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Method for preparing sacubitril intermediate in continuous flow microreactor

A micro-reactor, sacubitril technology, applied in chemical instruments and methods, chemical/physical/physical-chemical reactors, organic chemical methods, etc., can solve the problems of low efficiency, low yield, low purity, etc. The effect of good selectivity, high reaction yield and high purity

Active Publication Date: 2021-12-07
NANJING VCARE PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved in the present invention is the problem of low yield, low purity and low efficiency in the industrial scale-up preparation of sacubitril intermediate by conventional kettle reaction

Method used

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  • Method for preparing sacubitril intermediate in continuous flow microreactor
  • Method for preparing sacubitril intermediate in continuous flow microreactor
  • Method for preparing sacubitril intermediate in continuous flow microreactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050]

[0051] (1) Preparation of material a solution: Compound II (100 kg, 305.42 mol, 1.0 Eq.) And TEMPO (9.54 kg, 61.06 mol, 0.20 Eq.) Were dissolved in dichloromethane (680 kg);

[0052] (2) Preparation of Material B Solution: Sodium bicarbonate (38.48 kg, 458.12 mol, 1.5 Eq.) And sodium bromide (1.88 kg, 18.27 mol, 0.06 Eq.) Were dissolved in water (600 kg);

[0053] (3) Material C solution: aqueous solution of sodium hypochlorite, the measurement content is: 9.6%;

[0054] (4) Preparation of the material D solution: Water (200 kg), dichloromethane (132.5 kg), and etched by Ethoxyethyl triphenylphosphine (110 kg, 305.42 mol, 1.0 Eq) were added. ) And sodium thiosulfate (15.16 kg, 61.08 mol, 0.2 Eq.), Stirring and cooling to 0 to 5 ° C;

[0055] (5) First mix the material A solution and the material B in the microcomputer 1, and the residence time is 4 to 6 s, and then mixed with the material C solution in the micro-mixer 2, the residence time is 3 ~ 5 s, then Entering the ...

Embodiment 2

[0060]

[0061] (1) Preparation of material a solution: Compound II (100 kg, 305.42 mol, 1.0 Eq.) And TEMPO (2.39 kg, 15.27 mol, 0.05 Eq.) Were dissolved in dichloromethane (680 kg);

[0062] (2) Preparation of material B solution: sodium carbonate (32.36 kg, 305.37 mol, 1.0 Eq.) And sodium bromide (1.57 kg, 15.225 mol, 0.05 eq.) Were dissolved in water (600 kg);

[0063] (3) Material C solution: aqueous solution of sodium hypochlorite, the measurement content is: 8.3%;

[0064] (4) Preparation of material D solution: Water (200 kg), dichloromethane (132.5 kg), and etched by Ethoxyethyl triphenylphosphine (94 kg, 259.61 mol, 0.85 Eq) were added. ) And sodium thiosulfate (15.16 kg, 61.08 mol, 0.2 Eq.), Stirring and cooling to 0 to 5 ° C;

[0065] (5) The material A solution and the material B solution are mixed in the micromixer 1, and the residence time is 3 to 5 s, and then mix with the material C solution in the microcomputer 2, the residence time is 2 to 6 s, then Entering th...

Embodiment 3

[0070]

[0071] (1) Preparation of Material a solution: Compound II (100 kg, 305.42 mol, 1.0 Eq.) And TEMPO (23.85 kg, 152.65 mol, 0.5 Eq.) Were dissolved in isopropyl acetate (700 kg);

[0072] (2) Preparation of material B solution: sodium bicarbonate (30.79 kg, 366.50 mol, 1.2 Eq), sodium carbonate (9.71 kg, 91.61 mol, 0.3 Eq.) And sodium bromide (15.67 kg, 152.27 mol, 0.5) EQ.) dissolved in water (800 kg);

[0073] (3) Material C solution: aqueous sodium hypochlorite, 8.3% measurement content;

[0074] (4) Preparation of the material D solution: water (300 kg), isopropyl acetate (135 kg), ankyl acetyl group (121 kg, 610.83 mol, 2.0 Eq) And sodium thiosulfate (15.16 kg, 61.08 mol, 0.2 Eq.), Stirring is lowered to 0 to 5 ° C;

[0075] (5) The material A solution and the material B solution are mixed in the micromixer 1, and the residence time is 1 to 5 s, and then mixed with the material C solution in the microcomputer 2, the residence time is 1 ~ 5 s, then Entering the micror...

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Abstract

The invention relates to a preparation method of a sacubitril intermediate, in particular to a method for preparing the sacubitril intermediate in a continuous flow microreactor, and belongs to the technical field of medicinal chemistry. According to the method disclosed by the invention, a compound III is prepared by carrying out TEMPO oxidation on a compound II in the continuous flow microreactor, so that the mass transfer efficiency is greatly improved, and the reaction selectivity is better; and the reaction liquid of the compound III directly flows into a reaction kettle containing ethoxyformyl ethylene triphenylphosphine and sodium thiosulfate, sodium hypochlorite is quenched during reaction, the production efficiency is high, the yield is high, the purity is high, and the method is suitable for industrial large-scale production.

Description

Technical field [0001] The present invention relates to a method for preparing intermediate Sha Kuba song, and particularly to a process for preparing intermediates Sha Kuba curved continuous flow microreactor, belonging to the field of pharmaceutical chemistry. Background technique [0002] An estimated 26 million worldwide suffer from heart failure, heart failure with age, the prevalence increases significantly, 18 to 34 age incidence 0.02 ~ 1 ‰, 65 above the age of 6 to 10% incidence . In 2014, an estimated 4.5 million Chinese people suffer from heart failure. [0003] Sha Kuba song sodium valsartan tradename Entresto, as enkephalinase inhibitors Sha Kuba song (Sacubitril) and angiotensin receptor blocker valsartan (the Valsartan) co-crystal by Qu Sha Kuba inhibition of enkephalinase enhance the beneficial effects of the natriuretic peptide system, natriuretic functions, protect the heart and vasodilating and the like; while valsartan by inhibition of the renin - angiotensin -...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22C07C271/16C07C271/18B01J19/00
CPCC07C269/06B01J19/0093C07B2200/07C07C271/22C07C271/16C07C271/18
Inventor 秦小飞周西朋郝昆明沙波廖文向刘永强龚彦春杨尚彦
Owner NANJING VCARE PHARMATECH CO LTD
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