Asymmetric hydrogenation process

1. An asymmetric hydrogenation process for the preparation of a compound of formula I or a salt thereof in at least 50% enantiomeric excess (ee)

wherein n is 1 or 2, R 1 is Br or SO 2 CH 3 , and R 2 is H, benzyl, 4-nitrobenzyl, 4-aminobenzyl, 4-trifluoromethylbenzyl or 4-chlorobenzyl, which comprises: treating a compound of formula II or a salt thereof

with a metal-chiral ligand and a hydrogen donor wherein when the hydrogen donor is H 2 , the process is carried out at a pressure of from about 0 to about 500 pounds per square inch gauge (psig), and wherein said metal-chiral ligand is (a) a ruthenium-axially chiral phosphine ligand complex, or (2) a rhodium chiral ferrocenyl phosphine ligand complex, or (3) a rhodium-TMBTP complex.

2. The process of claim 1 wherein said metal-chiral ligand is ruthenium-axially chiral phosphine ligand complex and said chiral ligand is selected from BINAP (formula (a) Ar=phenyl), tol-BINAP (formula (a) Ar=p-tolyl), xyl-BINAP (formula (a) Ar=3,5-xylyl), H8-BINAP (formula (b) Ar=phenyl), SYNPHOS™ (formula (c) Ar=phenyl), SEGPHOS (formula (d) Ar=phenyl), Solvias BINAP (formula (e) Ar=phenyl), SOLVIAS xyl-BINAP (formula (e) Ar3,5-xylyl), MeO-BIPHEP (formula (f) Ar=phenyl, Z=methyl, R a =R b =R c =H), hexaPHEMP (formula (f) Ar=phenyl, Z=R a =R b =methyl, R c =H), tunaphos (formula (g) Ar=phenyl and n is 1-6), TMBTP (formula (h) Ar=phenyl), P-Phos (formula (i) Ar=phenyl), tol-P-Phos (formula (i) Ar=tolyl), xyl-P-Phos (formula (i) Ar=3,5-xylyl),

3. The process of claim 1 wherein said metal-chiral ligand is (p-cymene)Ru(S)-BINAP-Cl 2 .

4. The process of claim 1 wherein said metal-chiral ligand is (chiral ligand)RuX 2 , wherein each occurrence of X is independently selected from Cl, Br, I, triflate, acetate, methanesulfonate, benzenesulfonate, BF 4 , and B(Ar) 4 , and Ar is phenyl, m- or p-toyl, xylyl and methoxyphenyl.

5. The process of claim 1 wherein said metal-chiral ligand is a rhodium-ferrocenyiphosphine ligand complex and said ferrocenyiphosphine ligand is selected from f-BINAPHANE of formula (m)

Walphos (formula (j) wherein R d and R e are each methyl or trifluoromethyl)

the josiphos of formula (k)

the taniaphos of formula (l)

6. The process of claim 1 wherein said metal-chiral ligand is a rhodium-TMBTP complex.

7. The process of claim 1 wherein said hydrogenation is carried out in the presence of a base and optionally in the presence of a Group I or Group II salt.

8. An asymmetric hydrogenation process for the preparation of a compound of formula Ia or a salt thereof in at least 50% enantiomeric excess (ee)

which comprises: treating a compound of formula IIa or a salt thereof

with a metal-chiral ligand and a hydrogen donor wherein when the hydrogen donor is H 2 , the process is carried out at a pressure of from about 0 to about 500 pounds per square inch gauge (psig), and wherein said metal-chiral ligand is (a) a ruthenium-axially chiral phosphine ligand complex, or (2) a rhodium chiral ferrocenyl phosphine ligand complex, or (3) a rhodium-TMBTP complex.

9. The process of claim 8 wherein said hydrogenation is carried out with hydrogen in the presence of a base, and wherein said metal-chiral ligand is selected from (1) ruthenium complex with BINAP (formula (a) Ar=phenyl), tol-BINAP (formula (a) Ar=-tolyl), xyl-BINAP (formula (a) Ar=3,5-xylyl), H 8 -BINAP (formula (b) Ar=phenyl), SYNPHOS™ (formula (c) Ar=phenyl), SEGPHOS (formula (d) Ar=phenyl), Solvias BINAP (formula (e) Ar=phenyl), SOLVIAS xyl-BINAP (formula (e) Ar3,5-xylyl), MeO-BIPHEP (formula (f) Ar=phenyl, Z=methyl, R a =R b =R c H), hexaPHEMP (formula (f) Ar=phenyl, Z=R a =R b =methyl, R c =H), tunaphos (formula (g) Ar=phenyl and n is 1-6), TMBTP (formula (h) Ar=phenyl), P-Phos (formula (i) Ar=phenyl), tol-P-Phos (formula (i) Ar=tolyl), xyl-P-Phos (formula (i) Ar3,5-xylyl)

(2) rhodium complex with from f-BINAPHANE of formula (m)

Walphos (formula (i) wherein R d and R e are each methyl or trifluoromethyl)

the josiphos of formula (k)

the taniaphos of formula (l)

10. The process of claim 8 wherein said hydrogenation is carried out at a pressure of from about 0 to about 20 psig.

11. A compound of the formula II or a salt thereof:

wherein n, R 1 and R 2 are as defined in claim 1 .

12. The compound of claim 11 or a salt thereof, wherein n is 1, R 1 is —SO 2 CH 3 , and R 2 is 4-chlorobenzyl.