Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine
AssigneesNeurocrine Biosciences, Inc., Sanofi
InventorsAndrew Becker, Scott Stirn, Joel Radisson, Christina Marie Costa
Life of this patent
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Abstract
The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).
Claims101
A process for preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof:
- comprising:
- alkylating (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:
- with a Compound of Formula (Ii):
- wherein:
- LG is a leaving group;
- in the presence of an alkylating-step solvent, a phase-transfer catalyst, an alkylating-step base, and water to form 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof.
A process for preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:
- comprising:
- cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:
- with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof:
- in the presence of a cyclizing-step solvent to form (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof.
A process for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:
- comprising:
- deprotecting a Compound of Formula (Ig), or a salt thereof:
- wherein
- R1c, R2c and R3c are each independently selected from:
- H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen;
- in the presence of a deprotecting-catalyst, hydrogen, and a deprotecting-step solvent to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.
A process for preparing a Compound of Formula (Ig), or a salt thereof:
- wherein
- R1c, R2c, and R3c are each independently selected from:
- H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen;
- comprising:
- reducing a Compound of Formula (Ie):
- in the presence of a reducing-catalyst, hydrogen, and a reducing-step solvent to form the Compound of Formula (Ig), or a salt thereof.
A process for preparing a Compound of Formula (Ie):
- wherein:
- R1c, R2c, and R3c are each independently selected from:
- H, C1-C6 alkoxy, C1-C6 alkyl, C1-6 haloalkyl, and halogen;
- comprising:
- condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A):
- with a Compound of Formula (Ie), or a salt thereof:
- in the presence of a condensing-step acid and a condensing-step solvent to form the Compound of Formula (Ie).
An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction (XRPD) pattern comprising at least three peaks, in terms of 2θ, selected from the group consisting of:
- 6.0°±0.2°, 11.9°±0.2°, 13.9°±0.2°, 14.3°±0.2°, 16.8°±0.2°, 17.9°±0.2°, 19.7°±0.2°, 20.2°±0.2°, 20.9°±0 2°, 21.8°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.9°±0.2°, 24.2°±0.2°, 25.7°±0.2°, 26.8°±0.2°, 28.7°±0.2°, 29.6°±0.2°, 36.1°±0.2°, and 43.5°±0.2°.
A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) wherein the anhydrous crystalline form has an X-ray powder diffraction XRPD pattern comprising at least three peaks in terms of 2θ, selected from the group consisting of:
- 9.1°±0.2°, 10.5°±0.2°, 11.3°±0.2°, 13.2°±0.2°, 16.3°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 20.4°±0.2°, 21.1°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.8°±0.2°, and 28.5°±0.2°.
A composition comprising:
- a. 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof;
- and
- b. at least one compound selected from:
- (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa);
- (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb);
- and
- ethanol;
- wherein the compound in the composition contains no more than:
- 0.8% of Compound IIa;
- 0.15% of Compound IIb;
- and
- 500 ppm of ethanol.
A Compound of Formula (Ie):
- wherein:
- R1c, R2c, and R3c are each independently selected from:
- H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen.
A Compound of Formula (g) or a salt thereof:
- wherein:
- R1c, R2c, and R3c are each independently selected from:
- H, C1-6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen.
A composition comprising:
- 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof;
- and
- (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-A-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa).
Dependencies are inferred from the claim text.