New preparation method of febuxostat intermediate

A sulfide and reagent technology, applied in the field of medicinal chemistry, can solve the problems of incomplete reaction, long time-consuming, loss of quantity, etc., and achieve the effect of reducing the amount of DMF wastewater, reducing the molar amount, and improving the utilization rate

Active Publication Date: 2020-02-14
内蒙古京东药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] (2) Allopurinol is a purine analog compound, which will affect the activity of other enzymes involved in purine metabolism
[0024] At present, the preparation of febuxostat intermediate 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazole ethyl carboxylate 152A4-00 mainly uses bromoisobutane as O- The disadvantages of alkylating reagents are: isobutane bro

Method used

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  • New preparation method of febuxostat intermediate
  • New preparation method of febuxostat intermediate
  • New preparation method of febuxostat intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Synthesis of 4-hydroxybenzaldehyde oxime, i.e. 152G1-00

[0048]

[0049] Add 1080g of water to the reaction flask, add 120g of methanol, add 300g (2.457mol) of 4-hydroxybenzaldehyde, add 180g (2.590mol) of hydroxylamine hydrochloride, and control the temperature not exceeding 20°C; add dropwise 102g (2.550mol) of sodium hydroxide A solution prepared with 300g of water; after the dropwise addition, keep warm at 20-25°C for 2-3 hours. After the reaction is completed, filter and collect the solid; air-dry at 55-65° C. to obtain about 318 g (theoretical amount: 336.9 g) of the dry product of 152G1-00. Yield 94.4%.

[0050] 1 H-NMR (400MHz, DMSO-d 6 ): 10.79ppm (bs, 1H,); 9.62ppm (bs, 1H); 7.96ppm (s, 1H,); 7.36ppm (d, 2H); 6.89ppm (d, 2H).

Embodiment 2

[0051] Example 2 Synthesis of 4-hydroxybenzaldehyde oxime, i.e. 152G1-00

[0052]

[0053] Add 180g methanol to the reaction flask, add 60g (491.3mmol) 4-hydroxybenzaldehyde, stir to dissolve, add 35g (503.7mmol) hydroxylamine hydrochloride, control the temperature not exceeding 30°C, add dropwise 55g (518.9mmol) anhydrous sodium carbonate A solution prepared with 500g of water; after the dropwise addition, keep warm at 20-30°C for 2-3 hours. After the reaction was completed, filter and collect the solid; air-dried at 55-65° C. to obtain about 61 g of the dry product of 152G1-00 (theoretical amount: 67.38 g). Yield 90.5%.

Embodiment 3

[0054] Embodiment 3 4-Hydroxythiobenzamide, the synthesis of 152A1-00

[0055]

[0056] Add 900g toluene to the reaction bottle; add 150g (1.094mol) 152G1-00; under stirring, add 245g (1.102mol) phosphorus pentasulfide, heat to 80-85°C, keep stirring for about 2-4hr; after the reaction is completed, cool down to 50 ~60°C, concentrate under reduced pressure to produce about 600g~700g of toluene, add 900g of water to the residue, continue to concentrate under reduced pressure to dry the remaining toluene, cool the remaining material to 5~15°C, keep warm and crystallize for about 2~4hr; filter , the filter cake was rinsed with water, and the solid was collected; air-dried at 75-85° C. to obtain about 153 g of dry product of 152A1-00 (theoretical amount: 167.6 g). Yield: 91.3%.

[0057] Take the 152A1-00 obtained above, refine it with ethanol / water, and submit the refined product for inspection 1 The H-NMR data are as follows:

[0058] 1 H-NMR (400MHz, DMSO-d 6 ): 9.98ppm ...

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Abstract

The invention relates to a new preparation method of a febuxostat intermediate. The method includes: taking cheap 4-hydroxybenzaldehyde as an initial raw material, firstly preparing aldoxime from 4-hydroxybenzaldehyde and hydroxylamine hydrochloride, then adding a corresponding thio reagent, and preparing a compound 4-hydroxythiobenzamide (152A1-00) by Beckmann rearrangement reaction; utilizing one-pot process, adopting cheap 4-hydroxybenzaldehyde as an initial raw material, carrying out a series of reactions, and then performing cyclization with 2-halogenated ethyl acetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate or different salt forms (152A2x) thereof; and using isobutyl sulfonate (152H1x) with more easily controllable quality to replace bromo-isobutane soas to prepare ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (152A4-00). In conclusion, the method provided by the invention is more beneficial to safe, simple and cost-efficientindustrial scale preparation of the febuxostat intermediate with higher purity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing some important intermediates of febuxostat. The structure of febuxostat is as follows: [0002] [0003] Among them, important intermediates for the preparation of febuxostat: 4-hydroxy thiobenzamide (152A1-00), 2-(4-hydroxyphenyl)-4-methyl-5-thiazole carboxylic acid ethyl ester or its corresponding The salt form of (152A2x) and ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (152A4-00) have the following structures: [0004] Background technique [0005] Febuxostat was jointly developed by Teijin Corporation and Takeda Pharmaceutical for the treatment of hyperuricemia (gout). It was first approved by the European Medicines Agency (EMA) on April 21, 2008; the US Food and Drug Administration (FDA) approved it on February 13, 2009; Japan Pharmaceuticals and Medical Devices Agency (PMDA) It was approved for marketing on Janua...

Claims

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Application Information

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IPC IPC(8): C07D277/56C07C303/28C07C309/73C07C309/66C07C327/48
CPCC07D277/56C07C303/28C07C327/48C07C309/73C07C309/66Y02P20/55
Inventor 吕关锋郭荣耀
Owner 内蒙古京东药业有限公司
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