Synthesis method of topiroxostat

A technique of topinastat and its synthetic method, which is applied in the field of drug synthesis, can solve the problems of low solubility, low yield of cyano group substitution reaction, difficult removal of by-products, etc., and achieve low production cost, high purity, and high yield Effect

Pending Publication Date: 2021-07-16
南京安一合医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In vitro test results show that the inhibitory effect on aldehyde oxidase and purine nucleotide oxidase is less than 10% when the concentration is 100 μmol / L
However, the yield of the last step of cyano substitution reaction is low, and it is difficult to purify and obtain topinastat crystals
[0014] First, the cyano group is added before the cyclization, and there are many by-products in the process of adding the cyano group, and the unreacted intermediate will preferentially close the ring under high temperature conditions, because the solubility of topicastat is extremely low, and the ring-closed The by-products are extremely difficult to remove by recrystallization, so the obtained topinastat fails to directly reach the level of the raw material drug; secondly, the patents whose authorized notification numbers are CN104411686B and CN105348264B all use alcohol and water as reaction solvents when synthesizing topinostat, and finally The initial product obtained from the buckle ring is a hydrate, which requires vacuum drying at a temperature above 80°C to remove water molecules to obtain a pharmaceutical crystal form (form I), and the product obtained if the drying is not in place is a mixed crystal

Method used

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  • Synthesis method of topiroxostat
  • Synthesis method of topiroxostat
  • Synthesis method of topiroxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A kind of synthetic method of topicastat provided in the present embodiment, the chemical reaction formula is as follows:

[0033]

[0034] The synthetic method of this topinostat comprises the following steps:

[0035] a. The raw material 4-cyanopyridine is reacted with 80% hydrazine hydrate under heat preservation and stirring in an alcohol solvent and an alkaline reagent, and the post-treatment is performed to obtain intermediate 1, or the hydrochloride of intermediate 1 is obtained after post-treatment under hydrochloric acid conditions form; wherein, the alcoholic solvent is ethanol, and the alkaline reagent is sodium methoxide; the specific process of post-processing to obtain intermediate 1 is: cooling to 0-10°C, slowly adding methyl tert-butyl ether, and controlling the temperature at 5± Stir and crystallize at 5°C for 11-13 hours to obtain a yellow solid, filter, rinse the filter cake with a small amount of methyl tert-butyl ether, and dry under vacuum at 25...

Embodiment 2

[0039] This embodiment provides a synthetic method for intermediate 1, the chemical reaction formula is as follows:

[0040]

[0041] The specific operation process is as follows: add 833g (8mol) of IIa 4-cyanopyridine into a 50L three-necked flask at room temperature, add 4.0L ethanol and 17g (0.31mol) of sodium methoxide, and stir at 25±5°C for 3h, thin layer Chromatographic detection showed that the reaction of raw materials was basically complete. Take another 10L four-neck flask, add 4.0L absolute ethanol and 303.6g (6.06mol) of 80% hydrazine hydrate, control the temperature at 25±5°C, keep stirring for 1-2h, and the transition state reaction is detected by TLC; Cool down to 0-10°C, slowly add 24L methyl tert-butyl ether dropwise, control the temperature at 5±5°C, stir and crystallize for 12 hours to obtain a yellow solid, filter, and rinse the filter cake with a small amount of methyl tert-butyl ether; 25 Vacuum drying at ~35°C gave 0.82kg of light yellow to red soli...

Embodiment 3

[0044]This embodiment provides a method for synthesizing the hydrochloride form of intermediate 1, the chemical reaction formula is as follows:

[0045]

[0046] Add 833g (8mol) of IIa4-cyanopyridine to a 5L three-neck flask at room temperature, add 4.0L of ethanol and 17g (0.31mol) of sodium methoxide, and stir at 25±5°C for 3h. TLC detection shows that the basic reaction of the raw materials is completely. Take another 10L four-neck flask, add 4.0L absolute ethanol and 303.6g (6.06mol) of 80% hydrazine hydrate, add 13.5mL concentrated hydrochloric acid dropwise under stirring, and stir for 5min; Slowly drop in, keep stirring for 1-2h, TLC detects that the transition state reaction is complete; slowly add 545g concentrated hydrochloric acid, control the temperature at 25±5°C, stir and crystallize for 2h to obtain a yellow solid, filter, filter the cake with a small amount of methyl Rinse with tert-butyl ether; vacuum-dry at 25-35°C to obtain 1.10 kg of a light yellow to r...

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Abstract

The invention provides a synthesis method of topiroxostat, and relates to the technical field of medicine synthesis. The synthesis method of topiroxostat comprises the steps of carrying out heat-preservation stirring reaction on a raw material 4-cyanopyridine and 80% hydrazine hydrate in the presence of an alcohol solvent and an alkaline reagent, and carrying out post-treatment to obtain an intermediate 1, or carrying out post-treatment under the condition of hydrochloric acid to obtain a hydrochloride form of the intermediate 1; reacting the intermediate 1 or the hydrochloride form of the intermediate 1 with 2-cyano-4-picolinic acid in the presence of a solvent and a condensing agent, and performing post-treatment to obtain an intermediate 2; and heating and refluxing the intermediate 2 for 2-4 hours under the condition of acetic acid, cooling to room temperature, filtering, and carrying out forced air drying to obtain the topiroxostat (crystal form I). The synthesis method has the advantages of low production cost, high yield, high purity and less three wastes, and is suitable for industrial production of topiroxostat and intermediates thereof.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of topinostat. Background technique [0002] Topiroxostat (Topiroxostat, chemical name: 4-[5-(4-pyridyl)-1H-1,2,4-triazol-3-yl]pyridine-2-cyano), manufactured by Japan Fuji Pharmaceutical Co., Ltd. Researched and developed by the company, it was approved by the Japanese Ministry of Health and Welfare in August 2013 and was first listed in Japan. A new drug for the treatment of hyperuricemia with gout symptoms. [0003] Topicastat is a highly selective non-purine skeleton selective xanthine oxidase inhibitor (XOR). The results of in vitro experiments show that when the concentration is 100 μmol / L, the inhibitory effect on aldehyde oxidase and purine nucleotide oxidase is less than 10%. Through the selective blocking effect on XOR (ki value: 5.1nmol / L), it can inhibit the formation of endogenous uric acid. [0004] In addition, topicastat has no blocki...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 翟洪
Owner 南京安一合医药科技有限公司
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