PROCESS FOR PREPARING N-(5-(3-(7-(3-FLUOROPHENYL)-3H-IMIDAZO[4,5-C]PYRIDIN-2-YL)-1H-INDAZOL-5-YL)PYRIDIN-3-YL)-3-METHYLBUTANAMIDE
Provided herein is a synthetic process for preparing a compound of Formula (1). The disclosure also provides useful intermediates and salts, amorphous and polymorph forms of the compound of Formula (1). These compounds are useful for various disease including cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, and osteoarthritis as well as Wnt-related diseases.
1 . (canceled)
2 . A process for preparing a polymorph form of a compound of Formula (1)
the process comprising:
(a) reacting a compound of Formula (8)
or a salt thereof, with bis(pinacolato)diboron and Pd(dppf)Cl 2 to produce a compound of Formula (9)
or a salt thereof;
(b) reacting the compound of Formula (9), or the salt thereof, with a compound of Formula (10)
or a salt thereof, Pd(PPh 3 ) 4 and K 3 PO 4 to prepare a compound of Formula (11)
or a salt thereof,
(c) reacting the compound of Formula (11), or the salt thereof, with a compound of Formula (6)
or a salt thereof, to prepare a compound of Formula (12)
or a salt thereof;
(d) deprotecting the compound of Formula (12), or the salt thereof, to prepare the compound of Formula (1), or a salt thereof, wherein deprotecting the compound of Formula (12) to prepare the compound of Formula (1) comprises reacting the compound of Formula (12) with TFA;
(e) reslurrying the compound of Formula (1) in a solvent, wherein the solvent is selected from acetonitrile, n-butyl acetate, n-butanol, dichloromethane (DCM), heptane, isopropyl alcohol, methanol, methyl acetate (MA), methyl tert-butyl ether (MtBE), methyl isobutyl ketone (MIBK), toluene, and water, or a mixture thereof; wherein reslurrying is performed at a temperature of about room temperature to about 50° C.; wherein reslurrying is performed for a time of about 10 hours to about 80 hours;
(f) filtering to provide the compound of Formula (1) as a residual solid;
(g) drying the residual solid;
(h) reslurrying the residual solid in a solvent to generate the polymorph; and
(i) filtering to provide the polymorph as a residual solid; wherein the polymorph has an XRPD pattern with at least peaks at 2θ° positions of 7.2±0.2, 22.2±0.2, and 24.4±0.2.
3 . The process of claim 2 , wherein the TFA in step (d) is neat TFA.
4 . The process of claim 2 , wherein reslurrying in step (e) is performed at room temperature.
5 . The process of claim 2 , wherein reslurrying in step (e) is performed at a temperature of about 50° C.
6 . The process of claim 2 , wherein reslurrying in step (e) is performed at a temperature of about 30° C. to about 35° C.
7 . The process of claim 2 , wherein reslurrying in step (e) is performed for a time of about 58 hours to about 80 hours.
8 . The process of claim 7 , wherein the solvent in step (e) is selected from methanol, water, or a mixture thereof.
9 . The process of claim 8 , wherein the solvent in step (e) is 90% methanol/water.
10 . The process of claim 8 , wherein the solvent in step (e) is methanol; and
wherein reslurrying is performed at a temperature of about 50° C.
11 . The process of claim 2 , wherein the drying in step (g) is performed under vacuum.
12 . The process of claim 11 , wherein the drying in step (g) is at a temperature of between about 60° C. and 90° C.
13 . The process of claim 12 , wherein the drying in step (g) is at a temperature of about 75° C.
14 . The process of claim 2 , wherein the solvent in step (h) is selected from IPAc or n-butyl acetate.
15 . The process of claim 14 , wherein the solvent in step (h) is IPAc.
16 . The process of claim 14 , wherein the solvent in step (h) is n-butyl acetate.
17 . The process of claim 2 , wherein reslurrying in step (h) is performed at a temperature of about room temperature.
18 . The process of claim 2 , wherein the polymorph in step (i) has an XRPD pattern with at least peaks at 2θ° positions 6.3±0.2, 7.2±0.2, 21.6±0.2, 22.2±0.2, and 24.4±0.2.
19 . The process of claim 18 , wherein the polymorph in step (i) has an XRPD pattern with at least peaks at 2θ° positions 6.3±0.2, 7.2±0.2, 11.0±0.2, 14.2±0.2, 17.8±0.2, 18.4±0.2, 19.0±0.2, 21.6±0.2, 22.2±0.2, and 24.4=0.2.
20 . The process of claim 2 , wherein the polymorph exhibits an exotherm between about 190-220° C. as measured by DSC.
21 . The process of claim 2 , wherein the polymorph exhibits an exotherm between about 225-235° C. as measured by DSC.
22 . The process of claim 2 , wherein the polymorph exhibits an exotherm between about 292-300° C. as measured by DSC.
23 . The process of claim 2 , wherein the polymorph undergoes a weight loss of about 1.7% between about 81° C. to about 169° C., as measured by TGA.