Process for making beta 3 agonists and intermediates

Patent metadata

Field	Value
Publication number	US-9822121-B2
Application number	US-201615057427-A
Country	US
Kind code	B2
Filing date	Mar 1, 2016
Priority date	Oct 27, 2011
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

The present invention is directed to processes for preparing beta 3 agonists of Formula (I) and Formula (II) and their intermediates. The beta 3 agonists are useful in the treatment of certain disorders, including overactive bladder, urinary incontinence, and urinary urgency.

First claim

What is claimed is:

1. A process of making compound I-11:

comprising:
(a) reducing compound I-8:

in the presence of a catalyst to produce compound I-9:

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

and
(c) reducing compound I-10 in the presence of a catalyst to produce compound I-11;
wherein P 1 and P 2 are each independently selected from the group consisting of Ac, Bn, Boc, Bz, Cbz, DMPM, FMOC, Ns, Moz, and Ts.

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

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

4. The process of claim 1 , wherein the reduction of step (c) is carried out in the presence of HMDS and the catalyst used 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 .

5. The process of claim 1 , further comprising reacting compound I-7;

with phosphonate compound A-4:

to produce compound I-8;
wherein the reaction is carried out at a temperature of about 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 the foregoing solvents; and
wherein P 1 and P 2 are each independently selected from the group consisting of Ac, Bn, Boc, Bz, Cbz, DMPM, FMOC, Ns, Moz, and Ts.

6. The process of claim 5 , wherein the compound I-7 is in a solution, and the solution containing compound I-7 is added to a solution containing compound A-4.

7. The process of claim 5 , further comprising oxidizing compound I-6:

with an oxidizing agent in the presence of a solvent and a catalyst 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.

8. The process of claim 7 , wherein:
the solvent is selected from the group consisting of THF, MTBE, CH 2 Cl 2 , MeCN, toluene and a mixture comprising two of the foregoing solvents;
the oxidizing agent is selected from the group consisting of NaOCl, NaClO 2 , hydrogen peroxide, pyridine sulfur trioxide, PCC, and DCC; and
the catalyst is TEMPO or a TEMPO analogue.

9. The process of claim 7 , further comprising reacting compound I-5b:

with acetone and Boc 2 O to produce compound I-6, wherein P 1 is Boc.

10. A process of producing compound I-11 comprising:
(a) reacting, compound I-5b;

with acetone and Boc 2 O to produce compound I-6:

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

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

to produce compound I-8:

wherein the reaction is carried out at a temperature of about 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 the foregoing solvents;
(d) reducing compound I-8 in the presence of a catalyst selected from the group consisting of Pd, Raney Ni, Pt, PdCl 2 , and Pd(OH) 2 to produce compound I-9:

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

and
(f) reducing compound I-10 in the presence of a catalyst to produce compound I-11:

wherein P 1 is Boc and P 2 is selected from the group consisting of Ac, Bn, Boc, Bz, Cbz, DMPM, FMOC, Ns, Moz, and Ts.

11. A crystalline anhydrous form of compound of Formula I-11

characterized by XRPD by the following reflections with the d-spacing,

Position [°2 Theta]
d-spacing [Å]

17.8453
4.97

25.1979
3.53

20.1002
4.42

23.9931
3.71

16.7073
5.31

25.5483
3.49

19.6576
4.52

13.8883
6.38

28.086
3.18

20.6498
4.30.

12. A crystalline hemihydrate form of compound of Formula I-11

characterized by XRPD by the following reflections with the d-spacing,

Assignees

• Merck Sharp & Dohme

Inventors

• Chung John Y L
• Campos Kevin
• Cleator Edward
• Dunn Robert F
• Gibson Andrew
• Hoerrner R Scott
• Keen Stephen
• Lieberman Dave
• Liu Zhuqing
• Lynch Joseph
• Maloney Kevin M
• Xu Feng
• Yasuda Nobuyoshi
• Yoshikawa Naoki
• Zhong Yong-Li

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P13/10

  of the bladder · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title