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Preparation method of sacubitril intermediate

A technology for sacubitril and intermediates, which is applied in the field of preparation of sacubitril intermediates, which can solve the problems of many impurities and low conversion rate, and achieve the effects of high purity, easy availability of raw materials, and short process routes

Pending Publication Date: 2021-07-20
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Aiming at the problems of low conversion rate and many impurities in the current preparation process of sacubitril, the present invention aims to provide a compound suitable for industrialization with simple operation, mild reaction conditions, high product yield and high purity. Technical method for producing Shakubatrol intermediate

Method used

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  • Preparation method of sacubitril intermediate
  • Preparation method of sacubitril intermediate
  • Preparation method of sacubitril intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Add 15.2g of 2-bromopropionic acid and 7.5g of zinc powder into the reaction flask, add toluene (152mL) into the reaction flask, cool down to 0-10°C, and add trimethylchlorosilane solution (32.6mL) dropwise under stirring After dropping, continue stirring for 1 h, TLC [developer: petroleum ether: ethyl acetate = 5:1] detects that the reaction is complete, adds water (150 mL) to the reaction solution, and separates the light yellow clear organic Phase is Compound I solution.

[0050]Add (2R)-1-((1,1'-biphenyl)-4-yl)-3-formylpropan-2-yl-carbamic acid tert-butyl ester (27.1g) to the reaction flask, Add isopropyl acetate (406mL) into the bottle, heat the reaction solution to 10-30°C, add compound I solution to it and stir for 2 hours, TLC [developer: petroleum ether: ethyl acetate = 5:1] to detect the reaction At the end, concentrate under reduced pressure at 35°C to dryness, dissolve in isopropyl acetate (115 mL) with a mass volume ratio of 3 times, and add n-heptane with...

Embodiment 2

[0053] Add 15.2g of 2-bromopropionic acid and 7.5g of zinc powder into the reaction flask, add toluene (230mL) into the reaction flask, cool down to 0-10°C, and add trimethylchlorosilane solution (37.6mL) dropwise under stirring After dropping, continue stirring for 1 h, TLC [developer: petroleum ether: ethyl acetate = 5:1] detects that the reaction is complete, adds water (230 mL) to the reaction solution, and separates the light yellow clear organic Phase is Compound I solution.

[0054] (2R)-1-((1,1'-biphenyl)-4-yl)-3-formylpropan-2-yl-aminofluorenylmethoxycarbonyl ester (37.3 g) was added to the reaction flask, Add isopropyl acetate (670mL) to the reaction flask, heat the reaction solution to 10-30°C, add the compound I solution to it and stir for 2h, TLC [developing solvent: petroleum ether: ethyl acetate = 5:1] After detecting the end of the reaction, concentrate under reduced pressure at 35°C to dryness, dissolve in isopropyl acetate (115mL) with a mass volume ratio of...

Embodiment 3

[0057] Add 15.2g of 2-bromopropionic acid and 7.5g of zinc powder into the reaction flask, add toluene (76mL) into the reaction flask, cool down to 0-10°C, add trimethylchlorosilane solution (30mL) dropwise under stirring, After dropping, continue to stir the reaction for 1 h, TLC [developer: petroleum ether: ethyl acetate = 5:1] detects that the reaction is complete, adds water (76 mL) to the reaction solution, and separates the light yellow clear organic phase. Compound I solution.

[0058] Add (2R)-1-((1,1'-biphenyl)-4-yl)-3-formylpropan-2-yl-carbamic acid tert-butyl ester (27.1g) to the reaction flask, Add isopropyl acetate (325mL) into the bottle, heat the reaction solution to 10-30°C, add compound I solution to it and stir for 2 hours, TLC [developing solvent: petroleum ether: ethyl acetate = 5:1] to detect the reaction At the end, concentrate under reduced pressure at 35°C to dryness, dissolve in isopropyl acetate (115 mL) with a mass volume ratio of 3 times, and add n...

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Abstract

The invention provides a preparation method of a sacubitril intermediate. According to the method, 2-bromopropionic acid is used as an initial raw material and reacts with three-level silicon halide under the catalytic action of metal to generate a silicon ylide reagent, compared with a phosphorus ylide reagent, the reaction condition is mild, a hydrogenation reduction reaction can be carried out without alkaline hydrolysis, and ethyl esterification of a SOCl2 catalytic compound III is not influenced. Meanwhile, intramolecular or intermolecular polymerization impurities formed by removal of N protecting groups during ethyl esterification of the compound III can be avoided. The method has the advantages of short preparation process route, low cost, easily available raw materials, high yield and high purity, and is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a sacubitril intermediate. Background technique [0002] LCZ696 is a new type of antihypertensive drug developed by Novartis for the treatment of patients with NYHA II-IV heart failure. Co-crystals, in which valsartan can improve vasodilation, stimulate the body to excrete sodium and water, and sacubitril can block the action of two polypeptides that threaten to lower blood pressure, so LCZ696 is called angiotensin II receptor and enkephalin Dual inhibitors of peptidases. The structural formula is as follows: [0003] [0004] LCZ696 is superior to standard drugs in reducing blood pressure and reducing heart failure, making the drug eligible for fast-track review by the US FDA and the EU EMEA. The industry generally believes that LCZ696 will bring about innovations in traditional heart failure treatment options. [0005] Sacub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/22
CPCC07C269/06C07F7/1896C07C2603/18C07C271/22Y02P20/55
Inventor 张贵民李文姣白文钦刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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