Method for producing a spirooxindole derivative

Patent metadata

Field	Value
Publication number	US-10851111-B2
Application number	US-201816031165-A
Country	US
Kind code	B2
Filing date	Jul 10, 2018
Priority date	Sep 4, 2013
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

The present disclosure provides a method for efficiently producing and providing compounds having a spirooxindole skeleton, for example compounds having a spirooxindole skeleton and having antitumor activity that inhibit the interaction between Mdm2 protein and p53 protein, or intermediates thereof, using an asymmetric catalyst. Compounds having optically active tricyclic dispiroindole skeletons are obtained through catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate and using a chiral ligand and a Lewis acid.

First claim

The invention claimed is:

1. A method of stereoselectively producing a compound of formula (IV):

or a salt thereof, comprising:
reacting a compound of formula (I):

and a compound of formula (V):

in a solvent using an asymmetric catalyst prepared from a Lewis acid and a chiral ligand,
wherein
R 1 is a hydrogen atom, a C 1 -C 6 alkylcarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, or a C 1 -C 6 alkoxycarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A,
R 2 is a 5- or 6-membered heteroaryl group containing, 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 are each optionally substituted with 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 substituted with 1 to 3 substituents independently selected from group A, a C 3 -C 4 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from group A, a C 1 -C 6 alkoxy group optionally substituted with 1 to 3 substituents independently selected from group A, a C 3 -C 4 cycloalkoxy group optionally substituted with 1 to 3 substituents independently selected from group A, a C 1 -C 6 alkylamino group optionally substituted with 1 to 3 substituents independently selected from group A, a di-C 1 -C 6 alkylamino group optionally substituted with 1 to 3 substituents independently selected from group A, a 4- to 7-membered saturated heterocyclic group containing one nitrogen atom in the ring and optionally substituted with 1 to 3 substituents independently selected from group B, a C 1 -C 6 alkoxycarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, a C 3 -C 4 cycloalkoxycarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, a C 1 -C 6 alkylaminocarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, and a C 3 -C 4 cycloalkylaminocarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A,
R 3 and R 4 are each independently a C 1 -C 6 alkyl group optionally substituted with 1 to 3 substituents independently selected from group C, or
R 3 and R 4 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 is each optionally substituted with 1 to 8 substituents independently selected from group D,
R 5 is a C 1 -C 6 alkoxy group optionally substituted with 1 to 3 substituents independently selected from group E, a C 3 -C 8 cycloalkoxy group optionally substituted with 1 to 3 substituents independently selected from group E, a C 2 -C 6 alkenyloxy group, or —NR 51 R 52 ,
R 51 and R 52 are each independently a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted with 1 to 3 substituents independently selected from group E, a C 3 -C 8 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from group E, or a 3- to 6-membered saturated heterocyclic group containing, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally substituted with 1 to 3 substituents independently selected from group E,
ring Z is a benzene ring optionally substituted with 1 to 4 substituents independently selected from group E, a pyridine ring optionally substituted with 1 to 3 substituents independently selected from group E, or a pyrimidine ring optionally substituted with 1 or 2 substituents independently selected from group E,
group A: a halogen atom, a hydroxy group, a C 1 -C 6 alkyl group, an amino group, and a phenyl group,
group B: a C 1 -C 6 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 substituted with 1 to 3 halogen atoms,
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 substituted with 1 to 3 halogen atoms,
the Lewis acid is 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 selected from the group consisting of
a compound of formula (VI):

a compound of formula (VII):

a compound of formula (VIII):

a compound of formula (IX):

a compound of formula (X):

a compound of formula (XI):

and a compound of formula (XII):

wherein
R 6 is a phenyl group optionally substituted with 1 to 3 substituents independently selected from group F,
ring Y is a benzene ring, a cyclohexane ring, or a dioxolane ring optionally substituted with 1 to 4 halogen atoms,
R 7 is a phenyl group optionally substituted with 1 to 3 substituents independently selected from group G, or a furanyl group optionally substituted with 1 to 3 substituents independently selected from group G,
R 8 is a hydrogen atom or a C 1 -C 6 alkoxy group,
R 9 is a C 1 -C 6 alkoxy group, or
two R 9 moieties together form a 7- to 12-membered heterocyclic ring containing two oxygen atoms in the ring,
X is CH, CR 10 , or a nitrogen atom,
R 10 is a C 1 -C 6 alkoxy group,
V is P(R 11 ) 2 or a phenyl group substituted with a substituent selected from P(R 11 ) 2 and PH(O)R 12 ,
R 11 is a C 1 -C 6 alkyl group, a cyclohexyl group, or a phenyl group optionally substituted with two trifluoromethyl groups,
R 12 is a C 1 -C 6 alkyl group or a phenyl group,
W is a C 1 -C 6 alkylthio group, a dihydrooxazolyl group optionally substituted with one C 1 -C 6 alkyl group, CH(CH 3 )P(R 13 ) 2 , or CHR 14 R 15 ,
R 13 is a cyclohexyl group, a C 1 -C 6 alkyl group, or a phenyl group optionally substituted with 1 or 2 substituents independently selected

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Yamauchi Motoshi
• Nakayama Keiji

Classifications

• C07D491/20

  Spiro-condensed systems · CPC title

• C07D487/10 Primary

  Spiro-condensed systems · CPC title

• Y02P20/54

  using solvents, e.g. supercritical solvents or ionic liquids · CPC title

• B01J2540/10

  Non-coordinating groups comprising only oxygen beside carbon or hydrogen · CPC title

• B01J2531/842

  Iron · CPC title