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

Patent metadata

Field	Value
Publication number	US-2019106438-A1
Application number	US-201816156955-A
Country	US
Kind code	A1
Filing date	Oct 10, 2018
Priority date	Oct 10, 2017
Publication date	Apr 11, 2019
Grant date	—

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.

First claim

We claim:

1 . A process for preparing a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein the process comprises treating a compound of formula 16

or a salt thereof with 6-methoxynicotinaldehyde and a reducing agent to form the compound of Formula I or a pharmaceutically acceptable salt thereof.

2 . The process of claim 1 , further comprising preparing the compound of formula 16, the process comprising treating a compound of formula 15

or a salt thereof, wherein R 1 is an amine protecting group, with a deprotecting agent to form the compound of formula 16 or a salt thereof.

3 . The process of claim 2 , further comprising preparing the compound of formula 15 or a salt thereof, wherein R 1 is an amine protecting group, comprising:
treating a compound of formula 13

or a salt thereof, wherein X represents a halogen or a sulfonate, with a compound of formula 14

or a salt thereof, wherein R 1 is an amine protecting group, to form the compound of formula 15 or a salt thereof.

4 . The process of claim 3 , further comprising preparing the compound of formula 13 or a salt thereof, the process comprising treating a compound of formula 20

or a salt thereof, wherein X represents a halogen or a sulfonate, with a compound of formula 21

in the presence of 2,2-dimethyloxirane, a first catalyst comprising a metal, and a first weak base to form the compound of formula 13 or a salt thereof.

5 . The process of claim 3 , further comprising preparing the compound of formula 13 or a salt thereof, the process comprising:
treating a compound of formula 20 or a salt thereof with a first diboronic acid or ester in the presence of a second catalyst comprising a metal to form a compound of formula 22

or a salt thereof, wherein X represents a halogen or a sulfonate and R 5 represents a boronic acid or ester with the boron atom as the point of attachment to the pyrazolopyridine ring of compound 22 or a salt thereof;
treating the compound of formula 22 or a salt thereof with a first strong base and hydrogen peroxide to form a compound of formula 23

or a salt thereof, wherein X represents a halogen or a sulfonate; and
treating the compound of formula 23 or a salt thereof with 2,2-dimethyloxirane in the presence of a second strong base to form the compound of formula 13 or a salt thereof.

6 . The process of claim 3 , further comprising preparing the compound of formula 13 or a salt thereof, the process comprising:
treating a compound of formula 35

or a salt thereof with a first triflating reagent to form a compound of formula 36

or a salt thereof; and
treating the compound of formula 36 or a salt thereof with a compound of formula 12

or a salt thereof, wherein X represents a halogen or a sulfonate and R 6 represents a boronic acid or ester with the boron atom as the point of attachment to the pyridine ring of compound 12, in the presence of a third catalyst comprising a metal to form the compound of formula 13 or a salt thereof.

7 . The process of claim 6 , further comprising preparing the compound of formula 35 or a salt thereof, the process comprising:
treating a compound of formula 33

or a salt thereof with 2,2-dimethyloxirane in the presence of a third strong base to form the compound of formula 34

or a salt thereof; and
treating the compound of formula 34 or a salt thereof with a first dealkylating agent to form the compound of formula 35 or a salt thereof.

8 . The process of claim 7 , further comprising preparing the compound of formula 33 or a salt thereof, the process comprising:
treating a compound of formula A

or a salt thereof with a second diboronic acid or ester in the presence of a fourth catalyst comprising a metal to form a compound of formula 32

or a salt thereof, wherein R 9 represents a boronic acid or ester with the boron atom as the point of attachment to the pyrazolopyridine ring of compound 32 or a salt thereof; and
treating the compound of formula 32 or a salt thereof with a first oxidant to form the compound of formula 33 or a salt thereof.

9 . The process of claim 4 or claim 5 , further comprising preparing the compound of formula 20 or a salt thereof, the process comprising treating a compound of formula 19

or a salt thereof with a compound of formula 12

or a salt thereof, wherein X represents a halogen or a sulfonate and R 6 represents a boronic acid or ester with the boron atom as the point of attachment to the pyridine ring of compound 12, in the presence of a eighth catalyst comprising a metal to form the compound of formula 20 or a salt thereof.

10 . A process for preparing a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein the process comprises treating a compound of formula 29

or a salt thereof with a compound of formula 21

in the presence of 2,2-dimethyl dioxirane, a sixth catalyst comprising a metal, and a second weak base to form the compound of Formula I or a pharmaceutically acceptable salt thereof.

11 . A process for preparing a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein the process comprises:
a) treating a compound of formula 29

or a salt thereof wit

Assignees

• Loxo Oncology Inc
• Array Biopharma Inc

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

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title