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Novel synthesis method of key component Sacubitril of novel anti-heart-failure drug

A technology of sakubiqu and key components, applied in the field of medicine and chemical industry, can solve the problems of high process amplification cost, high process cost, low selectivity, etc., and achieves reduced process cost, low process experimental condition requirements, and high yield. Effect

Inactive Publication Date: 2017-03-15
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route is currently the main process route for the synthesis of Shakubiqu, but there are still many steps in the route; the starting material needs to be synthesized in multiple steps, and a large equivalent of strong acid is used in the production process and a large amount of waste liquid is generated, and the pressure on environmental protection is relatively high. Large; In addition, a large amount of noble metal catalyst is required in the chiral reduction step, the selectivity is not high, and the process cost is high
[0013] At present, these routes for synthesizing Shakubiqu have certain limitations, and the cost of process amplification is relatively high, so it is necessary to develop a synthetic method with lower cost and high efficiency

Method used

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  • Novel synthesis method of key component Sacubitril of novel anti-heart-failure drug
  • Novel synthesis method of key component Sacubitril of novel anti-heart-failure drug
  • Novel synthesis method of key component Sacubitril of novel anti-heart-failure drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] Add triphenylphosphine (28.85g, 110mmol) and dichloromethane (129mL) into the three-necked flask, stir to dissolve, cool to 0-5°C, add bromine (17.58g, 110mmol) dropwise, raise to room temperature and stir for 30 Minutes later, compound formula 1 (12.92 g, 100 mmol) was added and reacted at room temperature for 10-16 hours. At the end of the reaction, sodium bisulfite solution (5%, 129 mL) was added to quench the reaction, stirred and separated, the aqueous phase was extracted twice with dichloromethane (65 mL), and the combined organic phase was washed once with saturated brine (65 mL). After drying over sodium sulfate and concentrating, compound 2a (16.52 g, 86%) was obtained by column chromatography with a mixed solvent of petroleum ether and ethyl acetate. ESI m / z=192.0,194.1(M+1) 1 H NMR (400MHz, CDCl 3 )4.05-3.80(m,1H),3.55-3.20(m,2H),2.68-2.43(m,1H),2.15-2.00(m,1H),1.65-1.54(m,1H),1.18(d, J=6.8Hz,3H);

[0041] In embodiment 1, replace triphenylpho...

Embodiment 2

[0043]

[0044] Add compound formula 1 (28.85g, 110mmol) and dichloromethane (140mL) into the three-necked flask, stir and dissolve, add triethylamine (18.18g, 150mmol), stir for 5 minutes, then drop into the dichloromethane solution of p-toluenesulfonyl chloride (20.97g, 110mmol, dissolved in dichloromethane), react at room temperature for 8-10 hours. After the reaction was completed, water (140 mL) was added to quench the reaction, stirred and separated, the aqueous phase was extracted twice with dichloromethane (140 mL), the combined organic phase was washed once with saturated brine (70 mL), dried over anhydrous sodium sulfate, concentrated and used The compound 2b (24.93 g, 88%) was separated by column chromatography with a mixed solvent of petroleum ether and ethyl acetate. ESI m / z=284.2(M+1) 1 H NMR (400MHz, CDCl 3)δ7.80(d, J=8.4Hz, 2H), 7.39(d, J=8.0Hz, 2H), 4.10-4.00(m, 1H), 3.95-3.75(m, 2H), 2.70-2.45(m ,1H),2.45(s,3H),2.05-1.90(m,1H),1.60-1.40(m,1H),1.16(d,J=6...

Embodiment 3

[0047]

[0048] Under nitrogen protection, add 4-bromobiphenyl (6.99g, 30mmol), magnesium chips (5.34g, 220mmol), 1-2 grains of iodine and tetrahydrofuran (70mL) into the three-neck flask A, stir well and cool to 0-5°C , switch 3 times with nitrogen, heat to reflux until the color of iodine disappears, Grignard reaction is triggered, slowly continue to drop 4-bromobiphenyl tetrahydrofuran solution (41.96g, 180mmol, dissolved in 80mLTHF and degassed) to keep the solution slightly boiling, add After completion, it was raised to 55-60°C for 1-2 hours, and after the reaction, it was cooled to 0-5°C for later use; in another three-necked flask B, compound 2a (19.21g, 100mmol), catalyst iron triacetylacetonate (0.96g) and Tetrahydrofuran (40mL), stir and dissolve, cool to 0-5°C and switch nitrogen for 3 times under vacuum, transfer the biphenylmagnesium bromide solution in bottle A into reaction bottle B with a syringe, and warm up to room temperature for reaction after dropping ...

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Abstract

The invention discloses a novel synthesis method of key component Sacubitril of a novel anti-heart-failure drug. The method includes transforming a starting material compound 1 to a compound 2; coupling the compound 2 with (1'1)-4-biphenylmagnesium bromide to obtain a compound 3; subjecting the compound 3 to hydrolysis reaction by loading a Boc protecting group, and preparing a compound 5 by means of one-pot reaction; subjecting the compound 5 to Boc group removal and esterification reaction to obtain a compound 6, and reacting the compound 6 with succinic anhydride without separation to obtain a compound 7, namely Sacubitril, wherein the route is as following.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new preparation method of a key component of a new anti-heart failure drug. Specifically, the invention discloses a new synthesis method of Sacubitril, a key component of a new anti-heart failure drug LCZ696. Background technique [0002] According to statistics, there are currently about 117 million heart failure patients in the world, of which there are about 29.971 million in my country, accounting for a quarter of the world's total. Although there are currently available drugs for the treatment of heart failure, patients still face a high risk of death and poor quality of life, and the development of new drugs is urgent. Novartis's blockbuster antihypertensive and anti-heart failure drug LCZ696 (trade name Entresto) is a dual-action angiotensin receptor neprilysin inhibitor that combines Novartis' high blood pressure drugs Valsartan and Sacubit Sacubitril, used ...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/47
CPCY02P20/55C07C231/02C07C227/12C07C269/00C07D207/26C07D207/263C07D207/267C07C233/47C07C271/22C07C229/34
Inventor 俞炜蒋怀志
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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