| 摘要 |
The invention relates to an improved process for synthesizing N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide of the formula: (I) Compound (I) is currently in clinical trials for the treatment of myeloproliferative disorders, such as polycythaemia vera, thrombocythaemia and primary myelofibrosis.; |
| 主权项 |
1. A process for the preparation of Compound I of the formula comprising the steps of a) reacting Compound 1 of the formula with a halogenating agent, such as NBS, in a suitable solvent to afford Compound 2 of the formula wherein X is Cl, Br or I; b) reacting Compound 2 with an alcohol to afford Compound 3 of the formula wherein R is Me, Et, iPr, nPr, nBu, sec-Bu or tBu; and X is as defined above; c) subsequently reacting Compound 3 with a nitrating agent to afford Compound 4 of the formula d) reacting Compound 4, first, with an ethylating agent to afford Compound 5 of the formula wherein
R and X are as defined above; and subsequently with a suitably substituted imidazole of the formula, wherein
Y is H, Cl, Br, I or B(OR′)2; andR′ is Me, Et, i-Pr, n-Pr, n-Bu, sec-Bu, t-Bu, —(CH2)n or —C(Me)2C(Me)2-; andn is 2, 3, 4 or 5; in the presence of a suitable catalytic metal, a ligand, an inorganic salt and optionally an organic base, to afford Compound 6 of the formula e) which is then reacted with hydrogen in the presence of a suitable catalytic metal and optionally a base, to afford Compound 7 of the formula wherein R is as defined above; f) which is reacted with Compound 24 of the formula wherein Z is Cl, Br, I, —OP(O)(OR″)2 or —OS(O)CF3; in the presence of a suitable metal, a ligand, and base, to afford Compound 26 of the formula wherein R″ is Ph or t-Bu and M is Li, Na, K, Cs, Rb, Mg or Ca; g) which is reacted with Compound 27 of the formula in a the presence of a suitable activator, a suitable solvent, such as DCM, and optionally a base, to afford Compound I. |
