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Preparation method for Sacubitril intermediate

An intermediate and methyl technology, applied in the field of organic synthesis route design API intermediate preparation, can solve the problems of inability to apply chiral adjuvant, raw materials are not easy to obtain, cost increase, etc., achieve high purity and yield, and novel method , the effect of easy availability of raw materials

Inactive Publication Date: 2016-05-11
张伯引
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In this route, the raw materials are not easy to obtain, and the chiral auxiliaries cannot be applied mechanically, resulting in a greatly increased cost

Method used

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  • Preparation method for Sacubitril intermediate
  • Preparation method for Sacubitril intermediate
  • Preparation method for Sacubitril intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Add 2.3g of (3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone into a 250ml three-neck flask, then add 100ml of tetrahydrofuran, add 16ml of 10% sodium hydroxide solution under stirring, and put in an ice-water bath Cool, when the internal temperature drops to 5°C, slowly add a solution of 7.76g of p-toluenesulfonyl chloride and 50ml of tetrahydrofuran dropwise, keep the internal temperature below 10°C during the dropwise addition, remove the cooling bath, stir overnight at room temperature, and The reaction solution was poured into 200ml of ice water, adjusted to PH=6-7 with 37% HCl, evaporated to remove tetrahydrofuran, added 250ml of n-hexane, stirred to precipitate a solid, filtered with suction, and dried to obtain 4.5g. Yield: 88.9%

[0046] 1HNMR(DMSO-d6ppm)0.97(d,J=7.2,3H),1.66-1.74(m,1H),1.89-1.94(m,1H),2.25-2.29(m,1H),2.43(s,3H) ,3.6-3.7(m,1H),3.87-3.90(m,1H),3.94-3.99(m,1H),7.48-7.50(d,J=8,2H),7.76(brs,1H),7.79- 7.81 (d,J=8,2H).

Embodiment 2

[0048] Add 2.3g of (3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone into a 250ml three-neck flask, then add 100ml of dichloromethane, 5.6ml of triethylamine, and 0.02g of DMAP, ice Cool in a water bath. When the internal temperature drops to 5°C, slowly add a solution of 7.76g of p-toluenesulfonyl chloride and 50ml of dichloromethane dropwise. During the dropwise addition, keep the internal temperature below 10°C. After dropping, remove the cooling bath and stir at room temperature Overnight, the reaction solution was poured into 200ml of ice water, adjusted to PH=6-7 with 37% HCl, separated into layers, the water layer was extracted once with 100ml of dichloromethane, the dichloromethane layers were combined, dried over anhydrous magnesium sulfate, evaporated Remove dichloromethane, recrystallize with ethyl acetate, filter with suction, and dry to obtain 3.1g. Yield: 91.1%

Embodiment 3

[0050] Add 2.72g of (3R,5S)-5-(methyl p-toluenesulfonate)-3-methyl-2-pyrrolidone into a 100ml three-neck flask, then add 50ml of acetone and 2.25g of sodium iodide, and heat up and reflux for 24 hours , cooled, evaporated to remove acetone, added 40ml of water, extracted three times with 150ml of ethyl acetate, combined the ethyl acetate layers, dried over anhydrous magnesium sulfate, evaporated to remove ethyl acetate, recrystallized with ethyl acetate, and dried to obtain 2.1g. Yield: 92.1% 1HNMR (DMSO-d6ppm) 1.03 (d, 3H), 1.74-1.82 (m, 1H), 1.96-2.02 (m, 1H), 2.42-2.49 (m, 1H), 3.27-3.28 (m ,2H), 3.58-3.59(m,1H), 7.79(brs,1H).

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Abstract

The invention relates to a preparation method for a Sacubitril intermediate. The preparation method comprises the following steps that (3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone is esterified with toluene sulfochloride or methanesulfonyl chloride to obtain (3R,5S)-5-(methyl p-toluenesulfonate)-3-methyl-2-pyrrolidinone or (3R,5S)-5-(methyl methanesulfonate)-3-methyl-2-pyrrolidinone; (3R,5S)-5-(methyl p-toluenesulfonate)-3-methyl-2-pyrrolidinone or (3R,5S)-5-(methyl methanesulfonate)-3-methyl-2-pyrrolidinone is coupled with 4-diphenylmagnesium bromide or 4-diphenylmagnesium chloride to obtain (3R,5S)-3-methyl-5-(1,1'-diphenyl-4-yl-methyl)-2-pyrrolidinone. According to the preparation method, the method is novel, the raw materials are easy to obtain, the technology is simple, and the purity and yield of the product are both very high.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design raw material drug intermediate preparation, in particular to a preparation method of an enprilysin inhibitor Sacubitril intermediate. Background technique [0002] Entresto (sacubitril + valsartantrisodium hemipentahydrate) is a new antihypertensive drug developed by Novartis. It is used for heart failure patients with reduced ejection fraction and will reduce the risk of cardiovascular death and hospitalization for heart failure. The drug combines two components of Novartis' Diovan (generic name: valsartan) and Sacubitril (AHU-377), in which valsartan can improve vasodilation and stimulate the body to excrete sodium and water, while Sacubitril can block Therefore, Entresto is known as a dual inhibitor of angiotensin II receptor and neprilysin. [0003] Entresto is a first-in-class innovative drug for the treatment of patients with NYHA II-IV heart failure. It acts on the n...

Claims

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Application Information

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IPC IPC(8): C07D207/267
CPCC07D207/267C07B2200/07
Inventor 张伯引
Owner 张伯引
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