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Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride

A synthesis method and pyrazolo technology are applied in the field of synthesis of intermediates, can solve problems such as troublesome operation, expensive raw materials, low total yield, etc., and achieve the effects of easy operation, cheap raw materials, and improved yield

Inactive Publication Date: 2014-10-08
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

[0014] In order to overcome the technical problems of low total yield, cumbersome operation and expensive raw materials in the prior art, the inventor has completed the present invention after conducting a large amount of in-depth research.

Method used

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  • Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride
  • Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride
  • Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride

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Embodiment A1-A3

[0034] The synthesis of embodiment A1-A3 compound (3)

Embodiment A1

[0036] This embodiment relates to a synthetic method of compound (3), comprising the following steps:

[0037] Step 1: In a 2 L three-neck flask, add compound (1), namely 2-fluoro-3-trifluoroacetylpyridine (19 g, 90 mmol), 500 mL of ethanol, and hydrazine hydrate (30.6 mL, 630 mmol) in sequence, and react The system was heated to reflux for 10 hours. After the reaction of the raw materials was completed, the system was cooled to room temperature, and the solvent was evaporated under reduced pressure to obtain a solid. An equal volume of water and ethyl acetate (200 mL) was added, and the aqueous phase was extracted again with ethyl acetate. The organic phases were combined, washed twice with salt water, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness to obtain a light yellow solid product compound (2), namely 3-trifluoromethyl-1H-pyrazolo[3,4-b] Pyridine (14g, 84% yield, directly used in the next reaction);

[0038]

...

Embodiment A2

[0042] The difference between this example and Example A1 is that the moles of compound (1) and hydrazine hydrate are 90 mmol and 450 mmol respectively, and the final product compound (3) is 25.0 g, 0.174 mol, and the yield is 92.4%. 1 H-NMR (500 MHz, DMSO-d 6 ): δ=7.46 (dd, J=8.2, 4.5Hz, 1H), 8.44 (dd, J=8.2, 1.5Hz, 1H), 8.72 (dd, J=4.5, 1.5Hz, 1H), 14.98 (brs , 1H).

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Abstract

The invention relates to a synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride, which comprises the following steps: reacting a compound (3) and fluorobenzyl bromide in the presence of DMF (N,N-dimethylformamide) and potassium carbonate to obtain a compound (4); dissolving the compound (4) in absolute methanol, adding sodium methoxide, stirring and reacting to obtain a solution containing a compound (5); and reacting the solution containing the compound (5) with ammonium chloride and glacial acetic acid, and salifying with hydrogen chloride. The synthesis method provided by the invention has the advantages of cheap raw materials, mild reaction conditions and high total yield, is simple to operate, and is suitable for large-scale synthesis of the important intermediate 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride of riociguat for treating adult chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary artery hypertension (PAH).

Description

technical field [0001] The present invention relates to a kind of synthetic method of the intermediate of anti-thromboembolic disease drug riociguat, in particular to a kind of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3 -The synthetic method of formamidine hydrochloride. Background technique [0002] Riociguat (riociguat) can be used to treat chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH), and its structural formula is as follows: [0003] [0004] Chem.Med.Chem.2009,4,853-865 discloses the synthetic method of above-mentioned riociguat, and its steps are as follows: [0005] [0006] Therefore, 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride is an important intermediate for the synthesis of riociguat, and the study of 1-(2-fluoro The synthesis method of benzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride is of great significance. [0007] US20020173514A1 (published on Nove...

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
Owner 安徽联创生物医药股份有限公司
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