Novel method for preparing (-)-cibenzoline succinate
AssigneeCelltrion Inc.
InventorsSrinivas Reddy Desi Reddy, Vijayavitthal Thippannachar Mathad, Dnyandev Ragho Rane, Vikas Shivaji Patil
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Abstract
The present invention relates to a crystal form of (−)-Cibenzoline succinate. In addition, the present invention relates to a method for preparing (−)-Cibenzoline succinate having a chiral purity of 99.9% or higher. Additionally, the present invention provides a method for preparing (−)-Cibenzoline succinate and a crystal form thereof.
Claims18
(−)-Cibenzoline.chiral acid salt of formula (IVA),
- wherein the chiral acid is selected from the group consisting of L-(+)-Tartaric acid, D-(−)-Tartaric acid, (R)-(−)-Mandelic acid, (S)-(+)-Mandelic acid, Dibenzoyl-L-tartaric acid, (+)-2,3-Dibenzoyl-D-tartaric acid, (−)-O,O′-Dibenzoyl-L-tartaric acid monohydrate, (+)-O,O-Dibenzoyl-D-tartaric acid monohydrate, (−)-O,O′-Dibenzoyl-L-tartaric acid mono(dimethylamide), Di-p-toluoyl-D-tartaric acid monohydrate, Di-p-toluoyl-L-tartaric acid monohydrate, (−)-O,O′-Di-p-toluoyl-L-tartaric acid, (+)-O,O′-Di-p-toluoyl-D-tartaric acid, (+)-O,O′-Di-p-toluoyl-D-tartaric acid, D-Glutamic acid, L-Glutamic acid, L-(−)-Malic acid, D-(+)-Malic acid, (−)-Menthyloxyacetic acid, (+)-Menthyloxyacetic acid, (R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid, (S)-(−)-α-Methoxy-α-trifluoromethylphenylacetic acid, (R)-(−)-5-Oxo-2-tetrahydrofurancarboxylic acid, (S)-(+)-5-Oxo-2-tetrahydrofurancarboxylic acid, (R)-(+)-N-(1-Phenylethyl)phthalamic acid, (S)-(−)-N-(1-Phenylethyl)phthalamic acid, (R)-(−) Phenylpropionic acid, (S)-(+)-2-Phenylpropionic acid, L-Pyroglutamic acid, D-Pyroglutamic acid, D-(−)-Quinic acid, L-(+)-Quinic acid, L-Aspartic acid, D-Aspartic acid, (R)-1,4-Benzodioxane-2-carboxylic acid, (S)-1,4-Benzodioxane-2-carboxylic acid, N,N-Bis[(S)-(−)-1-phenylethyl]phthalamic acid, N,N-Bis[(R)-(+)-1-phenylethyl]phthalamic acid, (1S)-(+) Bromocamphor-10-sulfonic acid hydrate, (1R)-(−)-3 -Bromocamphor-10-sulfonic acid hydrate, (1S)-(−)-Camphanic acid, (1R)-(+)-Camphanic acid, (1R,3 S)-(+)-Camphoric acid, (1S,3R)-(−)-Camphoric acid, (1R)-(−)- 10-Camphorsulfonic acid, and (1 S)-(+)-10-Camphorsulfonic acid.
A process for the preparation of enantiomerically pure (−)-Cibenzoline succinic acid salt of formula (IA),
- which comprises the steps of:
- a) a step of preparing the racemic Cibenzoline free base of formula (III) by treating the racemic Cibenzoline succinic acid salt of formula (II) with a base;
- b) a step of obtaining the racemic Cibenzoline.chiral acid salt of formula (IIIA) by treating the racemic Cibenzoline free base of formula (III) with a chiral acid in the presence of solvent;
- c) a step of isolating (−)-Cibenzoline.chiral acid salt of formula (IVA);
- d) a step of preparing the (−)-Cibenzoline free base of formula (VA) by neutralizing the (−)-Cibenzoline.chiral acid salt of formula (IVA) with a base;
- and
- e) a step of preparing (−)-Cibenzoline succinic acid salt of formula (IA) by treating the (−)-Cibenzoline free base of formula (VA) with succinic acid in presence of solvent.
A crystalline form of (−)-Cibenzoline succinic acid salt of formula
A process for the preparation of a crystalline form of (−)-Cibenzoline succinic acid salt, which comprises the steps of:
- a′) a sep of preparing a mixture by reacting (−)-Cibenzoline free base of Formula (VA) with succinic acid in the presence of a straight or branched C1-C5 alcohol;
- and
- b′) a step of obtaining solid (−)-Cibenzoline succinic acid salt of Formula (IA) by cooling the mixture.
Dependencies are inferred from the claim text.