Method for recycling precious metal catalyst in preparation process of ledipasvir midbody

A precious metal catalyst and recovery method technology, applied in physical/chemical process catalysts, chemical recovery, chemical instruments and methods, etc., can solve the problems of low effective concentration and high drug plasma concentration, and achieve the effects of reduced production cost and simple process

Inactive Publication Date: 2019-07-23
NANTONG WANNIANCHANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For HCV1a, the main drug-resistant mutation is Tyr93His, but even with drug-resistant mutations

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Add 2000g tetrahydrofuran to the reaction kettle, add 353g compound 1, 254g biboronic acid pinacol ester, 5.6g bis(di-tert-butylphenylphosphine) palladium dichloride (II), 276g potassium carbonate under stirring, and fill with nitrogen Protection, control the temperature at 50-60°C under neutral conditions until the end of the reaction, filter the reaction solution to remove potassium carbonate, after the filtrate is concentrated to dryness, add acetonitrile with 5 times the weight of the concentrated crude product, control the temperature at 60-70°C, and beat the beating time for 5 -6 hours, then cooled to 20-30°C and centrifuged to obtain compound 2 with a purity of 99.5% and a molar yield of 90.8%. After concentrating the centrifuged mother liquor to dryness, add 2000g of tetrahydrofuran, 2g of di-tert-butylphenylphosphine and 13.8g of potassium carbonate, and stir the reaction for 1 hour at 50-55°C to obtain bis(di-tert-butylphenylphosphine) Palladium(II) dichloride...

Embodiment 2

[0022] Add 2000g tetrahydrofuran to the reaction kettle, stir and add 392g compound 1, 267g pinacol diborate, 6.2g bis(di-tert-butylphenylphosphine) palladium dichloride (II), 276g potassium carbonate, and fill with nitrogen Protection, control the reaction to the end under neutral conditions of 50-60°C, filter the reaction solution to remove potassium carbonate, after the filtrate is concentrated to dryness, add ethyl acetate 5 times the weight of the concentrated crude product, at 60-70°C, the beating time is 5 hours , and then cooled to 20-30°C and centrifuged to obtain compound 2 with a purity of 99.2% and a molar yield of 88.2%. After concentrating the centrifuged mother liquor to dryness, add 2000g tetrahydrofuran, 2.2g di-tert-butylphenylphosphine and 10.6g sodium carbonate, and stir and react for 2 hours at 55-60°C to obtain bis(di-tert-butylphenylphosphine ) Palladium(II) dichloride.

[0023] Then add 392g of compound 1, 267g of pinacol diborate, and 276g of potassiu...

Embodiment 3

[0025] Add 2000g tetrahydrofuran to the reaction kettle, add 403g compound 1, 273g pinacol diborate, 6.5g bis(di-tert-butylphenylphosphine) palladium dichloride (II), 276g potassium carbonate under stirring, and fill with nitrogen Protection, control the reaction to the end under neutral conditions of 50-60°C, filter the reaction solution, remove potassium carbonate, and concentrate the filtrate to dryness, add 5 times the weight of the crude product toluene, at 60-70°C, the beating time is 6 hours, and then cool down to Centrifuge at 20-30°C to obtain compound 2 with a purity of 99.4% and a molar yield of 89.9%. After concentrating the centrifuged mother liquor to dryness, add 2000g tetrahydrofuran, 2.4g di-tert-butylphenylphosphine and 6g potassium hydroxide, and stir the reaction for 1 hour at 50-55°C to obtain bis(di-tert-butylphenylphosphine ) Palladium(II) dichloride.

[0026] Then add 403g of compound 1, 273g of pinacol diborate, and 276g of potassium carbonate to the ...

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PUM

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Abstract

The invention relates to a method for recycling a precious metal catalyst in the preparation process of a ledipasvir midbody. The method comprises the following steps that a, a compound 1, bisdiboron,the catalyst palladium, dichlorobis(di-tert-butylphenylphosphine) and potassium carbonate are stirred and added into tetrahydrofuran in a reactor at the temperature of 50-60 DEG C, the reaction fluidis filtered so as to remove the residual potassium carbonate after the reaction is end, the filtrate is concentrated to be dry, then an organic solvent is added, the mixture is subjected to beating for 5-6 hours at the temperature of 60-70 DEG C, then the product is centrifugated when the temperature is decreased to be 20-30 DEG C, and a compound 2 is obtained; and b, the residual mother liquor being centrifugated in the last step is collected and concentrated to be dry, tetrahydrofuran, di-tert-butylphenylphosphine and an assistant with the weight being 5 times of the concentrated crude product are added to react for 1-2 hours at the temperature of 50-65 DEG C, and the catalyst palladium, dichlorobis(di-tert-butylphenylphosphine) can be obtained. The preparation technology is simple, thereaction yield is high, the production cost is lowered, and the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a method for recovering precious metal catalysts in the preparation process of ledipasvir intermediates. Background technique [0002] Ledipasvir is an approved all-oral regimen for hepatitis C that eliminates the need for the traditional injectable drug interferon (IFN). Ledipasvir is an NS5A inhibitor with picomolar activity, its EC50 values ​​for HCV genotype 1a and 1b replication are 50 pmol / L and 9 pmol / L, respectively, and it has a very high therapeutic index (CC50 / EC50> 100000), in addition it has good selectivity to HCV, and its EC50 values ​​to other RNA or DNA viruses are all greater than 10 μmol / L. In clinical trials, a single oral dose of 100 mg was safe and tolerated in patients with chronic HCV, and its plasma elimination half-life was 10-14 hours. For HCV1a, the main drug-resistant mutation is Tyr93His, but even if the drug-resi...

Claims

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Application Information

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IPC IPC(8): C07F15/00B01J31/24
CPCB01J31/2404B01J2531/824C07F15/0066Y02P20/584
Inventor 王敏鲍烨华李凯朱红涛
Owner NANTONG WANNIANCHANG PHARMA
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