Method for preparing polycyclic carbamoyl pyridone compound

A technology for polycyclic carbamoyl pyridone and compound, which is applied in the field of preparation of polycyclic carbamoyl pyridone compound, can solve the problems of difficulty in removing isomers, long preparation period, many isomers in cyclization steps and the like , to avoid the risk of impurities, save production time, and shorten the process cycle.

Pending Publication Date: 2022-08-02
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Subsequent CN102933080 and CN106565747 disclosed another improved preparation method of dolutegravir. After the reaction of the preparation method, it needs to be prepared by concentration under reduced pressure, extraction and washing, and recrystallization. The operation is cumbersome and the preparation cycle is long; The ratio of intermediates and isomers obtained by cyclization is about 9:1-10:1, and there are many isomers. It is difficult to remove isomers in the post-treatment process and the yield is low.
[0004] WO2014 / 100323 and WO2018 / 229798 disclose the preparation method of bictegravir, but there is also the problem that the post-treatment of the intermediate is cumbersome, and there are many isomers in the cyclization step, and it is difficult to remove the isomers after post-treatment

Method used

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  • Method for preparing polycyclic carbamoyl pyridone compound
  • Method for preparing polycyclic carbamoyl pyridone compound
  • Method for preparing polycyclic carbamoyl pyridone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: 1-(2,2-Dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzylaminoyl ) ethyl pyridine-2-carboxylate

[0109]

[0110] 30.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ( 87.38 mmol, 1.0 eq) was added to 300 ml of tetrahydrofuran, and 15.6 g of CDI (96.21 mmol, 1.1 eq) was added with stirring. The mixture was refluxed for 3 hours, cooled, cooled to -10~0°C, 13.8 g of 2,4-difluorobenzylamine (96.41mmol, 1.1eq) was added, the addition was completed, and stirred at -10~0°C for 0.5 hours, washed with dilute hydrochloric acid and sodium bicarbonate solution, and concentrated under reduced pressure to obtain crude compound 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo as an oil. Substituted-5-(2,4-difluorobenzyl)pyridine-2-carboxylic acid ethyl ester. The oil was used directly in the next step without further purification.

Embodiment 2

[0111] Example 2: 1-(2,2-Dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzyl)pyridine -2-ethyl formate

[0112]

[0113] 164.0 g of formic acid (4.0 M, 134 ml) was added to the oil obtained in Example 1 (theoretical amount 40.9 g, 1.0 M), and the mixture was stirred at 75-85° C. for 2 hours. Add 269ml of purified water at ℃, stir, filter, wash with purified water, and dry to obtain 37.6g of compound 1-(2,2-dihydroxyethyl)-1,4-dihydro-3-ethoxy-4-oxo -5-(2,4-Difluorobenzyl)pyridine-2-carboxylic acid ethyl ester (97.8% yield).

Embodiment 3

[0114] Example 3: 1-(2,2-Dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo-5-(2,4-difluorobenzylaminoyl ) ethyl pyridine-2-carboxylate

[0115]

[0116] 30.0 g of 1-(2,2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ( 87.38 mmol, 1.0 eq) was added to 300 ml of tetrahydrofuran, and 18.4 g of CDI (113.48 mmol, 1.3 eq) was added with stirring. The mixture was refluxed for 3 hours, cooled, cooled to 5-15°C, 16.3 g of 2,4-difluorobenzylamine (113.87mmol, 1.3eq) was added, the addition was completed, and the mixture was stirred at 5-15°C for 0.5 hour, Wash with diluted hydrochloric acid and sodium bicarbonate solution, and concentrate under reduced pressure to give crude compound 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-ethoxy-4-oxo- 5-(2,4-Difluorobenzyl)pyridine-2-carboxylic acid ethyl ester. The oil was used directly in the next step without further purification.

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Abstract

The invention provides a preparation method of a polycyclic carbamoyl pyridone compound, which is suitable for industrialization. According to the invention, 1-(2, 2-dimethoxyethyl)-5-ethoxy-6-(ethoxycarbonyl)-4-oxo-1, 4-dihydropyridine-3-formic acid is used as an initial raw material, and the polycyclic carbamoyl pyridone compound is prepared through condensation, deprotection, cyclization and dealkylation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a polycyclic carbamoyl pyridone compound. Background technique [0002] Polycyclic carbamoyl pyridone derivatives as antiviral, antiretroviral, anti-HIV, anti-HTLV-1 (human T-cell leukemia virus type 1) drug, anti-FIV (feline immunodeficiency virus) ) drugs or anti-SIV (simian immunodeficiency virus) drugs, especially anti-HIV drugs or anti-AIDS drugs. Dolutegravir, a polycyclic carbamoyl pyridone derivative developed by ViiV Healthcare, a subsidiary of GlaxoSmithKline, and bictegravir, developed by Gilead, are used in the treatment of AIDS and are recommended by most international treatment guidelines It is the first-line drug of choice for combination therapy for newly diagnosed AIDS patients. [0003] US8129385 discloses the preparation method of dolutegravir for the first time. The preparation method has a long route, and an oxidant is u...

Claims

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Application Information

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IPC IPC(8): C07D498/18C07D498/14C07D213/82
CPCC07D498/18C07D498/14C07D213/82
Inventor 齐宪亮周豪杰逄楠楠孙海峰戚云鹤彭发波
Owner QILU PHARMA
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