合成路线:An improved process for the synthesis of omeprazole has been developed that incorporates the oxidation of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfanyl)-1H-benzimidazole (I) by means of meta-chloroperbenzoic acid in ethyl acetate cooled below 0 C and keeping the temperature below 5 C during the addition of the oxidant.
参考文献标题:Improved process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole
文献作者:Hafner Milac,N.; Jereb,D.(LEK Pharmaceutical and Chemical Co.)
参考来源:WO 0002876
合成路线:The deoxygenation of 3.5-dimethyl-4-nitropyridine N-oxide (I) gives the corresponding pyridine (II),which is treated with trimethylksilyl cyanide to yield 3,5-dimethyl-4-nitropyridine-2-carbonitrile (III).The hydrolysis of (III) affords the corresponding carboxylic acid (IV),which by a nucleophillic substitution of the NO2 group with sodium methoxide gives 4-methoxy-3,5-dimethylpyridine-2-carboxylic acid (V).The reduction of (V) with borane or LiAlH4 yields the carbinol (VI),which by reaction with SOCl2 is converted into the chloromethylpyridine (VII).The condensation of (VII) with 5-methoxy-1H-benzimidazole-2-thiol (VIII) by means of NaOH in refluxing water affords the thioether (IX),which is finally oxidized to the target sulfoxide by means of MCPBA or peracetic acid.
参考文献标题:Method for the synthesis of a benzimidazole cpd.
文献作者:Gustavsson,A.; K鋖lstr鰉,A.(AstraZeneca plc)
参考来源:JP 2000502101; WO 9722603
合成路线:The deoxygenation of 3.5-dimethyl-4-nitropyridine N-oxide (I) gives the corresponding pyridine (II),which is treated with trimethylksilyl cyanide to yield 3,5-dimethyl-4-nitropyridine-2-carbonitrile (III).The hydrolysis of (III) affords the corresponding carboxylic acid (IV),which by a nucleophillic substitution of the NO2 group with sodium methoxide gives 4-methoxy-3,5-dimethylpyridine-2-carboxylic acid (V).The reduction of (V) with borane or LiAlH4 yields the carbinol (VI),which by reaction with SOCl2 is converted into the chloromethylpyridine (VII).The condensation of (VII) with 5-methoxy-1H-benzimidazole-2-thiol (VIII) by means of NaOH in refluxing water affords the thioether (IX),which is finally oxidized to the target sulfoxide by means of MCPBA or peracetic acid.
参考文献标题:Method of omeprazole preparation
文献作者:Heleyov? K.; Gattnar,O.; Jezek,L.; Varga,I.; Stalmach,V.; Smahovsky,V.; Oremus,V.; Zlatoidsky,P.(Slovakofarma AS)
参考来源:WO 9809962
合成路线:The deoxygenation of 3.5-dimethyl-4-nitropyridine N-oxide (I) gives the corresponding pyridine (II),which is treated with trimethylksilyl cyanide to yield 3,5-dimethyl-4-nitropyridine-2-carbonitrile (III).The hydrolysis of (III) affords the corresponding carboxylic acid (IV),which by a nucleophillic substitution of the NO2 group with sodium methoxide gives 4-methoxy-3,5-dimethylpyridine-2-carboxylic acid (V).The reduction of (V) with borane or LiAlH4 yields the carbinol (VI),which by reaction with SOCl2 is converted into the chloromethylpyridine (VII).The condensation of (VII) with 5-methoxy-1H-benzimidazole-2-thiol (VIII) by means of NaOH in refluxing water affords the thioether (IX),which is finally oxidized to the target sulfoxide by means of MCPBA or peracetic acid.
参考文献标题:Improved method for synthesis
文献作者:Br鋘dstr鰉,A.E.(AstraZeneca plc)
参考来源:US 5386032; WO 9118895
合成路线:An improved process for the synthesis of omeprazole has been developed that incorporates the oxidation of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfanyl)-1H-benzimidazole (I) by means of magnesium monoperoxyphthalate (MMPP) in water cooled at -5 C to 0 C and keeping the temperature in this range during the addition of the oxidant.The oxidation can also be performed with the same oxidant in either water/toluene/methanol cooled at -5 C to -10 C,methanol/water cooled at -10 C,or dichloromethane cooled at 0 C to 4 C.
参考文献标题:Process for the preparation of antiulcer agents
文献作者:Weinstock,L.M.; Shinkai,I.; Hoerrner,R.S.; Liu,T.M.-H.; Amato,J.S.; Friedman,J.J.(Merck & Co.,Inc.)
参考来源:EP 0533264; US 5391752
合成路线:The reaction of ethyl 2-methylacetoacetate (X) with NH3 in ethanol in an autoclave at 80 C gives ethyl 3-amino-2-methylcrotonate (XI),which is cyclized with diethyl 2-methylmalonate (XII) yielding 2,4-dihydroxy-3,5,6-trimethylpyridine (XIII).The reaction of (XIII) with POCl3 at 150 C affords 2,4-dichloro-3,5,6-trimethylpyridine (XIV),which is partially dechlorinated with H2 over Pd/C in ethanol/H2SO4 giving 4-chloro-2,3,5-trimethylpyridine (XV).The reaction of (XV) with sodium methoxide in hot DMSO yields 4-methoxy-2,3,5-trimethylpyridine (XVI),which is oxidized with H2O2 in AcOH affording the corresponding N-oxide (XVIII).The reaction of (XVIII) with acetic anhydride in hot acetic acid provides the acetate ester (XIX),which is finally hydrolyzed in the usual way to the target intermediate the 4-methoxy-3,5-dimethylpyridine-2-methanol (VI).The intermediate 4-chloro-2,3,5-trimethylpyridine (XV),can be oxidized with H2O2 in AcOH as before to give the corresponding N-oxide (XVII),which is treated with sodium methoxide in DMSO/methanol affording the previously described 4-methoxy-2,3,5-trimethylpyridine N-oxide (XVIII).
参考文献标题:Chemical intermediates and method for their preparation
文献作者:Junek,H.; Mittelbach,M.; Schmidt,H.-W.; Uray,G.(H鋝sle L鋕emedel AB)
参考来源:EP 0226558
产品链接: CAS No. 73590-58-6›› 产品链接: CAS No.95510-70-6››