Processes for preparing 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole

Patent metadata

Field	Value
Publication number	US-10266525-B2
Application number	US-201615578258-A
Country	US
Kind code	B2
Filing date	May 31, 2016
Priority date	Jun 2, 2015
Publication date	Apr 23, 2019
Grant date	Apr 23, 2019

Abstract

The present invention provides novel processes for preparing compounds of formula (IV) and salts thereof

novel intermediates, and a novel salt and polymorph thereof.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (IV) according to Scheme (I):
Scheme (I)

wherein:
R 1 is

 and
R 2 is

which process comprises the following steps:
(a) reacting a compound of formula (VII):

or a salt thereof,
wherein:
R 1a is

with a compound of formula (X):

or a salt thereof,
wherein:
X is halogen; and
P is tetrahydro-2H-pyran-2-yl;

in the presence of a palladium catalyst, to give a compound of formula (XI):

or a salt thereof,
wherein:
R 1a is

 and
P is tetrahydro-2H-pyran-2-yl;

(b) reacting the compound of formula (XI) above, or a salt thereof, with pinacolborane in the presence of (1,5-cyclooctadiene)(methoxy)iridium (I) dimer, to give a compound of formula (XII):

or a salt thereof,
wherein:
R 1a is

 and
P is tetrahydro-2H-pyran-2-yl;

(c) reacting the compound of formula (XII) above, or a salt thereof, with a compound of formula (XIV):
R 2 —X 1    (XIV)

or a salt thereof,
wherein:
R 2 is

 and
X 1 is halogen;

in the presence of a palladium catalyst, to give a compound of formula (XIII):

wherein:
R 1a is

R 2 is

 and
P is tetrahydro-2H-pyran-2-yl; and

(d) reacting the compound of formula (XIII) above with a reducing agent selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride, followed by deprotection, to give the compound of formula (IV) above; or
A process for preparing a compound of formula (IV) according to Scheme (II):

Scheme (II)

wherein:
R 1 is

 and
R 2 is

which process comprises the following steps:
(a) reacting a compound of formula (VII):

or a salt thereof,
wherein:
R 1a is

with a compound of formula (X):

or a salt thereof,
wherein:
X is halogen; and
P is tetrahydro-2H-pyran-2-yl;

in the presence of a palladium catalyst, to give a compound of formula (XI):

or a salt thereof,
wherein:
R 1a is

 and
P is tetrahydro-2H-pyran-2-yl;

(b) reacting the compound of formula (XI) above, or a salt thereof, with pinacolborane in the presence of (1,5-cyclooctadiene)(methoxy)iridium (I) dimer, to give a compound of formula (XII):

or a salt thereof,
wherein:
R 1a is

 and
P is tetrahydro-2H-pyran-2-yl;

(c) reacting the compound of formula (XII) above, or a salt thereof, with a compound of formula (XIV):
R 2 —X 1    (XIV)

or a salt thereof,
wherein:
R 2 is

 and
X 1 is halogen;

in the presence of a palladium catalyst, to give a compound of formula (XIII):

wherein:
R 1a is

R 2 is

 and
P is tetrahydro-2H-pyran-2-yl; and

(d) reacting the compound of formula (XIII) above with a reducing agent selected from the group consisting of sodium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride, followed by deprotection, to give the compound of formula (IV) above.

2. The process according to claim 1 , wherein:
R 1 is

 and
R 2 is

3. The process according to claim 1 , wherein:
R 1 is

 and
R 2 is

4. The process according to claim 1 , wherein the reducing agent is lithium aluminium hydride.

5. The process according to cla

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Bream Robert Nicholas
• Hayler John David
• Ironmonger Alan Geoffrey
• Szeto Peter
• Webb Michael Robert
• Wheelhouse Katherine Marie Penelope
• Willacy Robert David

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title