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Preparation method of deuterium labeled Ritonavir

A technology of halides and intermediates, applied in the field of preparation of deuterium-labeled ritonavir, to achieve high reaction efficiency, high yield, and high yield

Active Publication Date: 2014-07-02
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, there is no report about the isotopic label of ritonavir and its preparation method

Method used

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  • Preparation method of deuterium labeled Ritonavir
  • Preparation method of deuterium labeled Ritonavir
  • Preparation method of deuterium labeled Ritonavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Synthesis of intermediate (II)

[0050] The reaction process is:

[0051] Take 4.0g isobutyric acid-D6[2-methyl-d 3 -propionic acid-3,3,3-d 3 , 2-Methyl-d 3 -propionic-3,3,3-d 3 Acid (CAS: 29054-08-8)] was dissolved in dry chloroform, added 0.5mL of dry DMF to catalyze, stirred in ice bath and nitrogen, slowly added 10g of phosphorus pentachloride dropwise, after the dropwise addition, at 40°C The mixture was stirred for five hours. Then the reaction mixture was cooled in an ice bath, 120mL of concentrated ammonia water was slowly added, stirred overnight at room temperature, then 100mL of dichloromethane was added to the reaction mixture, stirred and left to extract, the aqueous phase was extracted twice with 100mL of dichloromethane, and the organic phase, dried with anhydrous sodium sulfate, filtered and spin-dried to obtain 4.3g of intermediate (II), which was a white solid. 1H NMR: (CDCl3) 2.39 (m, 1H). MS: 93.

[0052] Synthesis of intermediate (III)

...

Embodiment 2

[0079] Synthesis of intermediate (II)

[0080] The reaction process is:

[0081] Take 4.0g isobutyric acid-D6 (2-Methyl-d 3 -propionic-3,3,3-d 3 Acid) was dissolved in dry dichloromethane, catalyzed by adding 0.5 mL of dry DMF, stirred in ice bath and nitrogen, and slowly added 10 g of oxalyl chloride dropwise. After the dropwise addition, the mixture was stirred and reacted at 30° C. for five hours. Then the reaction mixture was cooled with an ice bath, 200mL of 20% ammonia-containing methanol solution was slowly added, stirred overnight at room temperature, then 100mL of dichloromethane was added to the reaction mixture, stirred and left to extract, and the water phase was extracted twice with 100mL of dichloromethane , the organic phases were combined, dried with anhydrous sodium sulfate, filtered and spin-dried to obtain 4.2 g of intermediate (II), which was a white solid. 1H NMR of intermediate (II): (CDCl3) 2.39 (m, 1H). MS: 93.

[0082] Synthesis of intermediate ...

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Abstract

The invention discloses a preparation method of deuterium-labeled Ritonavir. According to the method, isobutyric acid-D6 is used as a starting raw material, and deuterium-labeled Ritonavir is synthesized through seven reactions. Optimal preparation steps and reaction conditions are screened through a lot of experiments, the whole process is reasonable in design and strong in operability; the purity of deuterium-labeled Ritonavir prepared by the preparation method provided by the invention is greater than 98 percent; the yield of the deuterium-labeled Ritonavir can be greater than 80 percent; and the isotope abundance is greater than 99 percent. The deuterium-labeled Ritonavir prepared by the preparation method provided by the invention can provide a test sample for research on metabolic mechanism of Ritonavir and has an important application value.

Description

technical field [0001] The invention relates to a method for synthesizing and preparing a deuterium-labeled drug, in particular to a method for preparing a deuterium-labeled ritonavir. Background technique [0002] Ritonavir is an HIV protease inhibitor with anti-human immunodeficiency virus (HIV) activity. It is developed by Abbott Pharmaceuticals of the United States. The capsules and soft capsules of this product are approved for marketing for the treatment of HIV infection. [0003] The structural formula of ritonavir is: [0004] [0005] A human immunodeficiency disease caused by HIV (Human Immunodeficiency Virus), namely AIDS (acquired immune syndrome). Our country and the world are facing the threat of the AIDS epidemic. There are about 650,000 HIV-infected people in my country, of which about 75,000 are AIDS patients. On average, more than 190 people are newly infected every day, and the epidemic trend will continue to increase. Although there is still no cure ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/28
CPCC07D277/28
Inventor 魏德胜刘继汉张池刘春王忠义
Owner TLC NANJING PHARMA RANDD CO LTD
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