Process for Preparation of Optically Active Compounds using Transfer Hydrogenation
AssigneeNovartis AG
InventorsChristian Mathes, Michael Foulkes, Martin Kesselgruber
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Abstract
A catalytic process for the preparation of optically active compounds and their conversion thereafter to desired drug substances. In particular, the process relates to the preparation of (S)-3-(1-Dimethylamino-ethyl)-phenol using asymmetric catalytic reduction and transfer hydrogenation, thereby providing an improved route to forming drug substances such as rivastigimine and rivastigimine hydrogen tartrate.
Claims37
1-39. (canceled)
A process for the preparation of a compound according to the following general formula (I):
- wherein
- R1=C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C2-20 organohalide, an aryl, an amine or amide group;
- n=1 to 5;
- and
- said process comprising:
- (a) performing an asymmetric catalytic reduction on a hydroxyphenone according to the following general formula (II):
- wherein
- R1=C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C2-20 organohalide, an aryl, an amine or amide group;
- n=1 to 5;
- and
- wherein said asymmetric catalytic reduction is performed using transfer hydrogenation, and
- wherein said asymmetric catalytic reduction is performed using a chiral metal catalyst.
The process of claim 54, wherein the transition metal M is Ru, Rh or Ir.
A process for the preparation of (S)-3-(1-dimethylamino-ethyl)-phenol of formula (IX)
- comprising:
- (a) performing an asymmetric catalytic reduction using transfer hydrogenation on 1-(3-hydroxy-phenyl)-ethanone (compound V) to form (R)-3-(1-hydroxy-ethyl)-phenol (compound VI) as shown below:
- (b) performing an activation step on the hydroxyl groups of the formed (R)-3-(1-hydroxy-ethyl)-phenol to form activated hydroxy alcoholic groups and activated hydroxy phenolic groups on the (R)-3-(1-hydroxy-ethyl)-phenol;
- (c) performing a nucleophilic substitution on the activated hydroxy alcoholic groups;
- and
- (d) cleaving the activated hydroxy phenolic groups;
- wherein (S)-3-(1-dimethylamino-ethyl)-phenol is formed.
A process for the preparation of (S)-3-(1-dimethylamino-ethyl)-phenol (compound IX), comprising:
- (a) reducing 1-(3-hydroxy-phenyl)-ethanone of formula (V) to form (R)-3-(hydroxy-ethyl)phenol of formula (VI)
- (b) mesylating (R)-3-(hydroxy-ethyl)phenol (compound VI) to form (R)-methanesulfonic acid 3-(1-methanesulfonyloxy-ethyl)-phenyl;
- (c) performing a nucleophilic substitution on the activated hydroxy alcoholic groups utilizing dimethyl amine;
- and
- (d) cleaving the mesylate group from (S)-methanesulfonic acid 3-(1-dimethylamino-ethyl-phenyl ester to form the chiral (S)-3-(1-dimethylamino-ethyl-phenol.
A composition comprising (R)-methanesulfonic acid 3-(1-methanesulfonyloxy-ethyl-phenyl ester or (S)-methanesulfonic acid 3-(1-methanesulfonyloxy-ethyl-phenyl ester or a mixture thereof.
A composition comprising (R)-methanesulfonic acid 3-(1-dimethylamino-ethyl)-phenyl ester or (S)-methanesulfonic acid 3-(1-dimethylamino-ethyl)-phenyl ester or a mixture thereof.
A composition comprising (R)-3-(1-hydroxyethyl)-phenyl methanesulfonate or (S)-3-(1-hydroxyethyl)-phenyl methanesulfonate or a mixture thereof.
A composition comprising (R)-1-(3-hydroxyphenyl)-ethyl methanesulfonate or (S)-1-(3-hydroxyphenyl)-ethyl methanesulfonate or a mixture thereof.
The process of claim 30, further comprising:
- (i) treating the rivastigmine with a pharmaceutically acceptable base to form the rivastigmine as a free base.
Dependencies are inferred from the claim text.