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

Patent metadata

Field	Value
Publication number	US-10899745-B2
Application number	US-201816498442-A
Country	US
Kind code	B2
Filing date	Mar 29, 2018
Priority date	Mar 30, 2017
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

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.

First claim

We claim:

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.

Assignees

• Bristol Myers Squibb Co

Inventors

• Chen Ke
• Deerberg Joerg
• Lin Dong
• Dummeldinger Michael
• Inankur Bahar
• Kolotuchin Sergei
• Li Jun
• Rogers Amanda J
• Rosso Victor W
• Simmons Eric M
• Treitler Daniel S
• Wang Jianji
• Smith Michael J
• Benkovics Tamas

Classifications

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07C309/73

  to carbon atoms of non-condensed six-membered aromatic rings · CPC title

• C07C303/28

  by reaction of hydroxy compounds with sulfonic acids or derivatives thereof · CPC title

• C07C233/90

  having nitrogen atoms of carboxamide groups further acylated · CPC title

• C07C231/08

  from amides by reaction at nitrogen atoms of carboxamide groups · CPC title