METHODS OF MAKING NETUPITANT AND INTERMEDIATES THEREOF
Methods are disclosed for the preparation of netupitant and pharmaceutically acceptable salts thereof which are novel, easily reproducible, environmentally safe and cost effective. The methods may employ inexpensive starting materials and the preparation processes for intermediates are simple and highly reproducible. Novel intermediates for the preparation of netupitant and pharmaceutically acceptable salts thereof are also disclosed. Amorphous netupitant and methods of making same are disclosed.
1 . A process of making netupitant or a pharmaceutically acceptable salt thereof comprising reducing a compound of the formula 3H
and subsequently coupling the resulting compound with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride
2 . Ethyl(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridine-3-yl)carbamate of the formula 3H
3 . A process for making netupitant and pharmaceutically acceptable salts thereof comprising coupling a compound of the formula 2J
wherein X is an alcohol protecting group, with o-tolyl boronic acid (2L).
4 . The process according to claim 3 further comprising forming a hydrochloride of the formula I
5 . The process according to claim 3 wherein X is Cl, Br, OCH3, OTf, OBz, or o-pivaloyl.
6 . The process according to claim 3 wherein X is Cl.
7 . The process according to claim 3 wherein the coupling takes place in the presence of a catalyst and a base.
8 . The process according to claim 7 wherein the catalyst is tetrakis (triphenyl phosphine) palladium (0).
9 . The process according to claim 7 wherein the base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate.
10 . The process according to claim 4 , wherein the hydrochloride formation is carried out using hydrochloric acid and an organic solvent.
11 . The process according to claim 10 wherein the organic solvent is selected from the group consisting of acetone, isopropanol, methanol, and diisopropyl ether.
12 . A process for making netupitant and pharmaceutically acceptable salts thereof comprising coupling of a compound having the formula 2H
with a 2-halo substituted toluene.
13 . The process according to claim 12 further comprising forming a hydrochloride of the formula I
14 . The process according to claim 13 , wherein the hydrochloride formation is carried out using hydrochloric acid and an organic solvent.
15 . The process according to claim 12 wherein the coupling takes place in the presence of a catalyst and a base.
16 . The process according to claim 15 wherein the catalyst is tetrakis (triphenyl phosphine) palladium (0) or bis(triphenylphosphine)palladium (II) dichloride.
17 . The process according to claim 15 wherein the base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate.
18 . The process according to claim 14 wherein the organic solvent is selected from acetone, isopropanol, methanol, and diisopropyl ether.
19 . The process according to claim 12 wherein the 2-halo substituted toluene is a compound of the formula 2K
wherein Y is selected form the group consisting of Cl, Br, and I.
20 . The process according to claim 12 wherein the 2-halo substituted toluene is 1-iodo-2-methylbenzene.
21 . A compound of the formula 2J
wherein X is Cl, Br, OCH3, OTf, OBz, or o-pivaloyl.
22 . A process for making the compound according to claim 21 comprising condensing 4-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-amine with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoyl chloride in the presence of an organic base.
23 . A compound of the formula 2H
24 . Amorphous netupitant.