Tenofovir disoproxil fumarate analog preparation method

A technology of tenofovir fumarate and dipivoxil, which is applied in the field of medicinal chemistry and can solve problems such as unsuitable for large-scale preparation, large amount of organic solvents, and large pollution

Active Publication Date: 2019-02-26
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Simultaneously because two-step reaction all needs silica gel chromatographic column to purify, needs a large amount of organic solvents, pollutes big, and yield is low, is not suitable for preparing this impurity reference substance in large quantities
[0011] In the reaction process of the above three methods, there is the problem that intermediates and f

Method used

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  • Tenofovir disoproxil fumarate analog preparation method
  • Tenofovir disoproxil fumarate analog preparation method
  • Tenofovir disoproxil fumarate analog preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] first step:( R )-1-(6-amino-9H-purin-9-yl)propyl-2-alcohol (Ⅱ) preparation

[0054] Add 80.00g (0.592mol) of adenine into a three-necked flask, add 380ml of N,N-dimethylformamide (DMF), add 9.48g (0.237mol) of sodium hydroxide under stirring, and then add ( S )-propylene carbonate 78.60g (0.770mol), heat up to 130°C, react for 18 hours, stop the reaction, cool down to 40°C, add a mixed solution of methanol 240ml and isopropanol 240ml, cool down to 12°C, constant temperature crystallization 1 hours, filtered, and the filter cake was washed with a mixed solution (4°C) of 40ml of methanol and 40ml of isopropanol, drained, and dried in a vacuum oven at 45°C for 4.5 hours to obtain 87.70g (0.454mol) of a white solid, with a molar yield of was 76.7%.

[0055] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.15 (s, 1H), 8.05 (s, 1H), 7.18 (s,2H), 5.03 (d, J = 4.0 Hz, 1H), 4.11 (q, J = 7.4 Hz, 1H), 4.07 – 3.98 (m, 2H), 1.07 (d, J = 5.8 Hz, 3H) ppm.

[0056] 13 C NMR (100 MHz, ...

Embodiment 2

[0061] first step:( R )-1-(6-amino-9H-purin-9-yl)propyl-2-alcohol (Ⅱ) preparation

[0062] Add 40.00g (0.296mol) of adenine into a three-necked flask, add 190ml of N,N-dimethylformamide (DMF), add 0.94g (0.0235mol) of sodium hydroxide under stirring, and then add ( R )-propylene carbonate 39.20g (0.384mol), heat up to 120°C, react for 27 hours, stop the reaction, cool down to 70°C, add a mixed solution of methanol 120ml and isopropanol 120ml, cool down to 15°C, constant temperature crystallization 12 hours, filtered, the filter cake was washed with a mixed solution of methanol 20ml and isopropanol 20ml (4°C), drained, and placed in a vacuum oven at 60°C for 2 hours to obtain 45.51g (0.215mol) of white solid, molar yield was 72.6%.

Embodiment 3

[0064] The second step: ( R )-diethyl (((1-(6-amino-9H-purin-9-yl) propyl-2-ol) oxygen) methyl) phosphate (Ⅲ) preparation

[0065] Add 40.00g (0.207mol) of intermediate (Ⅱ) and N-methylpyrrolidone (NMP) (160ml) into a dry three-necked flask and stir to dissolve. o Add 70.00g (0.414mol) of magnesium tert-butoxide to C, then raise the temperature to 70 o C, then slowly add 100.00g (0.311mol) of (diethoxyphosphono)methyl-4-methylbenzenesulfonate, react at a constant temperature of 70°C for 4h, then cool down to 20±5°C, and slowly add 36.75g (0.612mol) of acetic acid was used to adjust the pH to 6-7, and the temperature was kept at 15-25°C. Add 900ml of ethyl acetate to the mixture, stir for 30min, let stand, and pour out the supernatant. Put the filter cake in a bottle, add 300ml of ethyl acetate, stir at 15-25°C for 30 minutes, filter, combine with the first filtrate, filter the combined filtrate again, concentrate the filtrate under reduced pressure to obtain a light yellow o...

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Abstract

The present invention discloses a tenofovir disoproxil fumarate analog preparation method, which comprises: carrying out a substitution reaction on adenine as a raw material and (R)-propylene carbonate in the presence of an alkali, carrying out a substitution reaction with (diethoxyphosphoryl)methyl-4-methylbenzenesulfonate, hydrolyzing with a concentrated hydrochloric acid solution, crystallizingto obtain anhydrous tenofovir, carrying out a reaction on the anhydrous tenofovir and chloromethyl isopropyl carbonate to obtain tenofovir monoester, and carrying out a reaction with 2-bromopropane to obtain the target compound. According to the present invention, the selected starting raw materials are inexpensive and easy to obtain, the process is simple, and the material utilization rate and total yield are improved; and the intermediate of the method is purified by re-crystallization, such that the yield is high, and the purity is high.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to an antiviral drug tenofovir disoproxil fumarate analogue ((((((R)-1-(6-amino-9 H - Process for the preparation of purin-9-yl)propyl-2-yl)oxy)methyl)(isopropoxy)phosphine)oxy)methyl isopropyl carbonate. Background technique [0002] The present invention relates to an antiviral drug tenofovir disoproxil fumarate analogue ((((((R)-1-(6-amino-9 H -Purin-9-yl)propyl-2-yl)oxy)methyl)(isopropoxy)phosphine)oxy)methyl isopropyl carbonate (formula VI) preparation method. [0003] [0004] Tenofovir disoproxil fumarate (Formula VII) is a nucleotide reverse transcriptase inhibitor (nucleotide reverse transcriptase inhibitors, NtRTIs) developed by Gilead Sciences, which was approved by the FDA in 2001. Listed for the treatment of AIDS (HIV infection), it was approved for the treatment of chronic hepatitis B (HBV infection) in 2008. Tenofovir disoproxil fumarate has the characteristic...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 黄小光朱少璇陈红英陈溪肖颖陈金瑞
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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