Processes for preparing ASK1 inhibitors
AssigneeGilead Sciences, Inc.
InventorsBrandon Heath Brown, Brenda J. Burke Chan, Anna Chiu, Nolan Griggs, Lars V. Heumann, Stephen P. Lathrop, Troy Evan Reynolds, Keshab Sarma, David Allen Siler, Andrew S. Thompson, Tao Wang
Life of this patent
Estimating the term…
Abstract
The present disclosure provides processes for the preparation of a compound of formula: which exhibits apoptosis signal-regulating kinase (“ASK1”) inhibitory activity and is thus useful in the treatment of diseases such as kidney disease, diabetic nephropathy and kidney fibrosis. The disclosure also provides compounds that are synthetic intermediates.
Claims152
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) carboxylating a compound of formula (E) or a salt thereof:
- under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate, or salt thereof:
- (b) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof:
- and
- (c) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to yield a compound of formula (A).
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) cyclizing a compound of formula (F):
- under reaction conditions sufficient to form a compound of formula (E) or a salt thereof:
- (b) carboxylating a compound of formula (E) or a salt thereof under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate or salt thereof:
- (c) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof:
- and
- (d) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to yield a compound of formula (A).
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) formylating a compound of formula (G):
- under reaction conditions sufficient to form a compound of formula (F):
- (b) cyclizing a compound of formula (F) under reaction conditions sufficient to form a compound of formula (E) or a salt thereof:
- (c) carboxylating a compound of formula (E) or a salt thereof under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate or salt thereof:
- (d) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof:
- and
- (e) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to yield a compound of formula (A).
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) contacting a compound of formula (H):
- with a compound of formula (I):
- under reaction conditions sufficient to form a compound of formula (G):
- (b) formylating a compound of formula (U) under reaction conditions sufficient to form a compound of formula (F):
- (c) cyclizing a compound of formula (F) under reaction conditions sufficient to form a compound of formula (E) or a salt thereof:
- (d) carboxylating a compound of formula (E) or a salt thereof under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate or salt thereof:
- (e) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof:
- and
- (f) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to yield a compound of formula (A).
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) tosyloxylating a compound of formula (J):
- under reaction conditions sufficient to form a compound of formula (H):
- (b) contacting a compound of formula (H) with a compound of formula (I):
- under reaction conditions sufficient to form a compound of formula (G):
- (c) formylating a compound of formula (G) under reaction conditions sufficient to form a compound of formula (F):
- (d) cyclizing a compound of formula (F) under reaction conditions sufficient to form a compound of formula (E) or a salt thereof:
- (e) carboxylating a compound of formula (E) or a salt thereof under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate or salt thereof:
- (f) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof:
- and
- (g) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to yield a compound of formula (A).
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) contacting a compound of formula (K) or a salt thereof:
- with a compound of formula (L):
- under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate or salt thereof:
- (b) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof:
- and
- (c) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to yield a compound of formula (A).
- wherein Z is a leaving group.
A method for preparing a compound of formula (D), or a hydrate, solvate or salt thereof:
- comprising the steps of:
- (a) carboalkoxylating a compound of formula (E) or a salt thereof:
- under reaction conditions sufficient to form a compound of formula (Q):
- and
- (b) hydrolyzing a compound of formula (Q) under reaction conditions sufficient to form a compound of formula (D).
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) contacting a compound of formula (E) or a salt thereof:
- with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to form a compound of formula (A).
A method for preparing a compound of formula (A):
- or a salt or solvate thereof,
- comprising the steps of:
- (a) carboxylating a compound of formula (E) or a salt thereof:
- under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate or salt thereof:
- (b) contacting a compound of formula (D) or a hydrate, solvate, or salt thereof with propylphosphonic anhydride under reaction conditions sufficient to form a compound of formula (R):
- and
- (c) contacting a compound of formula (R) or a salt thereof with a compound of formula (C) or a salt thereof:
- under reaction conditions sufficient to yield a compound of formula (A).
Crystalline 5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid hydrochloride (Compound of formula (D-a) Form I) characterized by an X-ray powder diffractogram comprising the following peaks:
- 7.3, 22.3, 23.4, 23.9, and 26.8 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.
Crystalline 5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid hydrochloride (Compound of formula (D-a) Form II) characterized by an X-ray powder diffractogram comprising the following peaks:
- 8.7, 12.1, 25.7, and 26.3 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.
Crystalline 5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid hydrate (Compound of formula (D) hydrate Form I) characterized by an X-ray powder diffractogram comprising the following peaks:
- 9.5, 20.4, 24.3, 26.5, and 28.7 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.
Crystalline 5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compound of formula (D) Form I) characterized by an X-ray powder diffractogram comprising the following peaks:
- 8.7, 15.2, 21.5, and 23.8 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.
Crystalline 5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compound of formula (D) Form II) characterized by a calculated X-ray powder diffractogram comprising the following peaks:
- 8.4, 13.6, and 15.5 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.
Crystalline 5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compound of formula (D) Form III) characterized by an X-ray powder diffractogram comprising the following peaks:
- 10.3, 17.1, 18.0, and 25.7 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.
Dependencies are inferred from the claim text.