Isoindolinone inhibitors of the mdm2-p53 interaction and process for making them

Patent metadata

Field	Value
Publication number	US-2025074900-A1
Application number	US-202418785847-A
Country	US
Kind code	A1
Filing date	Jul 26, 2024
Priority date	Mar 28, 2017
Publication date	Mar 6, 2025
Grant date	—

Abstract

The invention relates to processes for preparing isoindolin-1-one derivatives, and in particular processes for preparing (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid. The invention also relates to crystalline forms of the compound (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid and its salts.

First claim

1 . A process for preparing an amine of formula (7):

wherein R 10 is selected from C 1-4 alkyl, C 1-7 alkeneyl, C 1-7 haloalkyl, triC 1-7 alkylsilyl-C 1-7 alkyl, C 5-20 aryl and C 5-20 aryl-C 1-7 alkyl,
the process starting from an aldehyde of formula (12):

the process comprising the steps of:
(i) reacting the aldehyde of formula (12) with H 2 NBoc and PhSO 2 Na to give a compound of formula (13):

(ii) an elimination reaction on the compound of formula (13) in the presence of a base to give an imine of formula (14):

(iii) an imino-aldol reaction catalysed by (S)-proline between imine (14) and propan-2-al to give an aldehyde of formula (15):

(iii) oxidation of aldehyde (15) to provide acid (16):

(iii) conversion of acid (16) to provide ester (17):

(iv) and then removal of the Boc protecting group to give the amine of formula (7).

2 . A process for preparing a compound of formula (6), the process comprising taking a compound of formula (6′):

and resolving the compound of formula (6′) using a chiral-non-racemic base, for example a chiral-non-racemic base that is an amine, for example bis[(1S)-1-phenylethyl]amine.

3 . A process for preparing a compound of formula (6″), the process comprising taking a compound of formula (28):

wherein R 11 is hydrogen, C 1-7 alkyl, C 1-7 alkeneyl, C 1-7 haloalkyl, triC 1-7 alkylsilyl-C 1-7 alkyl, C 5-20 aryl and C 5-20 aryl-C 1-7 alkyl (e.g. —CH 2 CH═CH 2 , —CH 2 CH 2 Si(CH 3 ) 3 , and phenyl) and reacting the compound of formula (28) with a compound of the formula (29) in the presence of a base:

wherein X═—OC 1-4 alkyl (e.g. —OCH 3 , —OCH 2 CH 3 ), halogen (e.g. —C 1 ), —N(OCH 3 )CH 3 , —OC 1-4 haloalkyl (e.g. —OCH 2 CF 3 ), 2-thiopyridine or 2-pyrrolyl),
and then converting the —OSi(C 1-4 alkyl) 3 group to an —OH group by removing the silicon protecting group and when R 11 is other than hydrogen de-esterification to convert R 11 to hydrogen,
for example wherein R 11 is hydrogen and the base is added in greater than one equivalent, for example greater than 1.5, 1.7, 1.8 or 1.9 equivalents, relative to the compound of formula (6′), e.g. in two equivalents.

4 . A process for preparing a compound of formula (6′) according to claim 3 , wherein:
the base is LDA, LHMDS, LTMP, BuLi, HexLi, sec-BuLi or tBuLi, for example n-BuLi, Hex-Li or sec-BuLi; and/or
the step of treating the compound of formula (6′) with a base takes place by adding the compound of formula (6′) to a solution of the base; and/or
the step of converting the —OSi(C 1-4 ) 3 group to an —OH group takes place using an acid, for example HCl, TFA, H 3 PO 4 or H 2 SO 4 e.g. H 3 PO 4 .

5 . A process for preparing a 1-methoxyisoindoline which is (2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid (3) according to claim 2 , wherein the compound of formula (6′) is prepared by a process comprising taking a compound of formula (28):

wherein R 11 is hydrogen, C 1-7 alkyl, C 1-7 alkeneyl, C 1-7 haloalkyl, triC 1-6 alkylsilyl-C 1-7 alkyl, C 5-20 aryl and C 5-20 aryl-C 1-7 alkyl (e.g. —CH 2 CH═CH 2 , —CH 2 ′CH 2 Si(CH 3 ) 3 , and phenyl) and reacting the compound of formula (28) with a compound of the formula (29) in the presence of a base:

wherein X═—OC 1-4 alkyl (e.g. —OCH 3 , —OCH 2 CH 3 ), halogen (e.g. —Cl), —N(OCF 3 )CH 3 , —OC 1-4 haloalkyl (e.g. —OCH 2 CF 3 ), 2-thiopyridine or 2-pyrrolyl),
and then converting the —OSi(C 1-4 alkyl) 3 group to an —OH group by removing the silicon protecting group and when R 11 is other than hydrogen de-esterification to convert R 11 to hydrogen,
for example wherein R 11 is hydrogen and the base is added in greater than one equivalent, for example greater than 1.5, 1.7, 1.8 or 1.9 equivalents, relative to the compound of formula (6), e.g. in two equivalents.

6 . A process for preparing a 1-methoxyisoindoline which is (2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-5-[(1 S)—1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid (3) according to claim 5 , wherein the compound of formula (28) is prepared by reacting a compound of formula (33):

with (C 1-4 alkyl) 3 Si-T, wherein T is Cl or —OTf, wherein R 11 is hydrogen, C alkyl, C 1-7 alkeneyl, C 1-7 haloalkyl, triC 1-7 alkylsilyl-C 1-7 alkyl, C 5-20 aryl and C 5-20 aryl-C 1-7 alkyl (e.g. —CH 2 CH═CH 2 ,
—CH 2 CH 2 Si(CH 3 ) 3 , and phenyl),
and when R 11 is other than hydrogen, optionally de-esterification to convert R 11 to hydrogen.

7 . A process for preparing a 1-methoxyisoindoline which is (2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid (3) according to claim 6 , wherein the compound of formula (33) is prepared by a process comprising reacting a compound of formula (34) and a compound of formula (35) in the presence of a base:

for example wherein the base is HexLi or BuLi
wherein R 11 is hydrogen, C 1-7 alkyl, C 1-7 alkeneyl, C 1-7 haloalkyl, triC 1-7 alkylsilyl-C 1-7 alkyl, (C 5-20 aryl and C 5-20 aryl-C 1-7 alkyl (e.g. —CH 2 CH═CH 2 , —CH 2 CH 2 Si(CH 3 ) 3 , and phenyl), for example wherein the base is added to a mixture of the compounds of formula (34) and (35);
and when R 11 is other than hydrogen, optionally de-esterification to convert R 11 to hydrogen.

8 . A process for preparing a 1-methoxyisoindoline which is (2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid (3):

or a tautomer or a solvate or a pharmaceutically acceptable salt thereof,
the process comprising the steps of, in any order:
(i) de-esterifying a compound of the formula (4″):

wherein R 10 is selected from

Assignees

• Astex Therapeutics Ltd
• Cancer Research Tech Ltd

Inventors

• Howard Steven
• Cons Benjamin David
• St Denis Jeffrey David
• Griffiths-Jones Charlotte Mary
• Hiscock Steven Douglas
• Holvey Rhian Sara
• Burns Alan Richard
• Cousin David
• Dexter Hannah Louise
• Parra Guillaume François
• Watts John Paul
• Jewell Robert
• Stockwell Jennifer Ann
• Hirst Kim Louise
• Lemasson Isabelle Anne
• Nash David John
• Osborne James Daniel
• Priede Jonas Calleja
• Richards Nicholas Paul
• Dumas Aaron Michael
• Bishop Brian Christopher
• Parry-Jones David
• Scott Jeremy Peter
• Shanmugham Meenakshi Sundaram
• Mullens Peter Richard
• Lathbury David Charles
• Dixon Darren James
• Gaunt Matthew James

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4035

  Isoindoles, e.g. phthalimide · CPC title

• C07D405/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title