Manufacture of compounds and compositions for inhibiting the activity of SHP2

Patent metadata

Field	Value
Publication number	US-11873307-B2
Application number	US-201917280632-A
Country	US
Kind code	B2
Filing date	Sep 18, 2019
Priority date	Sep 29, 2018
Publication date	Jan 16, 2024
Grant date	Jan 16, 2024

Abstract

The present invention relates to a method for the manufacture of a compound of Formula I or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said method comprising reacting a compound of the formula II with a compound of the formula III according to the following reaction scheme: wherein LG, A, n, m and p are as defined in the Summary of the Invention.

First claim

The invention claimed is:

1. A method for the manufacture of a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said method comprising reacting a compound of formula II with a compound of formula III according to the following reaction scheme:

wherein LG is a leaving group, A is the anion of a protic acid, and n, m and p are independently 1, 2 or 3, so that the compound of formula II is electrically neutral.

2. The method according to claim 1 , wherein the compound of formula II is obtained either (i) by deprotecting or (ii) by reducing a compound of the formula IV,

wherein in case (i) R 1 is a secondary amino protecting group and R 2 is a protected amino group and R 3 is hydrogen, or in case (ii) R 1 is a secondary amino protecting group, R 2 is amino and R 3 is hydroxyl, and if required, reacting the resulting compound of formula IVa:

with an acid of the formula H n A to yield the compound of formula II.

3. The method according to claim 2 , wherein the compound of formula IV is a compound of formula IX:

wherein R 1 is a secondary amino protecting group;
wherein the compound of formula IX is obtained by reducing a compound of formula VIII:

wherein R 1 is a secondary amino protecting group, to yield the compound of formula IX.

4. The method of claim 3 , wherein the compound of formula VIII is obtained by hydrogenating a compound of formula VII:

wherein R 1 is a secondary amino protecting group, to yield the compound of formula VIII.

5. The method of claim 4 , wherein the compound of formula VII is obtained by cyclizing a compound of formula VI:

wherein R 1 a secondary amino protecting group and R 5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, with hydroxylamine, or a salt thereof, to yield the compound of formula VII;
or alternatively by reacting a compound of formula VI*:

wherein R 1 is a secondary amino protecting group, with hydroxylamine, or a salt thereof, to yield the compound of formula VII.

6. The method of claim 5 , wherein the compound of formula VI or the compound of formula VI* is obtained by reacting a compound of formula V:

wherein R 1 is a secondary amino protecting group and R 4 is a carboxyl (—COOH) protecting group, in the presence of a strong base with L-lactide of the formula:

to yield the compound of formula VI or alternatively the compound of formula VI*.

7. The method of claim 4 , wherein the compound of formula VII is obtained by reacting a compound of formula V:

wherein R 1 is a secondary amino protecting group and R 4 is a carboxyl (—COOH) protecting group, in the presence of a strong base with L-lactide of the formula:

to provide an intermediate; and
subsequently reacting the intermediate with hydroxylamine, or a salt thereof, to yield the compound of formula VII.

8. The method of claim 2 , wherein the compound of formula IV is a compound of formula XIII*:

wherein R 1 is a secondary amino protecting group and *R 2 is an acylated amino group;
wherein the compound of formula XIII* is obtained by hydrogenating a compound of formula VIII*:

wherein R 1 is a secondary amino protecting group and *R 2 is an acylated amino group; in the presence of a chiral hydrogenation catalyst to yield a compound of formula X*:

wherein R 1 is a secondary amino protecting group and *R 2 is an acylated amino group;
reducing the compound of formula X* to yield a compound of formula XI*:

wherein R 1 is a secondary amino protecting group and *R 2 is an acylated amino group;
reacting the compound of formula XI* with a leaving group forming agent of the formula LG*-X wherein LG* is an electrophilic radical capable of forming, with a hydroxy to which it is bound, a leaving group LG2, and X is halogen, to yield a compound of formula XII*:

wherein R 1 is a secondary amino protecting group, *R 2 is an acylated amino group, and LG2 is a leaving group; and
cyclizing the compound of formula XII* under basic conditions to yield the compound of formula XIII*.

9. The method of claim 8 , wherein the compound of formula VIII* is obtained by acylating a compound of formula VII:

wherein R 1 a secondary amino protecting group, under reducing conditions to yield the compound of formula VIII*.

10. The method of claim 9 , wherein the compound of formula VII is obtained by cyclizing a compound of formula VI:

wherein R 1 a secondary amino protecting group and R 5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, with hydroxylamine, or a salt thereof, to yield the compound of formula VII;
or alternatively by reacting a compound of formula VI*:

wherein R 1 is a secondary amino protecting group, with hydroxylamine, or a salt thereof, to yield the compound of formula VII.

11. The method of claim 10 , wherein the compound of formula VI or the compound of formula VI* is obtained by reacting a compound of formula V:

wherein R 1 is a secondary amino protecting group and R 4 is a carboxyl (—COOH) protecting group, in the presence of a strong base with L-lactide of the formula:

to yield the compound of formula VI or alternatively the compound of formula VI*.

12. The metho

Assignees

• Novartis Ag

Inventors

• Fei Zhongbo
• Jia Huanqing
• Li Wei
• Lin Xiaohui
• Min Zhongcheng
• Wang Hui
• Wang Jianhua
• Zhang Hao

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07D491/107 Primary

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

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D211/26

  with hydrocarbon radicals, substituted by nitrogen atoms · CPC title

• C07D211/22

  by oxygen atoms · CPC title