Method for synthesizing riociguat

A synthesis method and compound technology, applied in organic chemistry and other directions, can solve the problems of low total yield, difficult purification, troublesome operation, etc., and achieve the effects of simple operation, mature process method and thorough reaction.

Active Publication Date: 2015-04-22
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In order to overcome the technical problems of low total yield, cumbersome operation and difficult purific

Method used

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  • Method for synthesizing riociguat
  • Method for synthesizing riociguat
  • Method for synthesizing riociguat

Examples

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Embodiment 1

[0030] This embodiment relates to a synthetic method of high-purity riociguat, comprising the following steps:

[0031] Step 1, in a 2 L three-necked flask, sequentially add 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride (compound 1, 94.5 g, 0.31mol), 1.2L toluene, add sodium methoxide (17g, 0.31mol) and phenyl azomalononitrile (compound 2, 252.5g, 0.31mol) successively under stirring, heat to reflux at 120°C, TLC detects that the reaction is complete, Cool to room temperature, filter with suction, wash the filter cake once with toluene, beat the solid with water, filter with suction, and dry to obtain intermediate compound 3 (129 g, 0.29 mol, yield 95%, content 99%), 1 H-NMR (400 MHz, DMSO-d 6 ): δ=9.20 (dd, J=1.5, 8.1Hz, 1H), 8.66 (dd, J=1.5, 4.5Hz, 1H), 8.52 (dd, brs, 2H), 8.02 (d, J=7.2Hz , 2 H), 7.90 (brs, 2H), 7.47~7.51 (m,2H), 7.34~7.43(m, 3H), 7.14~7.27(m, 3H), 5.85 (s, 2H);

[0032] Step 2: Add the above-mentioned compound 3 (129 g, 0.2...

Embodiment 2

[0038] This embodiment relates to a synthetic method of high-purity riociguat, comprising the following steps:

[0039] Step 1, in a 2 L three-necked flask, sequentially add 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride (compound 1, 94.5 g, 0.31mol), 2L toluene, add sodium methoxide (25.5g, 0.46mol) and phenyl azomalononitrile (compound 2, 78.7g, 0.46mol) sequentially under stirring, heat to reflux at 115°C, TLC detects that the reaction is complete, Cool to room temperature, filter with suction, wash the filter cake once with toluene, beat the solid with water, filter with suction, and dry to obtain intermediate compound 3 (132 g, 0.30 mol, yield 98%, content 99%);

[0040] Step 2: Add the above-mentioned compound 3 (132 g, 0.30 mol) and 5 L DMF to a 10 L hydrogenation kettle in sequence, add 20 g of wet Raney nickel at room temperature, replace with nitrogen, and then fill with hydrogen, the pressure is 3 MPa, and the temperature is controlled ...

Embodiment 3

[0044] This embodiment relates to a synthetic method of high-purity riociguat, comprising the following steps:

[0045] Step 1, in a 2 L three-necked flask, sequentially add 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride (compound 1, 0.31mol) , 2L toluene, add sodium methoxide (0.39mol) and phenyl azomalononitrile (compound 2, 0.39mol) sequentially under stirring, heat to reflux at 110°C, TLC detects that the reaction is complete, cool to room temperature, filter with suction, filter cake Wash once with toluene, beat the solid with water, suction filter, and dry to obtain intermediate compound 3 (132 g, 0.30 mol, yield 98%, content 99%);

[0046] Step 2: Add the above-mentioned compound 3 (132 g, 0.30 mol) and 5 L DMF to a 10 L hydrogenation kettle in sequence, add 26 g of wet Raney nickel at room temperature, replace with nitrogen, and then fill with hydrogen, the pressure is 3.5 MPa, and the temperature Control the reaction at 55°C for 20 hours,...

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Abstract

The invention relates to a method for synthesizing riociguat. The method includes the following steps: 1, a compound 1-(2-fluorobenzyl)-1H-[3,4-b] pyridine derivative-3-formamidine hydrochloride (1) and a compound benzeneazomalononitrile (2) are reacted in methylbenzene under the condition that sodium methylate exists to obtain a compound (3); 2, the compound (3) is dissolved into DMF, then raney nickel is added to serve as catalysts, and hydrogenation reduction is carried out to obtain a compound (4); 3, a formyl group is firstly synthesized into the compound (4), then reduction is carried out through boron hydride to obtain a single-methyl compound (5a); 4, isopropyl alcohol is used as solvents to be reacted with methylclhlorofonmate to obtain the product riociguat. The synthesizing method has the advantages of being easy and convenient to operate, gentle in condition, high in total yield and high in product purity, and is suitable for large-scale synthesizing of the high-purity riociguat.

Description

technical field [0001] The invention relates to a synthesis method of antithromboembolic disease medicine, in particular to a synthesis method of riociguat. Background technique [0002] Riociguat is a drug used to treat pulmonary hypertension (PH), mainly for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). The chemical name is: N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4- b ]pyridin-3-yl]-5-pyrimidinyl]-N-methylcarbamate methyl ester, its structural formula is as follows. [0003] [0004] The disclosed 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, phenyl azomalononitrile, under the condition of sodium methoxide as alkali, directly close the pyrimidine ring to obtain intermediate 3, intermediate 3 is hydrogenated and reduced with palladium carbon or Raney nickel as a catalyst to obtain tr...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 葛德培吴其华刘涛
Owner 安徽联创生物医药股份有限公司
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