Preparation method of 5-fluoro-3-iodo-1H-pyrazolo [3, 4-b] pyridine

Abstract

The invention discloses a preparation method of 5-fluoro-3-iodo-1H-pyrazolo [3, 4-b] pyridine, and belongs to the field of medicinal chemistry. The method specifically comprises the following steps: S1, carrying out reduction reaction on 2-chloro-5-fluoronicotinic acid serving as a starting point to obtain 2-chloro-3-hydroxymethyl-5-fluoropyridine; S2,carrying out oxidation reaction on the 2-chloro-3-hydroxymethyl-5-fluoropyridineto obtain 2-chloro-3-formyl-5-fluoropyridine; S3, enabling that the 2-chloro-3-formyl-5-fluoropyridine is subjected to ring closing through hydrazine hydrate, so that 5-fluoro-1H-pyrazolo [3, 4-b] pyridine is obtained; and S4, carrying out an iodination reaction on the 5-fluoro-1H-pyrazolo [3, 4-b] pyridine, so as to obtain the 5-fluoro-3-iodo-1H-pyrazolo [3, 4-b] pyridine. The four-step reaction of the preparation method does not use strongly corrosive acidic materials, so that the preparation method has the advantages of high safety operability, small damage to equipment and facilities, high safety operability in material storage, transfer and use links, avoidance of diazonium salt reaction for releasing nitrogen in the prior art, high safety controllability, mild reaction conditions, higher safety, simplicity in operation, high yield, and suitability for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine. Background technique [0002] Vericiguat, CAS number: 1350653-20-1, structural formula VI, is an oral, once-daily, first-in-class direct stimulator of soluble guanylate cyclase for adult patients with symptomatic chronic heart failure, 2020 The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for vericiguat and granted Priority Review. [0003] [0004] In the patent WO2011147809 of the original Bayer company, the synthesis method of Vericiguat is disclosed, and the synthesis route is as follows: [0005] [0006] Using 3-cyano-2,6-dichloro-5-fluoropyridine as raw material, it undergoes hydrolysis reaction of concentrated sulfuric acid, zinc powder reduction reaction, dehydration reaction of trifluoroacetic anhydride, ring-closing reaction of hydrazine hydrate and ...

AI Technical Summary

Problems solved by technology

[0007] In the process of synthesizing 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine, strong corrosive materials such as concentrated sulfuric acid and trifluoroacetic anhydride were used in the first and third steps, which corroded the equipment The second step uses zinc powder that is easy to catch fire when exposed to the air, which has great safety hazards; the fifth step uses diazonium salt reaction to introduce iodine, and uses boron trifluoride ether, which is difficult to handle, and the reaction is heavy. Nitrogen salts will release a large amount of nitrogen gas, and the operation safety risk is high

The 5-step reaction includes the hydrolysis of cyano group and then the reaction of building cyano group, the utilization rate of atoms is low, and the total yield is 16%

In summary, the original patented conditions for the synthesis of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine are not only low yield, complicated operation, but also not conducive to safe production

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