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A kind of synthetic method of cobicistat

A synthesis method and compound technology, which can be applied in the direction of organic chemistry, etc., can solve the problems such as the long route of comparablystatin

Active Publication Date: 2019-12-13
江苏阿尔法集团福瑞药业(宿迁)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The cobicistat synthesized by this method has a long route, requires the use of various organometallic reagents and dangerous chemicals, and is a challenge to be environmentally friendly, and the obtained crude product needs to be separated and purified by reverse-phase HPLC

Method used

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  • A kind of synthetic method of cobicistat
  • A kind of synthetic method of cobicistat
  • A kind of synthetic method of cobicistat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of Compound III:

[0031] Compound II (see CN104876888A for the synthesis method) (100g, 0.29mol, 1 equiv) was dissolved in dichloromethane (90ml), cooled to -20~-18°C, and compound I (see CN104876888A for the synthesis method) (0.35mol, 1.2 equiv), control the temperature -20~-18℃ and react for 1h. HOBT (0.41 mol, 1.4 equiv) was added and stirred for 1 h. A pre-cooled -20°C EDC·HCl (0.58mol, 2equiv) dichloromethane solution (130ml) was added, the temperature was controlled below -20°C, and the reaction was completed in 24h. The reaction was warmed to 3°C and quenched with 10% citric acid solution (100 ml). Separation, the organic phase was washed with 15% sodium bicarbonate solution (145ml) and water (45ml) respectively, the organic phase was distilled under reduced pressure, and then co-evaporated with absolute ethanol to obtain compound III (0.28mol) with a yield of 96%.

[0032] 1 H NMR (500MHz, Chloroform): δ 1.39-1.42 (m, 8H), 1.54-1.56 (m, 2H), 1.57...

Embodiment 2

[0038] Synthesis of compound III:

[0039] Dissolve compound II (100g, 0.29mol, 1equiv) in dichloromethane (90ml), cool down to -20~-18°C, add compound I (0.35mol, 1.2equiv), control the temperature -20~-18°C for reaction 1h. Add DMAP (0.41 mol, 1.4 equiv) and stir for 1 h. A pre-cooled -20°C EDC·HCl (0.58mol, 2equiv) dichloromethane solution (130ml) was added, the temperature was controlled below -20°C, and the reaction was completed within 24h. The temperature of the reaction system was raised to 3° C., and the reaction was quenched with 10% citric acid solution (95 ml). Liquid separation, the organic phase was washed with 15% sodium bicarbonate solution (145ml) and water (45ml) respectively, the organic phase was distilled under reduced pressure, and then co-evaporated with absolute ethanol to obtain the product (0.28mol) with a yield of 96%.

[0040] Synthesis of Cobicistat:

[0041] Under nitrogen protection, compound III (100g, 0.16mol, 2equiv) was dissolved in dichl...

Embodiment 3

[0044] Synthesis of compound III:

[0045] Compound II (100g, 0.29mol, 1equiv) was dissolved in toluene (90ml), cooled to -20~-18°C, compound I (0.35mol, 1.3equiv) was added, and the temperature was controlled at -20~-18°C for 1h. Add N,N'-carbonyldiimidazole (0.41mol, 1.4equiv) toluene solution, control the temperature below -20°C, and complete the reaction within 24h. The temperature of the reaction system was raised to 3° C., and the reaction was quenched with 10% citric acid solution (95 ml). The liquid was separated, the organic phase was washed with 15% sodium bicarbonate solution (145ml) and water (45ml) respectively, the organic phase was distilled under reduced pressure, and then co-evaporated with absolute ethanol to obtain the product (0.27mol) with a yield of 93%.

[0046] Synthesis of Cobicistat:

[0047] Under the protection of nitrogen, compound III (100g, 0.16mol, 2equiv) was dissolved in toluene (300ml), compound IV (0.104mol, 1.3equiv) was added, after stir...

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Abstract

Belonging to the field of pharmaceutical chemical synthesis, the invention discloses a synthesis method of cobicistat. According to the invention, cobicistat free alkali is obtained by two-step reaction. With the route method and optimized reaction conditions adopted by the invention, the preparation conditions are mild, also the product yield and the product purity are high, influence factor and accelerated stability investigation result finds that the cobicistat obtained by the method has high stability, and the method has advantages in removal of impurities peculiar to cobicistat and long-term preservation of the product.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry synthesis, and in particular relates to a method for synthesizing cobicistat. Background technique [0002] Human Immunodeficiency Virus (Human Immunodeficiency Virus; abbr: HIV), namely AIDS (AIDS, Acquired Immune Deficiency Syndrome) virus, is a virus that causes human immune system deficiency. Human immunodeficiency virus was first discovered in the United States in 1983. HIV is a type of retrovirus. HIV destroys the human body's T lymphocytes, thereby blocking the process of cellular immunity and humoral immunity, resulting in paralysis of the immune system, resulting in the spread of various diseases in the human body, eventually leading to AIDS. Due to the extremely rapid mutation of HIV, it is difficult to produce a specific vaccine, and there is no effective treatment method, which poses a great threat to human health. [0003] [0004] Cobicistat is a new CYP3A inhibitor developed...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/28
CPCC07D277/28
Inventor 陈本顺
Owner 江苏阿尔法集团福瑞药业(宿迁)有限公司
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