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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

AI Technical Summary

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 bromide has a low boiling point, low reaction temperature, long time consumption, and incomplete reaction; high temperature, isobutane bromide is easy to volatilize and cause losses so that the amount participating in the reaction is not enough. It may be that the reaction can be carried out completely only when an excessive amount of brominated isobutane is fed.

Method used

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  • New preparation method of febuxostat intermediate
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  • 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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