Process for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Inventors

Eary, Charles Todd • Spencer, Stacey • Crane, Zack • Chando, Katelyn • Asselin, Sylvie • Liu, Weidong • Welch, Mike • Cook, Adam • Kolakowski, Gabrielle R. • Metcalf, Andrew T. • Moreno, David A. • Tang, Tony P.

Assignees

Array Biopharma Inc • Loxo Oncology Inc

Abstract

In some embodiments, provided herein is a process for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof, as disclosed herein.

Core Innovation

The invention describes a process for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof through sequential conversion of specified intermediates. The disclosed routes include triflating, metal-catalyzed coupling using a compound of formula 12 in which X represents a halogen or a sulfonate and R6 represents a boronic acid or ester with the boron atom as the point of attachment to the pyridine ring, handling of intermediates bearing an amine protecting group R1, deprotecting, and final reaction with 6-methoxynicotinaldehyde and a reducing agent to form Formula I.

Alternative embodiments vary the route by using 2,2-dimethyloxirane in the presence of a strong base, dealkylating and triflating sequences to form earlier intermediates, and diboronic acid or ester treatment followed by oxidation with hydrogen peroxide and a strong base. Another disclosed variant uses a palladium catalyst with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to form an intermediate prior to amine-protected coupling, deprotection, and conversion to Formula I.

Across the disclosed routes, the common downstream sequence forms an intermediate of formula 15 from a precursor with R1 as an amine protecting group, converts formula 15 to formula 16 with a deprotecting agent, and then treats formula 16 with 6-methoxynicotinaldehyde and a reducing agent to obtain Formula I or a pharmaceutically acceptable salt thereof. The description also reports additional reagent classes used across the route, including triflating reagents, bases, oxidants including hydrogen peroxide, and catalyst metals.

Claims Coverage

The consolidated claims coverage includes six inventive features across the independent process claims, all directed to preparation of Formula I or a pharmaceutically acceptable salt thereof. The claims center on triflating and metal-catalyzed coupling, epoxide-mediated intermediate formation using 2,2-dimethyloxirane, diboronic acid or ester oxidation with hydrogen peroxide, palladium coupling with a dioxaborolanyl pyridine, amine protecting group handling with deprotecting, and final conversion with 6-methoxynicotinaldehyde and a reducing agent.

Across the independent claims, the inventive coverage centers on processes that reach Formula I by building or converting named intermediates through triflating and metal-catalyzed coupling with a pyridine-attached boronic acid or ester, epoxide-mediated transformations using 2,2-dimethyloxirane, diboronic acid or ester oxidation with hydrogen peroxide, amine protecting group introduction and removal, and final reaction with 6-methoxynicotinaldehyde and a reducing agent.

Stated Advantages

Documented Applications

No documented applications found