Process for Preparing an FGFR Inhibitor
Disclosed herein are processes for preparing 8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one and FGFR inhibitor, as well as polymorphs and/or salt forms thereof.
1 - 38 . (canceled)
39 . A process of preparing a compound of formula (I):
comprising:
reacting a compound of formula (5):
or a salt thereof with a compound (iii) wherein LG is a leaving group
40 . The process of claim 39 , wherein LG in compound (iii) is a halo.
41 . The process of claim 39 , wherein the resultant compound of formula (I) is crystalline.
42 . The process of claim 39 , wherein the compound of formula (5)
or a salt thereof is prepared by a process comprises removing PG of compound (4)
wherein PG is a protecting group.
43 . The process of claim 42 , wherein the PG is a tert-butoxycarbonyl protecting group.
44 . The process of claim 42 , wherein the compound (4)
is prepared by a process comprising treating a compound of formula (2) or (3):
wherein each PG is an amino protecting group,
with methylamine.
45 . The process of claim 44 , wherein each PG is a tert-butoxycarbonyl protecting group.
46 . The process of claim 44 , wherein compound (2)
is prepared by a process of comprising reacting compound (1)
or a salt thereof, with N-chlorosuccinimide
wherein each PG is an amino protecting group.
47 . The process of claim 46 , wherein each PG is a tert-butoxycarbonyl protecting group.
48 . The process of claim 46 , wherein compound (1)
or salt thereof, is prepared by a process of comprising reacting a compound of formula (e):
wherein R is alkyl, with a compound of formula (f):
and
treating a compound of formula (g)
formed from the reaction of compound (e) and (f), with a compound of formula (h)
or a salt thereof under alkylating reaction conditions to provide a compound of formula (1),
wherein each PG is an amino protecting group and LG in formula (h) is a leaving group.
49 . The process of claim 48 , wherein each PG is a tert-butoxycarbonyl protecting group.
50 . The process of claim 48 , wherein the LG in formula (h) is a mesylate group.
51 . The process of claim 48 , wherein the compound of formula (e):
is prepared by a process comprising reacting 2-(3,5-dimethoxyphenyl)acetic acid with an alcohol and an acid.
52 . The process of claim 51 , wherein R is methyl and the alcohol is methanol.
53 . The process of claim 51 , wherein the acid is sulfuric acid.
54 . A process for preparing a compound of formula (2) and/or formula (3), comprising reacting a compound of formula (1):
or a salt thereof, with a N-chlorosuccinimide to provide a compound of formula (2) and/or (3):
where each PG is an amino protecting group.
55 . The process of claim 54 , wherein the reaction of a compound of formula (1) or a salt thereof with N-chlorosuccinimide provides a compound of formula (2).
56 . The process of claim 54 , wherein each PG is a tert-butoxycarbonyl protecting group.
57 . A process for preparing a compound of formula (4), comprising treating a compound of formula (2) or (3):
with methylamine to give a compound of formula (4)
wherein each PG is an amino protecting group.
58 . The process of claim 57 , wherein the compound of formula (4) is prepared by treating a compound of formula (2) with methylamine.
59 . The process of claim 57 , wherein each PG is a tert-butoxycarbonyl protecting group.