Method for preparation of (s)-(+)-and(r)-(-)10,11-dihydro-10-hydrodoxy-5h-dibenz/b,f/azephine-5-carboxamide

A method for the preparation of optically pure (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, the method comprising the steps of:

• (1) reacting racemic (±)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide with (2S,3S)-di-O,O′-substituted-tartaric acid anhydride to give a separable mixture of diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-esters;
• (2) precipitation of the less soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester formed in step (1) by addition of water and separation of the same by filtration;
• and
• (3) base-catalysed hydrolysis of the less soluble 10-O-di-O,O′-substituted-tartrate half-ester obtained in step (2) to give the optically pure (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide,
• wherein the (2S,3S)-di-O,O′-substituted-tartaric acid anhydride has the formula:
• where each R is the same and is C1 to C6 alkyl, or each R is phenyl.

A method for the preparation of optically pure (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide and (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, the method comprising the steps of:

• (1) reacting racemic (±)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide with (2R,3R)-di-O,O′-substituted-tartaric acid anhydride to give a separable mixture (1:1) of diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-esters of (±)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide;
• (2) precipitation of the less soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester formed in step (1) by addition of water and separation of the same by filtration;
• (3) base-catalysed hydrolysis of the less soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester obtained in step (2) to give the optically pure (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide;
• (4) recovery from the organic filtrate from step (2) of the more-soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester;
• (5) base-catalysed hydrolysis of the recovered, more-soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester from step (4) to give enriched (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide;
• (6) reaction of enriched (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide from step (5) with (2S,3S)-di-O,O′-substituted-tartaric acid anhydride to give a separable mixture of diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-esters;
• (7) precipitation of the less soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester formed in step (6) by addition of water and separation of the same by filtration;
• and
• (8) base-catalysed hydrolysis of the less soluble 10-O-di-O,O′-substituted-tartrate half-ester obtained in step (7) to give the optically pure (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide,
• wherein the (2R,3R)-di-O,O′-substituted-tartaric acid anhydride has the formula:
• where each R is the same and is C1 to C6 alkyl, or each R is phenyl, and wherein the (2S,3S)-di-O,O′-substituted-tartaric acid anhydride has the formula:
• where each R is the same and is C1 to C6 alkyl, or each R is phenyl.

A method for the preparation of optically pure (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide and (R)-(−)-10,11-dihydro-10-hydroxy-5H -dibenz[b,f]azepine-5-carboxamide, the method comprising the steps of:

• (1) reacting racemic (±)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide with (2S,3S)-di-O,O′-substituted-tartaric acid anhydride to give a separable mixture (1:1) of diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-esters of (±)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide;
• (2) precipitation of the less soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester formed in step (1) by addition of water and separation of the same by filtration;
• (3) base-catalysed hydrolysis of the less soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester obtained in step (2) to give the optically pure (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide;
• (4) recovery from the organic filtrate from step (2) of the more-soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester;
• (5) base-catalysed hydrolysis of the recovered, more-soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester from step (4) to give enriched (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide;
• (6) reaction of enriched (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide from step (5) with (2R,3R)-di-O,O′-substituted-tartaric acid anhydride to give a separable mixture of diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-esters;
• (7) precipitation of the less soluble diastereoisomeric 10-O-di-O,O′-substituted-tartrate half-ester formed in step (6) by addition of water and separation of the same by filtration;
• and
• (8) base-catalysed hydrolysis of the less soluble 10-O-di-O,O′-substituted-tartrate half-ester obtained in step (7) to give the optically pure (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide,
• wherein the (2R,3R)-di-O,O′-substituted-tartaric acid anhydride has the formula:
• where each R is the same and is C1 to C6 alkyl, or each R is phenyl, and wherein the (2S,3S)-di-O,O′-substituted-tartaric acid anhydride has the formula:
• where each R is the same and is C1 to C6 alkyl, or each R is phenyl.