Synthetic method of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine

Abstract

The invention discloses a synthetic method of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. The compound is an important intermediate for synthesizing rheumatoid arthritis JAK inhibitors: ruxolitinib and tofacitinib. The synthetic method comprises the following steps: by taking a compound I (4,6-dichloro-5-allyl pyrimidine) as an initial raw material, performing a nucleophilic substitution reaction with ammonia water to generate a compound II; then performing a reaction on the compound II and ozone and performing a reduction reaction to generate a compound III; and finally, performing self ring-closing reaction in an acidic environment to generate a compound IV, that is, the 4-chloro-7H-pyrrolo[2,3-d] pyrimidine. The synthetic route is as shown in the formula in the description. According to the synthetic process provided by the invention, the raw material is cheap and easily available, the synthetic route is simple, the cost is low, the yield is high, and the synthetic method is easy for industrial production.

Description

technical field [0001] The present invention relates to the technical field of compound preparation, in particular to the technical field of intermediate preparation of ruxolitinib and tofacitinib, more specifically, a kind of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine resolve resolution. Background technique [0002] Rheumatoid arthritis (RA) also affects approximately 1% of adults worldwide. JAK / STAT is an important cytokine signaling pathway, which is related to rheumatoid arthritis. In recent years, drugs for the treatment of rheumatoid arthritis (RA) have developed rapidly. Tofacitinib, a JAK inhibitor developed by Pfizer, can selectively inhibit JAK3 kinase. It was released on November 6, 2012. Approved by the U.S. Food and Drug Administration (FDA) through Risk Evaluation and Mitigation Strategy (REMS) for the treatment of adults with active and moderate to severe rheumatoid arthritis (RA) who do not respond well to methotrexate )patient. It is also the first oral disea...

AI Technical Summary

Problems solved by technology

[0013] Although this method is greatly improved than the former, its cost of raw materials is still high, and the yield of cyclization reaction and chlorination reaction is low.

It can be seen that the current methods for synthesizing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine no matter starting from the pyrrole ring or from the pyrimidine ring have the disadvantages of expensive raw materials, difficult availability and low overall reaction yield. The shortcoming of this kind of synthesis method is limited, so it is not suitable for industrial production

[0014] Domestic about the synthetic method of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine intermediate, adopted the starting raw material (4,6-dichloro-5-allyl) identical with the present invention in some bibliographical reports base pyrimidine), first carry out the oxidation reaction to the starting material, then react with ammonia gas and finally close the ring, but in the second step of the synthesis route, although the yield of the second step ammoniated ring-closing can reach 80%, but in many specific experiments The yield in the attempt is lower than 20%. This route has the problem that the reaction yield is too low. In addition, the reaction conditions of this synthetic route are more complicated, some expensive reagents are used and the cost is higher, which is not conducive to industrial production.

Images