The condensation of 5-methoxy-2-mercaptobenzimidazole (I) with 2-chloromethyl-3,5dimethyl-4-methoxypyridine (II) by means of NaOH in refluxing ethanol gives 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (III), which is then oxidized with m-chloroperbenzoic acid (IV) in chloroform. Benzimidazole (I) is obtained by cyclization of 4-methoxy-o-phenylenediamine (V) with potassium ethylxanthate (VI). Pyridine (II) is obtained by reaction of 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine (VII) with SOCl2.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

4) The reaction of racemic omeprazole (VII) with formaldehyde in dichloromethane gives, after crystallization in acetonitrile, 1-(hydroxymethyl)-6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole (VIII), which is treated with SOCl2 in dichloromethane to afford, after crystallization in acetonitrile, the corresponding chloromethyl derivative (IX). The condensation of (IX) with (R)-2-hydroxy-2-phenylacetic acid (X) by means of NaOH and tetrabutylammonium hydrogen sulfate in water gives the corresponding ester (XI) as a diastereomeric mixture, which is resolved by reverse phase chromatography. Finally, the suitable isomer is hydrolyzed to esomeprazole by treatment with NaOH in methanol. (Scheme 27259802a) Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water. (Schemes 27259801a and 27259802a)

4) The reaction of racemic omeprazole (VII) with formaldehyde in dichloromethane gives, after crystallization in acetonitrile, 1-(hydroxymethyl)-6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole (VIII), which is treated with SOCl2 in dichloromethane to afford, after crystallization in acetonitrile, the corresponding chloromethyl derivative (IX). The condensation of (IX) with (R)-2-hydroxy-2-phenylacetic acid (X) by means of NaOH and tetrabutylammonium hydrogen sulfate in water gives the corresponding ester (XI) as a diastereomeric mixture, which is resolved by reverse phase chromatography. Finally, the suitable isomer is hydrolyzed to esomeprazole by treatment with NaOH in methanol. (Scheme 27259802a) Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water. (Schemes 27259801a and 27259802a)

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

4) The reaction of racemic omeprazole (VII) with formaldehyde in dichloromethane gives, after crystallization in acetonitrile, 1-(hydroxymethyl)-6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole (VIII), which is treated with SOCl2 in dichloromethane to afford, after crystallization in acetonitrile, the corresponding chloromethyl derivative (IX). The condensation of (IX) with (R)-2-hydroxy-2-phenylacetic acid (X) by means of NaOH and tetrabutylammonium hydrogen sulfate in water gives the corresponding ester (XI) as a diastereomeric mixture, which is resolved by reverse phase chromatography. Finally, the suitable isomer is hydrolyzed to esomeprazole by treatment with NaOH in methanol. (Scheme 27259802a) Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water. (Schemes 27259801a and 27259802a)

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

4) The reaction of racemic omeprazole (VII) with formaldehyde in dichloromethane gives, after crystallization in acetonitrile, 1-(hydroxymethyl)-6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole (VIII), which is treated with SOCl2 in dichloromethane to afford, after crystallization in acetonitrile, the corresponding chloromethyl derivative (IX). The condensation of (IX) with (R)-2-hydroxy-2-phenylacetic acid (X) by means of NaOH and tetrabutylammonium hydrogen sulfate in water gives the corresponding ester (XI) as a diastereomeric mixture, which is resolved by reverse phase chromatography. Finally, the suitable isomer is hydrolyzed to esomeprazole by treatment with NaOH in methanol. (Scheme 27259802a) Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water. (Schemes 27259801a and 27259802a)

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

4) The reaction of racemic omeprazole (VII) with formaldehyde in dichloromethane gives, after crystallization in acetonitrile, 1-(hydroxymethyl)-6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole (VIII), which is treated with SOCl2 in dichloromethane to afford, after crystallization in acetonitrile, the corresponding chloromethyl derivative (IX). The condensation of (IX) with (R)-2-hydroxy-2-phenylacetic acid (X) by means of NaOH and tetrabutylammonium hydrogen sulfate in water gives the corresponding ester (XI) as a diastereomeric mixture, which is resolved by reverse phase chromatography. Finally, the suitable isomer is hydrolyzed to esomeprazole by treatment with NaOH in methanol. (Scheme 27259802a) Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water. (Schemes 27259801a and 27259802a)

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

Esomeprazole can be obtained by several related ways: 1) The NaOH-mediated condensation of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (II), obtained by reaction of the hydroxymethylpyridine (I) with SOCl2, with 5-methoxy-1H-benzimidazole-2-thiol (V), obtained by cyclization of 4-methoxy-o-phenylenediamine (III) with potassium ethylxanthate (IV), gives 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VI), which is oxidized with m-chloroperbenzoic acid, yielding racemic omeprazole (VII). The optical resolution of (VII) can be performed by chiral chromatography using several different chiral stationary phases, or by stereoselective bioreduction of the undesired (+)-enantiomer with a purified preparation of DMSO reductase from Rhodobacter capsulatus DSM 938 that, after reversed phase HPLC separation of the reduced sulfanyl derivative (VI), affords an enantiomerically enriched (15:85) mixture of the (+)- and (-)-enantiomers. Finally, this mixture is submitted to chiral HPLC separation or fractional crystallization in either acetonitrile, 2-butanone or acetone. (Scheme 27259801a) 2) The asymmetric oxidation of the pro-chiral sulfide (VI) carried out by biooxidation with various microorganisms; among them, the best results (>99% e.e.) were obtained with Penicillium frequentans BPFC 386, Penicillium frequentans BPFC 585, and Brevibacterium praffinoliticum ATCC 21195. (Scheme 27259801a) 3) The asymmetric oxidation of the pro-chiral intermediate (VI) performed with titanium(IV) isopropoxide and cumene hydroperoxide in the presence of (-)-diethyl D-tartrate and DIEA in toluene. Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water.

4) The reaction of racemic omeprazole (VII) with formaldehyde in dichloromethane gives, after crystallization in acetonitrile, 1-(hydroxymethyl)-6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole (VIII), which is treated with SOCl2 in dichloromethane to afford, after crystallization in acetonitrile, the corresponding chloromethyl derivative (IX). The condensation of (IX) with (R)-2-hydroxy-2-phenylacetic acid (X) by means of NaOH and tetrabutylammonium hydrogen sulfate in water gives the corresponding ester (XI) as a diastereomeric mixture, which is resolved by reverse phase chromatography. Finally, the suitable isomer is hydrolyzed to esomeprazole by treatment with NaOH in methanol. (Scheme 27259802a) Esomeprazole magnesium can be obtained by three different ways: i) by reaction of esomeprazole with magnesium sulfate heptahydrate in aqueous ammonia; ii) by reaction of esomeprazole with magnesium methoxide in methanol or iii) by reaction of esomeprazole sodium, obtained by treatment of esomeprazole with NaOH in 2-butanone, with hydrated magnesium chloride in water. (Schemes 27259801a and 27259802a)