PROCESS OF MAKING 2-[(3R)-2-[4-AMINO-3-(2-FLUORO-4-PHENOXY-PHENYL)PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDINE-1-CARBONYL]-4-METHYL-4[4-(OXETAN-3-YL)PIPERAZIN-1-YL]-PENT-2-ENENITRILE AND SOLVATE FORMS THEREOF
Disclosed herein are novel methods for preparing 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-pent-2-enenitrile, including various solvate forms and intermediates thereof. Also disclosed herein are novel solvate forms and intermediates of 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]-pent-2-enenitrile.
1 . A method of preparing a compound of Formula (I):
or a salt thereof, comprising:
reacting a compound of Formula (I-g):
or a salt thereof, with a compound of Formula (I-n):
or a salt thereof, with amide-coupling reagent, organic base, and acid in organic solvent to form the compound of Formula (I).
2 . The method of claim 1 , wherein the amide-coupling reagent is propylphosphonic anhydride.
3 . The method of claim 1 , wherein the organic base is N-methylmorpholine, triethylamine, or diisopropylamine.
4 . The method of claim 1 , wherein the acid is hydrochloric acid, methanesulfonic acid, paratoluenesulfonic acid, or chlorotoluenesulfonic acid.
5 . The method of claim 1 , wherein the organic solvent comprises dichloromethane, dichloroethane, acetonitrile, chloroform, 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, toluene, chlorobenzene, methanol, ethanol, or isopropanol.
6 . (canceled)
7 . The method of claim 1 , wherein the compound of Formula (I-n), or a salt thereof, is prepared by reacting a compound of Formula (I-l):
or a salt thereof, with a compound of Formula (I-m):
or a salt thereof, with inorganic or organic base in organic solvent to form the compound of Formula (I-n).
8 . The method of claim 7 , wherein the inorganic base is sodium hydroxide, lithium hydroxide, or potassium hydroxide.
9 . The method of claim 7 , wherein the organic base is sodium methoxide.
10 . The method of claim 7 , wherein the organic solvent is alcohol.
11 . (canceled)
12 . The method of claim 1 , wherein the compound of Formula (I-g), or a salt thereof, is prepared by reacting a compound of Formula (I-f):
or a salt thereof, with base in alcohol and water to form the compound of Formula (I-g).
13 . The method of claim 12 , wherein the base is sodium hydroxide.
14 . The method of claim 12 , wherein the alcohol is methanol.
15 . The method of claim 1 , wherein the compound of Formula (I), or a salt thereof, is at least 95% by weight a compound of Formula (I-(E)):
or a salt thereof.
16 . A method of preparing a compound of Formula (I-n):
or a salt thereof, by reacting a compound of Formula (I-l):
or a salt thereof, with a compound of Formula (I-m):
or a salt thereof, with inorganic or organic base in organic solvent to form the compound of Formula (I-n).
17 . The method of claim 16 , wherein the inorganic base is sodium hydroxide, lithium hydroxide, or potassium hydroxide.
18 . The method of claim 16 , wherein the organic base is sodium methoxide.
19 . The method of claim 16 , wherein the organic solvent is alcohol.
20 . (canceled)
21 . A method of preparing a compound of Formula (I-g):
or a salt thereof, by reacting a compound of Formula (I-f):
or a salt thereof, with base in alcohol and water to form the compound of Formula (I-g).
22 . The method of claim 21 , wherein the base is sodium hydroxide.
23 . The method of claim 21 , wherein the alcohol is methanol.
24 . A compound of Formula (I-n):
or a salt thereof.
25 . An ester solvate of a compound of Formula (I-(E)):
26 . The solvate form of claim 25 , wherein the ester solvate is a methylacetate solvate.
27 . The solvate form of claim 26 , wherein the methylacetate solvate has XRPD pattern comprising one or more peaks chosen from peaks at about 4.676° 2θ, 10.798° 2θ, 14.027° 2θ, 14.280° 2θ, 16.198° 2θ, and 16.704° 2θ.
28 . A carbonate solvate of a compound of Formula (I-(E)):
29 . The solvate form of claim 28 , wherein the carbonate solvate is a dimethylcarbonate solvate.
30 . The solvate form of claim 29 , wherein the dimethylcarbonate solvate characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about 4.765° 2θ, 9.519° 2θ, 10.668° 2θ, 10.829° 2θ, 14.264° 2θ, and 16.976° 2θ.
31 . A method of preparing the methylacetate solvate of claim 26 , wherein crystalline Form B of the compound of Formula (I-(E)) is dissolved in methylacetate to form a solution.
32 . The method of claim 31 , wherein the solution is heated at a temperature ranging from 30 to 50° C. followed by cooling to a temperature ranging from 0 to 15° C.
33 . A method of preparing the methylacetate solvate of claim 26 , wherein the amorphous compound of Formula (I-(E)) is dissolved in methylacetate to form a solution.
34 . The method of claim 33 , wherein the solution is seeded with crystalline Form B of the compound of Formula (I-(E)) to form a suspension followed by stirring at a temperature ranging from 20 to 30° C.
35 . A method of preparing the dimethylcarbonate solvate of claim 29 , wherein crystalline Form C of the compound of Formula (I-(E)) is dissolved in dimethylcarbonate to form a solution.
36 . The method of claim 35 , wherein the solution is frozen, thawed, and stirred at a temperature ranging from 20 to 30° C. to induce particles that stay suspended in solution and do not sediment.
37 . A method of preparing the dimethylcarbonate solvate of claim 29 , wherein the amorphous compound of Formula (I-(E)) is dissolved in dimethylcarbonate to form a solution.
38 . The method of claim 37 , wherein the solution is seeded with crystalline Form B of the compound of Formula (I-(E)) to form a suspension.
39 . The method of claim 38 , wherein the suspension is frozen at a temperature ranging from −10 to −30° C.
40 . The method of claim 39 , wherein the frozen solution is thawed and stirred at a temperature ranging from 20 to 30° C.
41 . A method of preparing a mixture of crystalline Form A and crystalline Form B of a compound of Formula (I-(E)) from the methylacetate solvate of claim 26 , wherein the methylacetate solvate is crystallized in 2-10% dichloromethane in methylacetate with seeds of crystalline Form B, a mixture of crystalline Form A and crystalline Form B, or wet methylacetate solvate of the compound of Formula (I-(E)) to form a suspension.
42 . The method of claim 41 , wherein the methylacetate solvate is crystallized in 5-8% dichloromethane in methylacetate.
43 . The method of claim 41 , wherein the suspension is cooled, filtered, and dried to yield a mixture of crystalline Form A and crystalline Form B of the compound of Formula (I-(E)).
44 . The method of claim 43 , wherein the drying process is carried out at a pressure ranging from 0 to 800 mbars and a temperature ranging from 0 to 70° C.
45 . A method of preparing crystalline Form B of the compound of Formula (I-(E)), wherein the suspension of claim 41 is partially dissolved in ethanol and subjected to heating and cooling cycles at a temperature ranging from 0 to 50° C.
46 . (canceled)
47 . The method of claim 45 , wherein the crystalline mixture is further cooled to a temperature of 0° C.
48 . A method of preparing crystalline Form B of the compound of Formula (I-(E)), wherein the suspension of claim 41 is partially dissolved in isopropylacetate and subjected to heating, cooling, and stirring.
49 . The method of claim 48 , wherein the heating is carried out in 3-5 steps at a temperature ranging from 20 to 70° C. for 1 to 3 hours.
50 . (canceled)
51 . The method of claim 48 , wherein the cooling is carried out at a temperature ranging from 15 to 40° C. within 1 to 3 hours followed by stirring for 8-16 hours.
52 . (canceled)
53 . A method of preparing crystalline Form B of the compound of Formula (I-(E)), wherein the suspension of claim 41 is subjected to pressure.
54 . The method of claim 53 , wherein the pressure ranges from 30 to 70 bars.
55 . The method of claim 53 , wherein the pressure is applied with inert gas.