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A kind of preparation method of riociguat

A technology of riociguat and compounds, applied in the field of preparation of riociguat, can solve the problems of difficult purification, troublesome operation, low total yield, etc., and achieve the goal of improving reaction yield, improving total yield, and high total yield Effect

Active Publication Date: 2017-03-22
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

[0011] 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 the existing synthetic technology of riociguat, the present invention provides a kind of high total yield, simplified operation, easy The preparation method of the riociguat of industrialized production

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  • A kind of preparation method of riociguat
  • A kind of preparation method of riociguat

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Experimental program
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Effect test

Embodiment 1

[0049] The preparation method of riociguat of the present invention, detailed steps are as follows:

[0050] a. First, add 31 g (0.1 mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, namely compound 1, into a 500 mL reaction flask, then Add 150mL methanol and 5.4g (0.1mol) sodium methoxide, heat to reflux; add 2-aminomalonamide dropwise at 65°C, that is, compound 2 solution (this solution is dissolved in 11.7g (0.1mol) 2-aminomalonamide prepared in 50 mL of methanol), the dropwise addition time was 30 min, and after the dropwise addition, the reflux reaction was carried out for 2 h to stop the reaction; the obtained reaction solution was cooled to room temperature, and then the solvent was evaporated under reduced pressure, and 100 mL of ethyl acetate was added to the obtained residue. Ester, a large amount of solids were generated and filtered, and the obtained filter cake was washed and filtered with 100 mL of water and 100 mL of ethyl acet...

Embodiment 2

[0055] The preparation method of riociguat of the present invention, detailed steps are as follows:

[0056] a. First, add 31 g (0.1 mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, namely compound 1, into a 500 mL reaction flask, then Add 150 mL of methanol and 5.94 g (0.11 mol) of sodium methoxide, heat to reflux; add 2-aminomalonamide dropwise at 60°C, that is, compound 2 solution (this solution is dissolved in 10.5 g (0.09 mol) of 2-aminomalonamide. It was prepared in 50 mL of methanol), the dropwise addition time was 30 min, and the reflux reaction was carried out for 2 h after the dropwise addition to stop the reaction; the obtained reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and 100 mL of ethyl acetate was added to the obtained residue. , a large amount of solids were generated and filtered, and the obtained filter cake was washed and filtered with 100 mL of water and 100 mL of ...

Embodiment 3

[0061] The preparation method of riociguat of the present invention, detailed steps are as follows:

[0062] a. First, add 31 g (0.1 mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride, namely compound 1, into a 500 mL reaction flask, then Add 150 mL methanol and 8.1 g (0.15 mol) sodium methoxide, heat to reflux; add 2-aminomalonamide, that is, compound 2 solution, dropwise at 65°C (this solution is dissolved in 12.9 g (0.11 mol) 2-aminomalonamide It was prepared in 50 mL of methanol), the dropwise addition time was 30 min, and the reflux reaction was carried out for 2 h after the dropwise addition to stop the reaction; the obtained reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and 100 mL of ethyl acetate was added to the obtained residue. , a large amount of solids were generated and filtered, and the obtained filter cake was washed and filtered with 100 mL of water and 100 mL of ethyl acet...

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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

[0001] 1. Technical field: [0002] The invention relates to a method for synthesizing an antithrombotic disease drug, in particular to a method for preparing riociguat. [0003] 2. Background technology: [0004] Riociguat is a drug used to treat pulmonary hypertension (PH), mainly for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Name is: N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5 -Pyrimidyl]-N-methylcarbamate, its structural formula is shown below. [0005] [0006] 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 amphiphiles The nuclear reagent, and phenylazomalononitrile, directly synthesize the pyrimidine ring under the condition of sodium methoxide strong base to obtain intermediate 3, intermediate 3 is hydrogenated and reduced with palladium carbon or Raney nickel as ca...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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