COFORMER SALTS OF (2S,3S)-METHYL 7-FLUORO-2-(4-FLUOROPHENYL)-3-(1-METHYL-1H-1,2,4-TRIAZOL-5-YL)-4-OXO-1,2,3,4-TETRAHYDROQUINOLINE-5-CARBOXYLATE AND METHODS OF PREPARING THEM
Described herein are coformer salts of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate optionally as a solvate and additionally optionally as a hydrate, including crystalline forms, and methods of preparing the (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate optionally as a coformer salts.
1 : A coformer salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate optionally as a solvate and additionally optionally as a hydrate thereof.
2 : The coformer salt of claim 1 , wherein the coformer salt is in a substantially pure crystalline form.
3 : The coformer salt of claim 1 , wherein the coformer salt is a [(1S)-endo]-(+)-3-bromo-10-camphor sulfonic acid salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5carboxylate.
4 : The coformer salt of claim 1 , wherein the coformer salt is a crystalline form exhibiting at least one of:
a solid state 13 C NMR spectrum with peaks at 210.3, 25.3, 21.8, 20.8, 19.5, and 18.5 ppm±0.2 ppm;
a differential scanning calorimetry thermogram having a broad endotherm between 25° C. and 90° C. and an endotherm with a maximum between about 135° C. and 147° C.;
a thermogravimetric analysis thermogram indicative of a solvated material; or
a X-ray powder diffraction pattern comprising peaks at 2θ angle degrees±0.2 2θ angle degrees of 6.7, 9.7, 18.5, 19.5, and 22.
5 : The coformer salt of claim 1 , wherein the coformer salt is in a crystalline form exhibiting at least one of:
a solid state 13 C NMR spectrum with peaks at 210.3, 25.3, 21.8, 20.8, 19.5, and 18.5 ppm±0.2 ppm; or
a X-ray powder diffraction pattern comprising peaks at 2θ angle degrees±0.2 2θ angle degrees of 6.7, 9.7, 18.5, 19.5, and 22.
6 : The coformer salt of claim 1 , wherein the coformer salt is a (S)-1-phenylethanesulfonic acid salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate.
7 : A method of preparing a coformer salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate comprising:
(1) treating methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate with a coformer in one or more step 1a) solvent(s) at an elevated temperature to form a step 1a) solution;
wherein the step 1a) solvent(s) are selected from the group consisting of C 1-6 ketone, C 1-6 alcohol, ethyl acetate, tetrahydrofuran, toluene, acetonitrile, heptane, dioxane, and water;
(2) allowing the step 1a) solution to stand under conditions sufficient to precipitate the coformer salt in a solid form; and
(3) isolating the coformer salt solid form.
8 : The method of claim 7 , wherein the coformer salt is a [(1S)-endo]-(+)-3-bromo-10-camphor sulfonic acid salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate, and the step 1a) solvent(s) are selected from the group consisting of acetone, methylethylketone, methylisobutylketone, methanol, ethanol, propanol, isopropanol, and butanol.
9 : The method of claim 7 , wherein the coformer salt is a [(1S)-endo]-(+)-3-bromo-10-camphor sulfonic acid salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate, and the step 1a) solvents are methylisobutylketone, water, and ethanol.
10 : The method of claim 7 , wherein the coformer salt is a [(1S)-endo]-(+)-3-bromo-10-camphor sulfonic acid salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate, and the step 1a) solvents are methylisobutylketone and ethanol.
11 : The method of claim 7 , further comprising recrystallizing or reslurrying the coformer salt in one or more step 1b) solvent(s).
12 : The method of claim 1 , wherein the coformer salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate is in crystalline form.
13 : The method of claim 7 , further comprising:
(4) suspending the coformer salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate in one or more step 2a) solvent(s) at room temperature or at elevated temperature, to form a step 2a) solution and treating the step 2a) solution with a base selected from the group consisting of NaOH, aqueous NH 3 , NaCO 3 , NaOAc, and NaHCO 3 ;
wherein step 2a) solvent(s) are selected from the group consisting of C 1-6 ketone, C 1-6 alcohol, and water;
(5) allowing the step 2a) solution to stand under conditions sufficient to precipitate a solid form of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazo1-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate; and
(6) isolating the solid form of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate.
14 : The method of claim 13 , wherein the step 2a) solvent(s) are selected from the group consisting of acetone, methylethylketone, methylisobutylketone, methanol, ethanol, propanol, or isopropanol; and the base is aqueous NH 3 .
15 . (canceled)
16 : The method of claim 13 , wherein the step 2a) solvents are acetone, methanol, and isopropanol; and the base is aqueous NH 3 .
17 : The method of claim 13 , further comprising recrystallizing or reslurrying the solid form of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate in one or more step 2b) solvent(s).
18 : The method of claim 13 , where the solid form of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate is in a crystalline form.
19 : A compound (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate optionally as a solvate and additionally optionally as a hydrate prepared by treating a coformer salt of (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate with a base and isolating the (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate.