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-carbontrile

Patent metadata

Field	Value
Publication number	US-11098064-B2
Application number	US-202016902424-A
Country	US
Kind code	B2
Filing date	Jun 16, 2020
Priority date	Oct 10, 2017
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

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 the steps of:
a) 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;
b) 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;
c) treating the compound of formula 13 or a salt thereof with a compound of formula 14

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

or a salt thereof;
d) treating the compound of formula 15 or a salt thereof with a deprotecting agent to form the compound of formula 16

or a salt thereof; and
e) treating the 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; the process further comprising preparing the compound of formula 35 or a salt thereof, by:
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.

2. The process of claim 1 , 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.

3. The process of claim 1 , wherein the metal of the third catalyst is selected from the group consisting of nickel, palladium, and platinum.

4. The process of claim 2 , wherein the first oxidant is selected from the group consisting of O 2 , N-methylmorpholine N-oxide (NMO), chloranil (CA), 7,7,8,8-tetracyanoquinodimethane (TCNQ), benzylidene-malononitrile (BMCN), tetracyanoethylene (TCNE), 2,3-dicyano-1,4-benzoquinone (DCBQ), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

5. A process for preparing a compound of Formula I

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

or a salt thereof with a compound of formula 24

or a salt thereof, wherein R 1 is an amine protecting group and R 3 represents a boronic acid or ester with the boron atom as the point of attachment to the pyridine ring of compound 24, in the presence of a ninth catalyst comprising a metal to form a compound of formula 25

or a salt thereof;
b) treating the compound of formula 25 with a fourth diboronic acid or ester in the presence of a tenth catalyst comprising a metal to form a mixture, and treating the mixture with a seventh strong base and hydrogen peroxide to form the compound of formula 26

or a salt thereof;
c) treating a compound of formula 26 or a salt thereof with 2,2-dimethyloxirane in the presence of a sixth strong base to form the compound of formula 15

or a salt thereof;
d) treating a compound of formula 15 or a salt thereof with a deprotecting agent to form the compound of formula 16

or a salt thereof; and
e) 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.

6. The process of claim 5 , further comprising preparing the compound of formula B or a salt thereof by a process comprising:
a) treating a compound of formula 8

or a salt thereof with O-(mesitylsulfonyl)hydroxylamine to form the compound of formula 9

b) treating the compound of formula 9 with acrylonitrile or an acrylonitrile derivative in the presence of a second non-nucleophilic base to form a mixture, and treating the mixture with a second oxidant to form the compound of formula B.

7. The process of claim 5 , wherein the sixth strong base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide.

8. The process of claim 6 , wherein the second oxidant is selected from the group consisting of O 2 , N-methylmorpholine N-oxide (NMO), chloranil (CA), 7,7,8,8-tetracyanoquinodimethane (TCNQ), benzylidene-malononitrile (BMCN), tetracyanoethylene (TCNE), 2,3-dicyano-1,4-benzoquinone (DCBQ), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

9. A compound of formula 25a:

or a pharmaceutically acceptable salt thereof.

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