CN112592294B

CN112592294B - Synthetic method of shakubatu drug intermediate

Info

Publication number: CN112592294B
Application number: CN202011526203.6A
Authority: CN
Inventors: 陈本顺; 叶金星; 石利平; 徐春涛; 朱萍; 程瑞华; 孙伟振; 张维冰; 万新强; 童林; 王欢
Original assignee: Jiangsu Alpha Pharmaceutical Co ltd
Current assignee: Jiangsu Alpha Pharmaceutical Co ltd
Priority date: 2020-12-22
Filing date: 2020-12-22
Publication date: 2022-05-13
Anticipated expiration: 2040-12-22
Also published as: CN112592294A

Abstract

The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthetic method of a shakubaqu drug intermediate, which comprises the following synthetic route:

adding a compound II and a solvent into a reaction bottle under the protection of nitrogen, stirring to dissolve, and then adding diisobutylaluminum hydride, wherein the feeding molar ratio of the compound II to the diisobutylaluminum hydride (DIBAH) is 1: 1-2, controlling the temperature, stirring for reaction, and monitoring the reaction by TLC; after the reaction is finished, KHSO is added₄Quenching reaction with aqueous solution; the resulting solution was combined with 1N HCl solution, stirred for 5 minutes and the organic phase separated; the aqueous phase was extracted with EtOAc and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I. The invention adopts diisobutyl aluminum hydride to replace lithium aluminum hydride which is easy to be explosively decomposed when meeting water. The reaction is simple to operate, has high yield and is suitable for industrial large-scale production.

Description

Synthetic method of shakubatu drug intermediate

Technical Field

The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthesis method of a Sacubitril drug intermediate [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] tert-butyl carbamate.

Background

Heart failure is an extremely important global public health problem which endangers human health, is the terminal stage of occurrence and development of cardiovascular diseases, and the morbidity, the rehospitalization rate and the mortality of the cardiovascular diseases are continuously increased year by year, so that more effective novel heart failure treatment medicines are urgently developed, and the marketing of the Sacubitril/valsartan with the dual action mechanism of an angiotensin receptor enkephalinase inhibitor brings new revolution for treating heart failure patients.

Sacubitril/valsartan (Entresto) is a dual-effect angiotensin receptor-enkephalinase inhibitor developed by Nowa company, and can be clinically used for treating hypertension and heart failure. The medicine consists of the Sacubitril acting on enkephalinase and the valsartan acting on a renin-angiotensin-aldosterone system, can effectively improve heart failure symptoms, reduce blood pressure and positively improve renal function, and is an ideal heart failure treatment medicine.

Because the synthesis process of the valsartan part is relatively mature, the synthesis focus falls on the Sacubitril fragment. Sacubitril (Sacubitril), chemically known as 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopropan-2-yl) amino) -4-oxobutanoic acid, having the following structure:

the [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] carbamic acid tert-butyl ester shown in the compound I is an important intermediate for preparing the Shakubaqu medicament. The original patent US5217996 used the following method for the synthesis of compound I:

the compound I is obtained by reducing the lithium aluminum hydride in the route, but the lithium aluminum hydride in the method is easy to be explosively decomposed when meeting water, so that the danger is brought to large-scale production. In view of the importance of the drug of Sacubitril in the treatment of heart failure, it is necessary to develop a more economical and industrially advantageous process for the preparation of intermediate I.

Disclosure of Invention

The invention aims to provide a preparation method of a Sacaba drug intermediate [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] carbamic acid tert-butyl ester, which has the advantages of mild reaction, low cost and high yield and is suitable for industrial production, so as to solve the problems of expensive reagent, high risk and the like in the preparation process of the Sacaba drug intermediate in the prior art.

In order to achieve the purpose, the invention provides the following technical scheme:

a synthetic method of a shakubatu drug intermediate comprises the following synthetic route:

the method specifically comprises the following steps:

adding a compound II and a solvent into a reaction bottle under the protection of nitrogen, stirring to dissolve, and then adding diisobutylaluminum hydride, wherein the feeding molar ratio of the compound II to the diisobutylaluminum hydride (DIBAH) is 1: 1-2, controlling the temperature, stirring for reaction, and monitoring the reaction by TLC; after the reaction is finished, KHSO is added₄Quenching reaction with aqueous solution; the resulting solution was combined with 1N HCl solution, stirred for 5 minutes and the organic phase separated; the aqueous phase was extracted with EtOAc and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I.

Wherein the solvent is one of tetrahydrofuran, diethyl ether, toluene or dichloromethane.

Wherein the reaction temperature is-20-0 ℃.

Compared with the prior art, the invention has the beneficial effects that:

the synthetic method of the invention is to improve the existing synthetic route of the intermediate [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] carbamic acid tert-butyl ester of the Shakubaqu drug, and diisobutyl aluminum hydride is selected to replace lithium aluminum hydride which is easy to be explosively decomposed when meeting water.

The method has the advantages of simple experimental operation and high yield, and is suitable for industrial large-scale production.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

Under the protection of nitrogen, compound II (10g, 26mmol) and 100mL tetrahydrofuran were added to a reaction flask, stirred to dissolve, and then diisobutylaluminum hydride (5.5g, 39mmol) was added, the temperature was controlled at-10 deg.C, the reaction was stirred, and the reaction was monitored by TLC. After the reaction was complete, 6.6g KHSO was added₄The reaction was quenched with 35mL of aqueous solution. The resulting solution was combined with 1N HCl (75mL) solution, stirred for 5 minutes and the organic phase separated. The aqueous phase was extracted with EtOAc (3X 100mL) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I (8g, 24.7mmol) in 95% yield and 99.6% purity.

Example 2

Under the protection of nitrogen, compound II (10g, 26mmol) and 100mL of diethyl ether were added to a reaction flask, stirred to dissolve, then diisobutylaluminum hydride (7.3g, 51mmol) was added, the temperature was controlled at 0 ℃, the reaction was stirred, and the reaction was monitored by TLC. After the reaction was complete, 6.6g KHSO was added₄The reaction was quenched with 35mL of aqueous solution. The resulting solution was combined with 1N HCl (75mL) solution, stirred for 5 minutes and the organic phase separated. The aqueous phase was extracted with EtOAc (3X 100mL) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound I (7.9g, 24.3mmol) which was collectedThe rate was 93.5% and the purity was 99.4%.

Example 3

Under the protection of nitrogen, compound II (10g, 26mmol) and 100mL of toluene were added to a reaction flask, stirred to dissolve, and then diisobutylaluminum hydride (4.1g, 29mmol) was added, the temperature was controlled at-20 ℃, the reaction was stirred, and the reaction was monitored by TLC. After the reaction was complete, 6.6g KHSO was added₄The reaction was quenched with 35mL of aqueous solution. The resulting solution was combined with 1N HCl (75mL) solution, stirred for 5 minutes and the organic phase separated. The aqueous phase was extracted with EtOAc (3X 100mL) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I (7.8g, 24mmol) in 92.3% yield and 99.3% purity.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A synthetic method of a shakubatu drug intermediate is characterized by comprising the following steps: the synthetic route is as follows:

2. The method for synthesizing the intermediate of the shakubatu drug according to claim 1, wherein the method comprises the following steps: the solvent is one of tetrahydrofuran, diethyl ether, toluene or dichloromethane.

3. The method for synthesizing the intermediate of the shakubatu drug according to claim 1, wherein the method comprises the following steps: the reaction temperature is-20 to 0 ℃.