Method for producing spirooxindole derivative

Patent metadata

Field	Value
Publication number	US-2016194331-A1
Application number	US-201414916677-A
Country	US
Kind code	A1
Filing date	Sep 3, 2014
Priority date	Sep 4, 2013
Publication date	Jul 7, 2016
Grant date	—

Abstract

The present invention is intended to provide a method for efficiently producing and providing a compound having a spirooxindole skeleton, for example, a compound having a spirooxindole skeleton and having antitumor activity that inhibits the interaction between Mdm2 protein and p53 protein, or an intermediate thereof, using an asymmetric catalyst. A compound having an optically active tricyclic dispiroindole skeleton is efficiently obtained through a catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate and using a chiral ligand and a Lewis acid.

First claim

1 . A method for reacting a compound represented by formula (I):

a compound represented by formula (II):

and a compound represented by formula (III):

in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof:

wherein
R 1 represents a hydrogen atom, a C 1 -C 6 alkylcarbonyl group optionally having 1 to 3 substituents independently selected from group A below, or a C 1 -C 6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below,
R 2 represents a 5- or 6-membered heteroaryl group having, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenyl group, a C 3 -C 6 cycloalkyl group, or a C 3 -C 6 cycloalkenyl group, wherein
the 5- or 6-membered heteroaryl group, the phenyl group, the C 3 -C 6 cycloalkyl group, and the C 3 -C 6 cycloalkenyl group each optionally have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a vinyl group, an ethynyl group, a cyano group, a hydroxy group, an amino group, a carboxy group, an aminocarbonyl group, a C 1 -C 6 alkyl group optionally having 1 to 3 substituents independently selected from group A below, a C 3 -C 4 cycloalkyl group optionally having 1 to 3 substituents independently selected from group A below, a C 1 -C 6 alkoxy group optionally having 1 to 3 substituents independently selected from group A below, a C 3 -C 4 cycloalkoxy group optionally having 1 to 3 substituents independently selected from group A below, a C 1 -C 6 alkylamino group optionally having 1 to 3 substituents independently selected from group A below, a di-C 1 -C 6 alkylamino group optionally having 1 to 3 substituents independently selected from group A below, a 4- to 7-membered saturated heterocyclic group containing one nitrogen atom in the ring and optionally having 1 to 3 substituents independently selected from group B below, a C 1 -C 6 alkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below, a C 3 -C 4 cycloalkoxycarbonyl group optionally having 1 to 3 substituents independently selected from group A below, a C 1 -C 6 alkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from group A below, and a C 3 -C 4 cycloalkylaminocarbonyl group optionally having 1 to 3 substituents independently selected from group A below,

R 3 and R 4 each independently represent a C 1 -C 6 alkyl group optionally having 1 to 3 substituents independently selected from group C below, or
R 3 and R 4 optionally together form a C 4 -C 6 cycloalkyl ring, a tetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring, wherein
the C 4 -C 6 cycloalkyl ring, the tetrahydrofuran ring, the tetrahydropyran ring, and the piperidine ring each optionally have 1 to 8 substituents independently selected from group D below,

R 5 represents a C 1 -C 6 alkoxy group optionally having 1 to 3 substituents independently selected from group E below, a C 3 -C 8 cycloalkoxy group optionally having 1 to 3 substituents independently selected from group E below, a C 2 -C 6 alkenyloxy group, or —NR 51 R 52 ,
R 51 and R 52 each independently represent a hydrogen atom, a C 1 -C 8 alkyl group optionally having 1 to 3 substituents independently selected from group E below, a C 3 -C 8 cycloalkyl group optionally having 1 to 3 substituents independently selected from group E below, or a 3- to 6-membered saturated heterocyclic group having, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 to 3 substituents independently selected from group E below, and
ring Z represents a benzene ring optionally having 1 to 4 substituents independently selected from group E below, a pyridine ring optionally having 1 to 3 substituents independently selected from group E below, or a pyrimidine ring optionally having 1 or 2 substituents independently selected from group E below:
group A: a halogen atom, a hydroxy group, a C 1 -C 8 alkyl group, an amino group, and a phenyl group,
group B: a C 1 -C 8 alkyl group and a hydroxy group
group C: a halogen atom, a hydroxy group, a phenyl group, a pyridyl group, and an amino group
group D: a halogen atom and a C 1 -C 6 alkyl group optionally having 1 to 3 halogen atoms, and
group E: a halogen atom, a hydroxy group, a vinyl group, an ethynyl group, a cyano group, a C 1 -C 6 alkoxy group, an aminocarbonyl group, and a C 1 -C 6 alkyl group optionally having 1 to 3 halogen atoms.

2 . A method for reacting a compound represented by formula (I):

and a compound represented by formula (V):

in a solvent using an asymmetric catalyst to stereoselectively produce a compound represented by formula (IV) or a salt thereof:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and Z are as defined in claim 1 .

3 . A method according to claim 1 or 2 , wherein the asymmetric catalyst is a catalyst prepared from a Lewis acid and a chiral ligand, wherein
the Lewis acid is a Lewis acid selected from the group consisting of a Zn(II) Lewis acid, a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co(II) Lewis acid, a Ru(I) Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewis acid, and
the chiral ligand is a chiral ligand selected from the group consisting of a compound represented by the following formula (VI):

a compound represented by the following formula (VII):

a compound represented by the following formula (VIII):

a compound represented by the following formula (IX):

a compound represented by the following formula (X):

a compound represented by the following formula (XI):

and a compound represented by the following formula (XII):

wherein
R 6 represents a phenyl group optionally having 1 to 3 substituents independently selected from group F below,
ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring optionally having 1 to 4 halogen atoms,
R 7 represents a phenyl group optionally having 1 to 3 substituents independently selected from group G below, or a furanyl group optionally having 1 to 3 substituents independently selected from group G below,
R 8 represents a hydrogen atom or a C 1 -C 6 alkoxy group,
R 9 repres

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Yamauchi Motoshi
• Nakayama Keiji

Classifications

• B01J31/2452

  with more than one complexing phosphine-P atom · CPC title

• B01J31/22

  Organic complexes · CPC title

• B01J31/2414

  comprising aliphatic or saturated rings · CPC title

• B01J2231/328

  Cycloadditions involving more than 2 components or moieties, e.g. intra-/intermolecualar [2+2+2] or [2+2+1], e.g. Pauson-Khand type · CPC title

• B01J2231/32

  Addition reactions to C=C or C-C triple bonds · CPC title