US2015087832A1PendingUtilityA1
Process for making beta 3 agonists and intermediates
Est. expiryOct 27, 2031(~5.3 yrs left)· nominal 20-yr term from priority
Inventors:John Y. L. ChungKevin R. CamposEdward CleatorRobert F. DunnAndrew GibsonR. Scott HoerrnerStephen KeenDave LiebermannZhuqing LiuJoseph E. LynchKevine M. MaloneyFeng XuNobuyoshi YasudaNaoki YoshikawaYong-Li Zhong
A61P 43/00A61P 13/10A61K 31/4196A61K 31/519C07D 263/06C07B 2200/13C07D 487/04C07D 207/09C07D 403/12
60
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat 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 phosphate 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 phosphate 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 process of making a compound of Formula (I):
comprising reacting compound I-11:
with compound i-12 in the presence of a coupling reagent, a solvent and an acid:
wherein the coupling agent is selected from the group consisting of CDI, DCC, EDC, EDC methiodide, T3P, HATU, HBTU and mix-anhydrides; and
wherein the solvent is selected from the group consisting of MeOH, EtOH, IPA, n-PrOH, MeCN, DMF, DMAc, THF, EtOAc and IPAc.
12 . A process of making a compound of Formula (II):
comprising reacting compound I-11:
with compound i-30 in the presence of an acid and a solvent:
13 . 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
14 . A crystalline hemihydrate form of compound of Formula I-11 characterized by XRPD by the following reflections with the d-spacing.
Position [°2 Theta]
d-spacing [Å]
17.9681
4.94
17.8666
4.96
23.1905
3.84
15.3049
5.79
19.7955
4.49
19.9483
4.45
23.1076
3.85
25.3415
3.51
16.0859
5.51
25.6746
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