Riociguat intermediate and preparation method thereof

A technology of methyl and aminomalononitrile, which is applied in the design of organic synthesis routes and the preparation of raw materials and intermediates, can solve the problems of rare raw materials, many steps, and inconsistencies, and achieve easy-to-obtain raw materials, simple processes, and promote The effect of development

Inactive Publication Date: 2015-09-09
SUZHOU MIRACPHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods all have defects such as rare raw materials, many steps, and high cost. In particular, the above methods are all prepared by continuously changing and accumulating the functional groups of the starting materials. Obviously, such a synthesis idea does not conform to modern green chemistry. philosophy of economics

Method used

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  • Riociguat intermediate and preparation method thereof
  • Riociguat intermediate and preparation method thereof
  • Riociguat intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Add 2-aminomalononitrile (IV) (8.1 g, 0.1 mol), dimethyl sulfate (25.2 g, 0.20 mol) and 150 mL of toluene into the reaction flask, raise the temperature to 35-45 ° C, and stir until the system is uniformly dissolved. Potassium carbonate (27.6 g, 0.2 mol) was added in batches, and the reaction was continued to stir at the temperature for 3 hours, and the reaction was detected by TLC. The solvent was recovered under reduced pressure, the residue was recrystallized with hydrochloric acid / methanol, and dried in vacuo to obtain the hydrochloride salt of N-methyl-2-aminomalononitrile as a pale yellow solid. Add the solid to ethyl acetate, adjust to alkalinity with 10% by weight sodium bicarbonate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain light brown liquid N-methyl-2-amino Malononitrile (V) 8.1g, yield 85.3%; EI-MS m / z: 96[M+H] + .

Embodiment 2

[0038] Add 2-aminomalononitrile (IV) (8.1g, 0.1mol), anhydrous potassium carbonate (41.3g, 0.3mol) and N,N-dimethylformamide (150mL) in a dry reaction flask, and Methane iodide (28.4 g, 0.2 mol) was slowly added dropwise, and the reaction was continued for 3-5 hours after the addition was complete, and the reaction was detected by TLC. Concentrate under reduced pressure, and the residue is post-treated as in Example 1 to obtain 8.2 g of N-methyl-2-aminomalononitrile (V), with a yield of 87.4%.

Embodiment 3

[0040] Add 2-aminomalononitrile (IV) (8.1g, 0.1mol) and 50mL of formic acid into the reaction flask, raise the temperature to 45-55°C, stir the reaction for 5-6 hours, recover the excess formic acid under reduced pressure, and wash the residue with tetrahydrofuran Dissolve, cool to 0-5°C, add sodium borohydride (7.6g, 0.2mol) three times, heat up to reflux, react for 4-6 hours, TLC detects that the reaction is complete. Cool to room temperature, quench the reaction with methanol, concentrate under reduced pressure, and carry out the post-treatment of the residue as in Example 1 to obtain 7.7 g of N-methyl-2-aminomalononitrile (V), with a yield of 81.1%.

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Abstract

The invention discloses a Riociguat (I) intermediate, namely, N-methyl-N-methyl formate-2-amino malononitrile (II), and a preparation method thereof. The preparation method comprises preparation steps as follows: 2-amino malononitrile has an N-methylation reaction to prepare N-methyl-2-amino malononitrile (IV); N-methyl-2-amino malononitrile (IV) and methyl chloroformate or methyl bromoformate have an amidation reaction to prepare N-methyl-N-methyl formate-2-amino malononitrile (II). The intermediate II and 1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-formamidine (III) have a cyclization reaction to prepare Riociguat (I). According to the preparation method, the raw materials are easy to obtain, the process is concise, and the preparation method is economic and environment-friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of riociguat for treating adult chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Background technique [0002] Riociguat is the first stimulator of soluble guanylate cyclase developed by Bayer and the first drug proven to be effective in patients with thromboembolic pulmonary hypertension (CTEPH). The drug was approved by the US FDA in October 2013 for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) in adults, with the trade name Adempas. The successful development of the drug provides another important treatment option for hypertensive patients. [0003] The chemical name of Riociguat (Riociguat, I): 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-y...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/22C07C269/04C07D471/04
CPCC07C271/22C07D471/04
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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