- 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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- Ti-Salan catalyzed asymmetric sulfoxidation of pyridylmethylthiobenzimidazoles to optically pure proton pump inhibitors
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The asymmetric sulfoxidation of two pyridylmethylthiobenzimidazoles to anti-ulcer drugs of the PPI family (S)-omeprazole and (R)-lansoprazole with hydrogen peroxide, mediated by a series of chiral titanium(IV) salan complexes is reported. High sulfoxide yields (up to?>95%) and enantioselectivities (up to 94% ee) have been achieved. The introduction of electron-withdrawing substituents leads to less active and less enantioselective catalysts. Like for the previously reported Ti-salalen catalyzed sulfoxidations, the temperature dependence of the sulfoxidation enantioselectivity in the presence of Ti-salan complexes is nonmonotonic, demonstrating isoinversion behavior with decreasing temperature. The oxidation is likely rate-limited by the formation of the active (presumably peroxotitanium(IV)) species, followed by a faster oxygen transfer to the substrate.
- Talsi, Evgenii P.,Bryliakov, Konstantin P.
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- Asymmetric synthesis of esomeprazole
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A highly efficient synthesis of esomeprazole-the (S)-enantiomer of omeprazole-via asymmetric oxidation of prochiral sulphide 1 is described. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide (CHP) in the presence of (S,S)-diethyl tartrate [(S,S)-DET]. The enantioselectivity was provided by preparing the titanium complex in the presence of 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of 1 in the presence of an amine. An enantioselectivity of >94% ee was obtained using this method. Copyright (C) 2000 Elsevier Science Ltd.
- Cotton, Hanna,Elebring, Thomas,Larsson, Magnus,Li, Lanna,Soerensen, Henrik,Von Unge, Sverker
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- Factors influencing the selectivity in asymmetric oxidation of sulfides attached to nitrogen containing heterocycles
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Asymmetric oxidation of heterocyclic sulfides, including imidazole, benzimidazole, indole and pyrimidine derivatives, were studied using a tartrate/Ti(iOPr)4 catalyst system. The Royal Society of Chemistry.
- Seenivasaperumal, Muthu,Federsel, Hans-Juergen,Ertan, Anne,Szabo, Kalman J.
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- Asymmetric Bio-oxidation Using Resting Cells of Rhodococcus rhodochrous ATCC 4276 Mutant QZ-3 for Preparation of (S)-Omeprazole in a Chloroform–Water Biphasic System Using Response Surface Methodology
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(S)-Omeprazole is a very effective anti-ulcer medicine that is difficult to be prepared using whole cells at elevated substrate concentrations. In the chloroform–water biphasic system, resting cells of the mutant QZ-3 of Rhodococcus rhodochrous (R. rhodochrous) ATCC 4276 were used to catalyze the bio-oxidation of omeprazole sulfide for preparation of (S)-omeprazole. Using response surface methodology (RSM), the reaction was optimized to work at a substrate concentration of 180?mM and a cell concentration of 100?g/L. The optimal yield of (S)-omeprazole obtained was 92.9% with enantiomeric excess (ee) (> 99%), and no sulfone by-product was detected under the optimal working conditions; reaction temperature 37?°C, pH 7.3 and reaction time, 43?h. A quadratic polynomial model was established, which predicts the experimental data with very high accuracy (R2 = 0.9990). The chloroform–water biphasic system may contribute to the significant improvement in substrate tolerance because almost all substrates are partitioned in the organic phase (water solubility of omeprazole sulfide is only about 0.5?mg/mL), resulting in little damage and inhibition to cells by substrates. The mutant QZ-3 of R. rhodochrous ATCC 4276 exhibited high enantioselectivity, activity and substrate and product tolerance. The aerated flask provides enough oxygen for a high concentration of cells. Accordingly, bio-oxidation is thus more promising for efficient preparation of chiral sulfoxides.
- Zhang, Yuanyuan,Lv, Kuiying,Deng, Yashan,Li, Huiling,Wang, Zhiyong,Li, Depeng,Gao, Xin,Wang, Fanye
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- Catalytic Asymmetric Synthesis of Esomeprazole by a Titanium Complex with a Hexa-aza-triphenolic Macrocycle Ligand
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An efficient synthesis of esomeprazole via catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl sulfide by a titanium complex with a hexa-aza-triphenolic macrocycle ligand is described. Esomeprazole was prepared with 99.6% ee, which meets the high requirement of the European Pharmacopeia on enantiomeric purity.
- Song, Weiguo,Dong, Liangjun,Zhou, Yuhan,Fu, Yongqiang,Xu, Wenfang
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- Synthesis of optically active omeprazole by catalysis with vanadyl complexes with chiral Schiff bases
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A new method for the preparation of optically active omeprazole, consisting in asymmetric oxidation of the corresponding sulfide with the use of vanadyl complexes with chiral Schiff bases as the catalysts has been elaborated. The best results of the oxidation were achieved by the use of the combination VO(acac)2-2-[{(1S,2S,3R,5S)-3-hydroxymethyl-2,6,6-trimethyl- bicyclo[3.1.1]hept-2-ylimino}methyl]phenol-N-ethyl-N,N-diisopropylamine.
- Koneva,Khomenko,Kurbakova,Komarova,Korchagina,Volcho,Salakhutdinov,Tolstikov,Tolstikov
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- Baeyer-Villiger Monooxygenase-Mediated Synthesis of Esomeprazole As an Alternative for Kagan Sulfoxidation
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A wild-type Baeyer-Villiger monooxygenase was engineered to overcome numerous liabilities in order to mediate a commercial oxidation of pyrmetazole to esomeprazole, using air as the terminal oxidant in an almost exclusively aqueous reaction matrix. The developed enzyme and process compares favorably to the incumbent Kagan inspired chemocatalytic oxidation, as esomeprazole was isolated in 87% yield, in >99% purity, with an enantiomeric excess of >99%.
- Bong, Yong Koy,Song, Shiwei,Nazor, Jovana,Vogel, Michael,Widegren, Magnus,Smith, Derek,Collier, Steven J.,Wilson, Rob,Palanivel,Narayanaswamy, Karthik,Mijts, Ben,Clay, Michael D.,Fong, Ryan,Colbeck, Jeff,Appaswami, Amritha,Muley, Sheela,Zhu, Jun,Zhang, Xiyun,Liang, Jack,Entwistle, David
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- Asymmetric Sulfoxidation of Thioether Catalyzed by Soybean Pod Shell Peroxidase to Form Enantiopure Sulfoxide in Water-in-Oil Microemulsions: A Kinetic Model
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Esomeprazole with chiral sulfoxides structure is used to treat gastric ulcer disease. Soybean pod shell peroxidase (SPSP) is a peroxidase extracted from soybean pods shells which are one of the most abundant natural resources in the world. In the production of chiral sulfoxides catalyzed by SPSP, it is very important to establish the reaction kinetic model and explore the reaction mechanism for the development of the process, however, there is no report on the establishment of the model. Asymmetric sulfoxidation reactions catalyzed by SPSP in water-in-oil microemulsions were carried out, and the King-Altman approach was used to establish a kinetic model. A yield of 91% and e.e. value of 96% for esomeprazole were obtained at the activity of SPSP of 3200 U ml?1 and 50 °C for 5 h. The mechanism with a two-electron reduction of SPSP-I is accompanied with a single-electron transfer to SPSP-I and nonenzymatic reactions, indicating that three concomitant sub-mechanisms contribute to the asymmetric oxidation involving five enzymatic and two nonenzymatic reactions, which can represent the asymmetric sulfoxidation of organic sulfides to form enantiopure sulfoxides. With 5.44% of the average relative deviation, a kinetic model fitting experimental data was developed. The enzymatic reactions may follow ping-pong mechanism with substrate inhibition of H2O2 and product inhibition of esomeprazole, while nonenzymatic reactions follow a power law. Those results indicate that SPSP with a lower cost and higher thermal stability may be used as an effective substitute for horseradish peroxidase.
- Li, Huiling,Deng, Yashan,Du, ShanShan,Liu, Cui,Li, Kaiyuan,Xue, Xiao,Xu, Hui,Zhang, Yuanyuan,Yi, Tingting,Gao, Xin
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- Resolution of omeprazole by inclusion complexation with a chiral host BINOL
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Both (S)-(-)- and (R)-(+)-enantiomers of omeprazole were directly resolved by inclusion complexation with a chiral host compound (S)-(-)- or (R)-(+)-2,2'-dihydroxy-1,1'-binaphthyl in high enantiomeric excess (>99% e.e.). (C) 2000 Elsevier Science Ltd.
- Deng, Jingen,Chi, Yongxiang,Fu, Fangmin,Cui, Xin,Yu, Kaibai,Zhu, Jin,Jiang, Yaozhong
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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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- 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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- Scalable process for the premix of esomeprazole
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An efficient, scalable process for the premix of unstable esomeprazole base is described that allows accessibility to the stable amorphous form of esomeprazole 1.
- Reddy, Lekkala Amarnath,Malakondaiah, Golla China,Reddy, Alieti Sanjay,Bhaskar, Boluguddu Vijaya,Himabindu, Vurimidi,Bhattacharya, Apurba,Bandichhor, Rakeshwar
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- Enzymatic Preparation of the Chiral (S)-Sulfoxide Drug Esomeprazole at Pilot-Scale Levels
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Esomeprazole is the most popular proton pump inhibitor (PPI) for treating gastroesophageal reflux disease. Enzymatic asymmetric sulfoxidation is a green approach to produce chiral sulfoxides. In this report, we focused on optimizing asymmetric sulfoxidation catalyzed by prazole sulfide monooxygenase (AcPSMO). The costly redox cofactor NADPH utilized by AcPSMO was regenerated by formate dehydrogenase with CO2 as the coproduct, which can be removed easily. During the scale-up process, oxygen supply was found to be the main limiting factor during the early phase of the reaction, while the instability of AcPSMO and the lack of the cofactor NADPH hindered progress during the middle and late phases of the 0.6 L reaction. Finally, by adjusting oxygen mass transfer and increasing the dissolved oxygen, the enzymatic reaction was stepwise amplified to a 120 L scale using a 300 L thermostatic stirred reactor, affording 95.9% conversion and 99.9% enantiomeric excess after 12 h. Extraction and refinement of the product resulted in 0.39 kg of the isolated esomeprazole (sodium salt), with 57.8% overall yield (73.4% before the salt-forming reaction) and 99.1% purity. Thus, a green-by-design system was constructed for the efficient and precise oxidation of omeprazole sulfide into esomeprazole with molecular O2 as the green cosubstrate and CO2 and H2O as byproducts.
- Lin, Guo-Qiang,Wu, Yin-Qi,Xia, Jian-Ye,Xu, Jian-He,Xu, Na,Yu, Hui-Lei,Zhang, Yan,Zhao, Qian,Zhu, Jun
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- An efficient procedure for the synthesis of Esomeprazole using a titanium complex with two chiral ligands
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A procedure has been proposed for the selective preparation of Esomeprazole via asymmetric oxidation of the corresponding prochiral sulfide in the presence of a catalytic complex derived from titanium(IV) isopropoxide and two different chiral ligands, diethyl d-tartrate and (R)-N,N-dimethyl-1-phenyl-ethanamine.
- Khomenko,Volcho,Komarova,Salakhutdinov
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- Synthetic method of esomeprazole
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The invention discloses a synthetic method of esomeprazole, which comprises the following steps: first steps of preparation of omeprazole thioether. 2nd: The crude product is prepared by taking omeprazole thioether and the like as a raw material. The obtained crude product was subjected to a purification operation 3 times to give a refined intermediate. The third Steps. The purified intermediate is mixed with deionized water, filtered, mixed with magnesium chloride hexahydrate and deionized water, stirred, cooled, stirred 30 min, decompressed and suction filtered, and the obtained crystals are washed with distilled water and dried to obtain esomeprazole. Under the condition of ensuring 90%, the yield and purity of the subsequent processing process are improved, and the problems that in the prior art, the purity is not ideal, the total yield is low, the production cost is increased, and the industrial production is not conducive to industrial production are solved.
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Paragraph 0017; 0026-0027; 0031; 0034; 0037-0038; 0042;...
(2021/11/27)
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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 0039-0049
(2020/09/09)
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- Enzymatic kinetic resolution of chiral sulfoxides-an enantiocomplementary approach
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A new enzymatic assay for the preparation of chiral sulfoxides that is enantiocomplementary to the known (S)-enantiomer-reducing activity of methionine sulfoxide reductase A (MsrA) is described. To this end, we have utilized the enzyme DMSO reductase (DmsABC), recently discovered by us being highly upregulated in stationary phase E. coli bacteria.
- Nosek, Vladimír,Mí?ek, Ji?í
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supporting information
p. 10480 - 10483
(2019/09/07)
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- Preparation method and application of esomeprazole magnesium and application thereof
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The invention provides a preparation method of esomeprazole magnesium and an application thereof. Under the action of chiral thiourea catalyst, chiral sparteine-copper complex and chiral amino alcohol-tertiary amine, and under the condition of oxidant, ufiprazole is used as substrate and subjected to asymmetric oxidation to obtain esomeprazole under the condition of organic solvent and water. To improve the asymmetric oxidation reaction system of esomeprazole, the self-made chiral thiourea catalyst, chiral sparteine-copper complex and chiral amino alcohol-tertiary amine are used in asymmetricoxidation of ufiprazole. The process is simple and the reaction conditions are easy to obtain. It does not need special reaction temperature, room temperature, and strict control of water content. Moreover, the obtained esomeprazole has good quality and high purity, and does not need refining. Its purity is more than 99%, impurity D (sulfoxide) is less than 0.1%, ee value is more than 98%, which is favorable for subsequent salt formation and refining.
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Paragraph 0064-0120
(2019/05/15)
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- A preparation method of esomeprazole magnesium
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The invention relates to the field of chemical synthesis, in particular to a novel synthesis process for active pharmaceutical ingredients of a PPI (proton pump inhibitor), and especially relates to a preparation method of esomeprazole magnesium. According to the method, 5-methoxy-2-mercaptobenzimidazole and 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride are taken as the starting raw materials and subjected to condensation, asymmetric oxidation and salifying to prepare esomeprazole magnesium, a wet product is refined with water and methanol, an intermediate does not require crystallization, filtering and drying, the operation steps are simplified, the production cycle is shortened, material loss and energy consumption in a processing process are reduced, the yield is improved, and good economic benefits and social benefits are realized. The preparation method is good in repeatability and simple to operate, improves the yield and purity of esomeprazole magnesium and facilitates industrial production.
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Paragraph 0027; 0029; 0031; 0033; 0035; 0037; 0039; 0041
(2019/06/26)
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- Novel preparation method of esprazole magnesium trihydrate and intermediate thereof
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The invention relates to a novel preparation method of esprazole magnesium trihydrate and an intermediate thereof, and belongs to a pharmaceutical technology. The preparation method comprises the following steps: (1) performing condensation reaction to prepare omeprazole sulfide; and (2) performing chiral oxidation reaction to prepare esprazole, performing potassium salt forming reaction to prepare esprazole potassium, and performing ion exchange reaction to obtain the esprazole magnesium trihydrate. The method is high in product yield, high in product purity, mild and safe in reaction condition, low in energy consumption, easy to control and suitable for industrial mass production.
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Paragraph 0080-0086
(2019/07/04)
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- Synthesis method of esomeprazole serving as proton pump inhibitor
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The invention discloses a synthesis method of esomeprazole serving as a proton pump inhibitor, and belongs to the technical field of drug synthesis. According to the method, asymmetric oxidation on isconducted on omeprazole thioether under the condition that chiral phosphoric acid serves as a catalyst and hydrogen peroxide serves as an oxidizing agent to generate esomeprazole. Firstly, 5-methoxy-2-benzimidazolethiol and 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride generate omeprazole thioether in an aqueous phase, and then selective oxidation is conducted on omeprazole in the presence of a chiral phosphoric acid catalyst to generate esomeprazole. The method has the advantages of being high in yield, environmentally friendly, good in selectivity, free of heavy metal residuesand more suitable for large-scale industrial production.
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Paragraph 0032; 0035; 0036; 0039; 0040; 0043; 0044; 0047
(2019/11/20)
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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 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 12; 13; 14; 15; 17; 18
(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
(2020/02/07)
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- Preparation method for esomeprazole
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The invention discloses a method for preparing esomeprazole, belonging to the technical field of medicine. According to the invention, 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride and 2-mercapto-5-methoxybenzimidazole are used as starting materials and are subjected to condensation and oxidation so as to prepare an esomeprazole salt. The method has good reproducibility, and is simple to operate, easy for realizing industrial production and mild in preparation conditions; and the production of impurity nitrogen oxide and sulfone (peroxide) during the preparation is reduced, and the yield and purity of the esomeprazole salt are improved.
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Paragraph 0057; 0058; 0066; 0067; 0075; 0076
(2018/04/21)
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- Oxidative kinetic resolution of heterocyclic sulfoxides with a porphyrin-inspired manganese complex by hydrogen peroxide
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We have successfully reported here the low loading porphyrin-inspired high-valent manganese (IV)-oxo complex was applied in oxidative kinetic resolution (OKR) of racemic heterocyclic sulfoxides using the environmentally benign hydrogen peroxide for the first time. This approach allows for rapid OKR (0.5 h) of a variety of racemic sulfoxides (including pyridine, pyrimidine, pyrazine, thiazole, benzothiazole, thiophene) in excellent enantioselectivity (up to > 99% ee), simultaneously generating the corresponding sulfones in high yield (up to 80%). The catalytic system also showed an unexceptionable chemoselectivity for the sulfoxide substrates with hydroxyl groups in which only the sulfoxide group was oxidized. The practical utility of the method has been demonstrated in the OKR of gram-scale sulfoxides.
- Yang, Jinchuang,Wang, Lianyue,Lv, Ying,Li, Ning,An, Yue,Gao, Shuang
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supporting information
p. 156 - 159
(2017/12/15)
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- Ultrafast chiral separations for high throughput enantiopurity analysis
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Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
- Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
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supporting information
p. 509 - 512
(2017/01/13)
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- Synthesis method of proton pump inhibitors
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The invention discloses a synthesis method of proton pump inhibitors, and belongs to the technical field of medicine synthesis. On the basis of a chemical resolution method, asymmetrical synthesis is performed for overcoming the defects of the chemical resolution method; firstly, 2-sulfydryl-5-methoxybenzimidazole and 2-(chloromethyl)-4-methoxyl-3,5-dimethylpyridine hydrochloride are used as raw materials to take a reaction for obtaining a thioether product; then, selective oxidization is performed to obtain an (S)-form product; (R)- by products are fewer; the (R)-by products are further removed by a resolution method. Therefore the method has the advantages, better conforms to the atom economic rules, and is more suitable for large-scale industrial production.
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Paragraph 0008
(2017/07/13)
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- A esomeprazole magnesium trihydrate preparation method
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The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an esomeprazole magnesium trihydrate. The preparation method comprises steps as follows: 1) 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio-1H-benzimidazole (ufiprazole) is oxidized into esomeprazole with an oxidizing agent in an organic solvent in the presence of (R,R)-1,2-diphenyl-1,2-glycol, titanium alkoxide and isopropyl alcohol; 2) esomeprazole sodium is prepared through the reaction of the esomeprazole with sodium methoxide; 3) the esomeprazole sodium and magnesium chloride have salt exchange in methanol to produce the esomeprazole magnesium trihydrate. The method has the characteristics of high stereoselectivity and specificity and the like, can increase the yield of the target product, and is easy to operate and suitable for industrial production.
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Paragraph 0031; 0036-0038; 0041; 0044; 0047
(2017/09/26)
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- Preparation method for high-purity sodium esomeprazole
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The invention specifically relates to a preparation method for high-purity sodium esomeprazole, belonging to the technical field of preparation of bulk drugs. The preparation method is simple to operate, suitable for industrial large-scale production and capable of preparing the high-purity medicinal bulk drug sodium esomeprazole. Specifically, the preparation method employs an asymmetric oxidation process, uses 5-methoxy-2-[[4-methoxy-3,5-dimethy-2-pyridyl]methyl]sulfinyl-1H-benzimidazole (omeprazole sulfide) as a starting raw material, utilizes D-ethyl tartrate and tetraisopropyl titanate as inducers and prepares esomeprazole (S-omeprazole) from cumyl hydroperoxide through asymmetric oxidation; HPLC is used for controlling in the process of reaction; and finally, esomeprazole (S-omeprazole) reacts with sodium hydroxide to produce a sodium salt. High-performance liquid chromatographic results show that final sodium esomeprazole prepared by using the method has a purity of more than 99.5% and impurity sulfone content of less than 0.1% and can be directly used for production of corresponding drugs.
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Paragraph 0038; 0039; 0040; 0043; 0044; 0045; 0048-0050
(2017/03/08)
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- Esomeprazole sodium preparation method
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The invention discloses an esomeprazole sodium preparation method, which specifically comprises: (1) thioether forming: carrying out heating stirring on raw materials such as 2-mercapto-5-methoxybenzimidazole and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride in a mixed solvent in the presence of a strong alkali; (2) oxidizing: adding an organic alkali, a chiral agent and an oxidizing agent to the omeprazole thioether and the organic solvent, stirring, and controlling the temperature to obtain a reaction liquid containing esomeprazole; and (3) salt forming: extracting the reaction liquid obtained in the step (2) with ammonia water, taking the water phase, carrying out acidification, extracting with an organic solvent C, evaporating to achieve a dry state, carrying out reflux, and crystallizing to obtain the esomeprazole sodium. According to the present invention, the preparation method has advantages of simple operation, less environment pollution, high yield, low cost and high optical purity of the product, and is suitable for large-scale industrial production.
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Paragraph 0018; 0020; 0022
(2018/03/01)
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- Esomeprazole as well as preparation method and application thereof
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The invention discloses esomeprazole as well as a preparation method and application thereof, relates to the technical field of medicines and aims to solve the technical problems that the existing preparation method of esomeprazole is low in economy and cannot meet the requirements of energy economization, consumption reduction, green and environment protection. The preparation method of the esomeprazole comprises a step of selectively oxidizing prochiral thioether ufiprazole into esomeprazole with cooperation of catalysts, oxidants, organic solvents and pH regulators under the action of functional chiral ionic liquid taking (D)-(-)-tartaric acid as anion. After the functional chiral ionic liquid taking (D)-(-)-tartaric acid as anion is added, the dissoluvability of the prochiral sulfide ufiprazole used as the raw material is obviously improved; the higher raw material utilization rate and selectivity can be ensured. The method has the advantages of simple step, easy operation, low consumption of solvents and low raw material dissolving temperature, so that the method is low in energy consumption, can meet the requirements of energy economization, consumption reduction, green and environment protection, and is suitable for large-scale industrial production.
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Paragraph 0077; 0078; 0081; 0084; 0087; 0090; 0093
(2018/01/11)
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- An efficient silica supported Chitosan@vanadium catalyst for asymmetric sulfoxidation and its application in the synthesis of esomeprazole
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A new type of silica supported Chitosan@vanadium complex was used as a highly active heterogeneous catalyst for asymmetric oxidation of aryl alkyl sulfides. With the economic aqueous H2O2(30%) as the oxidant, the oxidation products were obtained in high yields (up to 95%) with good enantioselectivities (up to 68% ee). It is noted that the marketed drug Nexium (first proton-pump inhibitor, esomeprazole) could be synthesized easily by the newly developed asymmetric sulfoxidation reaction. In addition, the highly active catalyst can be reused five times without losing its catalytic activity.
- Shen, Chao,Qiao, Jun,Zhao, Linwei,Zheng, Kai,Jin, Jianzhong,Zhang, Pengfei
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p. 114 - 118
(2017/01/25)
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- Method for preparing esomeprazole sodium
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The invention discloses a method for preparing esomeprazole sodium. The method includes the specific steps that a thioether precursor as shown in formula (I) serves as the raw material, quaternary ammonium heteropolyphosphatotungstate serves as a catalyst, acetone serves as solvent, and under existence of sodium bicarbonate and chiral reagent (1S, 2S)-(-)-1, 2-cyclohexanediamine-D-tartrate, the thioether precursor as shown in the hydrogen peroxide oxidation formula serves as sulfoxide; after a reaction is ended, filtering is conducted, filtrate is poured in water, filtering is conducted, a filter cake is washed and dried, and (S)-(-)-omeprazole is obtained; the (S)-(-)-omeprazole is alkalified through the sodium bicarbonate, separation is conducted, and the esomeprazole sodium is obtained. The method has the advantages of being high in reaction yield and high in catalytic efficiency, and hydrogen peroxide and the sodium bicarbonate are in abundant supply, cheap, easy to obtain and low in cost; the reaction condition is mild, waste polluting the environment is not generated, environmental pollution is reduced, and the catalyst and the reaction solvent can be recycled; the reaction is easy to operate, and postprocessing is simple and easy to conduct.
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Paragraph 0020
(2016/11/28)
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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 85-88
(2016/02/03)
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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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supporting information
p. 110 - 112
(2016/03/01)
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- Method for synthesis and refining of esomeprazole sodium
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The invention relates to the field of chemical synthesis, and particularly relates to a new method for synthesis and refining of esomeprazole sodium; with omeprazole sulfide as a raw material, and through selection of the specific solvent type and proportion in the preparation process, the method has the advantages of simple operation, stable and reliable technology, high asymmetric oxidation selectivity and high yield of the obtained product, and high optical purity (ee% value), and is the production method quite suitable for large-scale industrialization of esomeprazole sodium.
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Paragraph 0035
(2016/12/22)
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- A one-pot synthesis of Esso draws thiazole magnesium method of preparation
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The invention discloses a method for preparing esomeprazole by a one-pot method, which comprises the following steps: dissolving 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride and 2-mercapto-5-methoxy benzimidazole in an organic solvent, performing a heat preservation reaction under an alkaline condition for 1.5-6 hours, performing water washing to obtain an organic phase; adding an asymmetric titanium catalyst into the organic phase, dropwise adding an oxidizing agent at -15-25 DEG C, performing a heat preservation reaction at 5-45 DEG C for 2-8 hours, performing extraction and separation with alkaline liquor to obtain an alkali phase; adjusting the pH of the alkali phase, dropwise adding a magnesium salt aqueous solution, and performing post-treatment to obtain the product. The method of the invention simplifies the operation steps, shortens the production period, reaches the purpose of energy saving, needs no intermediate separation, thus reduces loss in the treatment process, increases the yield, and realizes good economic benefits and social benefits.
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Paragraph 0004; 0024; 0026
(2017/05/18)
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- A method for preparing of ammonium salts of esomeprazole
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The invention relates to a synthesis method for preparing esomeprazole. The required protection method comprises the step that: Ufiprazole is subjected to asymmetric oxidation by using a mild and cheap oxidant in the existence of N substituted 1-amino-2-indanol ligand and a complex catalyst formed by titanium, so that an optical pure or esomeprazole-enriched product can be obtained.
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Paragraph 0028; 0029
(2017/02/24)
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- Method for realizing asymmetric oxidation reaction of thioether under aqueous-phase catalysis of chiral Salen Ti complex catalyst based on temperature-sensitive type ionic liquid
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The invention discloses a method for realizing an asymmetric oxidation reaction of thioether under aqueous-phase catalysis of a chiral Salen Ti complex catalyst based on a temperature-sensitive type ionic liquid. According to the method, a chiral thioether compound and hydrogen peroxide are subjected to an asymmetric oxidation reaction under the catalytic action of the chiral Salen Ti complex catalyst based on the temperature-sensitive type ionic liquid in a water medium, and a chiral sulfoxide compound is obtained; the chiral Salen Ti complex catalyst based on the temperature-sensitive type ionic liquid also contains a chiral Salen Ti complex catalyst unit and a temperature-sensitive material unit. Compared with a conventional chiral Salen Ti catalyst, the catalyst has good water solubility, can be subjected to a catalytic reaction in the water medium and is easily recycled; the catalyst is applicable to the aqueous-phase catalytic oxidation reaction of chiral thioether and has the characteristics of high catalysis efficiency and good chiral sulfoxide selectivity.
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Paragraph 0087-0089; 0090
(2017/02/24)
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- A catalytic asymmetric oxidation of sulfide method
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The invention provides a method for asymmetric catalytic oxidation of thioether. A chiral complex formed by a quadridentate nitrogen organic ligand and a metal manganese compound is adopted as the catalyst, hydrogen peroxide is employed as the oxidizing agent to carry out asymmetric catalytic oxidation reaction on thioether so as to obtain a corresponding chiral sulfoxide compound, and the yield and enantioselectivity are both greater than 95%. The reaction has the advantages of cleanliness, mild reaction conditions, high conversion rate and enantioselectivity, and has industrial prospect.
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Paragraph 0065
(2016/10/09)
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- Aqueous two-phase system chiral separation Prazole compound
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The invention discloses a new method for chiral resolution and racemization of a prazole compound, and particularly an aqueous two-phase resolution system is adopted. An aqueous phase contains a hydrophilic chiral resolving agent and the prazole compound, and the other phase contains an alcohol soluble chiral resolving agent; after the two phases are mixed, the pH is adjusted to neutral, and the prazole compound is resolved into optical-pure chiral compounds under the actions of the two chiral resolving agents. When a phase-separating salt is added into the system, the system can become two separable phases respectively containing two different chiral isomers.
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Paragraph 0013
(2016/12/01)
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- A process for preparing a novel method or its sodium salt of intermediate and its preparation method
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The invention provides an intermediate for preparing esomeprazole or esomeprazole sodium and a preparation method thereof. The intermediate is a compound show as a formula VI shown in the specification. The advantages and the active effects comprise that the intermediate is firstly obtained, and the product prepared by using the preparation method is good in purity and high the yield, the purity and the yield both reaches about 90%, and the preparation method is suitable for industrialized large-scale production.
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Paragraph 0156; 0157; 0158; 0159; 0160; 0161
(2017/04/29)
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- Method for preparing of ammonium salts of esomeprazole (by machine translation)
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The present invention provides a method for preparing of ammonium salts of esomeprazole. Preparation of ammonium salts of esomeprazole of the present invention method includes: shown in formula VI of the chiral compound of the formula III in the Grignard reaction of Grignard reagent of the following occurs, so as to get said [...] : Wherein M is magnesium or zinc, preferably magnesium; X is halogen, preferably chlorine, bromine or iodine, more preferably chloro. The invention has the following advantages and positive effects: the of ammonium salts of esomeprazole produced by the process of good purity, and high yield, respectively can be up to 90% the left and right; all of the present invention is relates to a process for preparing asymmetric oxidation step, therefore, will not cause the heavy metal pollution, and the operation is simple, low cost raw materials which are easy to get, is suitable to be applied to industrial mass production. (by machine translation)
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Paragraph 0170; 0171
(2017/02/24)
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- Method for preparing [...]
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The invention provides a preparation method for esomeprazole sodium. The preparation method for esomeprazole sodium comprises: 1) enabling a chiral compound shown as a formula VI and a Grignard reagent shown as a formula III to perform a Grignard reaction shown in the specification, so as to obtain esomeprazole, and in the reaction, M is magnesium or zinc, preferably is magnesium, and X is a halogen, preferably is chlorine, bromine or iodine, and more preferably is chlorine; and 2) performing the salt forming reaction shown in the specification on esomeprazole shown as a formula VII, so as to obtain esomeprazole sodium. The preparation method has the following advantages and active effects: esomeprazole sodium prepared by using the preparation method is good in purity and high in yield, and the purity and the yield respectively reach about 90%; the whole preparation technological process does not relate to an asymmetric oxidation step, so that the preparation method does not cause heavy metal pollution; and also the preparation method is simple in operation, easily available in raw materials and low in cost, and is suitable for industrialized large-scale production.
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- For the preparation of intermediates or its sodium salt [...] and its preparation method
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The invention discloses an intermediate for preparing esomeprazole or esomeprazole sodium and a preparation method thereof. The intermediate is a compound shown as a formula V shown in the specification. The advantages and the active effects comprise that the intermediate V is firstly obtained, the product obtained by using the preparation method is good in purity and high in yield, the purity and the yield can both reach about 90%, and the preparation method is suitable for industrialized large-scale production.
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- Enantioselective oxidation of sulfides with H2O2 catalyzed by a pre-formed manganese complex
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A facile and environmentally friendly method is presented for the asymmetric oxidation of sulfides with H2O2, utilizing a pre-formed manganese complex. Just in the presence of a low catalytic amount of carboxylic acid (CA), a variety of sulfide substrates, including aryl alkyl, aryl benzyl and cyclic sulfides, reacted to form chiral sulfoxides in high yields (up to 95%) and excellent enantioselectivities (>99% ee) under mild conditions. Moreover, the practical utility of the method has been demonstrated by the synthesis of esomeprazole and albendazole sulfoxide (ABZO).
- Dai, Wen,Li, Guosong,Wang, Lianyue,Chen, Bo,Shang, Sensen,Lv, Ying,Gao, Shuang
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p. 46545 - 46554
(2014/12/10)
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- Asymmetric oxidation catalysis by a porphyrin-inspired manganese complex: Highly enantioselective sulfoxidation with a wide substrate scope
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The first genuinely promising porphyrin-inspired manganese-catalyzed asymmetric sulfoxidation method using hydrogen peroxide has been successfully developed, allowing for rapidly oxidizing (0.5-1.0 h) a wide variety of sulfides in high yields with excellent enantioselectivities (up to >99% ee).
- Dai, Wen,Li, Jun,Chen, Bo,Li, Guosong,Lv, Ying,Wang, Lianyue,Gao, Shuang
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supporting information
p. 5658 - 5661
(2013/12/04)
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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 21
(2011/04/26)
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- OPTICAL PURIFICATION OF ESOMEPRAZOLE
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The present invention relates to process for optical purification of esomeprazole or a salt thereof. Thus, esomeprazole sodium having 20 to 1% R-omeprazole by weight of the sum of the contents of esomeprazole and R-omeprazole is precipitated from a solvent selected from an alcohol or a mixture of alcohols and the precipitated solid is collected to obtain optically pure esomeprazole sodium.
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Page/Page column 2
(2011/09/20)
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- A PROCESS FOR THE PREPARATION OF AMORPHOUS ESOMEPRAZOLE
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The present invention relates to a process for the preparation of esomeprazole in amorphous form by spray drying.
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Page/Page column 13
(2011/09/14)
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- A METHOD OF MANUFACTURING (S)-5-METHOXY-2-[[(4-METHOXY-3,5-DIMETHYL-2- PYRIMIDINYL)METHYL]SULFINYL]-1H-BENZIMIDAZOLE USING A CHIRAL COMPLEX WITH MANDELIC ACID
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The invention deals with a new manufacturing method of (S)-5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole of formula (I) and its salts of general formula (II), wherein the sulfide of general formula (III) is oxidized by hydroperoxides on a catalyst consisting of a chiral metallic complex containing ligands constituted by chiral functional derivatives of mandelic acid.
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Page/Page column 13; 14
(2011/10/13)
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- Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium
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A process for preparing esomeprazole sodium comprises the steps of providing a solution of esomeprazole sodium in a solvent constituted mainly of methanol or only of methanol; and carrying out precipitation or crystallisation of esomeprazole sodium from said solution. Esomeprazole sodium is preferably obtained from pure form of neutral racemate through chiral chromatography using methanol-based mobile phase, and a subsequent reaction with sodium source. Novel crystal and semicrystal forms of esomeprazole sodium can be provided repeatedly and in physically stable and highly pure form.
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Page/Page column 9
(2010/01/29)
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- POLYMORPHS OF ESOMEPRAZOLE SALTS
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The present invention relates to a high assayed esomeprazole magnesium dihydrate substantially free of its trihydrate form. The present invention further provides an improved and commercially viable process for preparation of high assayed esomeprazole magnesium dihydrate substantially free of its trihydrate form. The present invention also provides an improved process for preparation of pure amorphous esomeprazole magnesium. The present invention further provides an improved and commercially viable process for preparation of substantially enantiomerically pure esomeprazole in neutral form or as a pharmaceutically acceptable salt or as its solvates including hydrates. The present invention also provides solid form of esomeprazole calcium salt, its polymorphs (form 1, form 2 and amorphous form) and processes for their preparation thereof.
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Page/Page column 6
(2010/09/17)
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- OPTICAL PURIFICATION OF ESOMEPRAZOLE
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The present invention relates to process for optical purification of esomeprazole or a salt thereof. Thus, esomeprazole sodium having 20 to 1 % R-omeprazole by weight of the sum of the contents of esomeprazole and R-omeprazole is precipitated from a solvent selected from an alcohol or a mixture of alcohols and the precipitated solid is collected to obtain optically pure esomeprazole sodium.
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Page/Page column 6
(2010/07/10)
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- PROCESS FOR PREPARING AN OPTICALLY ACTIVE PROTON PUMP INHIBITOR
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An improved process for the preparation of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole of Formula I, (I) with high enantiomeric excess from racemic mixture.
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Page/Page column 5
(2010/06/13)
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