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Industrial synthesis method of propofovir disoproxil fumarate

A technology of propofol fumarate and tenofovir, which is applied in the field of drug synthesis, can solve the problems of long reaction cycle and no significant improvement in the purity of intermediates, etc., to reduce the treatment of three wastes, use less solvent, and save production cost effect

Pending Publication Date: 2021-01-22
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned technical content also has the problem that the reaction cycle is too long and the purity of its intermediates has not been significantly improved.

Method used

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  • Industrial synthesis method of propofovir disoproxil fumarate
  • Industrial synthesis method of propofovir disoproxil fumarate
  • Industrial synthesis method of propofovir disoproxil fumarate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation of embodiment 1 formula III compound

[0044] 1.0Kg formula PMPA, 2.2L of DMF, 704.3gTEA, 425.2gDMAP and 1619.7g Ph 3 o 3 Add P into a 10L three-necked flask, raise the temperature to 90-100°C, and react for 15-18 hours. After the reaction is complete, cool down to room temperature, add 5L of purified water, and wash the aqueous phase twice with ethyl acetate (3L×2). Adjust the pH of the water phase between 30°C to 2-3 with concentrated hydrochloric acid, cool down to 0-10°C, and crystallize for 2-3 hours. Centrifuge, wash the filter cake twice with dilute hydrochloric acid with pH=1.5, stir wash the wet filter cake with 7L ethyl acetate for 1-2 hours, centrifuge, and dry the obtained solid product in vacuum at 60-65°C for 24-26 hours to obtain 948.7g white solid That is formula III, the molar yield is 75.0%, and the HPLC purity is 99.75%.

Embodiment 2

[0045] The preparation of embodiment 2 formula III compound

[0046] The DMSO of 1.0Kg formula PMPA, 2.2L, 704.3gTEA, 425.2gDMAP and 1619.7g Ph 3 o 3Add P into a 10L three-necked flask, raise the temperature to 90-100°C, and react for 15-18 hours. After the reaction is complete, cool down to room temperature, add 5L of purified water, and wash the aqueous phase twice with ethyl acetate (3L×2). Adjust the pH of the water phase between 30°C to 2-3 with concentrated hydrochloric acid, cool down to 0-10°C, and crystallize for 2-3 hours. Centrifuge, wash the filter cake twice with dilute hydrochloric acid with pH = 1.5, stir wash the wet filter cake with 7L ethyl acetate for 1-2 hours, centrifuge, and dry the solid product under vacuum at 60-65°C for 24-26 hours to obtain 910.8g white solid That is formula III, the molar yield is 72.0%, and the HPLC purity is 99.54%.

Embodiment 3

[0047] The preparation of embodiment 3 formula IV compound

[0048] Add 800.0g of formula III and 6.4L of toluene into a 10L reaction flask, raise the temperature to an internal temperature of 75-80°C, and drop in 471.1g of SOCl 2 , Reaction 15~18h. The reaction solution was cooled to 50-60°C and concentrated until no distillate flowed out, added 6.4L of toluene, cooled to -25--20°C, added 922.0g of L-alanine isopropyl hydrochloride at one time, and dissolved 891.3g of TEA in 3.2 L of dichloromethane, slowly drop into the above reaction solution, temperature control -25 ~ -20 ℃, keep warm for 30 minutes after the drop is completed, warm up to room temperature, and react for 2 ~ 3 hours.

[0049] Post-processing process:

[0050] Add 4.8L of dichloromethane to the reaction solution and stir, the organic phase is washed twice with 10% sodium dihydrogen phosphate, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrat...

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Abstract

The invention provides a preparation process of propofovir disoproxil fumarate, which is short in production period, simple to operate and suitable for industrial production, and the high-purity propofovir disoproxil fumarate is prepared by taking the propofovir disoproxil fumarate as a starting material through special phosphorus chiral atom synthesis, purification and separation. The purity of the prepared propofovir disoproxil fumarate is greater than 99.90%, the diastereoisomer is less than 0.15%, the content of other single impurities is less than 0.10%, and the method has high commercialscale production value.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an industrial synthesis method of tenofovir alafenamide fumarate. Background technique [0002] Tenofovir alafenamide fumarate (TAF) is a new type of nucleoside reverse transcriptase inhibitor (NRTI). An upgraded version of TDF). In clinical trials, it has been proven that when the dose is less than one-tenth of TDF, it has very high antiviral efficacy, and at the same time shows better safety, with improved renal function and bone safety parameters. [0003] [0004] CN103842366B patent discloses the preparation method of the compound of formula TAF, as shown in the following formula: [0005] [0006] In this patent, the production cycle of the intermediate of formula III is long, and the operation steps of the intermediate of formula IV are cumbersome, with poor operability, harsh reaction conditions, high equipment requirements and long production cycle, whic...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07C51/41C07C57/15
CPCC07F9/65616C07C51/412C07C57/15
Inventor 黄辉刘保庆唐鲁赵国权
Owner NANJING HUAWE MEDICINE TECH DEV
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