Processes for preparing modulators of alpha-1 antitrypsin
This disclosure provides large-scale processes for preparing a modulator of alpha-1 antitrypsin (AAT) activity that may be useful for treating alpha-1 antitrypsin deficiency (AATD), such as 4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1), 3-[5-(4-fluorophenyl)-6-isopropyl-1H-pyrrolo[2,3-f]indazol-7-yl]propanoic acid (Compound 2), or a pharmaceutically acceptable salt of any of the foregoing.
1 . A process for preparing a solid form of Compound 1
or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting
or a pharmaceutically acceptable salt thereof with
to form
or a pharmaceutically acceptable salt thereof; and
(b) de-esterifying C58B or a pharmaceutically acceptable salt thereof to yield the solid form of Compound 1 or a pharmaceutically acceptable salt thereof.
2 . The process according to claim 1 , wherein
(i) step (a) comprises reacting B1 or a pharmaceutically acceptable salt thereof with D1 in the presence of a palladium-phosphine complex-based catalyst that is bis(tri-t-butylphosphine) Pd and a base that is potassium carbonate and wherein the reaction is optionally carried out at about 75° C.; or
(ii) step (a) comprises reacting B1 or a pharmaceutically acceptable salt thereof with D1 in the presence of a solvent that is 2-methyltetrahydrofuran and wherein the reaction is optionally carried out at about 75° C.; or
(iii) step (a) comprises reacting B1 or a pharmaceutically acceptable salt thereof with D1 in the presence of a palladium-phosphine complex-based catalyst that is bis(tri-t-butylphosphine) Pd and a base that is potassium carbonate and in the presence of 2-methyltetrahydrofuran and wherein the reaction is optionally carried out at about 75° C.
3 . The process according to claim 1 , wherein step (b) comprises de-esterifying C58B or a pharmaceutically acceptable salt thereof with a base that is sodium hydroxide and in the presence of a solvent that is tetrahydrofuran; and wherein step (b) is optionally carried out at about 55-65° C.
4 . The process according to claim 1 , wherein the process further comprises an additional step selected from:
step (a1) reacting
or a pharmaceutically acceptable salt thereof with pivaloyl chloride to form A1 or a pharmaceutically acceptable salt thereof,
wherein the reaction is optionally carried out in the presence of a base that is sodium tert-amylate and a solvent that is tetrahydrofuran; and
wherein the reaction is optionally carried out at about 10-20° C.; and/or
step (a2) reacting
or a pharmaceutically acceptable salt thereof with 4-fluorophenylboronic acid to form B1 or a pharmaceutically acceptable salt thereof,
wherein the reaction is optionally carried out in the presence of (1) a reducing agent that is dimethylsilyloxy(dimethyl)silane; or (2) a phosphetane oxide catalyst that is hexamethyloxophosphetane and a solvent that is toluene; and
wherein the reaction is optionally carried out at about 90° C.
5 . The process according to claim 1 , wherein the process further comprises an additional step selected from:
step (b1) reacting
with oxane-4-carbonyl chloride to form
wherein step (b1) is optionally carried out in the presence of a base that is potassium tert-butoxide and a solvent that is tetrahydrofuran; and/or
step (b2) reacting
with a sodium chloride aqueous solution to form
wherein step (b2) is optionally carried out in the presence of in the presence of a solvent that is dimethyl sulfoxide; and
wherein step (b2) is optionally carried out at about 150° C.