4-Chloro-7H-pyrrolo[2,3-d]pyrimidine

Chemical properties

Lightbrown to brown crystalline powder

The Uses of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine is used in the manufacture of Tofacitinib citrate.

Synthesis

The preparation process of pyrimidine includes the first α -alkylation reaction between diethyl malonate and allyl bromide, and the subsequent cyclization reaction with amidine to obtain a six-membered ring of bislactam. The chlorination of carbonyl with phosphorus oxychloride to obtain dichloro pyrimidine ring, followed by the oxidation of the terminal double bond with potassium osmate hydrate and sodium periodate to obtain the aldehyde group. The final reaction with ammonia water to produce SNAr/cyclization reaction, a five-step reaction, total yield of 45.8% to obtain 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine.

Synthesis

A mixture of compound 6-Chloro-5-(prop-2-en-1-yl)pyrimidin-4-amine (68 g, 0.41 mol), Et3N (60.9 g, 0.6 mol), and DMSO (47 g, 0.6 mol) in MeOH (320 ml) was cooled to –5–0°C and ozone was bubbled through the mixture for 2 h. After nitrogen was bubbled through the mixture to remove the excess of ozone, thiocarbamide (61.2 g, 0.81 mol) was added and mixture stirred for 1 h, until the starch-KI paper did not turn blue. Then AcOH (120 g, 2 mol) was added and stirring at room temperature continued for 14 h. The solvent was removed under reduced pressure. The residue was extracted with EtOAc (500 ml), washed with brine (2×200 ml) and aqueous NaHCO3 to neutralize the residual AcOH. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine, that was recrystallized from a mixture of petroleum ether – EtOAc, 2:1. Yield 26.1 g (43%), white solid.