Process for preparing modulators of cystic fibrosis transmembrane conductance regulator
The present invention relates to processes for preparing solid state forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, including Compound 1 Form A, Compound 1 Form A-HCl, Compound 1 Form B, and Compound 1 Form B-HCl, any combination of these forms, pharmaceutical compositions thereof, and methods of treatment therewith.
1. A process for producing the hydrochloride salt of Compound 1 having solid Form A-HCl:
comprising:
(a) reacting Compound 2 with the hydrochloride salt of Formula 3 (3-HCl) in the presence of a coupling agent selected from the group consisting of 2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate, HBTU, HCTU, 2-chloro-4,6-dimethoxy-1,3,5-triazine, HATU, HOBT/EDC, and propane phosphonic anhydride:
and
(b) treating a mixtures of the product of step (a) with HCl.
2. The process of claim 1 , wherein step (a) is performed in the presence of a base such as K 2 CO 3 , Et 3 N,N-methylmorpholine (NMM), pyridine or diisopropylethyl amine (DIEA).
3. The process of claim 2 , wherein step (a) is performed in the presence of pyridine or DIEA.
4. The process of claim 3 , wherein step (a) is performed in the presence of pyridine.
5. The process of claim 1 , wherein step (a) is performed in the presence of a polar aprotic solvent.
6. The process of claim 5 , wherein the polar aprotic solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, tetrahydrofuran, methylethyl ketone, N-Methyl-2-pyrrolidone, acetonitrile, N,N-dimethyl formamide, or 2-methyltetrahydrofuran.
7. The process of claim 1 , wherein the coupling of Compound 2 and 3-HCl is performed in the presence of 2-methyltetrahydrofuran.
8. The process of claim 1 , wherein step (a) is performed at a reaction temperature that is maintained between 10° C. and 80° C.
9. The process of claim 8 , wherein step (a) is performed at a reaction temperature that is maintained between 15° C. and 70° C.
10. The process of claim 1 , wherein the time of step (a) is from about 1.5 hours to about 72 hours.
11. The process of claim 1 , wherein HCl gas is used in step (b).
12. The process of claim 11 , wherein HCl gas is bubbled into a mixture comprising the product of step (a) and a polar aprotic solvent.
13. The process of claim 12 , wherein the polar aprotic solvent is 2-Methyltetrahydrofuran.
14. The process of claim 12 , wherein HCl gas is bubbled into the mixture comprising the product of step (a) and a polar aprotic solvent for a period of from about 0.5 hours to about 5 hours.