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Preparation method of tenofovir intermediate (R)-1-(6-aminopurine-9-yl)-2-propanol (I)

A technology of aminopurine and tenofovir, which is applied in the field of preparation of tenofovir intermediates, can solve the problems of producing process impurities, difficult quality control, many steps, etc., and achieves low cost, controllable quality, and easy availability of raw materials. Effect

Active Publication Date: 2015-07-01
淮北市儒伽医疗科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there are generally many steps in the existing process, and the quality is difficult to control
"Organic Process Research & Development" 2010, the 14th period, the 1194-1201 page research reports multiple existing process preparation methods, point out that in the synthetic process process that existing adenine is starting raw material, in generating intermediate ( While R)-1-(6-aminopurin-9-yl)-2-propanol (I), also can produce process impurity (V) and (VI) in varying degrees

Method used

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  • Preparation method of tenofovir intermediate (R)-1-(6-aminopurine-9-yl)-2-propanol (I)
  • Preparation method of tenofovir intermediate (R)-1-(6-aminopurine-9-yl)-2-propanol (I)
  • Preparation method of tenofovir intermediate (R)-1-(6-aminopurine-9-yl)-2-propanol (I)

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Effect test

Embodiment 1

[0023] Add 4,6-dichloro-5-nitropyrimidine (II) (1.93 g, 10 mmol) and 20 mL of N,N-dimethylformamide into the reaction flask, and stir at room temperature until dissolved. Cool down to 0-5°C, add potassium tert-butoxide (2.8g, 2.5eq) in batches, and simultaneously add (R)-1-amino-2-propanol (0.9g, 12mmol) dropwise. Warm up to room temperature and stir for 5-7 hours. Add toluene, cool down to crystallize, and filter. The filter cake was recrystallized with ethanol to obtain 2.1 g of off-white solid (R)-4-[N-(2-hydroxypropyl)amino]-5-nitro-6-chloropyrimidine (III), with a yield of 90.5% .

Embodiment 2

[0025] Add (R)-4-[N-(2-hydroxypropyl)amino]-5-nitro-6-chloropyrimidine (III) (2.32g, 10mmol) and hydrosulfite (4.35g, 2.5eq), methanol 25mL and distilled water 25mL, heated up to 50-60°C, and stirred for 6 hours. Concentrate under reduced pressure to half the volume, and extract 3 times with dichloromethane. The organic phases were combined, washed with water, concentrated to dryness, 25 mL of formic acid was added, the temperature was raised to 150-170° C., and the reaction was kept for 3 hours. Add activated carbon for decolorization. Concentrate, precipitate with solid, rinse with water and methanol, and filter to obtain 1.7 g of light yellow solid (R)-1-(6-chloropurin-9-yl)-2-propanol (IV), with a yield of 80.2% .

Embodiment 3

[0027] Add (R)-1-(6-chloropurin-9-yl)-2-propanol (IV) (1.1 g, 5 mmol) and 50 mL of saturated methanol solution of ammonia gas into the reaction flask, seal and stir for 16 hours. Concentrate to dryness under reduced pressure. Decolorize and recrystallize with distilled water, filter while hot, and cool to crystallize for 5 hours to obtain 0.8 g of off-white solid (R)-1-(6-aminopurin-9-yl)-2-propanol (I), with a yield of 83.1 %.

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Abstract

The invention discloses a preparation method of a tenofovir intermediate (R)-1-(6-aminopurine-9-yl)-2-propanol (I), which comprises the following steps: carrying out condensation on a raw material 4,6-dichloro-5-nitropyrimidine with (R)-1-amino-2-propanol to generate (R)-4-[N-(2-hydroxypropyl)amino]-5-nitro-6-chloropyrimidine (III), carrying out reduction cyclization on the intermediate (III) to generate (R)-1-(6-chloropurine-9-yl)-2-propanol (IV), and carrying out ammonolysis on the intermediate (IV) to generate the tenofovir intermediate (R)-1-(6-aminopurine-9-yl)-2-propanol (I). The preparation method has the advantages of accessible raw materials, simple technique and fewer side reactions, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of tenofovir intermediates. Background technique [0002] Tenofovir disoproxil fumarate (Tenofovir disoproxil fumarate, Tenofovir, TDF) is a new drug developed by Gilead Sciences in the United States for the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. It was approved to go on the market in the United States in 2001 under the trade name of Viread. More than 100 countries including China have approved tenofovir for the treatment of AIDS. In addition, in 2008, the US Food and Drug Administration (FDA) approved a new indication for tenofovir disoproxil for the treatment of chronic hepatitis B. At present, more than 30 countries and regions have obtained approval for this new indication. In 2011, the China Food and Drug Administration...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/34
Inventor 许学农
Owner 淮北市儒伽医疗科技有限公司
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