Process for preparing beta 3 agonists and intermediates

Patent metadata

Field	Value
Publication number	US-11649243-B2
Application number	US-202117399274-A
Country	US
Kind code	B2
Filing date	Aug 11, 2021
Priority date	Mar 15, 2013
Publication date	May 16, 2023
Grant date	May 16, 2023

Abstract

The application is directed to efficient and economical processes as described in more detail below for the preparation of the beta 3 agonists of the formula of I-7 and intermediate compounds that can be used for making these agonists. The present disclosure relates to a process for making beta-3 agonists and intermediates using ketoreductase (KRED) biocatalyst enzymes and methods of using the biocatalysts.

First claim

What is claimed is:

1. A process of making compound I-7:

comprising:
(a) 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:

(b) cyclizing the salt of compound I-5(b) to produce compound I-6-1:

(c) reducing compound I-6-1 in the presence of Catalyst E to produce compound I-6:

and
(d) 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;
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;
wherein Catalyst D is selected from the group consisting of Pd(PPh 3 ) 4 , PdCl 2 , (PPh 3 ) 2 PdCl 2 , Pd(dppe)Cl, Pd(dppp)Cl, Pd(dppf)Cl, and Pd(OAc) 2 /Ph 3 P, wherein each catalyst can optionally be accompanied by a catalytic amount of material selected from the group consisting of Cut CuBr, and CuCl; and
wherein Catalyst E is selected from the group consisting of Pt/Al 2 O 3 , Pd/Al 2 O 3 , Rh/Al 2 O 3 , Pd/C, Pd(OH) 2 —C, Pt on alumina-V on carbon or vanadate, Raney Ni, Rh/C, Rh/Al, Pt/C, Ru/C, and PtO 2 .

2. The process of claim 1 , wherein the reaction in step (a) 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.

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

4. The process of claim 1 , wherein step (b) is conducted in the presence of a base selected from the group consisting of Et 3 N, i-Pr 2 NEt, i-Pr 2 NH, pyridine, lutidine, N-methyl morpholine, t-BuOK, t-BuONa, t-BuOLi, NaH, NaHMDS, LiHMDS, and KHMDS.

5. The process of claim 1 , wherein compound I-6-1 is not isolated.

6. The process of claim 1 , wherein step (c) is conducted in the presence of hydrogen gas.

7. The process of claim 1 , wherein the coupling agent in step (d) is selected from the group consisting of CDI, DCC, EDC, EDC methiodide, T3P, HATU, HBTU, and mix-anhydrides.

8. The process of claim 1 , wherein compound I-6 is coupled with compound A-2 in the presence of a coupling agent and a base.

9. The process of claim 8 , wherein the base is pyridine or a pyridine salt.

Assignees

• Merck Sharp & Dohme

Inventors

• Xu Feng
• Liu Zhuqing
• Desmond Richard
• Park Jeonghan
• Kalinin Alexei
• Kosjek Birgit
• Strotman Hallena
• Li Hongmei
• Moncecchi Johannah

Classifications

• C07D207/12

  Oxygen or sulfur atoms · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07C215/30

  containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton · CPC title

• C12P17/10

  Nitrogen as only ring hetero atom · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title