Riociguat preparation method

A technology of 4-b and pyrazolo, which is applied in the field of drug synthesis, can solve problems such as low process yield, difficulty in removing impurities, and potential safety hazards in process production, and achieve simple process operation, improved yield and purity, and easy The effect of industrial production

Inactive Publication Date: 2017-09-01
SPRINGPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0022] Throughout the major domestic and foreign process routes, each has its own characteristics, which can be mainly divided into two categories: 1. No reduction reaction is required. This type of process generally has a low yield and has impurities that are difficult to remove; 2. Reduction reaction is required. , most of this type of process has been Ni / H 2 Preparation of key intermediates by reduction method, but there are safety hazards in process production

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: LA-1 preparation

[0063] Add 200ml of dioxane to a 500ml four-necked flask, and add LA-A (200.0g, 0.65mol, 1.0eq), LA-B (110.0g, 0.65mol, 1.0eq), sodium methoxide (70.0g , 1.3mol, 2.0eq), heated up to about 100°C, slowly refluxed, and reacted for 1.0h under stirring. After the reaction, the reaction solution was gradually cooled to room temperature with stirring, and continued to stir for 2.0 h in an ice bath. The reaction solution was suction filtered. Filter with suction, and dry the filter cake at 50°C for 12-16 hours. Obtain brick red solid LA-1: 27.97g (yield 97.4%, liquid phase purity 99.53%, melting point>250°C)

[0064] 1 H-NMR (DMSO-d 6 ): δ=5.850(s, 2H), 7.136~7.166(m, 1H), 7.183~7.257(m, 2H), 7.345~7.418(m, 3H), 7.478~7.509(t, 2H), 7.856(s , 2H) 8.003~8.019(d, 2H), 8.418(s, 2H) 8.468~8.660(dd, 1H), 9.192~9.211(dd, 1H)

Embodiment 2

[0074] Embodiment 2: LA-1 preparation

[0075] Add 60ml of methyl isopropyl ketone to a 100ml four-necked flask, and add LA-A (6.0g, 0.020mol, 1.0eq), LA-B (3.3g, 0.020mol, 1.0eq) and sodium methoxide sequentially under stirring (2.1g, 0.039mol, 2.0eq), heated up to 100°C, and reacted for 2.0h under stirring. After the reaction, the reaction solution was gradually cooled to room temperature with stirring, and continued to stir for 2.0 h in an ice bath. The reaction solution was filtered with suction, and the filter cake was suspended and washed with 60 ml of water. Suction filtration, the filter cake was dried at 50°C for 16h. Obtain brick red LA-1: 7.3g (yield 85.1%, liquid phase purity 99.13%, melting point>250°C)

Embodiment 3

[0076] Embodiment 3: LA-2 preparation

[0077] Add DMF (30ml) into a 100ml four-necked flask, and add LA-1 (5.0g, 0.012mol, 1.0eq), activated carbon (0.5g), FeCl 3 ·6H 2 O (0.8 g, 0.003 mol, 0.25 eq). The temperature was raised to 60° C. under stirring, and 80% hydrazine hydrate (15.0 g, 0.238 mol, 10.0 eq) was slowly added dropwise. After the dropwise addition, react at 60°C for 20-24h. After the reaction, filter with suction to remove the activated carbon, wash the filter cake with 25ml of DMF, and spin evaporate the obtained filtrate at 85°C to remove the solvent. Add 25ml of methanol to the concentrate after rotary evaporation, add 25ml of water dropwise under ice bath, continue to stir for 1h under ice bath after the dropwise addition, filter with suction, and dry the filter cake at 50°C for 16h to obtain khaki LA- 2: 3.4g (yield: 86.4%, liquid phase purity 98.1%, melting point 244.4~245.8°C)

[0078] 1 H-NMR (DMSO-d 6):4.068(s, 2H), 5.782(s, 2H), 5.836(s, 4H), 7.1...

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Abstract

The invention discloses a riociguat preparation method. According to the preparation method, 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride is utilized as a raw material. The preparation method comprises the four steps of reaction of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-[(E)-phenyl diazenyl]-4,6-thonzylamine preparation, intermediate of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-4,5,6-pyrimidine triamine preparation, intermediate of 4,6-diamido-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidyl methyl carbamate isopropanol solvate preparation and riociguat preparation. A technological path of the riociguat preparation method disclosed by the invention has the advantages of having high selectivity and high yield, being simple and safe to operate, having low equipment requirement, and being suitable for industrial production and the like.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically describes a new process for preparing Riociguat, an antithromboembolic disease drug. Background technique [0002] Riociguat, English name Riociguat, Chinese name: 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- Methyl 5-pyrimidinyl(methyl)carbamate. The drug was developed by Bayer and is mainly used for the treatment of chronic thromboembolic pulmonary hypertension. It was approved for marketing in 2013. In addition to Bayer's research on LA, domestic attention to LA has also increased in recent years, and CN104530044, CN105294686, CN1048924591, CN105367567, CN105367568, CN105367569 and other patents have been published successively. The structural formula of LA is as follows: [0003] [0004] In the synthetic route announced by Bayer, the target product riociguat is finally obtained through 10 steps of reaction with 2-bromobenzylfluorobenzene as the initi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘小红吴云登许建王凡
Owner SPRINGPHARMA CO LTD
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