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A kind of method for preparing riociguat

A riociguat and intermediate technology, which is applied in the field of pharmaceutical synthesis, can solve the problems of easy occurrence of side reactions, easy generation of impurities, difficult product purification, etc., and achieves the effects of high yield and purity, easy purification and production cost saving.

Active Publication Date: 2019-08-20
ZHEJIANG JINGXIN PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] 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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  • A kind of method for preparing riociguat
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  • A kind of method for preparing riociguat

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preparation example Construction

[0054] For the preparation method of the intermediate V in step (1), those skilled in the art can make various choices, and routinely select or determine through experiments the reagents and reaction conditions used in each method.

[0055] The carbamate reaction of step (4) is to introduce a formate group to the methylamino group at position 5 on the pyrimidine ring of the intermediate II. Those skilled in the art can make a variety of choices for this carbamate reaction, and the reagents and reaction conditions used for each mode are selected routinely or determined by experiment.

[0056] The yield and purity of the riociguat obtained by the synthesis process designed in the present invention are very high, the occurrence of side reactions is effectively reduced, the quality of the drug is improved, and the production cost is reduced.

Embodiment 1

[0065] Synthesis of 2-Methylaminomalononitrile VI

[0066]

[0067] Add bromomalononitrile (7.25g, 50mmol) and acetonitrile (100mL) into a 250mL three-necked flask, cool to 0°C, add potassium carbonate (13.8g, 100mmol), add methylamine hydrochloride (10.2g, 75mmol), stirred for 2 hours and filtered to remove the solid, the mother liquor was concentrated, dissolved in ethyl acetate (100mL), washed twice with saturated aqueous sodium bicarbonate (100mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated 3.8 g of brown solid was obtained, which was 2-methylaminomalononitrile, which could be directly used in the next reaction.

[0068] 1-H-NMR: (DMSO-d6,400M),5.0(S,1H),3.7(s,1H),3.0(s,3H)

Embodiment 2

[0070] Synthesis of 2-benzyl(methyl)aminomalononitrile V

[0071]

[0072] In a 250mL three-necked flask, the 2-methylaminomalononitrile (1.9g, 20mmol) prepared in Example 1 was added in acetonitrile (20mL), cooled to 0°C, then potassium carbonate (5.52g, 40mmol) was added, and Add benzyl chloride (2.77, 22mmol), stir for 2 hours and filter to remove the solid, concentrate the mother liquor, dissolve with ethyl acetate (100ml), wash twice with saturated aqueous sodium bicarbonate (100mL×2), and wash the organic phase with anhydrous sulfuric acid Sodium-dried, filtered, and concentrated to obtain 3.5 g of a brown solid, which is 2-benzyl (methyl) aminomalononitrile, which can be directly used in the next reaction.

[0073] 1-H-NMR: (DMSO-d6,400M),7.1-7.3(m,5H),5.0(s,2H),4.0(s,1H),3.2(s,3H)

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Abstract

The present invention discloses a new riociguat preparation method comprising the following steps: preparing intermediate N-substituted-benzyl-N-methyl-2-amino malononitrile shown in the structural formula V, preparing 5-(N-methyl) (R-substituted) benzyl amino-2-[1-(2-fluorobenzyl)-1 H-pyrazole [3, 4-b] pyridine-3-yl] pyrimidine-4, 6-diamine shown in the structural formula III, preparing 5-methyl amino-2-[1-(2-fluorobenzyl)-1 H-pyrazole [3, 4-b] pyridine-3-yl] pyrimidine-4, 6-diamine shown in the structural formula II, and preparing riociguat shown in the structural formula I. 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, and in particular relates to a new method for preparing Riociguat, an antithromboembolic disease drug. [0002] technical background [0003] 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 and unstable angina. The drug was developed by Bayer for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
Inventor 申屠晓波黄悦
Owner ZHEJIANG JINGXIN PHARMA
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