Preparation method, product and application for TAF intermediate

An intermediate and reaction technology, applied in the field of chemical synthesis of pharmaceuticals, can solve the problems of low phenol yield, difficulty in mass production, and long reaction time, and achieve the effects of improving purity, saving time and cost, and simple and clear steps

Active Publication Date: 2018-08-31
CHONGQING SANSHENG IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Compound A1 in the above synthetic route is [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy] methyl] monophenyl phosphate, these two methods There are certain defects in the preparation methods: 1. the phenol route yield is on the low side, only about 60%; The file only records ≥ 48 hours), and problems such as difficulty in crystallization and unstable yield, making it difficult to industrialize mass production

Method used

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  • Preparation method, product and application for TAF intermediate
  • Preparation method, product and application for TAF intermediate
  • Preparation method, product and application for TAF intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 1) Reaction: 10.0Kg of toluene was added to the reactor, and 1.0Kg of PMPA (Tenofovir, Chinese name Tenofovir), 2.2Kg of triphenyl phosphite, 704g of triethylamine and 425g of For DMAP, heat up to 90-95°C, keep the temperature and stir for 16 hours, then cool down to 10-30°C, stop stirring and separate naturally;

[0035] 2) Post-treatment: remove the light yellow oil in the lower layer, slowly add 3Kg of 20wt% NaOH aqueous solution dropwise, add ethyl acetate for extraction (5L*3), the extraction temperature is 35-40°C, collect the lower aqueous phase, and slowly add concentrated hydrochloric acid dropwise (36-37wt%), stirred and crystallized overnight.

[0036] 3) After suction filtration, dry at 70-80°C for 7 hours, the moisture is less than 1.0%, the yield is 90.80%, and the purity is 99.61%. figure 1 It is the HPLC report figure of this embodiment, wherein the HPLC peak result data refer to the report figure.

Embodiment 2

[0038] 1) Reaction: The xylene of 12.0Kg is joined in the reactor, then add the triphenyl phosphite of 1.0KgPMPA, 3.0Kg, the triethylamine of 720g and the DMAP (4-dimethylamino Pyridine), heat up to 100-110°C, keep the temperature for 12 hours, then cool down to 10-15°C, stop stirring and separate naturally;

[0039] 2) Post-treatment: remove the light yellow oil in the lower layer, slowly add 3Kg of 20wt% NaOH aqueous solution dropwise, add ethyl acetate for extraction (5L*3), the extraction temperature is 40-45°C, collect the lower aqueous phase, and slowly add concentrated hydrochloric acid dropwise , stirring and crystallizing overnight.

[0040] 3) After suction filtration, dry at 70-80°C for 6 hours, the moisture is less than 1.0%, the yield is 91.97%, and the purity is 99.58%. figure 2 It is the HPLC report figure of this embodiment, wherein the HPLC peak result data refer to the report figure.

Embodiment 3

[0042] 1) Reaction: Add 10Kg of toluene and 2Kg of xylene mixture into the reactor, then add 1.0KgPMPA, 3.0Kg of triphenyl phosphite, 730g of triethylamine and 450g of DMAP in a stirred state, and heat up to 100-110°C, keep the temperature for 12 hours, then lower the temperature to 10-15°C, stop stirring and separate naturally;

[0043] 2) Post-treatment: remove the light yellow oil in the lower layer, slowly add 3.2Kg of 20wt% NaOH aqueous solution dropwise, add ethyl acetate for extraction (5L*3), the extraction temperature is 40-45°C, collect the lower aqueous phase, and slowly add concentrated Hydrochloric acid, stirred and crystallized overnight.

[0044] 3) Suction filtration, drying at 70-80°C for 8 hours, yield 91.54%, purity 99.52%, image 3 It is the HPLC report figure of this embodiment, wherein the HPLC peak result data refer to the report figure.

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Abstract

The invention relates to a preparation method for a TAF intermediate. The preparation method comprises the following steps: adding an organic solvent A into a reaction vessel, adding PMPA, triphenyl phosphite, DMAP and triethylamine under stirring, carrying out heating to 60 to 140 DEG C, carrying out a reaction for 10 to 16 hours, carrying out cooling to 0 to 50 DEG C, carrying out standing and layering, then collecting a lower-layer oil-like substance, adding an alkali liquor, carrying out extraction with ethyl acetate, collecting a lower-layer water phase, dropwise adding concentrated hydrochloric acid, and carrying out crystallization under stirring for 2 to 30 hours; and carrying out vacuum filtering and drying so as to obtain the TAF intermediate. The preparation method provided by the invention greatly reduces reaction time, saves time cost for industrial production, improves efficiency, and further reduces energy consumption.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of pharmaceuticals, and relates to a preparation method, product and application of a TAF intermediate. Background technique [0002] Vemlidy (TAF, tenofovir alafenamide fumarate) is a novel nucleoside reverse transcriptase inhibitor (NRTI) indicated for the treatment of patients with chronic hepatitis B virus (HBV) infection with compensated liver disease . The drug is an upgraded version of the marketed drug Viread (tenofovir disoproxil, TDF, sold by GlaxoSmithKline in Japan, generic name: TENOFOVIR DISOPROXIL). In clinical trials, TAF has been proven to have a very high antiviral efficacy when the dose is less than one-tenth of Viread, and at the same time, it has better safety and can improve renal function and bone safety parameters. [0003] The Chinese name [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]monophenyl phosphate is one of the key intermediates of TAF. The preparation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 潘先文葛亚勤何伟彭磊李邦洪陈林海汪丹
Owner CHONGQING SANSHENG IND CO LTD
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