Processes 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. A process of preparing a compound of formula (I):
comprising:
(A) treating compound of formula (a), where X is a leaving group under elimination reaction conditions, with a base
to provide the compound of formula (I); or
(B) reducing the acetylene bond in compound (b)
to provide the compound of formula (I); or
(C) treating a compound of formula (c) with a reducing agent
to provide the compound of formula (I); or
(D) chlorinating a compound of formula (d)
to provide the compound of formula (I).
2. The process of claim 1 wherein the process comprises treating the compound of formula (a) with a base
to provide the compound of formula (I).
3. The process of claim 1 wherein the process comprises reducing the acetylene bond in compound (b)
to provide the compound of formula (I).
4. The process of claim 1 wherein the process comprises treating a compound of formula (c) with a reducing agent
to provide the compound of formula (I).
5. The process of claim 1 wherein the process comprises chlorinating the compound of formula (d)
to provide the compound of formula (I).
6. The process of claim 2 wherein X is halo, phosphate, mesylate, tosylate, or 1,1,1-trifluoro-N-[(trifluoromethyl)sulfonate.
7. The process of claim 2 wherein the reaction is carried out in an aprotic, polar organic solvent.
8. The process of claim 7 wherein the base is either an organic or an inorganic base.
9. The process of claim 3 wherein the reducing agent is Lindlar catalyst.
10. The process of claim 4 where the reducing agent is sodium borohydride or i-PrMgCl/THF and an organic or inorganic acid.
11. The process of claim 5 wherein the process comprises chlorinating with a chlorinating agent that is N-chlorosuccinimide (NCS), sulfonyl chloride, or sulfuryl chloride.
12. The process of claim 11 wherein the chlorinating agent is NCS, the reaction is carried out in a halogenated hydrocarbon, and in the presence of an organic acid or an organic base.