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Preparation method of riociguat intermediate

A technology for riociguat and intermediates, applied in the field of pharmaceutical synthesis, can solve the problems of difficult post-processing, increased impurities, complicated preparation process, etc., to avoid inflammable, explosive and toxic reagents, reduce equipment requirements, and simplify process operations. Effect

Inactive Publication Date: 2018-05-25
JIANGSU HANSOH PHARMA CO LTD
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Problems solved by technology

[0007] The method uses Raney nickel as a catalyst to prepare 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 4,5,6-Pyrimidine triamine and Raney nickel have high activity and are flammable in the air, which is not conducive to safe production in the workshop. The high temperature and high pressure catalytic hydrogenation process requires high equipment requirements, and long-term use may easily lead to equipment fatigue damage. Conducive to safe production in the workshop
The post-treatment of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine is salified using 5N hydrochloric acid, The dilute sodium bicarbonate solution is free and extracted with ethyl acetate, which wastes a large amount of materials and reduces the production yield (mass yield is lower than 60%)
[0016] This method uses iron powder-ammonium chloride as the reducing agent, avoiding the use of high-temperature and high-pressure catalytic hydrogenation equipment, but iron powder will produce a large amount of iron sludge in the ethanol / water system, and react with water to form viscous solid salt, which is difficult to filter , post-processing is very difficult; at the same time, ammonium chloride is likely to lead to an increase in residue, which reduces the purity of the product; post-processing uses high temperature 65 ° C to concentrate ethanol-water, resulting in an increase in impurities, which is not suitable for industrial production
[0017] In summary, the existing synthetic riociguat intermediate 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5, In the synthetic route of 6-pyrimidinetriamine, there are various deficiencies, such as complex preparation process, difficult to obtain starting materials, low overall yield of synthetic route, need to use high temperature and high pressure catalytic hydrogenation equipment, difficult post-treatment, unsuitable Industrialized production, therefore, it is very necessary to develop a kind of synthetic method of the riociguat intermediate that is easy, low-cost, suitable for industrialized production and has economic and practical value

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  • Preparation method of riociguat intermediate

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Embodiment 1

[0047] The preparation of embodiment 1 compound III

[0048] Add 1.5L of N,N-dimethylformamide, compound I (250g, 0.82mol), compound II (140g, 0.82mol), 30% sodium methoxide solution (150ml, 0.83mol), and reaction solution into a 2L reaction flask in sequence Raise the temperature to 105-115°C, and keep the reaction for 15-16 hours. The reaction solution was added into 10 L of purified water, and stirred at room temperature for 4-5 hours. After filtering, the filter cake was placed in a blast drying oven at a controlled temperature of 50-60° C. and dried for 23-24 hours to obtain 356 g (0.81 mol) of compound III as a reddish-brown solid, with a molar yield of 98.8% and an HPLC purity of 99.5%.

Embodiment 2

[0049] The preparation of embodiment two compound III

[0050] Add N,N-dimethylacetamide 1.5L, compound I (250g, 0.82mol), compound II (140g, 0.82mol), 50% sodium ethoxide solution (115ml, 0.83mol), reaction solution into 2L reaction flask successively Raise the temperature to 110-115°C, and keep the reaction for 14-16 hours. The reaction solution was added into 10 L of purified water, and stirred at room temperature for 4-5 hours. After filtering, the filter cake was placed in a blast drying oven at a controlled temperature of 50-60° C. and dried for 23-24 hours to obtain 351 g (0.80 mol) of compound III as a reddish-brown solid, with a molar yield of 97.6% and an HPLC purity of 99.2%.

Embodiment 3

[0051] The preparation of embodiment three compound IV

[0052] Add 750ml of absolute ethanol, compound III (15.0g, 34mmol), 85% hydrazine hydrate solution (80ml, 1.36mol) to the 1L reaction flask in turn, add 7.5g of 10% palladium carbon under stirring, heat to 70-80°C, keep warm React at 70-80°C for 12 hours. The reaction liquid was filtered, and the filtrate was concentrated to dryness under reduced pressure, and 100 ml of absolute ethanol was added and stirred for 2 hours. After filtration, the filter cake was air-dried at 45-55° C. for 7-8 hours to obtain 9.95 g (28.4 mmol) of Compound IV as a white solid, with a molar yield of 83.5%, an HPLC purity of 99.4%, and a heavy metal content of <20 ppm.

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Abstract

The invention relates to a preparation method of a riociguat intermediate, in particular to a chemical synthesis method of a riociguat intermediate 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-4,5,6-triamine. 1-(2-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride and (phenylhydrazono)malononitrile are used as initial materials and subjected to a cyclization reaction, 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-[(E)phenyldiazenyl-4,6-pyrimidinediamine is prepared and further subjected to a reduction reaction, and 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-4,5,6-triamine is obtained. The preparation method has the advantages as follows: raw materials are cheap and easy to obtain, the total yield is high, the productpurity is high, the operation is convenient, high-temperature catalytic hydrogenation equipment is not used, and industrial production is facilitated.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a riociguat intermediate. Background technique [0002] Riociguat, chemical name: N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine -3-yl]-5-pyrimidinyl]-N-methylcarbamate, the first novel soluble guanylate cyclase (sGC) agonist, can directly Activates sGC to catalyze the synthesis of cGMP. This product was developed by Bayer AG of Germany and is mainly used for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). It was first approved for marketing in the United States in December 2013. Its structural formula is as follows: [0003] [0004] There are many ways to prepare riociguat, mainly focusing on the preparation of intermediate 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] Pyrimidine-4,5,6-triamine, and then undergo acylation and methylation reactions to obtain t...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 杨勇陈安丰盛志辉周炳城
Owner JIANGSU HANSOH PHARMA CO LTD
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