Process for preparing beta 3 agonists and intermediates

Patent metadata

Field	Value
Publication number	US-10287289-B2
Application number	US-201414776366-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 15, 2013
Publication date	May 14, 2019
Grant date	May 14, 2019

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-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, met

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

• C07D207/12

  Oxygen or sulfur atoms · CPC title

• C12P17/10

  Nitrogen as only ring hetero atom · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title