PROCESS FOR PREPARING BETA 3 AGONISTS AND INTERMEDIATES
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.
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:
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:
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:
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:
(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:
where R N ═P 1 or I-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, CH 2 Cl 2 , 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 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 reaction product in step (d-1) or step (b-2) is isolated its solid HCl salt.
16 . The process of claim 2 , wherein compound I-5(b) salt reacts in step (c-2) with a base selected from the group consisting of Et 3 N, i-Pr 2 NEt, i-Pr 2 NH, pyridine, lutidine, N-methyl morphine, t-BuOK, t-BuONa, t-BuOLi, NaH, NaHMDS, LiHMDS, and KHIMIDS to produce compound I-6-1 through an intramolecular cyclization reaction.
17 . The process of claim 2 , compound I-6-1 is reduced to compound I-6 in step (c-2) in the presence of hydrogen gas and a catalyst.
18 . The process of claim 1 , wherein Compound I-5(b) is characterized by XRPD by the following reflections with the d-spacing
Position [°2 Theta]
d-spacing [Å]
4.2174
20.95196
8.5827
10.3028
12.9282
6.84784
13.5177
6.55051
16.65
5.32461
20.9425
4.24193
22.6974
3.91777
24.363
3.65356
24.6986
3.60468
28.1911
3.16555