合成路线: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)
参考文献标题:Benzimidazole derivs.
文献作者:Alminger,T.B.; Bergman,R.A.; Bundgaard,H.; Lindberg,P.L.; Sund閚,G.E.(H鋝sle L鋕emedel AB)
参考来源:AU 8783302; EP 0279149; EP 0332647; EP 0510719; JP 1990500744; US 5215974; WO 8803921
合成路线: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)
参考文献标题:Novel ethoxycarbonyloxymethyl derivs.of substd.benzimidazoles
文献作者:Von Unge,S.(AstraZeneca plc)
参考来源:WO 9532957
合成路线: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.
合成路线: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)
参考文献标题:Optically pure salts of pyridinylmethyl sulfinyl-1H-benzimidazole cpds.
文献作者:Lindberg,P.L.; Von Unge,S.(AstraZeneca plc)
参考来源:EP 1020460; EP 1020461; US 5693818; US 5714504; WO 9427988
合成路线: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.
参考文献标题:Enantioselective preparation of pharmaceutically active sulfoxides by biooxidation
文献作者:Holt,R.; Lindberg,P.; Taylor,S.; Reeve,C.(AstraZeneca plc)
参考来源:WO 9617076
合成路线: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.
合成路线: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)
参考文献标题:Multiple unit tableted dosage form I
文献作者:Bergstrand,P.J.A.; L鰒gren,K.I.(AstraZeneca plc)
参考来源:WO 9601623
合成路线: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.
合成路线: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)
参考文献标题:Process for the preparation of a magnesium salt of a substd.sulphinyl heterocycle
文献作者:Mattson,A.; H鰃berg,J.-A.; Ioannidis,P.(AstraZeneca plc)
参考来源:JP 2000509067; WO 9741114
产品链接: CAS No. 161973-10-0›› 产品链接: CAS No.161796-85-6››