Process and intermediates for the synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds
View Patent ↗This application discloses a novel process to synthesize 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds, which may be used, for example, as NK-1 inhibitor compounds in pharmaceutical preparations.
1. A process for making a lactam compound of Formula I
the process comprising reacting a compound of the Formula 27a-sulfonate
with zinc in the presence of acetic acid, thereby forming the lactam of Formula I, wherein:
R 1 is selected from linear, branched, or cyclic alkyl having up to 6 carbon atoms, phenyl, 2-methoxy-ethyl, 2-(dimethylamino)ethyl, (L)-menthyl, (D)-menthyl, dimethylamide, (R)-benzyl-oxazolidinonamide, (S)-benzyl-oxazolidinonamide, isobornyl, norbornyl, cis-pinan-2-yl, isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and (−)-8-phenylmenthyl; and
R 5 is selected from methyl, alkyl, benzyl, and p-toluoyl.
2. The process of claim 1 wherein the compound of Formula 27a-sulfonate is prepared by reacting the compound of Formula V,
with an R 1 -acrylate compound of Formula 28a,
in the presence of a base under Michael addition reaction conditions, and selectively precipitating the compound of Formula 27a-sulfonate by reacting the product with a sulfonic acid of the formula R 5 —SO 3 H,
wherein:
R 1 is selected from a linear, branched, or cyclic alkyl having up to 6 carbon atoms, phenyl, 2-methoxy-ethyl, 2-(dimethylamino)ethyl, (L)-menthyl, (D)-Menthyl, Dimethylamide, (R)-Benzyl-oxazolidinonamide, (S)-benzyl-oxazolidinonamide, isobornyl, norbornyl, cis-pinan-2-yl, isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and (−)-8-phenylmenthyl, and
R 5 is selected from methyl, alkyl, benzyl, and p-toluoyl.
3. The process of claim 2 wherein R 1 is selected from norbornyl and methyl.
4. The process of claim 2 wherein the base is a basic alumina.
5. The process of claim 3 , wherein the base is basic alumina having a Brockman activity of IV.
6. The process of claim 1 wherein the compound of Formula 27a-sulfonate is prepared by:
(a) reacting the compound of Formula IIIB,
with an R 1 -acrylate compound of Formula 28a,
in the presence of a base under Michael addition reaction conditions to form the compound of Formula IIIBa,
wherein R 1 is selected from linear, branched, or cyclic alkyl having up to 6 carbon atoms, phenyl, 2-methoxy-ethyl, 2-(dimethylamino)ethyl, (L)-menthyl, (D)-menthyl, dimethylamide, (R)-benzyl-oxazolidinonamide, (S)-benzyl-oxazolidinonamide, isobornyl, norbornyl, cis-pinan-2-yl, isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and (−)-8-phenylmenthyl;
(b) deprotecting the compound of Formula IIIBa by reaction with hydrogen in the presence of a palladium catalyst to form the compounds of Formula 27a and 27b
(c) selectively precipitating the compound of Formula 27a-sulfonate by reacting the compounds of Formula 27a and 27b with a sulfonic acid of the formula R 5 —SO 3 H, wherein R 5 is selected from methyl, alkyl, benzyl, and p-toluoyl.
7. The process of claim 1 wherein, R 1 is selected from methyl and isobornyl.
8. The process of claim 7 wherein R 1 methyl.
9. The process of claim 1 wherein R 1 is methyl, (−)-8-phenylmenthyl, isobornyl, 1-adamantanyl, 2-adamantanyl, adamantylmethyl or (+)-isopinocampheyl.
10. The process of claim 3 wherein the base is a basic alumina.
11. The process of claim 2 , wherein the base is basic alumina having a Brockman activity of IV.