Process for making beta 3 agonists and intermediates

1. A process for producing compound I-11:

comprising:

(a) reacting compound I-4:

with an acetonide protection reagent selected from the group consisting of 2,2-dimethoxy propane, 2,2-diethoxylpropane, 2-methoxypropene and acetone, to produce compound I-5:

(b) reducing said compound I-5 with a reducing agent at a temperature of 0° C. to 40° C. to produce compound I-6;

(c) oxidizing said compound I-6 with an oxidizing agent in the presence of a solvent and a catalyst to produce compound I-7:

(d) reacting said compound I-7 with phosphonate compound A-4:

to produce compound I-8:

(e) reducing said compound I-8 in the presence of a catalyst to produce compound I-9;

(f) reacting said compound I-9 with an acid to produce compound I-10:

and

(g) reducing said compound I-10 in the presence of a catalyst to produce compound I-11;

wherein said P 1 and said P 2 are each independently selected from the group consisting of acyl (Ac), benzyl (Bn), t-butyloxycarbonyl (Boc), benzoyl (Bz), carbobenzyloxy (Cbz), 3,4-dimethoxybenzyl (DMPM), 9-fluorenylmethyloxycarbonyl (FMOC), 4-nitrobenzene sulfonyl (Ns), p-methoxybenzyl carbonyl (Moz), and p-toluene sulfonyl (Ts); and

said R 1 is selected from the group consisting of C 1-6 alkyl, benzyl, and phenyl.

2. The process of claim 1 , wherein in step (c):

said solvent is selected from the group consisting of tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), dichloromethane (CH 2 Cl 2 ), acetonitrile (MeCN), toluene and a mixture comprising two of the said foregoing solvents;

said oxidizing agent is selected from the group consisting of sodium hypochlorite (NaOCl), sodium chlorite (NaClO 2 ), hydrogen peroxide, pyridine sulfur trioxide, pyridinium chlorochromate (PCC), and N,N′-dicyclohexycarbodiimide (DCC); and

said catalyst is 1-oxyl-2,2,6,6-tetramethylpiperidine (TEMPO) or a TEMPO analogue.

3. The process of claim 1 , wherein said reaction between said compound I-7 and said compound A-4 in step (d) is carried out at a temperature of 20 to 40° C. and in the presence of a solvent selected from the group consisting of THF, MTBE, CH 2 Cl 2 , MeCN, toluene and a mixture comprising two of said foregoing solvents.

4. The process of claim 1 , wherein said catalyst in step (e) is selected from the group consisting of Pd, Raney Ni, Pt, PdCl 2 , and Pd(OH) 2 ; and said reducing is carried out in the presence of hydrogen gas.

5. The process of claim 1 , wherein said acid in step (f) is selected from the group consisting of HCl, HBr, trifluoroacetic acid (TFA), MeSO 3 H, TfOH, H 2 SO 4 , para-toluenesulfonic acid, and RSO 3 H, wherein R is an alkyl, an aryl, or a substituted aryl.

6. The process of claim 1 , wherein said reducing in step (g) is carried out in the presence of hexamethyldisilazane (HMDS) and said catalyst is selected from the group consisting of Pt on alumina, Pd on alumina, Pd/C, Pd(OH 2 )—C, Raney Ni, Rh/C, Rh/Al, Pt/C, Ru/C, and PtO 2 .

7. The process of claim 1 , further comprising a step of reducing compound I-3:

in the presence of a ketoreductase (KRED) enzyme to produce compound I-4:

8. The process of claim 7 , wherein said KRED enzyme comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NOEL 1 and the amino acid sequence of SEQ ID NO: 2.

9. The process of claim 8 , further comprising a cofactor recycling system comprising an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 4.

10. The process of claim 9 , further comprising a cofactor selected from the group consisting of NADH and NADPH.

11. The process of claim 7 , further comprising a step of reacting compound I-1:

with benzoyl chloride and a protecting reagent to produce compound I-3:

12. A process for producing compound I-11:

comprising:

(a) reacting compound I-1:

with benzoyl chloride and a protecting reagent to produce compound I-3:

(b) reducing said compound I-3 in the presence of a ketoreductase (KRED) enzyme to produce compound I-4:

(c) reacting said compound I-4 with an acetonide protection reagent selected from the group consisting of 2,2-dimethoxy propane, 2,2-diethoxylpropane, 2-methoxypropene and acetone, to produce compound I-5:

(d) reducing said compound I-5 with a reducing agent at a temperature of 0° C. to 40° C. to produce compound I-6;

(e) oxidizing said compound I-6 with an oxidizing agent in the presence of a solvent and a catalyst to produce compound I-7:

(f) reacting said compound I-7 with phosphonate compound A-4:

to produce compound I-8:

(g) reducing said compound I-8 in the presence of a catalyst to produce compound I-9;

(h) reacting said compound I-9 with an acid to produce compound I-10:

and

(i) reducing said compound I-10 in the presence of a catalyst to produce compound I-11;

wherein said P 1 and said P 2 are each independently selected from the group consisting of acyl (Ac), benzyl (Bn), t-butyloxycarbonyl (Boc), benzoyl (Bz), carbobenzyloxy (Cbz), 3,4-dimethoxybenzyl (DMPM), 9-fluorenylmethyloxycarbonyl (FMOC), 4-nitrobenzene sulfonyl (Ns), p-methoxybenzyl carbonyl (Moz), and p-toluene sulfonyl (Ts); and

said R 1 is selected from the group consisting of C 1-6 alkyl, benzyl, and phenyl.

13. The process of claim 12 , wherein said KRED enzyme in step (b) comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 2.

14. The process of claim 13 , wherein step (b) further comprises a cofactor recycling system comprising an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 4.

15. The process of claim 14 , further comprising a cofactor selected from the group consisting of NADH and NADPH.

16. The process of claim 1 , wherein R 1 is C 1-6 alkyl.

17. The process of claim 7 , wherein R 1 is C 1-6 alkyl.

18. The process of claim 11 , wherein R 1 is C 1-6 alkyl.

19. The process of claim 12 , wherein R 1 is C 1-6 alkyl.