Synthesis method of riociguat

A synthesis method and compound technology, applied in organic chemistry and other directions, can solve problems such as being unsuitable for industrial production, reducing product generation, difficult post-processing, etc., and achieving favorable storage and subsequent reactions, convenient post-processing operations, and good chemical stability. sexual effect

Pending Publication Date: 2021-09-03
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, in the actual synthesis process, it is found that the synthesis method has the following problems: 1) pyridine is used as a solvent in the first step reaction, which has high toxicity, and the foul smell makes the operator unbearable; 2) post-processing is difficult and is not suitable for industrial production ; 3) Sodium hydride or lithium hexamethyldisilazide are used as dehydrogenating agent in the second step reaction, which is not only expensive, but also unsafe to operate, and produces many impurities, so the product must be controlled under 0.1%. Re-crystallization is required many times, and the loss is large
Although this synthetic technique has been greatly improved, the following problems still exist: the synthetic intermediate compound 2 is a free base, and its stability is not as good as its hydrochloride, especially its methyl ester is easily synthesized with the adjacent amino group in the reaction process. The ring reaction produces two impurities with a content of more than 5%, which not only reduces the yield of the product, but also these two impurities are difficult to remove in the post-treatment and purification process, which ultimately makes it difficult to obtain pharmaceutical grade riociguat
[0010] It can be seen that if the existing patented method is used to prepare the pharmaceutical grade riociguat product with a purity>99% and a single impurity<0.05%, the production cost is very high, and there are also production safety and environmental damage. And other issues

Method used

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  • Synthesis method of riociguat
  • Synthesis method of riociguat
  • Synthesis method of riociguat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] step 1

[0036] Under nitrogen protection, 20.0g (57.0mmol) of compound 3 was added to 300mL of acetonitrile, stirred, and 8.1g (86.0mmol) of methyl chloroformate was added at room temperature, the temperature was raised to 60°C, and the reaction was stirred for 2 hours, and the reaction was monitored by HLPC end. After the reaction was completed, the reaction liquid was cooled to room temperature, and the unreacted methyl chloroformate was destroyed, filtered by suction, stirred with 200 mL of acetonitrile, dried by suction, and dried by blowing air to obtain 25.7 g of a yellow solid.

[0037] step 2

[0038]Dissolve 20.0g (43.3mmol) of the intermediate product synthesized in the previous step in 100mL of N,N-dimethylformamide, stir, add 64.0g (86.6mmol) of lithium carbonate in batches, control the temperature at 30±5°C, and stir 8.0 g (56.3 mmol) of methyl iodide were added at the same time. The temperature was controlled at 30±5°C, and after stirring for 2 hours, ...

Embodiment 2

[0042] step 1

[0043] Under the protection of nitrogen, 1200g (3.42mol) of compound 3 was added to 1800mL of acetonitrile, stirred, and 486.0g (6.88mol) of methyl chloroformate was added at room temperature, the temperature was raised to 60°C, and after stirring for 2 hours, the reaction endpoint was monitored by HLPC. After the reaction, cool down to room temperature, add methyl chloroformate destroying reagent, stir, filter with suction, wash with 1200mL of acetonitrile, dry with suction, and blow dry to obtain 1536g of yellow solid.

[0044] step 2

[0045] Dissolve 1500.0g (3.25mol) of the intermediate product synthesized in the previous step in 750mL of N,N-dimethylformamide, add 4808g (6.5mol) of lithium carbonate in batches, control the temperature at 30±5°C, and add 600.0g (4.22mol) methyl iodide, temperature controlled at 30±5°C, after stirring for 2 hours, HPLC monitored the reaction end point, after the reaction was completed, add 8.25L of water, stir for 30min, f...

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Abstract

The invention relates to the field of drug synthesis, in particular to a preparation method of riociguat. The preparation method comprises the steps that a compound 3 is taken as a raw material and is reacted with methyl chloroformate to obtain a hydrochloride of a compound 2, and the hydrochloride of the intermediate 2 is reacted with a methylation reagent under base catalysis to obtain riociguat. In the synthesis of the compound 2, pyridine used as a solvent and alkali is avoided; in the synthesis of the compound 1, the use of unsafe and expensive reagents such as NaH and LiHMDS is avoided. The riociguat synthesis method provided by the invention has the advantages of simplicity and convenience in operation, mild conditions, environmental friendliness, high total yield and purity, low cost and the like, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, relates to a preparation method of sGC stimulator, in particular to a compound 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3, 4-b] Process for the preparation of pyridin-3-yl]-5-pyrimidinyl-N-methylcarbamate methyl ester (riociguat). Background technique [0002] 4,6-Diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl-N-methylcarbamate Methyl ester is a new type of stimulator of soluble guanylate cyclase, which can be used to treat cardiovascular diseases and pulmonary hypertension, etc. Its molecular formula is C 20 h 19 FN 8 o 2 , have structure as shown in formula I: [0003] [0004] CN1665811A, US7173037B2 patent discloses a synthetic method of riociguat, that is: material 3 is directly reacted with methyl chloroformate in an alkaline environment to obtain intermediate 2, which is prepared by sodium hydride or hexamethyldisilazol Lithium amide is extracted...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 郑志兵蔡旭李松钟武肖军海周辛波李行舟谢菲樊士勇王欣睿
Owner ACADEMY OF MILITARY MEDICAL SCI
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