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Lisinopril intermediate and purification method therefor

A purification method and pure product technology, applied in the field of lisinopril intermediates and its purification, can solve problems such as difficult product quality assurance

Active Publication Date: 2019-03-05
SHANGHAI SYNCORES TECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the post-processing process and lisinopril crude product purification process, high phenylalanine is difficult to be purified and removed, leaving about 0.1% in the finished product of lisinopril, and the quality of the product is difficult to guarantee between qualified and unqualified

Method used

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  • Lisinopril intermediate and purification method therefor
  • Lisinopril intermediate and purification method therefor
  • Lisinopril intermediate and purification method therefor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Lisinopril anhydride intermediate crude product preparation:

[0039] Under nitrogen protection, add 100g lisinopril hydride (formula II), 600mL dichloromethane, 58g triphosgene to the reaction vessel, heat up to 40±2°C and reflux for 20±4 hours; Concentrate under reduced pressure at 45°C to obtain 115g of the crude intermediate of lisinopril anhydride, LC-MS: 459[M+1] + .

[0040] Lisinopril anhydride intermediate purification:

[0041] Under nitrogen protection, add 400mL toluene to the crude lisinopril anhydride intermediate, adjust the temperature to 35-40°C and stir to dissolve, add 200mL of n-hexane, adjust the temperature to 35-45°C, keep stirring for 2 hours, Suction filtration at 35-45°C, wash the solid wet product with 100mL of n-hexane, and then vacuum-dry at ≤45°C for 1 hour to obtain 101g of white solid with a yield of 95.2% and a derivative HPLC purity of 98.1%, LC-MS: 459[M+1 ] + .

Embodiment 2

[0043] According to the preparation method of the crude lisinopril anhydride intermediate in Example 1, 125 g of the crude lisinopril anhydride intermediate was obtained, and 200 mL of toluene was added thereto under the protection of nitrogen, and the temperature was adjusted to 20-30° C., stirred and dissolved, and 800 mL of n-hexane was added. , adjust the temperature to 30-40°C, keep stirring for 2 hours, then suction filter at 30-40°C, wash the solid wet product with 100mL of n-hexane, and dry it in vacuum at ≤45°C for 1 hour to obtain 103g of white solid, with a yield of 97.2% , Derivative HPLC purity 97.5%, LC-MS: 459[M+1] + .

Embodiment 3

[0045] According to the preparation method of the crude lisinopril anhydride intermediate in Example 1, 108 g of the crude lisinopril anhydride intermediate was obtained, and 250 mL of toluene was added thereto under the protection of nitrogen, and the temperature was adjusted to 60-65 ° C and stirred to dissolve, and 250 mL of n-heptyl Alkanes, adjust the temperature to 25-35°C, heat and stir for 2 hours, then cool down to 10-20°C and filter with suction, wash the solid wet product with 100mL of n-heptane, and dry it in vacuum at ≤45°C for 1 hour to obtain 102g of white solid, which is collected Yield 96.2%, derivatized HPLC purity 98.3%, LC-MS: 459[M+1] + .

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Abstract

The invention relates to a lisinopril intermediate, i.e., (S)-2-((S)-2,5-dioxo-4-(4-(2,2,2-trifluoroacetylamino)butyl)oxazolidin-3-yl)-4-phenylethyl butyrate and a purification method therefor. The method comprises the following steps: adding toluene into a crude lisinopril anhydride intermediate under nitrogen protection, carrying out heating, stirring and dissolved clarification, then, adding aC5-10 alkane solvent, carrying out heat preservation and stirring, then, carrying out suction filtration, and carrying out baking, thereby obtaining a product I. According to the purification method,homophenylalanine impurities can be effectively removed, total impurities are also reduced, the finished product quality is improved, and high-quality lisinopril can be stably obtained through processproduction.

Description

technical field [0001] The present invention relates to lisinopril intermediate (S)-2-((S)-2,5-dioxo-4-(4-(2,2,2-trifluoroacetylamino)butyl)oxazole Alk-3-yl)-4-phenylbutyric acid ethyl ester and its purification method. technical background [0002] Lisinopril is a second-generation angiotensin-converting enzyme inhibitor developed by Merck of the United States, which was first launched in the United States in 1987. This product is an angiotensin-converting enzyme inhibitor that works through the renin-angiotensin-aldosterone system. It is suitable for the treatment of hypertension and has a good positive effect on congestive heart failure and myocardial infarction. , so that blood flow remains stable, and may even improve. In addition, this product has a long half-life and only needs to be administered once a day, so the global annual demand is large. There is an urgent need for a green, environmentally friendly, low-cost, and high-quality API preparation process. [00...

Claims

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Application Information

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IPC IPC(8): C07D263/44
CPCC07D263/44
Inventor 樊海生陈辉郭效文黄鲁宁陶安平安建国陈茜顾虹
Owner SHANGHAI SYNCORES TECH INC
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