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Preparation method of lisinopril dimer, and intermediate of lisinopril dimer and preparation method thereof

A technology for dimers and compounds, which is applied in the field of preparation of lisinopril dimers, can solve problems such as lack of preparation methods, and achieve the effect of improving safety and effectiveness

Active Publication Date: 2020-06-16
ZHEJIANG CHANGMING PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the technical defect that the existing lisinopril impurity J lacks an efficient preparation method and cannot be provided in large quantities, and provides a preparation method of lisinopril dimer, wherein Body and preparation method

Method used

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  • Preparation method of lisinopril dimer, and intermediate of lisinopril dimer and preparation method thereof
  • Preparation method of lisinopril dimer, and intermediate of lisinopril dimer and preparation method thereof
  • Preparation method of lisinopril dimer, and intermediate of lisinopril dimer and preparation method thereof

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preparation example Construction

[0062] (Preparation of lisinopril dimer)

[0063]

Embodiment 1

[0065] Suspend 5 g of lisinopril in a mixed solvent of water (50 ml) and THF (50 ml), add a THF (25 ml) solution containing 5.2 g of lisinopril anhydride and Na 2 CO 3 The solid was 1.2 g, and the reaction was stirred overnight at room temperature. Remove THF under reduced pressure, adjust pH to 6 with 1mol / L hydrochloric acid, add dichloromethane for extraction, anhydrous MgSO 4 After drying, dichloromethane was evaporated to dryness under reduced pressure to obtain 8.6 g of off-white solid lisinopril dimer, with a yield of 89.1%. Its molecular weight was 819 by MS analysis. 1 H NMR (400MHz, CD 3 OD)δ: 1.22-1.62(m,16H), 1.94-2.17(m,6H), 2.31-2.38(m,5H), 2.68-2.85(m,4H), 3.30-3.51(m,4H), 3.66 -3.74(m,2H), 3.91-4.13(m,2H), 4.25-4.34(m,3H), 4.50-4.60(m,1H), 7.14-7.33(m,10H), 7.53-7.55(m, 1H), 7.83-8.05 (m, 1H).

Embodiment 2

[0067] Suspend 5 g of lisinopril in a mixed solvent of water (50 ml) and THF (50 ml), add a THF (25 ml) solution containing 5.2 g of lisinopril anhydride and 1.2 g of triethylamine, and stir at room temperature overnight. Remove THF under reduced pressure, adjust pH to 6 with 1mol / L hydrochloric acid, add dichloromethane for extraction, anhydrous MgSO 4 After drying, dichloromethane was evaporated to dryness under reduced pressure to obtain 6.4 g of off-white solid lisinopril dimer, with a yield of 66.3%.

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Abstract

The invention discloses a preparation method of lisinopril dimer, and an intermediate of lisinopril dimer and a preparation method thereof. The invention provides the preparation method of the lisinopril dimer as shown in a formula I. The preparation method is characterized by comprising the following step: performing a deprotection reaction as described in the specification on a compound as shownin a formula II in water and an organic solvent 1 in the presence of an alkaline reagent 1 so as to obtain the lisinopril dimer as shown in the formula I, wherein the alkaline reagent 1 is alkali metal hydroxide. By adopting the compound intermediate as shown in the formula II and the preparation method provided by the invention, a large amount of a lisinopril impurity J can be prepared, so an analysis method for quality control of lisinopril can be established, and the safety and effectiveness of clinical application are improved.

Description

technical field [0001] The invention relates to a preparation method of lisinopril dimer, an intermediate thereof and a preparation method. Background technique [0002] Lisinopril (Lisinopril) is an oral ACE inhibitor. It can be used alone or in combination with other drugs to treat various degrees of hypertension and renal hypertension. It can also be used alone or in combination with diuretics and digitalis to treat congestive heart disease. decline. [0003] [0004] The study found that in the HPLC impurity profile of lisinopril, there was an impurity peak at a retention time of about 35 minutes, which was inconsistent with the previously reported impurities, and the impurity would increase as the heating time of the sample was prolonged. [0005] LC-MS studies show that the compound has a molecular weight of 695. According to the molecular weight, it is speculated that two molecules of lisinopril are heated and condensed to remove one molecule of proline at the sam...

Claims

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Application Information

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IPC IPC(8): C07K5/09C07K1/06C07K1/02
CPCC07K5/0815Y02P20/55
Inventor 王雨宁高杰王磊郭晔堃杨江伟郑程程钟静芬
Owner ZHEJIANG CHANGMING PHARMA
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