Process for preparing beta 3 agonists and intermediates

Patent metadata

Field	Value
Publication number	US-2017145014-A1
Application number	US-201414776366-A
Country	US
Kind code	A1
Filing date	Mar 12, 2014
Priority date	Mar 15, 2013
Publication date	May 25, 2017
Grant date	—

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 1-7 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-6:

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 product 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 l or 1-5(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:

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 Cl, I, Br, and OTf; and
R is limited to 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 product 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 l or 1-5(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:

(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
X is selected from Na, Li and K;
Y is selected from Cl, I, Br, and OTf; and
R is limited to 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 X-CN 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 product 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 l or 1-5(b) where, R N ═H;
(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
X is selected from Na and K;
Y is selected from Cl, I, Br, and OTf; and
R is limited to 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, CH2Cl2, MeCN, EtOAc, i- nPrOAc, Me-THF, hexane, heptane, DMAc, DMF, methyl cyclopentyl ether, toluene and combinations thereof; the oxidizing agent is selected from the group consisting of 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, TPAP/NMO; and the catalyst is TEMPO or a TEMPO analogue.

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

6 . The process of claim 3 , wherein the 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 dynamic kinetic reduction KRED enzyme in step (a-2), comprising the amino acid sequence set forth in SEQ ID NO.1 or an active fragment thereof.

9 . The process of claim 2 , further comprising a cofactor recycling system.

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, and NMP, and combinations thereof.

11 . The process of claim 2 , wherein the reaction in step (a-2) 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 the catalyst 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 catalytic amount of material selected from the group consisting of CuI, CuBr, or 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, and toluene, and combinations thereof.

15 . The process of claim 2 , wherein the react

Assignees

• Merck Sharp & Dohme

Inventors

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

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · 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

• C07D207/08

  with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D207/12

  Oxygen or sulfur atoms · CPC title