Process for the preparation of an enantiomeric trisubstituted 3,4-dihydro-isoquinoline derivative
View Patent ↗The present invention relates to a process for the preparation of the compound of formula (7) which process comprises the hydrogenation of the compound of formula (4) using bis[chloro-1,5-cyclooctadiene-iridium], (S)-i-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene as a catalyst.
1. A process for the preparation of the compound of formula 7
which process comprises the hydrogenation of the compound of formula 4
in the presence of bis[chloro-1,5-cyclooctadiene-iridium], (S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene, iodine and a solvent, under hydrogen pressure of 1-200 bar, to obtain the compound of formula 7.
2. The process according to claim 1 , for the preparation of the compound of formula 7, wherein the compound of formula 4
is first prepared by reaction of the compound of formula 4*mesylate
with a base, to obtain the compound of formula 4.
3. The process according to claim 2 , wherein the amount of base is between 0.9 and 1.5 mol equivalents.
4. The process according to claim 2 , wherein the base is sodium hydrogenocarbonate or sodium hydroxide.
5. The process according to claim 2 , wherein the reaction of the compound of formula 4*mesylate with a base is carried out in the presence of activated charcoal which is removed once the reaction is completed.
6. The process according to claim 1 , wherein the amount of iodine compared to the amount of iridium is between 0.2 and 10 mol equivalents.
7. The process according to claim 1 , wherein the molar ratio between iridium and the chiral ligand is between 0.5:1 and 1:0.5.
8. The process according to claim 1 , wherein the hydrogen pressure is between 1 and 50 bar.
9. The process according to claim 1 , wherein the mixture of bis[chloro-1,5-cyclooctadiene-iridium], (S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene and iodine used in the process is prepared beforehand by the following sequential steps:
a) the addition of 1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene to a solution of bis[chloro-1,5-cyclooctadiene-iridium] in a solvent; and
b) the addition of iodine to the mixture obtained in step a).
10. The process according to claim 9 , wherein the solvent used for the preparation of the mixture of bis[chloro-1,5-cyclooctadiene-iridium] and (S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene is selected from methanol, dichloromethane and a mixture of methanol and dichloromethane.
11. The process according to claim 10 , wherein the solvent used for the preparation of the mixture of bis[chloro-1,5-cyclooctadiene-iridium] and (S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene is methanol.
12. The process according claim 9 , wherein the process for the preparation of the mixture of bis[chloro-1,5-cyclooctadiene-iridium], (S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene and iodine comprises the following step after step b):
c) removal of the solvent.