Synthesis of copanlisib and its dihydrochloride salt

Patent metadata

Field	Value
Publication number	US-10494372-B2
Application number	US-201515524581-A
Country	US
Kind code	B2
Filing date	Nov 5, 2015
Priority date	Nov 7, 2014
Publication date	Dec 3, 2019
Grant date	Dec 3, 2019

Abstract

The present invention relates to a novel method of preparing copanlisib, copanlisib dihydrochloride, or hydrates of copanlisib dihydrochloride, to novel intermediate compounds, and to the use of said novel intermediate compounds for the preparation of said copanlisib, copanlisib dihydrochloride, or hydrates of copanlisib dihydrochloride. The present invention also relates to copanlisib dihydrochloride hydrates as compounds.

First claim

The invention claimed is:

1. A method of preparing copanlisib (10):

comprising the following step A9:
reacting a compound of formula (9):

with a compound of formula (9b):

in the presence of a catalyst, in the presence of a coupling agent, and in a solvent,
to provide copanlisib (10):

wherein the compound of formula (9):

is prepared by the following step A8:
reacting a compound of formula (8):

with a compound of formula (8a):

in the presence of a base, in a solvent, and optionally with heating,
to provide the compound of formula (9);
wherein the compound of formula (8):

is prepared by the following step A7:
reacting a compound of formula (7):

with a reducing agent, in the presence of a catalyst, dissolved in a solvent or in suspension in a solvent, and optionally in presence of an acid,
to provide the compound of formula (8);
wherein the compound of formula (7):

is prepared by the following step A6:
reacting a compound of formula (6):

with cyanogen bromide as annelating agent, in the presence of a base, and in a solvent,
to provide the compound of formula (7);
and wherein the compound of formula (6):

is prepared by the following step A5:
reacting a compound of formula (5):

with a reducing agent, in the presence of a catalyst, and dissolved in a solvent or in suspension in a solvent,
to provide the compound of formula (6).

2. The method according to claim 1 , wherein the compound of formula (6):

is prepared by the following step A5:
reacting a compound of formula (5):

with hydrogen in the presence of a bimetallic catalyst, which is 1% Pt/0.2% Fe/C which is water-wetted in suspension in tetrahydrofuran,
to provide the compound of formula (6).

3. The method according to claim 2 , wherein the compound of formula (5):

is prepared by the following step A4:
reacting a compound of formula (4):

with ethylenediamine, in the presence of N-bromosuccinimide, and in a solvent mixture,
to provide the compound of formula (5).

4. The method according to claim 3 , wherein the compound of formula (4):

is prepared by the following step A3:
reacting a compound of formula (3):

with benzyl bromide, in a solvent, in the presence of a base, and optionally with heating,
to provide the compound of formula (4).

5. The method according to claim 4 , wherein the compound of formula (3):

is prepared by the following step A2:
reacting a compound of formula (2):

with a base and in a solvent,
to provide the compound of formula (3).

6. The method according to claim 5 , wherein the compound of formula (2):

is prepared by the following step A1:
reacting a compound of formula (1):

in solution in a solvent, with nitric acid and sulphuric acid,
to provide the compound of formula (2).

7. The method according to claim 1 , wherein the compound of formula (9b):

is prepared by the following step A10:
a) reacting a compound of formula (9a):

with a base, in a solvent, with heating to form a reaction mixture;
b) cooling the reaction mixture from a), and adding methyl formate to the resulting reaction mixture;
c) adding guanidine hydrochloride to the reaction mixture from b), followed by heating;
d) adding water and an aqueous solution of a base to the reaction mixture from c), followed by heating;
e) adding an aqueous solution of a mineral acid to the reaction mixture from d);
f) adding an amine to the reaction mixture from e), and filtering off a resulting solid;
g) adding an aqueous solution of a strong base to the reaction mixture from f); and
h) adding an aqueous solution of a mineral acid to the reaction mixture from g),

to provide the compound of formula (9b):

8. The method according to claim 1 , which further comprises the following step A11:
reacting copanlisib (10):

with hydrogen chloride
to provide copanlisib dihydrochloride (11):

9. The method according to claim 8 , wherein copanlisib (10) or copanlisib dihydrochloride (11) is prepared by the following steps shown in Reaction Scheme 3:

wherein:
step A1 comprises nitration of the compound of formula (1) to provide the compound of formula (2);
step A2 comprises hydrolysis of the compound of formula (2) to provide the compound of formula (3);
step A3 comprises al

Assignees

• Bayer Pharma AG

Inventors

• Peters Jan-Georg
• Rubenbauer Philipp
• Götz Daniel
• Grossbach Danja
• Mais Franz-Josef
• Schirmer Heiko
• Stiehl Juergen
• Lovis Kai
• Lender Andreas
• Seyfried Martin
• Zweifel Theodor
• Marty Maurus
• Weingärtner Günter

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D295/088

  to an acyclic saturated chain · CPC title

• C07D233/22

  Radicals substituted by oxygen atoms · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title