Method for preparing midbody of heart failure medicine

A compound and reaction technology, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of harsh reaction conditions and high risk factors, and achieve the effects of simple operation, shortened reaction steps, and low cost of synthesis process

Active Publication Date: 2016-01-20
SHANGHAI BOC CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The disadvantage of this process is that the reaction conditions are relatively harsh, and the Mitsunobu reaction process needs to be carried out under strict anaerobic conditions, and the syn

Method used

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  • Method for preparing midbody of heart failure medicine
  • Method for preparing midbody of heart failure medicine
  • Method for preparing midbody of heart failure medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Disclosed in this embodiment is a method for preparing a compound of formula A, comprising the following steps:

[0073] a) Add compound 1L-serine methyl ester hydrochloride (155.58g, 1mol, 1eq) and triethylamine (303g, 3mol, 3eq) into dichloromethane (1.55L), and control the temperature at 10°C to 25°C After adding BOC anhydride (222.36g, 1.02mol, 1.02eq) dropwise, stir at room temperature until the reaction is complete, filter with suction, add water solution, wash the organic phase with hydrochloric acid (1mol / L) to PH=7, dry, remove the desiccant, Cool to 0°C, add tert-butyldimethylsilyl chloride (153.73g, 1.02mol, 1.02eq), and finally dissolve imidazole (201g, 3mol, 3eq) in dichloromethane (200ml) and add dropwise to the reaction solution, Then naturally warming up to room temperature to react, after the reaction is complete, quench the reaction with 2mol / L hydrochloric acid, adjust the pH to 5, separate the liquids, extract the aqueous phase with dichloromethane, ...

Embodiment 2

[0077] A method for preparing a compound of formula B is disclosed in this embodiment, specifically:

[0078] Add biphenylmagnesium bromide Grignard reagent (1.1L, 1.1mol, 1.1eq) into anhydrous tetrahydrofuran (550mL), control the temperature at 0 degrees, add cuprous iodide (3.8g, 0.02mol, 0.02eq) , stirred at this temperature for one hour, the compound tert-butyl (S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxothiazole-3-carboxy Acid 2,2-dioxide (367g, 1mol, 1eq) was dissolved in tetrahydrofuran (1050mL), added dropwise to the reaction solution at 0°C, stirred and reacted, and after the reaction was complete, 10% citric acid aqueous solution (1000mL ) to quench the reaction, stir for half an hour, separate the liquids, and concentrate the organic phase under reduced pressure to obtain a white solid, which is recrystallized with ethyl acetate and petroleum ether to obtain tert-butyl (R)-(1-([1,1'-biphenyl ]-4-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)carbamate. ...

Embodiment 3

[0080] This example is a compound A or compound B used to prepare tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)amino The method for formic acid also includes the steps:

[0081]The compound tert-butyl (R)-(1-([1,1'-biphenyl]-4-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-yl) Carbamic acid (442g, 1mol, 1eq) was dissolved in tetrahydrofuran (2200mL), a THF solution of tetrabutylammonium fluoride (2L, 2mol, 2eq) was added, and the reaction was completed at room temperature. The reaction solution was diluted with ethyl acetate, and water was added. The reaction was quenched, separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain an off-white solid, which was recrystallized with ethyl acetate and n-heptane to obtain The white solid is tert-butyl(R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate. In this step, ...

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PUM

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Abstract

The invention discloses a compound which is tert-butyl (S)-4-(((tert-butyl dimethyl silicane) oxy) methyl)-1,2,3-oxy thiazole-3-carboxylic acid 2,2-dioxide, a preparation method thereof, and a method for synthesizing a midbody of a heart failure medicine by using the compound. By using the method disclosed by the invention, DEAD which has exposure danger is not used, the reaction steps can be shortened, mitsunobu reaction can be avoided, the synthesis process is relatively low in cost, relatively environment-friendly and applicable to industrial capacity, and the method is simple to operate, and as API, can relatively well meet the requirements of the State Food and Drug Administration.

Description

technical field [0001] The invention relates to a method for preparing a drug intermediate, in particular to a method for preparing a key intermediate of a drug for chronic heart failure. Background technique [0002] AHU377 and angiotensin IIAT1 receptor antagonist valsartan compose LCZ696 at a molar ratio of 1:1. LCZ696 is a dual inhibitor of angiotensin II (AT2) receptor and neprilysin receptor. Hypertensive effect is better than standard antihypertensive drugs, is a new drug for the treatment of heart failure. AHU377 is a prodrug that converts the active form of the ethyl ester of the enzyme cleavage LBQ657. At present, the efficacy and safety of the drug milestone III surpasses the clinical standard drug enalapril. In a double-blind Phase 2 trial of the drug in patients with mild to moderate hypertension, the combination was used at doses of 100 to 400 mg, 80 to 320 mg of valsartan, and 200 mg of neprilysin inhibitor drug or placebo. The combined drug was more effec...

Claims

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Application Information

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IPC IPC(8): C07D291/04C07F7/18C07C271/16C07C269/06C07C229/34C07C227/18
CPCC07B2200/07C07C227/18C07C269/06C07D291/04C07F7/1804C07F7/1892C07C271/16C07C229/34
Inventor 李尚立董玉军丁杨
Owner SHANGHAI BOC CHEM CO LTD
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