Preparation method of riociguat

A technology for riociguat and compound, applied in the field of preparation of riociguat, can solve the problems of low total yield, troublesome operation, difficult purification and the like, and achieves high total yield, improved total yield and improved reaction yield. Effect

Active Publication Date: 2016-02-03
郑州大明药物科技有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0008] The technical problem to be solved in the present invention is: in order to overcome technical problems such as low total yield, troublesome operation and difficult purification that exist in...

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  • Preparation method of riociguat

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Embodiment 1

[0044] The preparation method of riociguat of the present invention, detailed steps are as follows:

[0045] a. First, add 31g (0.1mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, compound 1, into a 500mL reaction flask, and then Add 150mL methanol and 5.4g (0.1mol) sodium methoxide, and heat to reflux; add dropwise 2-aminomalonamide, that is, compound 2 solution (the solution is dissolved in 11.7g (0.1mol) 2-aminomalonamide) at 65°C prepared in 50mL of methanol), the dropwise addition time is 30min, after the dropwise addition, reflux reaction is carried out for 2h, and the reaction is stopped; Esters, a large amount of solids were formed, filtered, the resulting filter cake was washed with 100mL of water and 100mL of ethyl acetate, filtered, and the obtained solids were dried at 65°C and a vacuum of 0.09MPa for 5h to obtain 28.4g of 2-[1-(2-fluoro Benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine is compound 3 (yield 80%); ...

Embodiment 2

[0050] The preparation method of riociguat of the present invention, detailed steps are as follows:

[0051] a. First, add 31g (0.1mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, compound 1, into a 500mL reaction flask, and then Add 150mL of methanol and 5.94g (0.11mol) of sodium methoxide, and heat to reflux; add dropwise 2-aminomalonamide, that is, compound 2 solution at 60°C (the solution is dissolved in 10.5g (0.09mol) of 2-aminomalonamide prepared in 50mL of methanol), the dropwise addition time is 30min, after the dropwise addition, reflux reaction is carried out for 2h, and the reaction is stopped; after the obtained reaction solution is lowered to room temperature, the solvent is evaporated under reduced pressure, and 100mL of ethyl acetate is added to the obtained residue , a large amount of solids were formed and filtered. The resulting filter cake was washed with 100 mL of water and 100 mL of ethyl acetate and filtered. The obtai...

Embodiment 3

[0056] The preparation method of riociguat of the present invention, detailed steps are as follows:

[0057] a. First, add 31g (0.1mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, compound 1, into a 500mL reaction flask, and then Add 150mL of methanol and 8.1g (0.15mol) of sodium methoxide, and heat to reflux; dropwise add 2-aminomalonamide, that is, compound 2 solution at 65°C (the solution is dissolved in 12.9g (0.11mol) of 2-aminomalonamide prepared in 50mL of methanol), the dropwise addition time is 30min, after the dropwise addition, reflux reaction is carried out for 2h, and the reaction is stopped; after the obtained reaction solution is lowered to room temperature, the solvent is evaporated under reduced pressure, and 100mL of ethyl acetate is added to the obtained residue , a large amount of solids were formed and filtered, and the obtained filter cake was washed with 100 mL of water and 100 mL of ethyl acetate, and filtered, and th...

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Abstract

The invention discloses a preparation method of riociguat. The preparation method comprises the steps of firstly, taking 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride and 2-aminopropanediamide as basic raw materials, adding strong base and a solvent to perform a reflux reaction, so as to prepare 2-[1-(2-fluorobenzyl) -1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-4,5,6-triamine, namely a compound 3; then taking the compound 3 and dimethyl carbonate as basic raw materials, dissolving the same into methyl alcohol for reaction, so as to prepare 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl methyl carbamate, namely a compound 5, finally, dissolving the compound 5 and the strong base into the methyl alcohol, and adding methyl iodide for reacting, so as to prepare a riociguat crude product, and performing recrystallization on the riociguat crude product to obtain a riociguat refined product. The preparation method provided by the invention is relatively high in total recovery, simplified in operation and easy to industrialize.

Description

1. Technical field: [0001] The invention relates to a synthesis method of antithromboembolic disease medicine, in particular to a preparation method of riociguat. 2. Background technology: [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] At present, the existing synthetic method of riociguat uses two nitrogen atoms on 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride as the parent Nuclear reagent, and phenyl azomalononitrile, directly synthesize pyrimidine ring under the condition of sodium methoxide stro...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 毛影毕天昊李锦华刘志庆娄丽丽张佳美
Owner 郑州大明药物科技有限公司
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