- Monitoring and Quantification of Omeprazole Synthesis Reaction by In-Line Raman Spectroscopy and Characterization of the Reaction Components
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The development of a quantitative in-line Raman spectroscopic method for the monitoring of the active pharmaceutical ingredient, omeprazole synthesis reaction, and characterization of the reaction components is described. In-line monitoring was performed both with Fourier transform and dispersive Raman spectrometers. Prior to reaction monitoring, the reaction components were characterized off-line by means of Raman and NMR spectroscopy, both in solution and in solid state. To unequivocally confirm the presence of each component in the reaction mixture, a state of the art LC-SPE/NMR methodology was also used. Owing to its higher sensitivity, dispersive Raman spectroscopy was further employed for quantification purposes. The spectroscopic measurements and the complementary HPLC analyses, used in the calibration development, were gathered from a set of experiments, performed at a 1 L scale. On the basis of the data set obtained from the calibration experiments, a predictive partial least-squares (PLS) regression model was developed for all three reaction components, enabling an accurate determination of the percentage of each component present in the reaction mixture, at any time after the point when 25% of the starting material has been consumed. The model was successfully used to monitor the reaction progress in a kilo-lab scale experiment and can further be used as a fast response analytical tool in process optimization. It also has the potential to be used as part of a feedback control loop in the production plant.
- ?ahni?, Damir,Me?trovi?, Ernest,Jedna?ak, Tomislav,Habinovec, Iva,Parlov Vukovi?, Jelena,Novak, Predrag
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Read Online
- Synthetic method and application of omeprazole
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The invention belongs to the field of medicine synthesis, and discloses a synthetic method of omeprazole. The synthetic method comprises the following steps: reacting sodium (4-methoxy-3, 5-dimethyl pyridine-2-yl) methanesulfinate to generate (4-methoxy-3, 5-dimethyl pyridine-2-yl) methanesulfinic acid acyl chloride, and then carrying out Suzuki reaction on the (4-methoxy-3, 5-dimethyl pyridine-2-yl) methanesulfinic acid acyl chloride and (6-methoxy-1H-benzo [d] imidazole-2-yl) boric acid to generate omeprazole. According to the synthetic method of omeprazole, the omeprazole which is easy to purify and stable in yield is obtained by using raw materials which are easy to obtain, and a synthetic method which is simple, easy to operate and control, mild in reaction condition and capable of replacing high-risk reagents such as butyl lithium and the like by using a common reagent. The invention also provides an application of the synthetic method of omeprazole. The synthetic method is suitable for synthesis of omeprazole. The obtained omeprazole is used for preparing an omeprazole injection.
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Paragraph 0045; 0048-0049; 0051-0054
(2021/07/17)
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- Synthesis method of esomeprazole sodium
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The invention discloses a synthesis method of esomeprazole sodium. Belong to organic synthesis field. Of 5 - methoxy -2-mercaptobenzimidazole in ethanol - sodium hydroxide solution react with 2 - chloromethyl -3 and 5 -dimethyl -4 - methoxypyridine hydrochloride to obtain omeprazole thioether. The synthetic method is high in raw material utilization rate, reduces the content and kinds of impurities, greatly improves the extraction rate of esomeprazole sodium, can reach 75%, and has a purity of more than 99%. The synthetic route is short, and the synthesis cost is greatly reduced.
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- A mild and chemoselective CALB biocatalysed synthesis of sulfoxides exploiting the dual role of AcOEt as solvent and reagent
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A mild, chemoselective and sustainable biocatalysed synthesis of sulfoxides has been developed exploiting CALB and using AcOEt with a dual role of more environmentally friendly reaction solvent and enzyme substrate. A series of sulfoxides, including the drug omeprazole, have been synthesised in high yields and with excellent E-factors.
- Anselmi, Silvia,Liu, Siyu,Kim, Seong-Heun,Barry, Sarah M.,Moody, Thomas S.,Castagnolo, Daniele
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supporting information
p. 156 - 161
(2021/01/14)
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- Selective synthesis of sulfoxides and sulfonesviacontrollable oxidation of sulfides withN-fluorobenzenesulfonimide
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A practical and mild method for the switchable synthesis of sulfoxides or sulfonesviaselective oxidation of sulfides using cheapN-fluorobenzenesulfonimide (NFSI) as the oxidant has been developed. These highly chemoselective transformations were simply achieved by varying the NFSI loading with H2O as the green solvent and oxygen source without any additives. The good functional group tolerance makes the strategy valuable.
- Cao, Zhong-Yan,Li, Xiaolong,Lu, Hao,Wang, Panpan,Wang, Shengqiang,Xu, Xiaobo,Yan, Leyu,Yang, A-Xiu
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supporting information
p. 8691 - 8695
(2021/10/22)
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- Preparation method of omeprazole and omeprazole
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The invention is applicable to the technical field of medicines, and provides a preparation method of omeprazole and omeprazole, and the preparation method comprises the following steps: dropwise adding a catalyst solution containing ammonium molybdate and hydrogen peroxide into a methanol solution of a thioether intermediate in sequence, and controlling the oxidation reaction temperature to -5-10 DEG C for reaction to obtain an omeprazole reaction solution; and adding sodium sulfite and a sodium hydroxide aqueous solution into the omeprazole reaction solution, uniformly mixing, dropwise adding an acetic acid aqueous solution, adding omeprazole seed crystals, stirring, continuously dropwise adding the acetic acid aqueous solution to adjust the pH value to 7.0-9.0, and adjusting the crystallization endpoint temperature to 10-20 DEG C, thereby obtaining the omeprazole crystal. The one-pot method of reaction and refining in the same solvent system is adopted, convenience of production operation is remarkably improved, operation steps are reduced, production energy consumption and time cost are reduced, and in addition, by optimizing all key parameters, the high-yield and high-purity omeprazole preparation process is achieved. The total yield of 25kg-grade production and preparation reaches 91.1%, the purity is 99.99%, and the method is superior to the pharmacopeia standard.
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Paragraph 0049-0084
(2021/04/21)
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- Integrating hydrogen production with anodic selective oxidation of sulfides over a CoFe layered double hydroxide electrode
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Replacing the sluggish oxygen evolution reaction (OER) with oxidation reactions for the synthesis of complex pharmaceutical molecules coupled with enhanced hydrogen evolution reaction (HER) is highly attractive, but it is rarely explored. Here, we report an electrochemical protocol for selective oxidation of sulfides to sulfoxides over a CoFe layered double hydroxide (CoFe-LDH) anode in an aqueous-MeCN electrolyte, coupled with 2-fold promoted cathodic H2productivity. This protocol displays high activity (85-96% yields), catalyst stability (10 cycles), and generality (12 examples) in selective sulfide oxidation. We demonstrate its applicability in the synthesis of four important pharmaceutical related sulfoxide compounds with scalability (up to 1.79 g). X-ray spectroscopy investigations reveal that the CoFe-LDH material evolved into amorphous CoFe-oxyhydroxide under catalytic conditions. This work may pave the way towards sustainable organic synthesis of valuable pharmaceuticals coupled with H2production.
- Ma, Lina,Zhou, Hua,Xu, Ming,Hao, Peipei,Kong, Xianggui,Duan, Haohong
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p. 938 - 945
(2021/02/06)
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- Sulfoxide and sulfone compounds, as well as selective synthesis method and application thereof
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The invention discloses a method for selectively synthesizing a sulfoxide compound shown as a formula (II) and a sulfone compound shown as a formula (III). In a reaction solvent, thioether (I) is usedas a reaction raw material and oxygen as an oxidation reagent, under the catalytic action of visible light and a photosensitive reagent; under the assistance of an additive, when a large-polarity proton-containing additive such as an acid and an alcohol or a solvent or an additive with excellent electron donating ability is used, a sulfoxide compound (II) is selectively generated; and when a small-polarity aprotic additive or a solvent is used, a sulfone compound (III) is selectively generated. The synthesis method has the advantages of easily available and cheap raw materials, simple reaction operation, mild reaction conditions, high yield and excellent functional group tolerance. According to the invention, synthesis and modification of some medicines are realized, and an efficient method for selectively constructing sulfoxide and sulfone compounds is provided for medicinal chemistry research.
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Paragraph 0045-0048; 0190-0193
(2019/12/02)
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- Selective Late-Stage Oxygenation of Sulfides with Ground-State Oxygen by Uranyl Photocatalysis
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Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late-stage oxygenation of sulfur-containing complex molecules with ground-state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO22+) enabled the efficient synthesis of sulfones. The ligand-to-metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a UV center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late-stage oxygenation in an atom- and step-efficient manner.
- Li, Yiming,Rizvi, S. Aal-e-Ali,Hu, Deqing,Sun, Danwen,Gao, Anhui,Zhou, Yubo,Li, Jia,Jiang, Xuefeng
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supporting information
p. 13499 - 13506
(2019/08/21)
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- Tartaric acid ester compound as well as preparation method and applications thereof
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The invention discloses a compound shown in formula (I), wherein R1 and R2 are independently selected from optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-14 aryl and optionally substituted -(CH2)m-C3-8 cycloalkyl or -(CH2)n Ar; and Ar denotes the optionally substituted C6-14 aryl. The compound can be used for preparing prazole drugs during thetitanium-catalyzed asymmetric oxidation of pyrazole sulfides. (img file='DDA0001401304200000011.TIF' wi='669' he='551'/).
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Paragraph 0101-0106
(2019/03/29)
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- Method for preparing benzimidazole proton pump inhibitor
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The invention provides a novel method for preparing a benzimidazole proton pump inhibitor, and belongs to the field of medicine synthesis. According to the method provided by the invention, a complexformed by using graphene oxide and a transition metal salt is used as a catalyst, and the corresponding benzimidazole proton pump inhibitor is obtained through oxidizing a thioether by an oxidizing agent under an alkaline condition in an organic solvent. The method has the advantages of mild reaction condition, high yield, environmental friendliness, and less impurity, the catalyst can be recycled, and the method is suitable for industrial production.
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Paragraph 0059; 0060; 0061; 0063; 0064; 0065; 0083; 0084
(2018/09/08)
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- Method for preparing high-purity razole intermediate and medicine by using green technology instead of phosgene, thionyl chloride and other toxic and harmful substances
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The invention discloses a method for preparing a high-purity razole intermediate and a medicine by using a green technology instead of phosgene, thionyl chloride and other toxic and harmful substances. The preparation method comprises the following steps: dissolving Ph3PO in an organic solvent, placing the obtained solution in a reaction bottle, dropwise adding BTC to form a high-efficiency chloration reagent, carrying out a heat insulation reaction for a period of time after the dropwise addition is finished, dissolving a razole hydroxide in the organic solvent, dropwise adding the obtained solution to the above system, carrying out a heat insulation reaction for a period of time, carrying out suction filtration, and drying the obtained dried reaction product to obtain razole chloride. In the process, the Ph3PO is equivalently regenerated, a mother liquor part is concentrated to precipitate the Ph3PO at a low temperature, and the Ph3PO can be repeatedly used after being washed with a solvent with small polarity. The method has the advantages of few side reactions, high product quality, few "three wastes" pollutions, high atomic economy, and good promotion and application prospect. The invention also provides a relevant razole medicine prepared from the razole chloride obtained through the green technology. The medicine has obviously higher purity than medicines obtained through traditional methods.
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Paragraph 0084; 0085
(2017/09/01)
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- Metal- and additive-free oxygen-atom transfer reaction: an efficient and chemoselective oxidation of sulfides to sulfoxides with cyclic diacyl peroxides
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Metal- and additive-free oxidation of a series of sulfides/thioketones has been achieved using cyclic diacyl peroxides as mild oxygen sources. This protocol features simple manipulation, high chemo- and diastereoselectivity, and a broad substrate scope (up to 42 examples), tolerates many common functional groups, and is scalable and applicable to the late-stage sulfoxidation strategy. A preliminary mechanistic study by quantum mechanical calculations suggests that a single two-electron transfer process is energetically more favorable, and indicates the reactivity of cyclic diacyl peroxides distinct from conventional acyclic acyl peroxides.
- Gan, Shaoyan,Yin, Junjie,Yao, Yuan,Liu, Yang,Chang, Denghu,Zhu, Dan,Shi, Lei
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supporting information
p. 2647 - 2654
(2017/04/03)
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- An electronic circular dichroism study for the structurechiroptical relationship of chiral proton pump inhibitors
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In this paper, we investigated the electronic circular dichroism (ECD) of proton pump inhibitors (PPIs) using a method of combining experimental spectrum and time-dependent density functional theory (TD-DFT) calculations. In our research, an intriguing helicity-like phenomenon was discovered for the relationship between static dipole moment and ECD curves of different conformers in lansoprazole. The scope and validity of the precious phenomenon have been examined by four PPIs using the same method. Hence, it can be used as a reference to determine and verify the absolute configuration of PPIs-type and PPIs-like chiral sulfoxide.
- Zhou, Zhixu,Li, Linwei,Yan, Ning,Du, Lei,Sun, Changshan,Sun, Tiemin
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p. 110 - 112
(2016/03/01)
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- A method for preparing omeprazole (by machine translation)
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The invention discloses a method for preparing omeprazole, comprising: (a) the 5 - methoxy - 2 - [[ (4 - methoxy - 3, 5 - dimethyl - 2 - pyridinyl) - methyl] - thio] - 1H - benzimidazole, titanium (IV) tetra-alkane scar-proton in the organic solvent mixing; (b) dissolving clarification, cooling and dropping the oxidizing agent; (c) concentrating, agitation washing, filtering, drying to obtain the omeprazole. The method has good repeatability, simple and convenient operation, the product yield, high purity, is suitable for industrial production. (by machine translation)
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Paragraph 0038; 0039; 0040; 0041; 0042-0049; 0052; 0053
(2017/04/22)
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- Synthetic method of omeprazole
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The invention relates to a synthetic method of omeprazole, and belongs to the technical field of organic chemical synthesis. The synthetic method is as below: adding 2,3,5-trimethyl pyridine, molecular sieve loaded with phosphotungstic acid to a mixed solution of benzene and acetonitrile; then dropwise adding hydrogen peroxide, reacting, conducting nitration and methoxylation, adding trifluoroacetic anhydride and chloroform, heating to reflux and conducting a rearrangement reaction to obtain trifluoroacetate; then adding the trifluoroacetate, sodium hydroxide, 2-mercapto-5-methox benzimidazole to ethanol, and reacting; and recovering ethanol, dropwise adding hydrogen peroxide, oxidizing, cooling, conducting sucking filtration, and drying to obtain omeprazole. The method solves the problems of high production costs and low production yield in the prior art, uses molecular sieve supported phosphotungstic acid as the catalyst to achieve the recycling of phosphorous acid, saves production costs, and uses benzene and acetonitrile as the solvents to improve the yield of the oxidation reaction.
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Paragraph 0025; 0026
(2017/02/24)
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- Structure-induced catalysis enhancement of Cu-amino catalysts for rapidly selective oxidation of sulfides in the presence of H2O2
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With benzyl phenyl sulfide as a model substrate and H2O2 as an oxidant, high selectivity toward the desired sulfoxide is obtained when using two CuII-amino acid complexes as catalysts, while strong stereospecific obstruction in a 1D helical array of complex 2 enables speedy sulfoxidation with excellent conversion.
- Zhang, Zhi-Hui,Yang, Xu-Sheng,Zhang, Qing-Qing,Wang, Liang,He, Ming-Yang,Chen, Qun,Huang, Xian-Feng
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p. 104036 - 104040
(2016/11/17)
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- PRODUCTION OF RED BLOOD CELLS AND PLATELETS FROM STEM CELLS
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This disclosure provides methods of making a megakaryocyte-erythroid progenitor cell (MEP), comprising differentiating a stem cell into a MEP in culture in the presence of an aryl hydrocarbon receptor (AhR) agonist. In some embodiments the stem cell is a pluripotent stem cell. In some embodiments the MEP co-expresses CD41 and CD235. In some embodiments the number of MEPs produced in the culture increases exponentially. Methods of making a red blood cell (RBC) by culturing a MEP in the presence of an AhR agonist are also provided. Methods of making a megakaryocyte and/or a platelet, comprising culturing a MEP in the presence of an AhR modulator are also provided. In some embodiments the AhR modulator is an AhR antagonist. This disclosure also provides compositions comprising at least 1 million MEPs per ml and compositions in which at least 50% of the cells are MEPs.
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- OPTICAL RESOLUTION OF SUBSTITUTED 2-(2-PYRIDINYLMETHYLSULPHINYL)-1H-BENZIMIDAZOLES
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The present invention relates to process for preparation of optical resolution of substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles either as a single enantiomer or in an enantiomerically enriched form. Thus, for example, R-1,1′-binaphtyl-2-2′-diyl hydrogen phosphate was reacted with 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (Lansoprazole) in a mixture of benzene and cyclohexane to obtain diasteremeric complexes. The diasteremeric complexes were subjected to fractional crystallization to obtain R-2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.R-1,1′-binaphthyl-2-2′-diyl hydrogen phosphate. The separated isomer was treated with sodium bicarbonate in a mixture of ethyl acetate and water to obtain R-2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (dexlansoprazole).
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Page/Page column 8
(2012/08/08)
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- PROCESS FOR CONTROLLING THE CONTENT OF SINGLE ENANTIOMER OF OMEPRAZOLE
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The present invention relates to process for controlling the content of single enantiomer of omeprazole with respect to other enantiomers.
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Page/Page column 5
(2012/08/27)
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- PROCESS FOR THE RESOLUTION OF OMEPRAZOLE
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The present invention relates to process for the resolution of omeprazole. The present invention further provides a novel compound of enantiomers of omeprazole cyclic amine salt and a process for preparing it. The present invention also provides a solid of (R)- or (S)-omeprazole cyclic amine salt and a process for preparing it. The present invention also provides a process for the preparation of esomeprazole magnesium dihydrate substantially free of its trihydrate form. The present invention also provides a process for the preparation of recovery of chiral BINOL.
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Page/Page column 13-14
(2011/06/16)
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- Pharmaceutical Composition for the Eradication of Helicobacter Pylori and Preparation Method Thereof
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The present invention relates to a pharmaceutical composition and its preparation method for the eradication of Helicobacter pylorif in the forms of effervescent tablet, suspension or powder. The pharmaceutical composition comprises an effective dose of β-lactam antibiotic, an effective dose of macrolide antibiotic, an effective dose of antacid such as proton pump inhibitor and H2 blocker, and a pharmaceutical acceptable carrier. An effective dose of alkaline substance such as carbonate or bicarbonate can be added to increase the pH of the stomach when the PPI antacid is used, which can protect the degradation of acid-labile antibiotics or PPI to further increase the bioavailability of the pharmaceutical composition for the purpose of Helicobacter pylori eradication.
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- Novel approach to the synthesis of omeprazole: An antipeptic ulcer agent
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A novel approach for the synthesis of omeprazole, a potent antiulcer drug, is described. The synthetic procedure involved the formation of an ester of the 5-methoxy thiobenzimidazole followed by coupling of the ester with the Grignard reagent of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine. Copyright Taylor & Francis Group, LLC.
- Bhalerao, Dinesh S.,Kondaiah, Golla China Mala,Dwivedi, Namrata,Mylavarappu, Ravi Kumar,Reddy, Lekkala Amarnath,Roy, Arnab,Nagaraju, Gudimalla,Reddy, Padi Pratap,Bhattacharya, Apurba,Bandichhor, Rakeshwar
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experimental part
p. 2983 - 2987
(2010/11/04)
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- Floating pharmaceutical composition comprising an active phase and a non-active phase
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The invention concerns a floating pharmaceutical composition consisting of at least a first phase comprising at least a high dose active principle combined with one or several carriers and at least a second phase comprising at least a gas-generating system. The invention also concerns tablets comprising such a pharmaceutical composition and a method for preparing such tablets.
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- Oral Medicament Based on a Proton Pump Inhibitor
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The invention relates to oral medicaments having a modified release of proton pump inhibitors (PPI's) that are, in particular, useful in preventing and treating gastrointestinal disorders. The aim of the invention is to provide a novel oral medicament based on PPI's ideally having all or some of the following characteristics: a) quickly providing relief to the patient by increasing the gastric pH after oral administration of the medicament; b) accelerating the recovery of patients while maintaining this increase in the gastric pH for as long as possible after oral administration of the medicament and, in particular, during the night; c) improving the observance of the treatment and the comfort of the patient by taking the medicament once daily. To this end, the microcapsules of the invention, preferably non-enteric, are constituted of PPI microparticles coated with ethyl cellulose, an ammonio methacrylate copolymer (Eudragit? RL 100), polyvinylpyrrolidone, castor oil and polyoxyethylenated hydrogenated castor oil (40). This medicament is designed so that after its ingestion for a once daily administration, it makes it possible to maintain, from the first day of treatment onward, an average gastric pH, between 0 and 24 h, of greater than or equal to the average gastric pH between 0 and 24 h obtained by an enteric oral medicament having a reference* immediate release, administered under the same conditions. The invention also relates to these microcapsules per se.
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- ONE POT PROCESS FOR PREPARING OMEPRAZOLE AND RELATED COMPOUNDS
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The present invention relates to one pot process for preparing 2- [(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (I') or a pharmaceutically acceptable salt, hydrate, or solvate thereof. More particularly, the present invention relates to the process for preparation of omeprazole by in-situ oxidization of compound of general formula (II')
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Page/Page column 16-18
(2010/12/18)
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- Method for preparing 2- (2-pyridinylmethylsulfinyl) benzimidazoles
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The present invention provides a method for preparing an antiulcer agent, 2-(2-pyridinylmethylsulfinyl)benzimidazoles, such as Omeprazole, Lansoprazole, Pantoprazole and Rabeprazole, which includes oxidizing an intermediate having a linkage of methylthio group (—CH2S—) to methylsulfinyl (—CH2S(O)—) in the presence of an oxidation catalyst of an alkali metal salt of tungstate at a temperature of 10-50° C.
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Page/Page column 3
(2009/01/24)
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- SELECTIVE PRODUCTION OF SULPHOXIDES
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The invention pertains to a process for producing a sulphoxide compound, comprising oxidizing a thioether compound with an ozonide formed from a olefin and ozone, to obtain the corresponding sulphoxide compound, provided that the olefin is not ethene. The ozonide converts thio - ether compounds selectively, unlike its art - known oxidizing counterparts. The milder ozonide does not require manipulation of the stoichiometric amount of available oxidizing agent during the reaction, to prevent the formation of sulphones.
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Page/Page column 12
(2009/03/07)
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- Tetra-(tetraalkylammonium)octamolybdate catalysts for selective oxidation of sulfides to sulfoxides with hydrogen peroxide
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Tetra-(tetraalkylammonium)octamolybdate catalysts are successfully applied in the selective oxidation of various sulfides to sulfoxides with 30% aqueous hydrogen peroxide as oxidant under mild reaction conditions in 94-100% yield and 95-100% selectivity. The octamolybdate catalysts show high catalytic activity in a high ratio of substrate to catalyst (up to 10000:1) and are recyclable, with actively functional groups, including hydroxyl group and CC bonds, tolerated in the oxidation. The Royal Society of Chemistry 2009.
- Yang, Chuanbo,Jin, Qingping,Zhang, Hua,Liao, Jian,Zhu, Jin,Yu, Bin,Deng, Jingen
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supporting information; experimental part
p. 1401 - 1405
(2010/05/02)
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- Process for preparing 2-(2-pyridylmethyl)-sulfinyl-1H-benzimidazoles and the intermediate compounds used therein
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The present invention relates to a process for preparing 2-(2-pyridylmethyl)sulphinyl-1H-benzimidazoles that are proton pump inhibitors, using as intermediates 2-benzimidazolylsulphinic acid derivatives. The present invention also relates to said intermediate compounds, their use and a process for the preparation thereof. These novel intermediate compounds are 2-benzimidazolylsulphinic acid esters that are obtained from their corresponding alkaline salts, which are in turn obtained by oxidation of substituted 2-mercaptobenzimidazoles. The intermediate compounds of the invention are converted into 2-(2-pyridylmethyl)sulphinyl-1H-benzimidazoles by reaction with substituted 2-methylpyridines.
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Page/Page column 15-16
(2008/12/09)
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- Inhibitors of the gastric H+, K+-atpase with enhanced therapeutic properties
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Chemical syntheses and medical uses of novel inhibitors of the gastric H+, K+-ATPase for the treatment and/or management of duodenal ulcers, heartburn, acid reflux, other conditions mediated by gastric acid secretion and/or psoriasis are described.
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Page/Page column 42
(2008/06/13)
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- Novel process for the preparation of esomeprazole and salts thereof
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A novel process for the preparation of omeprazole and its enantiomers, such as esomeprazole, as well as the preparation of related 2-(2-pyridinylmethyl-sulphinyl)-1H-benzimidazoles, including pantoprazole, lansoprazole and rabeprazole, as recemates or single enantiomers, and their alkali or alkaline salts has been developed. The novel process involves the surprising discovery that protection of the free-base benzimidazole sulfoxide (e.g. omeprazole or esomeprazole), by reaction with an alkyl, aryl or aralkyl chloroformate following oxidation of the corresponding sulfide, eliminates the need for its direct isolation. Subsequent removal of the protecting group with a solution of alkali or alkaline earth alkoxide in a C1-C4 alcohol directly provides the corresponding salt. By eliminating the need to handle the free-base benzimidazole sulfoxide, this advantageous procedure provides increased chemical yields over processes described in the art.
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Page/Page column 6
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF PYRIDINE COMPOUNDS
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A process for preparation of a compound of formula (I), both as the isomeric mixture and individual isomers, wherein Q is ═CR8— or ═N—; each R1, R2, R3, R4 is independently selected from hydrogen, halogen, hydroxy; nitro; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen or C1-C6 alkoxy; phenyl-C1-C6 alkyl; phenyl-C1-C6 alkoxy; and —N(RaRb) wherein each Ra and Rb is independently hydrogen or C1-C6 alkyl or Ra and Rb, taken together with the nitrogen atom they are linked to, form a saturated heterocyclic ring; and each R5, R6, R7, R8 is independently selected from hydrogen, halogen, hydroxy; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen; C1-C6 alkyl-carbonyl, C1-C6 alkoxy-carbonyl, and oxazol-2-yl; comprising converting a compound of formula (IV), to said compound of formula (I), in the presence of a catalyst, if necessary in an organic solvent.
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Page/Page column 5
(2008/06/13)
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- A process for the preparation of pyridine compounds
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A process for the preparation of a compound of formula (I) or a salt thereof, both as the isomeric mixture and the individual isomers, wherein Q is =CR8- or =N-; each R1, R2, R3 and R4 is independently selected from hydrogen, halogen, hydroxy; nitro; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen or C1-C6 alkoxy; phenyl-C1-C6 alkyl; phenyl-C1-C6 alkoxy; and - N(RaRb) wherein each Ra and Rb is independently hydrogen or C1-C6 alkyl or Ra and Rb, taken together with the nitrogen atom they are linked to, form a saturated heterocyclic ring; and each R5, R6, R7 and R8 is independently selected from hydrogen, halogen, hydroxy; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen; C1-C6 alkyl-carbonyl, C1-C6 alkoxy-carbonyl, and oxazol-2-yl; comprising converting a compound of formula (IV), or a salt thereof, wherein Q, R1, R2, R3, R4, R5, R6 and R7 are as defined above, to said compound of formula (I), or a salt thereof, in the presence of a catalyst, if necessary in an organic solvent; and, if desired, converting a compound of formula (I) to a salt thereof to another compound of formula (I); and/or, if desired, resolving an isomeric mixture of a compound of formula (I) in the individual isomers.
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Page/Page column 7
(2008/06/13)
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- A PREPARATION METHOD FOR SUBSTITUTED 2-(2-PYRIDYLMETHOYLSULPHINYL)-l-H-BENZIMID AZOLES
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The invention relates to a process for the preparation of a substituted 2-(2-pyridylmethylsulphinyl)-l-H-benzimidazole involving the reaction of a corresponding 2-(2-pyridylrnethylthio)-l-H-benzirnidazole compound with a hypohalite oxidation agent in the presence of a phase transfer catalyst, wherein the reaction involves a biphasic reaction mixture containing an aqueous and an organic phase. The reaction can immediately succeed the formation of said 2-(2-pyridylmethylthio)-l-H-benzimidazole compound in a one pot synthesis, in order to avoid time-consuming and costly purification steps. Overoxidation, leading to sulphone impurities, is thus avoided and yields improved. Hence, the invention also relates to a substituted 2-(2-pyridylmethylsulphinyl)-l-H-benzimidazole containing less than 0.2 wt% sulphone impurities.
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Page/Page column 15 - 17
(2010/11/30)
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- METHOD FOR PREPARING 2- (2-PYRIDYLMETHYLSULPHINYL) BENZIMIDAZOLES
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The present invention provides a method for preparing an antiulcer agent, 2-(2-pyridylmethylsulphinyl)benzimidazoles, such as Omeprazole, Lansoprazole and Pantoprazole, which includes oxidizing an intermediate having a linkage of methylthio group (—CH2S—) to methylsulfinyl (—CH2S(O)—) in the presence of an oxidation catalyst of acetyl acetonate of molybdenium (II) [(CH3C(O)CH2C(O)CH2)2Mo].
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Page/Page column 3
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF SULPHINYL DERIVATIVES BY OXIDATION OF THE CORRESPONDING SULFIDES
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The present invention relates to a mild and industrially applicable process for preparing sulfinyl derivatives of Formula (II), useful as inhibitors of gastric acid secretion, comprising the selective oxidation of the corresponding sulfides of Formula (I), as represented in scheme (I) and (II) in which said oxidation is performed with hydrogen peroxide in the presence of low amounts of a rhenium compound as catalyst, at a temperature from 0° C to room temperature.
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- Process for the preparation of organic compounds containing a sulfinyl or sulfonyl group in the presence of epsilon-phthalimidoperhexanoic acid
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A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.
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- Process for the preparation of organic compounds containing a sulfinyl or sulfonyl group
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A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.
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- Method and compositions for treating gastric hyperacidity while diminishing the likelihood of producing vitamin deficiency
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A method for treatment of a human for gastric hyperacidity while diminishing the likelihood of producing vitamin deficiency is disclosed, the method comprising administering a therapeutically effective amount of one or more substances that neutralize or otherwise reduce gastric acid and administering an effective supplemental amount of one or more vitamins, wherein one of the one or more vitamins can be free Vitamin B12. Oral dosage formulations comprising a therapeutically effective amount of one or more substances that neutralize or otherwise reduce gastric acid and an effective supplemental amount of one or more vitamins, and methods of making such oral dosage forms, also are disclosed.
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- Processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles
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Improved processes for preparing substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles are disclosed.
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- Substituted 2-(2-methyl Pyridylpyrimidine) sulfinylation -1H-dihydrobenzo aminoalkaneimidazole manufacturing method
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Improved processes for preparing substituted 2-(2-pyridylmethyl) sulfinyl- 1H-benzimidazoles are disclosed.
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Page/Page column 12-13
(2008/06/13)
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- PAHARMACEUTICAL PROCESS AND COMPOUNDS PREPARED THEREBY
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The present invention relates to an improved process for the preparation of a sulfinyl compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, from a sulfide compound of formula (II), wherein in both formulae (I) and (II) R1 and R3 are selected from the group consisting of hydrogen, methyl or C1-4alkoxy, R2 is selected from the group consisting of substituted or unsubstituted C1-4alkoxy and R4 is selected from the group consisting of hydrogen or substituted or unsubstituted C1-4alkoxy.
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- METHOD FOR THE SYNTHESIS OF A BENZIMIDAZOLE COMPOUND
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A process for the manufacture of omeprazole or esomeprazole from pyrmethyl alcohol via pyrmethyl chloride and pyrmetazole characterized in that the whole reaction sequence is carried out without any isolation or purification of intermediates. Further, the reaction is carried out in a solvent system common for the whole reaction sequence and inert to the reactants formed during the process and used in the process and comprises a water immiscible organic solvent and a specified amount of water.
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- NEW METHOD FOR THE PREPARATION OF THE ANTI-ULCER COMPOUNDS OMEPRAZOLE, LANSOPRAZOLE AND PANTOPRAZOLE
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The present invention describes a new process for the preparation of omeprazole, lansoprazole and pantoprazole of formula (XXI), (XXXIII), and which involves the formation of pyridines N-oxide using a rhenium compound as a catralyst, followed by nitration of the 4-position with nitric acid fuming in presence of a claycop. The chlorination of the 2-methyl group of pyridine was achieved by using the POCI3/Et3N, which allowed the preparation of the derivates 2-chloromethylpyridines in only one step. These derivates reacted with the mercaptobenzimidazolic derivatives in presence of ultra-sonic radiation, giving the thioethers. The oxidation of these thioethers was done with several oxidizing agents and the required anti-ulcer compounds were obtained after the substitution of nitro group by the corresponding OR groups.
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Page/Page column 12
(2010/02/07)
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- Processes for the production fo substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles
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Improved processes for preparing substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles are disclosed.
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- Novel amorphous form of omeprazole salts
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The present invention relates to novel amorphous form of salts and process for the preparation thereof.
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- Process for purifying 6- methoxy omeprazole
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The present invention provides processes for purifying 6-methoxy omeprazole, products using such processes, pharmaceutical formulations using such products, and methods of using such products for gastric acid inhibition.
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- Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
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Compounds represented by formula (Ia) are disclosed by the invention, along with compositions and complexes thereof, optionally in combination with compounds of formula (Ib). Pharmaceutical formulations and methods of making and using such compounds are also disclosed.
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- Composition for the treatment and prevention of ischemic events
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The invention relates to pharmaceutical compositions comprising omeprazole and aspirin wherein the combination is useful for the treatment and prevention of cardiovascular events including heart attacks and platelet aggregation leading to a potential cardiac event. A variety of drug delivery systems may be utilized to deliver the combination of active ingredients. The preferred delivery system utilizes a tablet or capsule containing an inert sugar core particle that is coated with subparticles of a coated omeprazole wherein the coating contains omeprazole, a binder, a surface active agent and a basifying agent along with a filler. The aspirin may be combined with this formulation to coat the sugar sphere or it may be part of a separate coating composition that forms a multilayer system that is ultimately coated with an enteric coating and then formed into the tablet or capsule by conventional means.
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