Synthesis method of riociguat

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...

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

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