Paper
ZHANG Naihua, CUI Weichen , ZHU Anguo, WEN Hao, ZHANG Guimin
An improved synthetic process of ruxolitinib phosphate(1) was developed. Starting from (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate(2) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3), [4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin- 7-yl]methyl pivalate(5) was prepared via Suzuki-Miyaura coupling reaction. Compound 5 was deprotected by hydrochloric acid to afford [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate(6). Subsequent Michael addition of 6 with 3-cyclopentylacrylonitrile(4) furnished the racemic [4-[1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl]- 7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate(7). Chiral resolution of 7 using D-(+)-dibenzoyl-L-tartaric acid[D-(+)- DBTA] afforded (2S,3S)-2,3-Bis(benzoyloxy)succinate salt of (R)-[4-[1-(2-cyano-1-cyclopentylethyl)- 1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate(8). Deprotection and hydrolysis of 8 with sodium hydroxide yielded ruxolitinib(9). Finally, the target product 1 was available from 9 by saliffcation reaction with phosphoric acid and recrystallization. The overall yield was 27％ (based on 2), with the purity of 99.89％ and the chiral purity of 99.88％ , and the maximum single impurity less than 0.1％ . The improved process features simple operation and has been veriffed by pilot-scale production, which was suitable for industrial production.
