PROCESS OF PREPARING TYROSINE KINASE INHIBITOR
The invention relates to a process for preparing sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate.
1 . A process of preparing a compound of Formula I:
comprising:
(a) reacting a compound of Formula II:
with 4-aminobenzoic acid to form a compound of Formula III:
(b) reacting the compound of Formula III and 1-cyclohexyl piperazine to form a compound of Formula IV:
and
purifying the compound of Formula IV by recrystallization; and
(c) reacting the compound of Formula IV and sodium hydroxide to form the compound of Formula I.
2 . The process of claim 1 , wherein the compound of Formula IV is purified by recrystallization from a solution comprising an acid and an organic solvent.
3 . The process of claim 2 , wherein the acid is an inorganic acid.
4 . The process of claim 2 or claim 3 , wherein the inorganic acid is phosphoric acid or oxalic acid.
5 . The process of any one of claims 2 to 4 , wherein the inorganic acid is phosphoric acid.
6 . The process of any one of claims 2 to 5 , wherein the weight ratio of the acid to the compound of Formula IV is from about 1:8 to about 1:20.
7 . The process of any one of claims 2 to 6 , wherein the weight ratio of the acid to the compound of Formula IV is from about 1:10 to about 1:15.
8 . The process of any of claims 2 to 7 , wherein the organic solvent is selected from the group consisting of N-methyl pyrrolidone, dimethylsulfoxide, methanol, and a combination thereof.
9 . The process of any one of claims 2 to 8 , wherein the organic solvent is N-methyl pyrrolidone.
10 . The process of any one of claims 2 to 9 , wherein the weight ratio of the organic solvent to the compound of Formula IV is from about 10:1 to about 20:1.
11 . The process of any one of claims 2 to 10 , wherein the weight ratio of the organic solvent to the compound of Formula IV is from about 12:1 to about 16:1.
12 . The process of any one of claims 2 to 11 , further comprising adding water to crystallize the compound of Formula IV.
13 . The process of any one of claims 2 to 12 , comprising treating the solution with an adsorption filtration medium prior to crystallizing the compound of Formula IV.
14 . The process of claim 13 , wherein the adsorption filtration medium is charcoal.
15 . The process of claim 14 , wherein the charcoal is ECOSORB® C-941.
16 . The process of any one of claims 1 to 15 , wherein the reaction of step (a) is performed at a temperature of from about 45° C. to about 70° C.; or at a temperature of from about 45° C. to about 55° C.
17 . The process of any one of claims 1 to 16 , wherein the reaction of step (b) is performed at a temperature of from about 50° C. to about 70° C.; or at a temperature of from about 60° C. to about 65° C.
18 . The process of any of claims 1 to 17 , wherein the reaction of step (c) is performed at a temperature of from about 30° C. to about 60° C.; or at a temperature of from about 35° C. to about 45° C.; or at a temperature of from about 40° C. to about 45° C.; or at about 40° C.
19 . The process of any of claims 1 to 18 , wherein the compound of Formula III or Formula IV is prepared in a polar aprotic solvent in the presence of a base.
20 . The process of claim 19 , wherein the polar aprotic solvent is selected from the group consisting of dimethyl acetamide and dimethyl sulfoxide.
21 . The process of claim 19 or 20 , wherein the base is selected from the group consisting of lithium hydroxide and triethylamine.
22 . The process of any of claims 1 to 21 , wherein the recrystallization is performed at a temperature of from about 30° C. to about 70° C.; or from about 30° C. to about 50° C.
23 . The process of any one of claims 1 to 22 , wherein the recrystallization is performed at a temperature under about 40° C.
24 . The process of any of claims 1 to 23 , wherein the compound of Formula I contains no more than about 0.1% total impurity.
25 . The process of any of claims 1 to 24 , wherein the compound of Formula I is crystalline polymorph Form A.