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.
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.
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.
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.
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).
The reaction of 2-methylpropane-1,3-dial (XX) first with methanesulfonyl chloride and then with NaOMe gives 3-methoxy-2-methyl-2-propenal (XXI), which is cyclized with 1-(tert-butyldimethylsilyloxy)-2-butanone (XXII) in basic medium to yield the dihydropyridine (XXIII). Finally, this compound is dehydrogenated with DDQ and desilylated to afford the target intermediate 4-methoxy-3,5-dimethylpyridine-2-methanol (VI).
The reaction of 1-hydroxy-2-butanone (XXIV) with tosyl chloride gives the tosylate (XXV), which is condensed with 5-methoxy-1H-benzimidazole-2-thiol (VIII) yielding 5-methoxy-2-(2-oxobutylsulfanyl)-1H-benzimidazole (XXVI). The reaction of (XXVI) with 3-methoxy-2-methyl-2-propenal (XXI) in basic medium affords the 5-oxohexanal derivative (XXVII), which is cyclized by means of NH4OAc and NH3 to give the dihydropyridine (XXVIII). Finally, this compound is dehydrogenated and oxidized to the target sulfinyl derivative.
The reaction of tosylate (XXV) with potassium ethylxanthate (XXIX) gives the adduct (XXX), which is cyclized with 3-methoxy-2-methyl-2-propenal (XXI) by means of t-BuOK, NH4Cl and NH3 in THF yielding the dihydropyridine (XXXI). The oxidation of (XXXI) with MCPBA in chloroform affords the pyridine (XXXII), with simultaneous formation of the sulfinyl group. Finally, this compound is cyclized with 4-methoxyphenylene-1,2-diamine (XXXIII) by means of TFA in refluxing toluene.
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 dichloromethane or toluene/ethanol cooled below 0 C and keeping the temperature below 5 C during the addition of the oxidant.
The acetylation of 2,3,5-trimethyl-4-nitropyridine N-oxide (I) with acetic anhydride in hot acetic acid gives the 2-(acetoxymethyl)-3,5-dimethyl-4-nitropyridine (II), which, without isolation, is treated with NaOH in hot dichloromethane/water, yielding the corresponding 2-(hydroxymethyl) derivative (III). This compound, also without isolation, is treated with SOCl2 to afford 2-(chloromethyl)-3,5-dimethyl-4-nitropyridine (IV), which is condensed with 6-methoxy-1H-benzimidazole-2-thiol (V) by means of tetrabutylammonium bromide and NaOH in dichloromethane/water, providing the corresponding thioether (VI). The reaction of (VI) with sodium methoxide and K2CO3 in refluxing methanol yields 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VII), which is finally oxidized to the target sulfoxide with peracetic acid (VIII) in ethyl acetate.