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Method for compounding riociguat intermediate

A synthesis method and technology for intermediates, which are applied in the field of synthesis of riociguat intermediates, can solve the problems of high risk factor, low content, difficult purification and the like, and achieve the requirements of reducing equipment, reducing production costs and improving reaction yields. Effect

Active Publication Date: 2016-04-06
郑州大明药物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, according to the above synthesis route, it is found in the actual synthesis process that this synthesis method has the following problems: in the second step process, catalytic hydrogenation under high pressure is required, the risk factor is high, and special high-pressure reaction equipment is required in industrial production, which is not conducive to industrialization Large-scale production, at the same time, the yield of the reaction product in this step is low, the content is low, and there are many impurities. Some impurities are easily brought to the final product, resulting in many new impurities in the final product and difficult purification; making this step a limit for the large-scale industrial production of riociguat main factor

Method used

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  • Method for compounding riociguat intermediate
  • Method for compounding riociguat intermediate
  • Method for compounding riociguat intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] a. Add 50.0g (0.16mol) 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, 27.2g (0.16mol) to a 500ml reaction flask mol) phenylpropazomalononitrile, 8.6g (0.16mol) sodium methoxide and 350ml DMF, stirred and reacted at 110°C for 12h, cooled to 25°C, filtered to obtain a solid, stirred and washed with 250ml of ethanol for 10min, and filtered to obtain a solid, Repeat the above washing steps twice to obtain a solid, which was dried in a drying oven at 85°C for 5 hours to obtain 60.7 g of compound III with a yield of 84.6%;

[0035] b. Add 60.7g (0.138mol) of compound III, 7.4g (0.138mol) of ammonium chloride and 730ml of ethanol / water into a 1L reaction flask, add 5.8g (0.1mol) of iron powder under stirring, and stir the reaction at 79°C After 8 hours, cool down to 25°C, filter to obtain the filtrate, distill under reduced pressure (vacuum degree: 0.090MPa, temperature: 65°C) to obtain the residue, add 120ml of water to the residue and stir for 3...

Embodiment 2

[0037] a. Add 50.0g (0.16mol) 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, 29.9g (0.176 mol) phenylpropazomalononitrile, 21.8g (0.32mol) sodium ethoxide and 500ml DMF, stirred and reacted at 120°C for 15h, cooled to 20°C, filtered to obtain a solid, stirred and washed with 250ml of ethanol for 10min, and filtered to obtain a solid, The above washing steps were repeated twice to obtain a solid, which was dried in a drying oven at 80°C for 5 hours to obtain 57.4 g of compound III with a yield of 80.0%;

[0038] b. Add 57.4g (0.13mol) of compound III, 8.3g (0.156mol) of ammonium chloride and 860ml of ethanol / water into a 1L reaction flask, add 6.6g (0.117mol) of iron powder under stirring, and stir the reaction at 79°C After 10 hours, cool down to 30°C, filter to obtain the filtrate, distill under reduced pressure (vacuum degree: 0.090MPa, temperature: 70°C) to obtain the residue, add 120ml of water to the residue and stir for 30min, filter to obta...

Embodiment 3

[0040]a. Add 50.0g (0.16mol) 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, 33.4g (0.196 mol) phenylpropazomalononitrile, 5.9g (0.245mol) sodium hydride and 250ml DMF, stirred and reacted at 115°C for 10h, cooled to 30°C, filtered to obtain a solid, stirred and washed with 250ml of ethanol for 10min, and filtered to obtain a solid, The above washing steps were repeated twice to obtain a solid, which was dried in a drying oven at 90°C for 5 hours to obtain 59.8 g of compound III with a yield of 83.4%;

[0041] b. Add 59.8g (0.136mol) of compound III, 10.9g (0.2mol) of ammonium chloride and 598ml of medicinal ethanol / water into a 1L reaction flask, add 7.6g (0.136mol) of iron powder under stirring, and store at 79°C After stirring for 6 hours, cool down to 20°C, filter to obtain the filtrate, distill under reduced pressure (vacuum degree: 0.090MPa, temperature: 60°C) to obtain the residue, add 120ml of water to the residue, stir for 30min, and filte...

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Abstract

The invention discloses a method for compounding riociguat intermediate, firstly 1-(2-fluorine benzyl) 1H-pyrazolo [3, 4-b] pyridine-3-formamidine hydrochloride are used as starting materials, and 2-[1-(2-fluorine benzyl)-1 H- pyrazolo [3, 4-b] pyridine-3-yl]-4, 5, 6-pyrimidine triamine of the riociguat intermediate are prepared by catalyzing and hydrogenating in normal pressure through a catalyst. The method for compounding the riociguat intermediate is mild in reaction conditions, prevents using a high pressure reaction kettle, reduces process demands to equipment, enables product purity to be bigger than 99.0% at last, and is suitable for commercial process.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing a riociguat intermediate. Background technique [0002] Riociguat (riociguat) is a drug for the treatment of pulmonary hypertension (pulmonaryhypertension, PH), mainly for chronic thromboembolic pulmonary hypertension (chronicthrom-boembolicpulmonaryhypertension, CTEPH) and pulmonary arterial hypertension (pulmonaryarterialhypertension, PAH), its chemical name is: N- [4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]- Methyl N-methyl carbamate, its structural formula is as follows. [0003] [0004] In the synthetic method of disclosed riociguat, mostly through intermediate 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5 ,6-pyrimidinetriamine (compound Ⅳ) to synthesize riociguat. [0005] [0006] Using two nitrogen atoms on 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochlor...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 毛影朱赞梅段艳培罗峰毕天昊
Owner 郑州大明药物科技有限公司
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