Synthetic methods and intermediates for producing compounds for treating KIT- and PDGFRA-mediated diseases
The present disclosure provides methods and intermediates for making Compound A or a pharmaceutical salt thereof, and/or a solvate of, which are useful as methods and intermediates for producing compounds for treating diseases and conditions related to mutant KIT and PDGFRA.
1 . A method of preparing Compound A:
comprising reacting a first compound represented by formula (I-1) or a pharmaceutically acceptable acid salt thereof:
and a second compound represented by formula (II-1) or a pharmaceutically acceptable acid salt thereof:
wherein R 1 and R 2 are each independently selected from H and an amine protecting group, and
cleaving the R 1 and R 2 amine protecting groups, if present, to form Compound A.
2 . The method of claim 1 , wherein R 2 is H and R 1 is S(═O)C(CH 3 ) 3 ; or wherein R 2 is C(O)OC(CH 3 ) 3 and R 1 is S(═O)C(CH 3 ) 3 .
3 . The method of claim 1 , wherein the reaction is mediated by an agent that activates the aromatic hydroxyl group in the first compound (I-1) for nucleophilic displacement.
4 . The method of claim 3 , wherein the agent is a phosphonium salt selected from the group consisting of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP), 2-(benzotriazol-1-yloxy)-1,3-dimethyl-2-pyrrolidin-1-yl-1,3-diazaphospholidinium hexafluorophosphate (BOMP), (7-azabenzotriazol-1-yloxy)tris(di-methylamino)phosphonium hexafluorophosphate (AOP), (7-azabenzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyOxim), and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP).
5 . The method of claim 4 , wherein the agent is (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP); or the agent is chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP).
6 . The method of claim 3 , comprising reacting in the presence of a non-nucleophilic base.
7 . The method of claim 6 , wherein the non-nucleophilic base is an amine non-nucleophilic base.
8 . The method of claim 7 , wherein the amine non-nucleophilic base is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU); or the amine non-nucleophilic base is triethylamine (TEA).
9 . The method of claim 6 , wherein the second compound is a pharmaceutically acceptable acid salt of the compound of formula (II-1); or
wherein the second compound is the free base of the compound of formula (II-1).
10 . The method of claim 9 , wherein the amine non-nucleophilic base is present in a molar excess relative to the moles of the first compound (I-1).
11 . The method of claim 6 , wherein the first compound (I-1) and the second compound (II-1) are dissolved in a first solvent to form a solution.
12 . The method of claim 11 , wherein the first solvent is selected from the group consisting of acetonitrile (CH 3 CN), dimethylformamide (DMF), 2-methyl tetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), dichloroethane (DCE), dioxane and dimethylaminopyridine (DMAP).
13 . The method of claim 11 , wherein reacting is conducted at a temperature of 15-100° C.
14 . The method of claim 13 , wherein the temperature is 20-30° C. when PyBOP is the activating agent and the non-nucleophilic base is DBU; or the temperature is 80-90° C. when PyClOP is the activating agent and the non-nucleophilic base is TEA.
15 . The method of claim 11 , wherein the agent is added to the solution of the first compound (I-1) and the second compound (II-1) dissolved in the first solvent.
16 . The method of claim 11 , wherein the non-nucleophilic amine base is added prior to the additional addition of the first solvent.
17 . The method of claim 9 , wherein the pharmaceutically acceptable acid salt of compound of formula (II-1) is an HCl salt.
18 . The method of claim 10 , wherein the amine non-nucleophilic base is present in a 5.0 to 12.0 molar excess relative to the moles of the first compound (I-1).