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Synthesis method of etravirine

A synthesis method and compound technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of low purity, low yield, and increased cost of ingaverine, and achieve improved yield and purity, simple process, cleverly conceived effects

Active Publication Date: 2012-10-31
SICHUAN BAILI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The purity of ingavirin obtained by this method is not high, and high-purity medicinal ingavirin cannot be obtained by purification
By directly recrystallizing histamine, related impurities can be removed, but the yield is low, about 50%, and recrystallization is required twice, and the cost of industrialization is greatly increased

Method used

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  • Synthesis method of etravirine
  • Synthesis method of etravirine
  • Synthesis method of etravirine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: Compound III (R 1 =COCF 3 , R 2 = Trityl) Synthesis of

[0054]

[0055] Add 5g of histamine hydrochloride to 50ml of methanol, under ice bath, add 7.5ml of triethylamine, after the addition, the solid dissolves, add ethyl trifluoroacetate, turn to room temperature and stir for 3~5h, after the reaction is complete, put the reaction The liquid was spin-dried to obtain a white solid, and 50ml of dichloromethane was added, and the white solid was partially dissolved, and 7.5ml of triethylamine was added, and triphenylchloromethane was added under ice bath, and stirred at room temperature for 8~24h, the reaction was complete, and the reaction liquid was Sodium bicarbonate solution was added to the mixture, solids precipitated out, and then dichloromethane was added to dissolve the solids. The organic layer was separated, washed three times with water, dried over anhydrous sodium sulfate, and concentrated to obtain 11.29 g of off-white solids, yield: 87.5%. ...

Embodiment 2

[0056] Embodiment 2: Compound IV (R 2 = Trityl) Synthesis of

[0057]

[0058] Add 1g of raw material into methanol, if the raw material is not completely dissolved, add 4N sodium hydroxide dropwise under ice bath, turn to 30°C~80°C, react for 5~24h, spin the reaction solution to dry, add appropriate amount of water and dichloro methane, stirred for 30 min, separated the dichloromethane layer, extracted the water layer twice, combined the dichloromethane layers, washed twice with water, dried over anhydrous sodium sulfate, and concentrated to obtain 0.8 g of a brown oil.

Embodiment 3

[0059] Embodiment 3: Compound V (R 2 = Trityl) Synthesis of

[0060]

[0061] 0.8g compound IV (R 2 =trityl) was dissolved in acetonitrile, glutaric anhydride was added under ice bath, the solution was turbid, turned to room temperature and stirred for 5~20h, after which a white solid precipitated, filtered, the filter cake was washed 3 times with acetonitrile, dried to obtain White solid 985mg, yield 93%.

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Abstract

The invention discloses a synthesis method of etravirine, which comprises the following steps: A. protecting primary amino group with histamine or histamine salt in an alkaline environment to obtain a compound disclosed as General Formula (II); B protecting imino group R2 on an imidazole ring with the compound disclosed as General Formula (II) in an alkaline environment to obtain a compound disclosed as General Formula (III); C. removing primary amino protecting group R1 from the compound disclosed as General Formula (III) to obtain a compound disclosed as General Formula (IV); D. reacting the compound disclosed as General Formula (IV) with glutaric anhydride to generate a compound disclosed as General Formula (V); and E. removing R2 from the compound disclosed as General Formula (V) to generate the etravirine. The invention has the advantages of ingenious concept and simple process, and can effectively enhance the yield and purity of the synthetic etravirine.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a method for synthesizing ingaverine. Background technique [0002] Ingavirin (ingavirin, chemical name: 5-((2-(1 hydrogen-imidazol-4-yl) ethyl) amino)-5-oxopentanoic acid) is an effective drug against influenza virus and adenovirus infection. drug. Ingavirin is a new anti-influenza virus drug and an adjuvant drug for tumor chemotherapy. It has no mutagenic, carcinogenic, reproductive toxicity and other side effects, no sedative effect, and no psychomotor impact. It can be used by various professionals. [0003] Application No. WO9901103 first mentioned the compound 5-((2-(1 hydrogen-imidazol-4-yl) ethyl) amino)-5-oxopentanoic acid), i.e. Ingavirin, against virus Have better effect. The literature T. A. Kromova, G. A. Zheltukhina. Pharmaceutical Chemistry Journal. Vol. 39, No. 3, 2005 reported the synthesis method of ingaverine: using histamine dihydrochloride as raw ma...

Claims

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Application Information

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IPC IPC(8): C07D233/64
CPCY02P20/55
Inventor 吴勇朱义海俐刘威加余永国
Owner SICHUAN BAILI PHARM CO LTD
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