Process for making beta 3 agonists and intermediates
The present invention is directed to a process for preparing a compound of formula I-11 through multiple-step reactions:
1. A process for producing compound I-11:
comprising:
(a) reducing compound I-5:
with a reducing agent at a temperature of 0° C. to 40° C. to produce compound I-6:
(b) oxidizing said compound I-6 with an oxidizing agent in the presence of a solvent and a catalyst to produce compound I-7:
(c) reacting said compound I-7 with phosphonate compound A-4:
to produce compound I-8:
(d) reducing said compound I-8 in the presence of a catalyst to produce compound I-9:
(e) reacting said compound I-9 with an acid to produce compound I-10:
and
(f) 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 the reducing agent of step (a) is selected from the group consisting of LiAlH 4 , LiBH 4 , NaBH 4 —LiBr, and DIBAL.
3. The process of claim 1 , wherein in step (b) 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 said foregoing solvents.
4. The process of claim 1 , wherein in step (b) 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).
5. The process of claim 1 , wherein in step (b) said catalyst is 1-oxyl-2,2,6,6-tetramethylpiperidine (TEMPO) or a TEMPO analogue.
6. The process of claim 1 , wherein said reaction between said compound I-7 and said compound A-4 in step (c) 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.
7. The process of claim 1 , wherein said catalyst in step (d) is selected from the group consisting of Pd, Raney Ni, Pt, PdCl 2 , and Pd(OH) 2 .
8. The process of claim 1 , wherein said reducing in step (d) is carried out in the presence of hydrogen gas.
9. The process of claim 1 , wherein said acid in step (e) 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.
10. The process of claim 1 , wherein said reducing in step (f) is carried out in the presence of hexamethyldisilazane (HMDS).
11. The process of claim 1 , wherein said catalyst in step (f) 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 .
12. The process of claim 1 , wherein R 1 is C 1-6 alkyl.