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

1. A process for making compounds of Formula I

the process comprising:

(a) reacting the protected enamine of Formula III, wherein R 2 is an enamine protecting group removable by catalytic hydrogenation,

with a nitrating agent to form the corresponding protected nitro-enamine of Formula and subsequently reducing the product to a protected piperidine of Formula IV, wherein R 2 is as defined above;

(b) deprotecting the protected piperidine of Formula IV from step “a” by reacting it with hydrogen in the presence of a palladium catalyst to form the compound of Formula V,

(c) alkylating the compound of Formula V by reacting it under Michael addition conditions with an acrylate of the formula 28a,

to form the compounds of Formulae 27a and 27b,

(c) precipitating a sulfonate salt of Formula 27a-sulfonate by reacting the compounds of Formula 27a and 27b formed in Step “c” with a sulfonic acid of the formula R 5 —SO 3 H,

 and

(d) forming the lactam of Formula I by treating the compound of Formula 27a-sulfonate with acetic acid in the presence of zinc metal;

wherein R 5 is selected from benzyl, p-tolyl, and methyl and R 1 is 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, cis-pinan-2-yl, isopinocamphenyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and (−)-8-phenylmenthyl.

2. The process of claim 1 wherein R 1 is selected from methyl, (−)-8-phenylmenthyl, isobornyl, 1-adamantyl, 2-adamantyl, adamantylmethyl, and (+)-isopinocamphenyl.

3. The process of claim 1 , wherein R 2 is Cbz.

4. The process of claim 3 , wherein R 1 is methyl.

5. A composition comprising the mixture of the compounds of Formula I and Formula Ia1

6. A process for preparing the compound of Formula I from the compound of Formula Ia1,

the process comprising reducing the compound of Formula Ia1 with hydrogen in the presence of Raney Nickel.

7. A compound of the formula:

wherein

R 1 is 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, cis-pinan-2-yl, isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, or (−)-8 phenylmenthyl;

or

wherein:

R 1 is 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, cis-pinan-2-yl, isopinocampheyl, adamantylmethyl, 2-adamantyl, 1-adamantyl, and (−)-8-phenylmenthyl; and

R 5 is selected from alkyl, benzyl, and p-tolyl.

8. The compound of claim 7 , wherein said compound is a compound of

wherein R 5 is methyl.

9. The process of claim 1 , further comprising:

(e) precipitating an hydrochloride salt form of the compound of Formula I by reacting the free-base compound of Formula I with HCl.