A method for preparing sacubitril intermediate in a continuous flow microreactor

A shakubatri and micro-reactor technology, which is 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., and achieve Good selectivity, high reaction yield and high purity

Active Publication Date: 2022-02-22
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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  • A method for preparing sacubitril intermediate in a continuous flow microreactor
  • A method for preparing sacubitril intermediate in a continuous flow microreactor
  • A method for preparing sacubitril intermediate in a continuous flow microreactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050]

[0051] (1) Preparation of material A solution: Dissolve compound II (100 Kg, 305.42 mol, 1.0 eq.) and TEMPO (9.54 Kg, 61.06 mol, 0.20 eq.) in dichloromethane (680 Kg);

[0052] (2) Preparation of material B solution: Dissolve sodium bicarbonate (38.48 Kg, 458.12 mol, 1.5 eq.) and sodium bromide (1.88 Kg, 18.27 mol, 0.06 eq.) in water (600 Kg);

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

[0054] (4) Preparation of material D solution: In a reaction kettle, add water (200 Kg), dichloromethane (132.5 Kg), ethoxyformyl ethylene triphenylphosphine (110 Kg, 305.42 mol, 1.0 eq. ) and sodium thiosulfate (15.16 Kg, 61.08mol, 0.2 eq.), stirred and cooled to 0-5 ℃ for later use;

[0055] (5) Mix the material A solution and the material B solution in the micro-mixer 1 first, the residence time is 4-6 s, and then mix with the material C solution in the micro-mixer 2, the residence time is 3-5 s, and then Enter the mi...

Embodiment 2

[0060]

[0061] (1) Preparation of material A solution: Dissolve compound II (100 Kg, 305.42 mol, 1.0 eq.) and TEMPO (2.39 Kg, 15.27 mol, 0.05 eq.) in dichloromethane (680 Kg);

[0062] (2) Preparation of material B solution: Dissolve sodium carbonate (32.36 Kg, 305.37 mol, 1.0 eq.) and sodium bromide (1.57 Kg, 15.225 mol, 0.05 eq.) in water (600 Kg);

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

[0064] (4) Preparation of material D solution: In a reaction kettle, add water (200 Kg), dichloromethane (132.5 Kg), ethoxyformyl ethylene triphenylphosphine (94 Kg, 259.61 mol, 0.85 eq. ) and sodium thiosulfate (15.16 Kg, 61.08mol, 0.2 eq.), stirred and cooled to 0-5 ℃ for later use;

[0065] (5) Mix the material A solution and the material B solution in the micro-mixer 1 first, the residence time is 3-5 s, and then mix with the material C solution in the micro-mixer 2, the residence time is 2-6 s, and then Enter the mic...

Embodiment 3

[0070]

[0071] (1) Preparation of material A solution: Dissolve compound II (100 Kg, 305.42 mol, 1.0 eq.) and TEMPO (23.85 Kg, 152.65 mol, 0.5 eq.) 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: sodium hypochlorite aqueous solution, the measured content is 8.3%;

[0074] (4) Preparation of material D solution: In a reaction kettle, add water (300 Kg), isopropyl acetate (135 Kg), ethoxyformyl ethylene triphenylphosphine (221.37 Kg, 610.83 mol, 2.0 eq .) and sodium thiosulfate (15.16 Kg, 61.08 mol, 0.2 eq.), stirred and cooled to 0-5 ℃ for later use;

[0075] (5) Mix the material A solution and the material B solution in the micro-mixer 1 first, the residence time is 1-5 s, and then mix with the material C solution in the micro-mix...

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Abstract

The invention relates to a method for preparing a sacubitril intermediate, in particular to a method for preparing a sacubitril intermediate in a continuous flow microreactor, and belongs to the technical field of medicinal chemistry. The method of the present invention prepares compound III by TEMPO oxidation of compound II in a continuous flow microreactor, which greatly improves the mass transfer efficiency and makes the selectivity of the reaction better; and directly flows the reaction solution of compound III into In the reaction kettle of acyl ethylene triphenylphosphine and sodium thiosulfate, the sodium hypochlorite is quenched during the reaction, the production efficiency is high, the yield is high, the purity is high, and it is suitable for industrial scale-up production.

Description

technical field [0001] The invention relates to a method for preparing a sacubitril intermediate, in particular to a method for preparing a sacubitril intermediate in a continuous flow microreactor, and belongs to the technical field of medicinal chemistry. Background technique [0002] It is estimated that 26 million people worldwide suffer from heart failure, and the prevalence of heart failure increases significantly with age. The incidence rate of 18-34 age group is 0.02-1‰, and the incidence rate of 65-year-old age group is 6-10%. . In 2014, an estimated 4.5 million Chinese suffered from heart failure. [0003] Sacubitril valsartan sodium, trade name Entresto, is a co-crystal of the enkephalinase inhibitor Sacubitril (Sacubitril) and angiotensin receptor antagonist valsartan (Valsartan), through Sacubitril Inhibit enkephalinase, enhance the beneficial effect of natriuretic peptide system, play a role in natriuresis and diuresis, relax blood vessels and protect the hea...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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