Process for preparing beta 3 agonists and intermediates

1. A process of making compound I-6:

comprising:

(a-2) reducing compound I-3:

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

(b-2) coupling compound I-4 with compound A-1, in the presence of Catalyst D to produce compound I-5(a):

followed by deprotecting in situ with an acid to produce compound I-5(b) as a salt:

I-5(a), where R N =P 1 or I-5 (b), where R N =H I-5(a), where R N =P 1 or I-5(b) where, R N =H; and

(c-2) cyclizing and reducing compound I-5(b) in the presence of Catalyst E to produce compound I-6 via I-6-1:

wherein P 1 is selected from the group consisting of Ac, Bn, Boc, Bz, Cbz, DMPM, FMOC, Ns, Moz, and Ts; and

Y is selected from the group consisting of Cl, I, Br, and OTf; and

R is selected from the group consisting of H, TMS, TES, TBDMS, TIPS and TBDPS; and

R N is P 1 or H.

2. A process of making compound I-7:

comprising:

(a-2) reducing compound I-3;

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

(b-2) coupling compound I-4 with compound A-1, in the presence of Catalyst D to produce compound I-5(a):

followed by deprotecting in situ with an acid to produce compound I-5(b) as a salt:

I-5(a), where R N =P 1 or I-5 (b) where, R N =H I-5(a), where R N =P 1 or I-5(b) where, R N =H;

(c-2) cyclizing and reducing compound I-5(b) in the presence of Catalyst E to produce compound I-6 via I-6-1:

and

(d-2) coupling compound I-6 with compound A-2:

in the presence of a coupling agent and optionally including a base to produce compound I-7;

wherein P 1 is selected from the group consisting of Ac, Bn, Boc, Bz, Cbz, DMPM, FMOC, Ns, Moz, and Ts; and

Y is selected from the group consisting of Cl, I, Br, and OTf; and

R is selected from the group consisting of H, TMS, TES, TBDMS, TIPS and TBDPS; and

R N is P 1 or H.

3. A process of making compound I-6:

comprising:

(a-1) reacting compound I-1:

in the presence of a solvent, an oxidizing agent, and Catalyst A to form an aldehyde in situ, followed by a condensation in the presence of NaCN or KCN and ammonium chloride and a protective reagent to produce compound I-2:

(b-1) reacting compound I-2 in the presence of a phenyl Grignard reagent to produce compound I-3:

(c-1) reducing compound I-3 in the presence of a KRED enzyme to produce compound I-4:

(d-1) coupling compound I-4 with compound A-1, in the presence of Catalyst D to produce compound I-5(a):

followed by deprotecting in situ with an acid to produce compound I-5(b) as a salt:

I-5(a), where R N =P 1 or I-5 (b) where, R N =H I-5(a), where R N =P 1 or I-5(b) where, R N =H; and

(e-1) cyclizing and reducing compound I-5(b) in the presence of Catalyst E to produce compound I-6 via I-6-1:

wherein P 1 is selected from the group consisting of Ac, Bn, Boc, Bz, Cbz, DMPM, FMOC, Ns, Moz, and Ts; and

Y is selected from the group consisting of Cl, I, Br, and OTT; and

R is selected from the group consisting of H, TMS, TES, TBDMS, TIPS and TBDPS;

and R N is P 1 or H.

4. The process of claim 3 , wherein in step (a-1): the solvent is selected from the group consisting of THF, MTBE, CH 2 Cl 2 , MeCN, EtOAc, i-PrOAc, Me-THF, hexane, heptane, DMAc, DMF, methyl cyclopentyl ether, toluene and combinations thereof; the oxidizing agent is selected from the group consisting of NaOCl, NaClO 2 , PhI(OAc) 2 , hydrogen peroxide; pyridine sulfur trioxide/Et 3 N/DMSO and a Moffatt variant, PCC, DCC, a Swern oxidation or its variants, and TPAP/NMO; and Catalyst A is TEMPO or a TEMPO analogue.

5. The process of claim 3 , wherein P 1 in step (a-1) is Boc.

6. The process of claim 3 , wherein step (a-1) is carried out at a temperature of about 35° C.′ to about 45° C. in the presence of EtOAc or i-PrOAc.

7. The process of claim 3 , wherein in step (a-1) compound I-2 can be prepared via a hydrogensulfite adduct.

8. The process of claim 2 , wherein the KRED enzyme in step (a-2) comprises the amino acid sequence set forth in SEQ NO.1 or an active fragment thereof.

9. The process of claim 2 , wherein a cofactor recycling system is present in step (a-2).

10. The process of claim 2 , wherein the reaction in step (a-2) is carried out in a solvent selected from the group consisting of 2-propanol, sec-butanol, iso-butanol, DMSO, DMF, DMAc, NMP, and combinations thereof.

11. The process of claim 2 , wherein the reaction in step is carried out in a pH range of above about 8.

12. The process of claim 2 , wherein the reaction in step (a-2) is carried out at a temperature of about 30° C. to about 50° C.

13. The process of claim 2 , wherein Catalyst D used in the reaction in step (b-2) is selected from the group consisting of Pd(PPh 3 ) 4 , PdCl 2 , (PPh 3 ) 2 PdCl 2 , Pd(dppe)Cl, Pd(dppp)Cl 2 , Pd(dppf)Cl 2 , and Pd(OAc) 2 /Ph 3 P, in the presence or absence of a catalytic amount of material selected from the group consisting of CuI, CuBr, and CuCl.

14. The process of claim 2 , wherein the reaction in step (b-2) is carried out in the presence of a solvent selected from the group consisting of THF, IPA, MeOH, EtOH, n-PrOH, NMP, DMF, DMAc, MTBE, CH 2 Cl 2 , MeCN, Me-THF, methyl cyclopentyl ether, toluene, and combinations thereof.

15. The process of claim 2 , wherein the reaction product in step (b-2) is isolated as a solid HCl salt.

16. The process of claim 2 , wherein compound I-5(b) salt reacts in step (c-2) with a base selected from the group consisting of Et 3 N, i-Pr 2 NEt, i-Pr 2 NH, pyridine, lutidine, N-methyl morphine, t-BuOK, t-BuONa, t-BuOLi, NaH, NaHMDS, LiHMDS, and KHMDS to produce compound I-6-1 through an intramolecular cyclization reaction.

17. The process of claim 2 , wherein compound I-6-1 is reduced to compound I-6 in step (c-2) in the presence of hydrogen gas and Catalyst E.

18. The process of claim 3 , wherein the reaction product in step (d-1) is isolated as a solid HCl salt.

19. A process of making compound I- 6 :

comprising:

(c-2) cyclizing and reducing compound I-5(b) or a salt thereof:

in the presence of Catalyst E to produce compound I-6 via I-6-1:

wherein R is selected from the group consisting of H, TMS, TES, TBDMS, TIPS and TBDPS.

20. The process of claim 19 , further comprising:

(d-2) coupling compound I-6 with compound A-2:

in the presence of a coupling agent and optionally including a base to produce compound I-7: