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Synthesis of enkephalinase inhibitor

A technology of enkephalinase and inhibitors, which can be used in the preparation of carboxylic acid amide, cyanide reaction, organic compound, etc., and can solve the problems of high price and high cost

Active Publication Date: 2018-06-26
重庆博腾药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the use of expensive chiral catalysts and the use of Grignard reactions, the cost is high, and there is room for improvement and improvement

Method used

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  • Synthesis of enkephalinase inhibitor
  • Synthesis of enkephalinase inhibitor
  • Synthesis of enkephalinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the synthesis of compound V (R1=Ac)

[0027] The synthesis of compound V (R1=Ac) refers to the literature (Journal of Organic Chemistry, 1986, vol. 51, p. 3494-3498) method. Add 104g (0.80mol, 1eq) L-pyroglutamic acid and 300g (2.88wt.) methanol to the three-necked flask, and add 138g (2.2eq) acetyl chloride dropwise. After the dropwise addition, the temperature was raised to 55-65°C until the reaction of the raw materials was complete. After the solvent was distilled off under reduced pressure to obtain a white solid, add 300g (2.88wt) toluene, dropwise add 178g (2.2eq) triethylamine, then add dropwise 69g (1.1eq) acetyl chloride, after the reaction is completed, add 160g water, stir After layering, the organic phase was washed successively with dilute hydrochloric acid, sodium bicarbonate solution, and water, and after concentration, 122 g of white solid was obtained.

[0028]

Embodiment 2

[0029] Embodiment 2: compound VI (R 1 =Ac) synthesis

[0030] Compound VI(R 1 =Ac) synthetic reference literature (Synthesis, 1997, 863-865) method. 50g (0.27mol, 1.0eq) compound V (R 1 =Ac, the product in Example 1), 70.6g (1.5eq) tert-butoxybis(dimethylamino)methane (Bredereck reagent), 200mL ethylene glycol dimethyl ether are added in the reaction flask, heated to React at 68-70°C for 10h. Cooling and crystallization, filtering, filter cake washing with a small amount of solvent, compound VI (R 1 =Ac), weight 46.3g.

[0031]

Embodiment 3

[0032] Embodiment 3: compound VII (R 1 =Ac) synthesis

[0033] Compound VII(R 1 =Ac) was obtained by referring to the literature (Synthesis, 1997, 863-865).

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Abstract

The invention discloses a novel synthesis method of enkephalinase inhibitor Sacubitril. According to the novel synthesis method, L-Pyroglutamic acid is taken as a raw material, a plurality of steps ofreaction are carried out, and a compound I with the chirality identical to that of Sacubitril is obtained via epimerization crystallization; the compound I is subjected to acylation, and is reacted with biphenyl so as to obtain a compound II; and hydrolysis ring-opening is carried out so as to obtain a compound III; the compound III is reacted with succinic anhydride, and reduction reaction is carried out so as to obtain Sacubitril. According to the synthesis method, a novel chirality control strategy is adopted, a novel chiral center is constructed using a simple and reliable method; controlof the chiral key intermediate is carried out at the early part of the synthesis routine, so that it is beneficial for reduction of risk and cost.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry. Background technique [0002] LCZ696 (Entresto, Scheme 1) is a first-in-class compound drug developed by Novartis. The drug is composed of neprilysin inhibitor Sacubitril and angiotensin receptor blocker Valasartan at a ratio of 1:1. It was approved by the FDA in July 2015 and marketed in the United States for the treatment of patients with chronic heart failure (NYHA category II -IV) Reduce the risk of cardiovascular death and hospitalization for heart failure and reduce ejection fraction in patients with heart failure. The drug is safe and effective. It is a blockbuster drug for the treatment of heart failure and a great breakthrough in the field of heart failure treatment in the past 25 years. It has a good market prospect. [0003] [0004] The document WO2008083967A2 reports a method for synthesizing Sacubitril with L-pyroglutamic acid as the starting material (Scheme 2). T...

Claims

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Application Information

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IPC IPC(8): C07C233/47C07C231/12C07C229/34C07D207/26
CPCC07B2200/07C07C227/20C07C231/02C07C231/12C07D207/26C07D207/277C07C233/47C07C229/34Y02P20/55
Inventor 林文清郑宏杰刘小波高晓鹏朱剑平沈陈健
Owner 重庆博腾药业有限公司
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