Process For Preparing SHP2 Inhibitors

Patent metadata

Field	Value
Publication number	US-2025034160-A1
Application number	US-202418895975-A
Country	US
Kind code	A1
Filing date	Sep 25, 2024
Priority date	Mar 28, 2022
Publication date	Jan 30, 2025
Grant date	—

Abstract

Provided herein are methods for preparing a SHP2 inhibitor and intermediates useful therein.

First claim

1 . A method of preparing a compound of Formula (7):

comprising:
reacting a compound of Formula (6):

with a reducing agent to form the compound of Formula (7).

2 . The method of claim 1 , wherein the reducing agent is an organoaluminum hydride, an aluminum hydride, an organoborane hydride, or a borohydride reagent.

3 . The method of claim 1 or 2 , wherein the reaction is carried out using an alcohol, an aprotic solvent, or a mixture thereof as solvent.

4 . A method of preparing a compound of Formula (6):

comprising reacting a compound of Formula (5):

wherein R 2 is C 1 -C 6 alkyl, and TBDMS is tert-butyldimethylsilyl ether,
with a deprotecting agent to form the compound of Formula (6).

5 . The method of any one of claims 1-4 , wherein the compound of Formula (6) is prepared by reacting a compound of Formula (5):

wherein R 2 is C 1 -C 6 alkyl, and TBDMS is tert-butyldimethylsilyl ether,
with a deprotecting agent to form the compound of Formula (6).

6 . The method of claim 4 or 5 , wherein the deprotecting agent is a source of fluoride ion, acetyl chloride, N-iodosuccinimide, HCl, acetic acid, formic acid, phosphoric acid, FeCl 3 , AlCl 3 , CeCl 3 , oxalyl chloride, isobutyl chloroformate, ethyl chloroformate, or thionyl chloride.

7 . The method of any one of claims 4-6 , wherein the reaction of the compound of Formula (5) with the deprotecting agent is carried out using an aprotic solvent.

8 . The method of any one of claims 4-7 , wherein the compound of Formula (5) is prepared by reacting a compound of Formula (3):

with a compound of Formula (4):

wherein R 2 is C 1 -C 6 alkyl,
to form the compound of Formula (5).

9 . The method of claim 8 , wherein the reaction of the compound of Formula (3) with the compound of Formula (4) further comprises a base.

10 . The method of claim 8 or 9 , wherein the reaction of the compound of Formula (3) with the compound of Formula (4) is carried out using an aprotic solvent.

11 . The method of any one of claims 8-10 , wherein the compound of Formula (3) is prepared by reacting a compound of Formula (2):

wherein R 1 is C 1 -C 6 alkyl,
with a reducing agent to form the compound of Formula (3).

12 . The method of claim 11 , wherein the reducing agent used for the reaction of the compound of Formula (2) is an organoaluminum hydride, an aluminum hydride, an organoborane hydride, or a borohydride reagent.

13 . The method of claim 11 or 12 , wherein the reaction of the compound of Formula (2) with the reducing agent is carried out using an aprotic solvent.

14 . The method of any one of claims 11-13 , wherein the compound of Formula (2) is prepared by reacting a compound of Formula (1):

wherein R 1 is C 1 -C 6 alkyl,
with TBDMS-X, wherein X is a halide,
to form the compound of Formula (2).

15 . The method of claim 14 , wherein the reaction of the compound of Formula (1) with TBDMS-X further comprises a base.

16 . The method of claim 14 or 15 , wherein the reaction of the compound of Formula (1) with TBDMS-X is carried out using an aprotic solvent.

17 . A method of preparing a compound of Formula (8):

comprising reacting the compound of Formula (7) prepared according to the method of any one of claims 1 - 16 with a sulfonyl chloride or an acid chloride, and a base to form the compound of Formula (8).

18 . The method of claim 17 , wherein the sulfonyl chloride or the acid chloride is an arylsulfonyl chloride, an alkylsulfonyl chloride, or an aryl acid chloride.

19 . The method of claim 17 or 18 , wherein the reaction of Formula (7) with the sulfonyl chloride or the acid chloride and the base is carried out using a mixture of water and an aprotic solvent.

20 . A method of preparing a compound of Formula (9):

comprising reacting the compound of Formula (8) prepared according to the method of any one of claims 17 - 19 with an oxidizing agent to form the compound of Formula (9).

21 . The method of claim 20 , wherein the oxidizing agent is Dess-Martin periodinane, (2,2,6,6-tetramethylpiperidine-1-yl)oxyl (TEMPO), or sulfur trioxide pyridine complex.

22 . The method of claim 21 , wherein the reaction of the compound of Formula (8) with TEMPO further comprises (diacetoxyiodo)benzene or sodium hypochlorite, and optionally further comprises a salt.

23 . The method of any one of claims 20-22 , wherein the reaction of the compound of Formula (8) with the oxidizing agent is carried out using an aprotic solvent or a mixture of an aprotic solvent and water.

24 . A method of preparing a compound of Formula (10) or a salt thereof:

comprising reacting the compound of Formula (9) prepared according to the method of any one of claims 20 - 23 with an acid to form the compound of Formula (10) or a salt thereof.

25 . A method of preparing a compound of Formula (10)⋅HCl comprising the following steps:

wherein R 1 and R 2 are each independently methyl or ethyl.

26 . The method of any one of claims 20-25 , wherein the compound of Formula (9) and/or the compound of Formula (10), or a salt thereof, are prepared without use of column chromatography.

27 . A method of preparing a compound of Formula (11):

or a salt thereof, comprising converting the compound of Formula (10), or a salt thereof, prepared according to any one of claims 24 - 26 to the compound of Formula (11) or a salt thereof.

28 . A compound of Formula (6):

Assignees

• Genzyme Corp

Inventors

• Morana Fabio
• Gornati Davide
• Roletto Jacopo

Classifications

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title

• C07D211/22

  by oxygen atoms · CPC title

• C07D491/107 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D491/10

  Spiro-condensed systems · CPC title

• C07D211/20 Primary

  with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms · CPC title