药科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The intermediates used directly in the preparation process are not easy to obtain, and the amount of auxili

Method used

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  • Preparation method of Sacubitril intermediate
  • Preparation method of Sacubitril intermediate
  • Preparation method of Sacubitril intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: In the synthetic route shown in Formula 7, the acyl halide reagent is thionyl chloride, and R is a chlorine atom; the base used to convert compound 29 into compound 30 is sodium hydroxide.

[0041] Preparation of compound 26

[0042] Compound 25 (19.8 g, 0.1 mol) was added to a 500 mL three-necked flask, 100 mL of toluene was added, and thionyl chloride (14.3 g, 0.12 mol) was added dropwise under cooling in an ice-water bath. After dripping, the cold bath was removed, the temperature was raised to reflux for 5 hours, cooled to room temperature, and stored for later use.

[0043] Preparation of compound 27

[0044] Add 250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether into a 500mL three-necked flask, add methylnitrosourea (30g, 0.29mol) under cooling in an ice-water bath, stir for 10 minutes, and store at low temperature until use. Methyl nitrosourea solution and 30% potassium hydroxide solution (50 g, 0.89 mol) were prepared in ...

Embodiment 2

[0057] Example 2: In the synthetic route shown in formula 7, the acyl halide reagent is oxalyl chloride, R chlorine atom; the base used to convert compound 29 into compound 30 is sodium formate.

[0058] Preparation of compound 26

[0059] Compound 25 (19.8 g, 0.1 mol) was added to a 500 mL three-necked flask, 100 mL of dichloromethane was added, and oxalyl chloride (13.7 g, 0.12 mol) was added dropwise under cooling in an ice-water bath. After dripping, the cold bath was removed, raised to room temperature and reacted for 4 hours, cooled to room temperature, and stored for later use.

[0060] Preparation of compound 27

[0061] Add 250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether into a 500mL three-necked flask, add methylnitrosourea (30g, 0.29mol) under cooling in an ice-water bath, stir for 10 minutes, and store at low temperature until use. Methyl nitrosourea solution and 30% potassium hydroxide solution (50 g, 0.89 mol) were prepared in a m...

Embodiment 3

[0074] Example 3: In the synthetic route shown in Formula 7, the acyl halide reagent is phosphorus oxychloride, and R is a chlorine atom; the base used to convert compound 29 into compound 30 is potassium hydroxide.

[0075] Preparation of compound 26

[0076] Compound 25 (19.8 g, 0.1 mol) was added to a 500 mL three-necked flask, 100 mL of dichloromethane was added, and phosphorus oxychloride (18.4 g, 0.12 mol) was added dropwise under cooling in an ice-water bath. After dripping, the cold bath was removed, raised to room temperature and reacted for 2 hours, and stored for later use.

[0077] Preparation of compound 27

[0078] Add 250mL of methyl tert-butyl ether and 90mL of diethylene glycol dimethyl ether into a 500mL three-necked flask, add methylnitrosourea (30g, 0.29mol) under cooling in an ice-water bath, stir for 10 minutes, and store at low temperature until use. Methyl nitrosourea solution and 30% potassium hydroxide solution (50 g, 0.89 mol) were prepared in a m...

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Abstract

The invention discloses a preparation method of an intermediate compound (R)-tert-butyl (1-((1,1'-diphenyl)-4-yl)-3-hydroxypropane-2-yl) carbamate. The preparation method is represented as the formulashown in the description. According to the preparation method, the steps are simple and short, the reaction yield is increased, reaction conditions are mild, most of the intermediates obtained in thereaction process are not required to be purified and can be subjected to the next reaction directly, large-batch synthesis is facilitated, chiral amine with stereospecificity is efficiently synthesized with aminotransferase, and the preparation method is more suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of a compound, specifically a method for preparing the intermediate (R)-tert-butyl (1-((1,1'-biphenyl)-4-yl)- Process for the preparation of 3-hydroxypropan-2-yl) carbamate. Background technique [0002] LCZ696 is a dual-acting angiotensin receptor neprilysin inhibitor developed by Novartis, which was approved by the FDA on July 7, 2015, for the treatment of heart failure patients with reduced ejection fraction. LCZ696 is a complex composed of Sacubitril (AHU-377) and valsartan (Diovan), which has a unique mode of action and is believed to reduce strain in failing hearts. Among them, sacubitril can block the mechanism of action of two peptides responsible for lowering blood pressure, and valsartan can improve vasodilation and stimulate the body to excrete sodium and water. The safety threshold of cardiovascular drugs is extremely high, and LCZ696 has even shown a higher safety than conventional dr...

Claims

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Application Information

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IPC IPC(8): C07C269/04C07C271/16C12P13/00
CPCC07B2200/07C07C45/54C07C45/64C07C51/04C07C51/60C07C269/04C12P13/001C07C271/16C07C49/245C07C63/72C07C57/38C07C49/233C07C57/72
Inventor 程红应魏霖李毅王仕祥魏鹏飞
Owner 甘肃皓天医药科技有限责任公司
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