One pot process for the preparation of benzimidazole derivatives
AssigneeCadila Healthcare Limited
InventorsShriprakash Dhar DWIVEDI, Ashok PRASAD, Daya Ram PAL
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Abstract
The present invention discloses one pot process for enantioselective synthesis of single enantiomers of substituted sulphoxides 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles or said compounds in an enantiomerically enriched form.
Claims34
The pot process for preparing 2-[(pyridinyl)methyl]sulfinyl-benzimidazole derivative of Formula (II′) or a pharmaceutically acceptable salt of Formula (I′), hydrate or a solvate thereof,
- wherein M is alkali or alkaline earth metal salts;
- R1 is selected from the group consisting of hydrogen or substituted or unsubstituted C1-C4alkoxy;
- R2 and R4 are independently selected from the group consisting of hydrogen, C1-C4alkyl or C1-C4alkoxy;
- R3 is selected from the group consisting of substituted or unsubstituted C1-C4alkoxy, the process comprising:
- (a) reacting 2-chloromethyl-substituted pyridine of Formula (V′) or a salt thereof with 2-mercapto-5-substituted benzimidazole of Formula (IV′) in one or more suitable organic solvents, optionally in the presence of a base to obtain prochiral sulfide of Formula (III′);
- (b) asymmetrically oxidizing prochiral sulfide of Formula (III′) in-situ with a suitable oxidizing agent in one or more suitable organic solvents in the presence of a chiral transition metal complex, and optionally in the presence of a base to obtain optically active enantiomer or an enantiomerically enriched form of a compound of Formula (II′);
- wherein R1, R2, R3 and R4 are the same as described above;
- (c) optionally, converting the optically active enantiomer or an enantiomerically enriched form of the compound of Formula (II′) to a pharmaceutically acceptable salt thereof of Formula (I′), hydrate or solvate thereof;
- and
- (d) obtaining 2-[(pyridinyl)methyl]sulfinyl-benzimidazole derivative of Formula (II′) or a pharmaceutically acceptable salt of Formula (I′), hydrate or a solvate thereof.
One pot process for preparing esomeprazole magnesium of Formula (I), or a hydrate thereof,
- the process comprising:
- (a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine of Formula (V) or a salt thereof with 2-mercapto-5-methoxy benzimidazole of Formula (IV) in one or more suitable organic solvents, optionally in the presence of a base to obtain prochiral sulfide of Formula (III);
- (b) asymmetrically oxidizing prochiral sulfide of Formula (III) in-situ with a suitable oxidizing agent in one or more suitable organic solvents in the presence of a chiral transition metal complex, and optionally in the presence of a base to obtain esomeprazole compound of Formula (II);
- (c) reacting esomeprazole compound of Formula (II) in-situ with a magnesium source to obtain esomeprazole magnesium of Formula (I);
- and
- (d) converting the esomeprazole magnesium to esomeprazole magnesium dihydrate.
One pot process for preparing esomeprazole magnesium of Formula (I) or a dihydrate thereof,
- the process comprising:
- (a) reacting 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine of Formula (V) or a salt thereof with 2-mercapto-5-methoxy benzimidazole of Formula (IV) in one or more organic solvents in the presence of a base to obtain prochiral sulfide of Formula (III);
- (b) asymmetrically oxidizing prochiral sulfide of Formula (III) in-situ with a suitable oxidizing agent in one or more suitable organic solvents in the presence of a chiral transition metal complex, and optionally in the presence of a base to obtain esomeprazole compound of Formula (II) in a reaction mixture;
- (c) treating the reaction mixture with a chlorinated solvent under acidic conditions;
- (d) removing the chlorinated solvent to obtain a residue;
- (e) reacting the residue with a magnesium source to obtain esomeprazole magnesium of Formula (I) in a suitable first solvent;
- (f) removing the suitable first solvent to obtain a residue;
- and
- (g) treating the residue with a suitable second solvent to obtain esomeprazole magnesium dihydrate.
A pharmaceutical composition comprising a therapeutically effective amount of esomeprazole magnesium dihydrate having percentage crystallinity in the range of 45% to 65% together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Dependencies are inferred from the claim text.