- Biphasic recognition chiral extraction - Novel way of separating pantoprazole enantiomers
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This paper presents a biphasic recognition chiral extraction system developed as a new chiral separation technology for the separation of pantoprazole enantiomers, combining a hydrophilic β-CD derivative in the aqueous phase and a hydrophobic tartaric acid in the organic phase which preferentially recognise the (R)-enantiomer and (S)-enantiomer, respectively. In this study, a number of factors which influence the efficiency of the extraction were investigated including types of organic solvents, β-CD and tartaric acid esters and their concentrations, pH and temperature. As a result, enantioselectivity for pantoprazole enantiomers can be improved up to 1.42 under optimised conditions; in addition, it is clear that the combined action of β-CD and tartaric acid esters leads to formation of the biphasic chiral extraction system with a stronger separation capacity than a monophasic chiral extraction system.
- Liu, Jia-Jia,Liu, Chang,Tang, Ke-Wen,Zhang, Pan-Liang
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- Reversed-phase HPLC enantioseparation of pantoprazole using a teicoplanin aglycone stationary phase—Determination of the enantiomer elution order using HPLC-CD analyses
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A direct HPLC method was developed for the enantioseparation of pantoprazole using macrocyclic glycopeptide-based chiral stationary phases, along with various methods to determine the elution order without isolation of the individual enantiomers. In the preliminary screening, four macrocyclic glycopeptide-based chiral stationary phases containing vancomycin (Chirobiotic V), ristocetin A (Chirobiotic R), teicoplanin (Chirobiotic T), and teicoplanin-aglycone (Chirobiotic TAG) were screened in polar organic and reversed-phase mode. Best results were achieved by using Chirobiotic TAG column and a methanol-water mixture as mobile phase. Further method optimization was performed using a face-centered central composite design to achieve the highest chiral resolution. Optimized parameters, offering baseline separation (resolution = 1.91 ± 0.03) were as follows: Chirobiotic TAG stationary phase, thermostated at 10°C, mobile phase consisting of methanol/20mM ammonium acetate 60:40 v/v, and 0.6 mL/min flow rate. Enantiomer elution order was determined using HPLC hyphenated with circular dichroism (CD) spectroscopy detection. The online CD signals of the separated pantoprazole enantiomers at selected wavelengths were compared with the structurally analogous esomeprazole enantiomer. For further verification, the inline rapid, multiscan CD signals were compared with the quantum chemically calculated CD spectra. Furthermore, docking calculations were used to investigate the enantiorecognition at molecular level. The molecular docking shows that the R-enantiomer binds stronger to the chiral selector than its antipode, which is in accordance with the determined elution order on the column—S- followed by the R-isomer. Thus, combined methods, HPLC-CD and theoretical calculations, are highly efficient in predicting the elution order of enantiomers.
- Papp, Lajos Attila,Foroughbakhshfasaei, Mohammadhassan,Fiser, Béla,Horváth, Péter,Kiss, Eszter,Sekkoum, Khaled,Gyéresi, árpád,Hancu, Gabriel,Noszál, Béla,Szabó, Zoltán-István,Tóth, Gerg?
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- Method for preparing chiral sulfoxide drugs in water phase
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The invention relates to the field of chiral drug preparation, in particular to a method for preparing chiral sulfoxide drugs in a water phase. The method for preparing the chiral sulfoxide drugs in the water phase comprises the following steps: using a hydrogen peroxide solution as oxidant, using a temperature-sensitive ferrocene chiral amino acid titanium complex as a catalyst and using prochiral thioether as a substrate in the pure water phase to perform an asymmetric oxidation reaction to synthesize the chiral sulfoxide drugs. The temperature-sensitive ferrocene chiral amino acid titaniumcomplex catalyst can be utilized to catalyze the asymmetric oxidation reaction of thioether in the pure water phase and has the characteristics of high catalytic efficiency and easy recovery of the catalyst.
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Paragraph 0053-0055
(2020/09/09)
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- Method for producing proton pump inhibitor compound having optical activity
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A highly pure optically active proton pump inhibitor compound can be produced safely and inexpensively in a high yield and enantioselectivity by a method of producing an optically active sulfoxide of Formula 2 or a salt thereof, comprising oxidizing a sulfide of Formula 1 or a salt thereof with hydrogen peroxide using an iron salt in the presence of a chiral ligand of Formula 3; wherein A is CH or N; R1 is hydrogen atom, an alkyl optionally substituted by halogen(s), or an alkoxy optionally substituted by halogen(s); one to three R2 may exist, and each of R2 is independently an alkyl, a dialkylamino, or an alkoxy optionally substituted by halogen(s) or alkoxy(s); each of R3 is independently hydrogen atom, a halogen, cyano or the like; R4 is a tertiary alkyl; and * and ** represent respectively R configuration or S configuration.
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Page/Page column 16; 17
(2019/06/15)
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- A catalytic asymmetric oxidizing thioether preparation of chiral pharmaceutical method
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The invention provides a preparation method of a chiral sulfoxide medicament though catalysis of asymmetric oxidation of sulfides compounds. A chiral complex formed by quadridentate nitrogen organic ligand and metal manganese compound as a catalyst and hydrogen peroxide as an oxidant are used for asymmetric catalytic oxidation of prochiral thioether compound, so as to obtain the corresponding chiral sulfoxide medicament compounds including S-omeprazole, S-lansoprazole, S-pantoprazole, S-rabeprazole, R-Modafinil and R-sulindac. The reaction has the advantages of cleaness, mild reaction conditions, high conversion rate and antipodal selectivity, and shows industrial prospects.
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Paragraph 0038-0044; 0050-0052
(2020/02/07)
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- Synthesis of Esomeprazole and Related Proton Pump Inhibitors through Iron-Catalyzed Enantioselective Sulfoxidation
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We report here an application of iron catalysis for the kilogram scale asymmetric synthesis of a proton pump inhibitor, esomeprazole, in 87% yield and 99.4% ee by catalytic sulfoxidation with hydrogen peroxide using an iron salt/chiral Schiff base in combination with a carboxylate salt. Under similar reaction conditions, other proton pump inhibitors such as (S)-lansoprazole, (S)-rabeprazole, and (S)-pantoprazole, were also synthesized in high yield and ee. A carboxylate additive was crucial for the success of this reaction, and we consider that it coordinates to the active iron species, and it also acts as a hydrogen-bond acceptor to coordinate to the substrate through the imidazole NH.
- Nishiguchi, Shigenobu,Izumi, Takuhiro,Kouno, Takayoshi,Sukegawa, Junpei,Ilies, Laurean,Nakamura, Eiichi
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p. 9738 - 9743
(2018/10/09)
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- Preparation method for S-pantoprazole sodium
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The invention discloses a preparation method for S-pantoprazole sodium. The method comprises the following steps: performing oxidation and substitution reaction on a compound as shown in formula VII; adding soybean peptide hydrolase for hydrolyzing and resolving; adding sodium hydroxide into the hydrolysis product for salifying, and then performing extraction separation, thereby acquiring (-)S-enantiomer; and performing basic hydrolysis, acidifying crystallization and salifying, thereby acquiring pantoprazole sodium. According to the method, the soybean peptide hydrolase is taken as a chiral resolution reagent, the process is simple, the reaction conditions are mild, the method is environment-friendly, the purity of the acquired S-pantoprazole sodium and the chiral purity both can reach above 99.9%, and the preparation method is suitable for industrial production.
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Paragraph 0023; 0053; 0057
(2017/04/13)
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- (S)-pantoprazole preparation method
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The invention discloses a (S)-pantoprazole preparation method. The preparation method includes: in an organic solvent, subjecting pantoprazole thioether as shown in a formula I to contact reaction with N-methyl-N-morpholine oxide in existence of chiral quaternary ammonium salt to obtain (S)-pantoprazole. By adoption of the (S)-pantoprazole preparation method, wild conditions, high product yield and high selectivity are realized, generation of excessive oxidation products is avoided, and accordingly aftertreatment is simpler. In addition, the (S)-pantoprazole preparation method is high in conditional response efficiency, and reaction time is greatly shortened.
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Paragraph 0029-0030
(2017/07/07)
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- Preparation process of (S)-pantoprazole sodium
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The invention discloses a preparation process of (S)-pantoprazole sodium. The preparation process comprises steps as follows: 1), 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl] sulfur]-1H-benzimidazole and chiral quaternary ammonium salt are added to an organic solvent and are stirred and mixed for 30 min under the protection of nitrogen, an ether solution of dimethyldioxirane is dropwise added, the mixture reacts continuously, and (S)-pantoprazole is obtained; 2), (S)-pantoprazole and sodium alcoholate react, and (S)-pantoprazole sodium is obtained. According to the preparation method of (S)-pantoprazole sodium, the yield of (S)-pantoprazole sodium is quite high, stereoselectivity is high, excessively oxidized sulfone products cannot be produced, complicated aftertreatment and purification steps are omitted, conditions are mild, and the process is simple and convenient to operate and is beneficial to industrial production.
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Paragraph 0032-0035; 0038; 0040; 0042
(2017/08/29)
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- Synthesis process of (L)-pantoprazole
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The invention discloses a synthesis process of (L)-pantoprazole. The synthesis process comprises the following steps: 1) in the presence of iodine and alkali, 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole and 2-(chloromethyl)-3,4-dimethoxypyridine hydrochloride are subjected to stirring reaction to obtain the pantoprazole thioether as shown in the formula I, and the pantoprazole thioether represented by the formula I shown in the specification and hydrogen peroxide are subjected to oxidation reaction in the presence of (R)-(-)-binaphthol phosphate to obtain the (L)-pantoprazole. The synthesis process is good in stereo selectivity, high in the product yield, mild in the conditions, simple in the steps and easier in after-treatment and purification.
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Paragraph 0043-0045
(2017/07/06)
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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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- Synthesis of prazole compounds
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The present disclosure relates to non-naturally occurring monooxygenase polypeptides useful for preparing prazole compounds, polynucleotides encoding the polypeptides, and methods of using the polypeptides.
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Page/Page column 88-90
(2016/02/03)
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- A reaction method of the extraction and the separation of enantiomers of pantoprazole
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The invention discloses a new method for separating pantoprazole enantiomers by reaction extraction, and a preparation method of new chiral pure pantoprazole. Racemic pantoprazole can be separated by biphasic recognition chiral extraction technology, and water soluble beta-cyclodextrin and tartaric acid ester are respectively used as chiral extractants in aqueous and organic phases. The invention discloses preparation methods of the aqueous and organic phases and repeated usage methods of the aqueous and organic phases. The extraction system has a very good separation performance on the racemic pantoprazole, distribution coefficients (kR and kS) are respectively 1.56 and 2.15, and separation factor (alpha) can reach 1.38.
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Paragraph 0014; 0015; 0016
(2017/03/14)
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- Catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide catalyzed by a titanium complex with (S,S)-N,N′-dibenzyl tartramide ligand
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A chiral titanium complex, formed in situ from Ti(Oi-Pr)4, (S,S)-N,N′-dibenzyl tartramide and water was found to serve as an efficient catalyst for the asymmetric oxidations of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide (CHP) in the absence of a base. Several proton pump inhibitors (PPIs), such as esomeprazole, lansoprazole, rabeprazole and pantoprazole were obtained in high yield (up to 92%) and excellent enantiomeric excess (up to 96%).
- Che, Guoyong,Xiang, Jing,Tian, Tian,Huang, Qingfei,Cun, Linfeng,Liao, Jian,Wang, Qiwei,Zhu, Jin,Deng, Jingen
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experimental part
p. 457 - 460
(2012/07/28)
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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 22
(2011/04/26)
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- PROCESS FOR PREPARING SULFOXIDE COMPOUNDS
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Disclosed are a process for preparing a chiral sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form, and S-(-)-levo-omeprazole, S-(-)-levo-pantoprazole and S-(-)-le vo-lansoprazole prepared thereby. Formula (I) omeprazole: R 1=CH 3, R 2=OCH 3, R 3=CH 3, R 4= R 6= R 7=H, R 5=OCH 3 lansoprazole: R 1=H, R 2=OCH 2CF 3, R 3=CH 3, R 4= R 5= R 6= R 7=H pantoprazole: R 1=H, R2=OCH 3, R 3=OCH 3, R 4= R 6= R 7=H, R 5=OCHF 2
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Page/Page column 39-40
(2009/10/22)
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- Catalytic asymmetric oxidation of heteroaromatic sulfides with tert-butyl hydroperoxide catalyzed by a titanium complex with a new chiral 1,2-diphenylethane-1,2-diol ligand
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Heteroaromatic sulfoxides, especially 1H-benzimidazolyl pyridinylmethyl sulfoxides, usually used as the blockbuster gastric proton pump inhibitors (PPIs), have been prepared highly enantioselectivily by catalytic asymmetric oxidation of sulfides attached to nitrogen-containing heterocyles with tert-butyl hydroperoxide in the presence of a chiral titanium complex, formed in situ from Ti(iPrO)4, chiral 1,2-diphenylethane-1,2-diol 3c and water. The chiral sufoxides were obtained in high yield (97%) with excellent enantiomeric excess (up to 98%).
- Jiang, Biao,Zhao, Xiao-Long,Dong, Jia-Jia,Wang, Wan-Jun
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experimental part
p. 987 - 991
(2009/07/19)
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- An investigation on key parameters that influence the resolution of omeprazole sodium
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In this document are highlighted systematic studies on factors such as water content, temperature, solvent, and mole ratio of the resolving agents that influence the resolution of omeprazole sodium.
- Reddy, Lekkala Amarnath,Malakondaiah, Golla China,Babu, Karrothu Srihari,Bhattacharya, Apurba,Bandichhor, Rakeshwar,Himabindu, Vimmidi,Reddy, Padi Pratap,Anand, Ramasamy Vijaya
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- A PROCESS OF SULFOXIDATION OF BIOLOGICALLY ACTIVE COMPOUNDS
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The present invention relates to a new process for the preparation of sulfoxides, preferably stereoselective preparation of substituted or unsubstituted chiral sulfinyl derivatives 2-(2- pyridylmethyl) sulfinyl-l H-benzimidazole by oxidation with oxaziridine in presence of suitable solvent and base.
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Page/Page column 14
(2009/01/24)
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- PROCESS FOR PREPARING OPTICALLY PURE ACTIVE COMPOUNDS
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The invention relates to a novel process for preparing optically pure PPI having a sulphinyl structure using a chiral zirconium complex or a chiral hafnium complex.
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- PROCESS FOR PREPARING (S)-PANTOPRAZOLE
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The invention relates to a novel process for preparing (S)-pantoprazole using a chiral zirconium complex or a chiral hafnium complex.
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