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Compound and application thereof in preparation of riociguat

A compound and mixture technology, applied in the field of drug synthesis, can solve the problems of easy generation of impurities, difficult product purification, easy occurrence of side reactions, etc., and achieve the effects of mild reaction conditions, significant economic significance, and good product purity.

Inactive Publication Date: 2016-03-02
ZHEJIANG JINGXIN PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In order to solve the problems such as easy occurrence of side reactions, easy generation of impurities, and difficulty in product purification in the synthesis process for the above-mentioned preparation of riociguat, the present invention provides a new method for preparing riociguat, which can produce high-efficiency Riociguat

Method used

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  • Compound and application thereof in preparation of riociguat
  • Compound and application thereof in preparation of riociguat
  • Compound and application thereof in preparation of riociguat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] 5-bromo-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,6-diamine (compound III, LG is bromo ) preparation

[0072]

[0073] Add 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (compound IV) (2.7g, 10mmol) and sodium methoxide (0.7g , 15mmol) and toluene 35mL, 2-bromomalononitrile (1.43g, 10mmol) was added under stirring at room temperature, replaced with nitrogen three times, heated to reflux for 5 hours, then cooled to room temperature, solids were precipitated, filtered, and the filter cake was used Cold toluene (20 mL) washed. Obtained 3.39g of yellow solid, that is, 5-bromo-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,6-di Amine, yield 82%.

[0074] 1 HNMR (DMSO-d6): δ=8.92 (dd, 1H), 8.76 (dd, 1H), 7.63 (m, 2H), 7.54 (m, 2H), 7.10 (m, 1H), 6.76 (brs, 4H) , 5.68 (s, 2H).

Embodiment 2

[0076] 5-methylsulfonate-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,6-diamine (compound III, LG is the preparation of mesylate)

[0077]

[0078]Add 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (IV) (2.7g, 10mmol), potassium tert-butoxide (1.68 g, 15mmol) and 35mL N,N-dimethylformamide, 2-methanesulfonyl malononitrile (1.6g, 10mmol) was added under stirring at room temperature, replaced with nitrogen three times, heated to 80°C, and stirred for 5 hours, After cooling to room temperature, a solid precipitated out, filtered, and the filter cake was washed with cold toluene (20 mL). 3.65g of yellow solid was obtained, which was 5-mesylate-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4, 6-diamine, yield 85%.

[0079] 1 HNMR (DMSO-d6): δ=8.92 (dd, 1H), 8.72 (dd, 1H), 7.64 (m, 2H), 7.54 (m, 2H), 7.10 (m, 1H), 6.94 (brs, 4H) , 5.68(s, 2H), 3.59(s, 3H).

Embodiment 3

[0081] 5-iodo-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,6-diamine (compound III, LG is iodine ) preparation

[0082]

[0083] Add 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (IV) (2.7g, 10mmol) and potassium carbonate (0.7g, 15mmol) and 30mL dimethyl sulfoxide, added 2-iodomalononitrile (1.91g, 10mmol) under stirring at room temperature, replaced three times with nitrogen, stirred at room temperature for 48 hours, added 30mL of water, solids were precipitated, and the filter cake was used Washing with toluene (20 mL) gave 3.13 g of a yellow solid, namely 5-iodo-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine -4,6-diamine, the yield is 68%.

[0084] 1 HNMR (DMSO-d6): δ=8.92 (dd, 1H), 8.76 (dd, 1H), 7.63 (m, 2H), 7.54 (m, 2H), 7.10 (m, 1H), 6.76 (brs, 4H) , 5.72(s, 2H).

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Abstract

The present invention discloses compound 5-methylamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidine-4,6-diamine, which can be used as an intermediate of riociguat and riociguat derivatives. The present invention also discloses a new method for the preparation of the riociguat by use of the intermediate, and the obtained riociguat has high yield and purity, the occurrence of side effects can be effectively reduced, and production cost is saved.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a compound 5-methylamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine- 4,6-diamine, and its use as an intermediate for the preparation of anti-thromboembolic disease drug Riociguat (Riociguat) and its derivatives. technical background [0002] Riociguat, the English name is Riociguat, and the Chinese name is 4,6-diamino-2-[1-(2-fluorobenzyl)1H-pyrazolo[3,4-b]pyridin-3-yl]-5 -pyrimidinyl (methyl) methyl carbamate, or 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 shown in formula I, CAS number is 625115-55-1, this compound was first reported in WO03095451, as Stimulators of soluble guanylate cyclase function and are useful as medicaments for the prevention or treatment of cardiovascular diseases, eg for the treatment of hypertension and heart failure, stable a...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 黄悦张涛
Owner ZHEJIANG JINGXIN PHARMA
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