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Method for preparing LCZ696 impurity reference substance

An impurity reference substance and compound technology, applied in the direction of organic chemistry, etc., can solve the problems of LCZ696 drug impurity synthesis report and other problems that have not yet appeared, and achieve the effects of economical and environmentally friendly process route, reduction of use, and avoidance of use.

Inactive Publication Date: 2017-11-03
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the synthesis of the LCZ696 drug impurity represented by the following formula

Method used

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  • Method for preparing LCZ696 impurity reference substance
  • Method for preparing LCZ696 impurity reference substance
  • Method for preparing LCZ696 impurity reference substance

Examples

Experimental program
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Effect test

preparation example Construction

[0021] The drug source used in the preparation method of the embodiment of the present invention is shown in Table 1.

[0022] Table 1

[0023]

[0024]

Embodiment 1

[0025] The preparation of embodiment 1LCZ696 impurity reference substance

[0026] (S1) compound shown in preparation formula I

[0027] 1g (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid, 15ml ethanol, 0.25ml thionyl chloride (0.0034mol ) was added into the reaction bottle, and the temperature was raised to 78° C. for reaction for 4 to 9 hours. The reaction solution was a colorless transparent solution, which was concentrated to remove the solvent to obtain 0.75 g of a white solid, which was the compound represented by formula I, with a yield of 88%.

[0028]

[0029] (S2) compound shown in preparation formula II

[0030] Add 2g of the compound represented by formula I (0.0064mol), 30ml of ethyl acetate, and 1g of triethylamine (0.0099mol) into the reaction flask, and react at 77°C. The reaction solution is a colorless transparent liquid, and the reaction is stopped after 3 to 5 hours. Reaction, remove solvent to obtain 1.2g white solid, ...

Embodiment 2

[0041] The preparation of embodiment 2LCZ696 impurity reference substance

[0042] The other steps of this example are the same as Example 1, except that the preparation conditions of the compound represented by formula I are different. The steps of the compound shown in the preparation formula I are as follows:

[0043] 1g (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (0.0026mol), 15ml ethanol, 0.19ml chlorinated Sulfone (0.0026mol) was added into the reaction flask, and the temperature was raised to 78° C. for 7 hours of reaction. The reaction solution was a colorless transparent solution, which was concentrated to remove the solvent to obtain 0.6 g of a white solid, namely the compound represented by formula I, with a yield of 70%.

[0044]

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Abstract

The invention provides a method for preparing an LCZ696 impurity reference substance. The method comprises the following steps: performing a reaction on (2R, 4S)-5-(biphenyl-4-yl)-4-[(t-butyloxycarboryl) amino]-2-methylpentanoic acid and thionyl chloride in ethanol so as to obtain a compound of formula I; performing a reaction on the compound of the formula I under a weak alkali condition so as to obtain a compound of formula II; performing heating reflux on succinic anhydride in isopropanol so as to obtain a compound of formula III; performing a reaction on the compound of the formula III with thionyl chloride so as to obtain a compound of formula IV; preparing the LCZ696 impurity reference substance of formula V from the compound of the formula II and the compound of the formula IV under catalysis of a strong alkali catalyst. By adopting the method provided by the invention, consumption of raw materials is reduced as a whole, the method is economic and environmental-friendly, different steps of reactions can be relatively easily implemented and controlled, meanwhile the amount of heavy metal catalysts is reduced and avoided, and the quality indexes of final products are improved.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical reference substances, in particular to a preparation method of LCZ696 impurity reference substance. Background technique [0002] LCZ696 is a dual inhibitor of angiotensin receptor and neprilysin, which acts in serum with valsartan and LBQ657, the active ingredient of AHU377. LCZ696, as the first dual inhibitor of angiotensin receptor and neprilysin, can inhibit the activation of RAAS and increase the concentration of natriuretic peptide and other substances in the body, mainly manifested in the reduction of cardiovascular-related mortality, heart failure-related hospitalization rate and Relief of clinical symptoms, etc. At the same time, LCZ696 has a greater degree of blood pressure reduction than valsartan, and a smaller degree of eGFR reduction in HFpEF patients with renal insufficiency. In addition, LCZ696 also showed potential effects of anti-ventricular remodeling and myocardial fib...

Claims

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Application Information

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IPC IPC(8): C07D207/27
CPCC07D207/27
Inventor 诸海滨徐流龙邓威
Owner SOUTHEAST UNIV
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