Isoindolinone inhibitors of the MDM2-P53 interaction and process for making them

1. 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:

or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, the process comprising:

(i) taking a compound of the formula (4)

wherein R 10 is selected from 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;

and reacting the compound of formula (4) with a methylating agent in the presence of a base to give a compound of formula (5):

and

(ii) then a de-esterification step to convert the group R 10 to hydrogen and provide (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; and

(iii) optionally, a further step in which the compound of formula (3) is resolved to increase the proportion of the stereoisomer which is (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 of formula (3′)

or a tautomer or a solvate or a pharmaceutically acceptable salt thereof.

2. A process for preparing a 1-methoxyisoindoline according to claim 1 , wherein the compound of formula (4) is prepared by taking a compound of formula (6):

and coupling the compound of formula (6) with an amine of formula (7):

3. 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 a step of de-esterifying a compound of the formula (4′):

wherein R 10 is selected from C 1-7 alkyl, 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;

to provide (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 or a tautomer or a solvate or a pharmaceutically acceptable salt thereof; and

optionally, a further step in which the compound of formula (3) is resolved to increase the proportion of the stereoisomer which is (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 of formula (3′)

or a tautomer or a solvate or a pharmaceutically acceptable salt thereof.

4. 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 3 , wherein the compound of the formula (4′) is prepared by taking a compound of the formula (4)

wherein R 10 is selected from 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; and reacting the compound of formula (4) with a methylating agent in the presence of a base.

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 4 , wherein:

the base is selected from n-BuLi, t-BuLi, sec-BuLi, LDA, LHMDS, NaHMDS, KHMDS, LTMP, LiOtBu or KOtBu;

the methylating agent is selected from MeOTf and methylfluorosulfonate; and

the step of reacting with the methylating agent takes place in an ethereal solvent.

6. 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 4 , wherein the compound of formula (4) is prepared by taking a compound of formula (6):

and coupling the compound of formula (6) with an amine of formula (7):

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 (7) is prepared by a process comprising starting from an aldehyde of formula (12):

and:

(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 compound of formula (7).

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) according to claim 6 , wherein the compound of formula (6) is prepared by a process comprising taking a compound of formula (6′):

and resolving the compound of formula (6′) using a chiral-non-racemic base.

9. 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 wherein R 10 is selected from —CH 2 CH 2 Si(CH 3 ) 3 and phenyl.

10. 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 3 , wherein R 10 is CH 2 CH 2 Si(CH 3 ) 3 .

11. 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 8 , wherein the chiral-non-racemic base is a chiral-non-racemic base that is an amine.

12. 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 8 , wherein the chiral-non-racemic base is bis[(1S)-1-phenylethyl]amine.