Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
The invention relates to an improved process for synthesizing 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide of the formula: [INSERT CHEMICAL STRUCTURE HERE] Compound I is currently in clinical trials for the treatment of auto-immune and auto-inflammatory diseases such as psoriasis.
1. A process for the preparation of Compound I of the formula
comprising the steps of
a) reacting compound 1a of the formula,
where R is C 1 -C 6 alkyl or aryl;
with activating reagents to afford Compound 2a of the formula,
where X 1 and X 2 are independently halide or sulfonate; and R is defined as above,
b) subsequently reacting Compound 2a with an aqueous base to afford Compound 3a of the formula,
where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and X 1 and X 2 are as defined above,
c) reacting Compound 3a, with Compound 7 of the formula
in a suitable solvent, and optionally in the presence of an acid, a base, or metal salts to afford Compound 8a of the formula,
where M and X 2 are defined as above,
d) reacting Compound 8a with Compound 10 of the formula
in the presence of a suitable transition metal catalyst, a ligand, one or more bases, and one or more suitable solvents to afford Compound 9a of the formula,
where M is defined as above,
e) reacting Compound 9a with Compound 13, or a free base or salt thereof, of the formula,
D 3 C—NH 2 Compound 13
in the presence of one or more suitable activators, one or more suitable solvents, and optionally a base, to afford Compound I.
2. A process for the preparation of Compound I of the formula
comprising the steps of
a) reacting compound 1 of the formula
with POCl 3 and optionally an amine base, followed optionally by a buffered aqueous workup to afford Compound 2 of the formula
b) subsequently reacting Compound 2 with LiBr and DiPEA in water and acetonitrile to afford Compound 3 of the formula
c) reacting Compound 3, with Compound 7 of the formula
in the presence of zinc acetate in water and 2-propanol, to afford Compound 8 of the formula,
or a hydrate or solvate thereof;
d) reacting Compound 8 with Compound 10 of the formula
in a palladium catalyzed C—N coupling reaction in the presence of a phosphine ligand, and base, using a dual-base system comprised of potassium carbonate and DBU, followed optionally by isolation from aqueous acetic acid, to afford Compound 9 of the formula
or a hydrate or solvate thereof;
e) reacting Compound 9 with EDC or other coupling agents and Compound 13 of the formula
CD 3 NH 2 HCl Compound 13
to afford Compound I, which may be further purified by crystallization from NMP/IPA.