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 Compound 1 having solid Form B:
comprising:
(a) reacting Compound 2 with the hydrochloride salt of Compound 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-thazine, HATU, HOBT/EDC, and 2-propane phosphonic anhydride
wherein the Form B is characterized by a peak at about 165.3 ppm, a peak at about 145.9 ppm, a peak at about 132.9 ppm , and a peak about 113.4 ppm in a 13 C NMR spectrum.
2. The process of claim 1 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a base selected from K 2 CO 3 , Et 3 N, N-methylmorpholine (NMM), pyridine or DIEA.
3. The process of claim 2 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of pyridine.
4. The process of claim 1 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a solvent selected from EtOAc, IPAc, THF, MEK, NMP, acetonitrile, DMF, or 2-methyltetrahydrofuran.
5. The process of claim 4 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a 2-methyltetrahydrofuran.
6. The process of claim 1 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is s performed at a reaction temperature that is maintained between 15° C. and 70° C.
7. The process of claim 1 , wherein the Form B is characterized by a peak at about −56.1 ppm and a peak at about −62.1 ppm in a 19 F NMR spectrum.
8. The process of claim 7 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a base selected from K 2 CO 3 , Et 3 N, N-methylmorpholine (NMM), pyridine or DIEA.
9. The process of claim 8 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of pyridine.
10. The process of claim 7 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a solvent selected from EtOAc, IPAc, THF, MEK, NMP, acetonitrile, DMF, or 2-methyltetrahydrofuran.
11. The process of claim 10 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of 2-methyltetrahydrofuran.
12. The process of claim 7 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is s performed at a reaction temperature that is maintained between 15° C. and 70° C.
13. The process of claim 1 , wherein the solid Form B is characterized by a peak at about 6.7 degrees, a peak at about 10.0 degrees, a peak at about 11.2 degrees, a peak at about 13.4 degrees, and a peak at about 24.2 degrees in an X-ray powder diffraction, and wherein the XRPD peaks are measured on a 2-theta scale.
14. The process of claim 13 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a base selected from K 2 CO 3 , Et 3 N, N-methylmorpholine (NMM), pyridine or DIEA.
15. The process of claim 14 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of pyridine.
16. The process of claim 13 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a solvent selected from EtOAc, IPAc, THF, MEK, NMP, acetonitrile, DMF, or 2-methyltetrahydrofuran.
17. The process of claim 16 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of 2-methyltetrahydrofuran.
18. The process of claim 13 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is s performed at a reaction temperature that is maintained between 15° C. and 70° C.
19. The process of claim 1 , wherein the solid Form B is characterized by a single crystal which possesses a monoclinic crystal system, a P21/c space group, and the following unit cell dimensions:
a =13.5429(4) 521 ;
b =13.4557(4) 521 ;
c =12.0592(4) 521 ;
α=90°;
β=101.193°; and
γ=90°.
20. The process of claim 19 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a base selected from K 2 CO 3 , Et 3 N, N-methylmorpholine (NMM), pyridine or DIEA.
21. The process of claim 20 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of pyridine.
22. The process of claim 19 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of a solvent selected from EtOAc, IPAc, THF, MEK, NMP, acetonitrile, DMF, or 2-methyltetrahydrofuran.
23. The process of claim 22 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is performed in the presence of 2-methyltetrahydrofuran.
24. The process of claim 9 , wherein the coupling of Compound 2 and the hydrochloride salt 3-HCl is s performed at a reaction temperature that is maintained between 15° C. and 70° C.