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Crystal of tenofovir alafenamide hemifumarate and preparation method thereof

A technology of tenofovir alafenamide and hemifumarate, which is applied in the field of crystallization and preparation of tenofovir alafenamide hemifumarate, and can solve problems such as crystal form dominance

Pending Publication Date: 2021-07-06
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Changes in the solvent used for recrystallization, the rate of crystallization, or other factors may lead to a phenomenon in which one crystal form dominates

Method used

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  • Crystal of tenofovir alafenamide hemifumarate and preparation method thereof
  • Crystal of tenofovir alafenamide hemifumarate and preparation method thereof
  • Crystal of tenofovir alafenamide hemifumarate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation of embodiment 1 tenofovir alafenamide

[0037] Add 20kg of (R)-(+)-9-[2-(hydroxyphenoxyphosphorylmethoxy)propyl]adenine into the reaction kettle, add 140L of ethylene glycol dimethyl ether, 13.2kg of chlorinated Sulfoxide, heated to about 70-80°C, reacted for 24 hours, evaporated the solvent under reduced pressure, added 100L of toluene to obtain an acid chloride toluene solution. Add 28kg L-alanine isopropyl ester hydrochloride and 115kg dichloromethane into the reaction kettle, cool down to 0°C, add 20kg triethylamine under stirring, stir for 3 hours under nitrogen protection, filter, add 4A molecular sieve to the filtrate Dry overnight, filter, add 5.6kg of triethylamine, nitrogen protection, cool down to -20~-30°C, add acid chloride toluene solution dropwise, rise to room temperature for 30min reaction, use 100L×3 10% sodium dihydrogen phosphate solution Wash 3 times, 100L 15% KHCO 3 Wash once, wash once with 100L water, dry the organic phase with ...

Embodiment 2

[0038] Example 2 Preparation of tenofovir alafenamide hemifumarate seed crystals

[0039] Add 100mL of acetonitrile, 10g of tenofovir alafenamide, and 1.3g of fumaric acid into the reaction flask, heat to reflux to dissolve, filter, evaporate the solvent under reduced pressure, add 75mL of isopropanol and 25mL of ethanol, and crystallize at room temperature for 24 hours , dried under reduced pressure at 50°C for 4 hours to obtain 1.5 g of off-white solid.

Embodiment 3

[0040] Example 3 Preparation of tenofovir alafenamide hemifumarate crystals

[0041] Add 750ml of isopropanol, 250ml of ethanol, 100g of tenofovir alafenamide, and 13g of fumaric acid into the reaction flask, heat to 50-60°C to dissolve, filter, add a small amount of seed crystals, crystallize at room temperature for 6 hours, and filter , dried under reduced pressure at 50°C for 4 hours to obtain 103 g of off-white solid. Using Cu-Kα radiation, its X-ray powder diffraction data are shown in Table 1, and its XRD pattern is as follows figure 1 shown.

[0042] Table 1

[0043]

[0044]

[0045] Its thermogravimetric analysis (TGA) picture is as follows figure 2 shown.

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Abstract

The invention relates to the field of medicines, and discloses a crystal of tenofovir alafenamide hemifumarate and a preparation method thereof. The X-ray powder diffraction of the crystal has characteristic peaks at the following 2 theta angle positions: 7.02 degrees, 8.62 degrees, 11.02 degrees, 12.12 degrees, 13.90 degrees, 15.86 degrees, 16.30 degrees, 17.62 degrees, 18.32 degrees, 20.26 degrees, 20.82 degrees, 23.16 degrees, 26.60 degrees and 27.84 degrees. The tenofovir alafenamide hemifumarate crystal prepared by the invention has the advantages of good fluidity, low moisture absorption and stable crystal form, and is especially suitable for pharmaceutical preparations.

Description

[0001] Cross References to Related Applications [0002] The present invention is a branch of the Chinese invention application (invention name: a crystallization of tenofovir alafenamide hemifumarate and its preparation method; application date: November 28, 2016; application number: 201611060963.6) Application. technical field [0003] The invention belongs to the technical field of medicine, and in particular relates to a crystallization of tenofovir alafenamide hemifumarate and a preparation method thereof. Background technique [0004] Tenofovir alafenamide hemifumarate has a structure shown in formula (I), and its chemical name is N-[(S)-[[(1R)-2-(6-amino-9H-purine- 9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-L-alanine 1-methylethyl ester hemifumarate. [0005] [0006] Tenofovir alafenamide is a nucleoside reverse transcriptase inhibitor being developed by Gilead Sciences and is a prodrug of tenofovir for oral treatment of chronic hepatitis B virus (HBV) and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/20A61P31/18C07C57/15C07C51/41C07C51/43
CPCC07B2200/13C07C57/15C07F9/65616
Inventor 吴叔峰张爱明朱雪焱张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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