Processes for preparing an FGFR inhibitor

Patent metadata

Field	Value
Publication number	US-10538518-B2
Application number	US-201615748212-A
Country	US
Kind code	B2
Filing date	Aug 10, 2016
Priority date	Aug 11, 2015
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

To an appropriate reactor equipped with mechanical stirrer was charged acetic acid (12 L), tert-butyl 4-(3-(6-(3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-1-carboxylate (2000 g) and triethylamine (639 g, 2.3 eq.). Internal temperature was adjusted to approximately 20° C. and N-chlorosuccinimide (1651 g, 4.5 eq.) was added at 20-30° C. Reaction was stirred for 2 hours. Ethyl acetate (30 L) was added. 5% aqueous NaCl solution (20 L) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 30% aqueous potassium carbonate solution (14 L). The organic layer was concentrated to ˜12 L and used for next step directly.

First claim

What is claimed is:

1. A process of preparing a compound of formula (1):

comprising:
(G) reacting a compound of formula (e):

where R is alkyl; with a compound of formula (f):

and
(H) treating a compound of formula (g) formed in situ

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), where PG in formula (1) and formula (h) is an amino protecting group.

2. The process of claim 1 wherein Step G is carried out in the presence of a base, and in a polar organic solvent.

3. The process of claim 1 wherein the process of Step H is carried out in the presence of a base and in a polar organic solvent.

4. A process for preparing a compound of formula (2) and/or (3):

comprising reacting a compound of formula (1):

with a N-chlorosuccinimide (NCS) to provide the compound of formula (2) and/or (3):

where PG is an amino protecting group.

5. A process for preparing a compound of formula (4):

comprising treating a compound of formula (2) and/or (3):

with methylamine to give the compound of formula (4)

6. A process for preparing a compound of formula (5):

or a salt thereof; comprising removing the amino protecting group “PG” of compound (4)

to give the compound of formula (5):

or a salt thereof.

7. A process of preparing a compound of formula (d) comprising reacting a compound of formula (6) with a compound of formula (iii) where LG is a leaving group under acylating reaction conditions

to give a compound of formula (d); or
reacting a compound of formula (6) with propenoic acid under amide bond formation reaction conditions:

to give a compound of formula (d).

Assignees

• Principia Biopharma Inc

Inventors

• Zhu Jiang
• Masjedizadeh Mohammad

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07B35/06

  Decomposition, e.g. elimination of halogens, water or hydrogen halides · CPC title

• C07B45/04

  of sulfonyl or sulfinyl groups · CPC title