- An improved and single-pot process for the production of pantoprazole substantially free from sulfone impurity
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Pantoprazole (1), a substituted benzimidazole derivative, is an irreversible proton pump inhibitor, essentially used for the prevention and treatment of gastric acid-related diseases. The process for its preparation generally suffers from the drawback of producing a potential sulfone impurity (5). The present work details a report of the journey towards the development of a simple, single-pot process for the production of pantoprazole, substantially free from sulfone impurity (5). The detailed study of the different parameters affecting the purity and yield of the compound has been presented.
- Mathad, Vijayavitthal T.,Govindan, Shanmugam,Kolla, Naveen Kumar,Maddipatla, Madhavi,Sajja, Eswaraiah,Sundaram, Venkataraman
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- Application of continuous flow micromixing reactor technology for synthesis of benzimidazole drugs
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Synthesis of pharmaceutically active compounds by employing continuous flow micromixing reactor technology is an interesting research area. In this article we describe the synthesis of benzimidazole core drugs, such as lansoprazole (1a), pantaprazole (1b), and rabeprazole (1c) by using a continuous flow micromixing reactor technology. A key feature of the sulfoxidation includes the decreasing the reaction time from 3 h to ～1 s to minimize the formation of sulfone impurities and improve the yields.
- Reddy, Gunupati Sharathchandra,Reddy, Narra Santosh,Manudhane, Kushal,Rama Krishna, Medisetti Venkata,Ramachandra, Kopparapu Janardana Sarma,Gangula, Srinivas
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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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Read Online
- Preparation of Pantoprazole sodium method and Pantoprazole sodium (by machine translation)
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The invention relates to the preparation of Pantoprazole sodium method and pantoprazole sodium. In particular, the invention relates to a method of preparing pantoprazole sodium, comprising the following steps: 1) to 2 - hydroxymethyl - 3, 4 - dimethoxy pyridine (II) as the starting material, in under the action of chloride, the compound of formula III; 2) will be of the formula III compound in the presence of an inorganic base with 5 - difluoro - 2 - mercapto - 1 H - benzimidazole condensation, the compound of formula IV; 3) will be of the formula IV compound is oxidized by an oxidant generating 5 - difluoro - 2 - [(3, 4 - dimethoxy - 2 - pyridyl) methyl] sulfinyl - 1 H - benzimidazole is pantoprazole; 4) the obtained 5 - difluoro - 2 - [(3, 4 - dimethoxy - 2 - pyridyl) methyl] sulfinyl - 1 H - benzimidazole with sodium hydroxide reaction to produce salt that pantoprazole sodium (I); and optionally a 5) the resulting pantoprazole sodium is refined. The method of the invention said product has high purity, and the related impurities such as oxidation impurity, reducing the impurity, decomposition low impurity content. (by machine translation)
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Paragraph 0171; 0172; 0174; 0175-0178; 0181
(2019/02/27)
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- Triple Mode of Alkylation with Ethyl Bromodifluoroacetate: N, or O-Difluoromethylation, N-Ethylation and S-(ethoxycarbonyl)difluoromethylation
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In this report, we have explored a triple mode of chemical reactivity of ethyl bromodifluoroacetate. Typically, bromodifluoroacetic acid has been used as a difluorocarbene precursor for difluoromethylation of soft nucleophiles. Here we have disclosed nucleophilicity and base dependent divergent chemical reactivity of ethyl bromodifluoroacetate. It furnishes lithium hydroxide and cesium carbonate promoted difluoromethylation of tosyl-protected aniline and electron-deficient phenols respectively. Interestingly, switching the base from lithium hydroxide to 4-N,N-dimethylamino pyridine (DMAP) tosyl-protected anilines afforded the corresponding N-ethylation product. Whereas, highly nucleophilic thiophenols furnished the corresponding S-carboethoxydifluoromethylation product via a rapid SN2 attack to the bromine atom prior to the ester hydrolysis. This mechanistic divergence was established through several control experiments. It was revealed that difluoromethylation reaction proceeds through a tandem in situ ester hydrolysis/decarboxylative-debrominative difluorocarbene formation and subsequent trapping by the soft nucleophile-NHTs or electron-deficient phenolic ?OH groups. In the presence of DMAP the hydrolysis of the ester is perturbed instead a nucleophilic attack at the ethyl moiety provides the N-ethylation product. Hence, besides the development of a practical base-promoted N-difluoromethylation of amines and electron-deficient phenols, divergent reactivity pattern of inexpensive and user-friendly ethyl bromodifluoroacetate has been explored. (Figure presented.).
- Polley, Arghya,Bairy, Gurupada,Das, Pritha,Jana, Ranjan
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p. 4161 - 4167
(2018/09/21)
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- A pantoprazole sodium production process (by machine translation)
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Pantoprazole sodium (Pantoprazole Sodium), chemical name 5 - difluoro - 2 - [[ (3, 4 - dimethoxy - 2 - pyridyl) - methyl] sulfinyl] - 1 H - benzimidazole sodium monohydrate, is the treatment of peptic ulcer and acute gastric mucosal lesion caused by bleeding of a safe, effective drug, to peptic ulcer and reflux esophagitis have very high cure rate. For the injection of the injection by the German hectogram (Byk Gulden) the pharmaceutical Company (now renamed Takeda pharmaceutical companies) lead to the successful development of, for 1994 years 10 months in south Africa listed for the first time, tradenames for pan tuo lOOc. The present invention provides a pantoprazole sodium production process. A specific process comprises the following process: 1, pantoprazole sodium intermediate synthesis of IV; 2, pantoprazole sodium crude synthesis of V; 3, crude refined product. (by machine translation)
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Paragraph 0006; 0009
(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 0096; 0097
(2017/09/01)
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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 0032-0034
(2017/07/06)
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- A method for preparing divides the request to pull zuozuo the sodium nitrogen oxide impurity
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The present invention discloses a preparation method for a pantoprazole sodium oxynitride impurity. The preparation method comprises the following steps: 2-chloromethyl-3,4-dimethoxypyridine hydrochloride is used as a raw material to react with 5-difluoromethoxy-2-mercapto-1H-benzimidazole and produce 5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulphur}-1H-benzimidazole; then in a presence of hydrogen peroxide and acetic acid, with copper hydroxyphosphate as a catalyst, oxidation is performed to obtain an oxynitride product of the pantoprazole; and finally a sodium salt is obtained by a reaction with sodium hydroxide, and pantoprazole sodium oxynitride impurity is obtained. According to the preparation method, no extreme reaction condition is needed, and raw materials are easy to obtain; the oxidant is capable of selective oxidations, which can not only oxidate pyridine ring, but also can oxidate thioether to sulfoxide, and by controlling the dosage of the catalyst, i.e., copper hydroxyphosphate, a peroxidation is less likely to occur (oxidate thioether to sulphone); and a post-treatment is simple and easy in operation, and the resulting product is high in purity and high in yield.
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Paragraph 0012; 0027; 0028
(2017/10/05)
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- A method for preparing divides the request to pull zuozuo the sodium sulphone nitrogen oxide impurity
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The invention discloses a method for preparing a pantoprazole sodium sulfone-nitrogen oxidized impurity. The method comprises the steps: enabling 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride, which serves as a raw material, to react with 5-difluoromethoxy-2-mercapto-1H-benzimidazole so as to produce 5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfo}-1H-benzimidazole; then, oxidizing 5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfo}-1H-benzimidazole in the presence of hydrogen peroxide and acetic acid in a manner of using methyl rhenium trioxide as a catalyst, so as to produce a sulfone-nitrogen oxidized product of pantoprazole; and finally, forming a sodium salt by the sulfone-nitrogen oxidized product of pantoprazole and sodium hydroxide, thereby obtaining the pantoprazole sodium sulfone-nitrogen oxidized impurity. According to the method, the hydrogen peroxide-acetic acid system can oxidize a pyridine ring. The oxidizer methyl rhenium trioxide is adopted as the catalyst and can be complexed with hydrogen peroxide so as to produce peroxide of rhenium, oxygen in the peroxide of rhenium can be transferred to thioether needing oxidization, and thioether can be oxidized into sulfone through controlling the usage amount of the catalyst and the reaction temperature, so that the high-yield and high-purity product can be obtained.
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Paragraph 0029; 0030
(2018/11/04)
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- A process for the preparation of Pantoprazole sodium
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The invention belongs to the technical field of medicines and particularly relates to a preparation method of pantoprazole sodium. Aiming at operation of condensation, oxidization and salification by adopting a one-pot process in the prior art, a phase transfer catalyst is added into the condensation process, so that the reaction speed and yield are increased. By virtue of catalytic oxidation of hydrogen peroxide in the presence of tungstate, the selectivity of the reaction is improved and the impurities are reduced. The method provided by the invention is simple to operate, the yield and the purity of the product are improved, and the method is suitable for industrial production.
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Paragraph 0034; 0035
(2017/04/08)
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- PYRIDONE DERIVATIVES AS ACID SECRETION INHIBITORS AND PROCESS FOR PREPARATION THEREOF
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The present invention relates to the preparation of stable pyridone disulphide derivatives having general formula (I) and its stereoisomers, which are useful in the treatment of gastrointestinal disorders. Pyridone disulphide derivatives (I) wherein, R1, R2 and R3 are independently alkyl, alkoxy, halogen, halogenated alkoxy, halogenated alkyl, hydrogen and could be the same or different and X is CH or N. R1 is methyl, methoxy, fluorine, trifluoromethyl, difluoromethoxy and hydrogen, R2 is methyl, methoxy and hydrogen, and R3 is methyl and hydrogen.
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Paragraph 0070-0073
(2015/09/22)
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- PROCESS FOR THE PREPARATION OF PANTOPRAZOLE SODIUM AND PANTOPRAZOLE SODIUM SESQUIHYDRATE
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The present invention relates to a process for the preparation of pantoprazol sodium sesquihydrate of formula (I) and pantoprazole sodium.
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Page/Page column 4
(2010/08/22)
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- PROCESS FOR PREPARING PANTOPRAZOLE SODIUM SESQUIHYDRATE
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Disclosed herein is a process for preparation of pantoprazole sodium sesquihydrate represented by Formula 1 from pantoprazole as a starting material.
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Page/Page column 4
(2009/07/17)
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- PROCESS FOR THE PREPARATION OF PANTOPRAZOLE SODIUM
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Disclosed herein the improved and industrially viable process for the preparation of pantoprazole sodium in high yields and purity.
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Page/Page column 7
(2009/06/27)
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- PROCESS FOR THE PREPARATION OP PANTOPRAZOLE SODIUM AND PANTOPRAZOLE SODIUM SESQUIHYDRATE
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The present invention relates to a process for the preparation of pantoprazol sodium sesquihydrate of formula (I) and pantoprazole sodium.
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Page/Page column 11
(2009/03/07)
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- A PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVES AND THEIR SALTS
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The present relates to a process for the preparation of 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazole derivatives and their pharmaceutically acceptable salts substantially free from their sulfide and the sulfone impurities.
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Page/Page column 25-26
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PANTOPRAZOLE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention related to an improved process for the preparation of Pantoprazole sodium sesquihydrate comprising the reaction of 5-difluoromethoxy-2-mercapto benzimidazole with 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride in an aqueous alkali, which upon oxidation with sodium hypochlorite having pH of about 8.5-9.0 and assay of about 3.0-3.5 in chloro solvent followed by reaction with sodium hydroxide in acetone. The invention also relates to the process for the preparation of pantoprazole sodium sesquihydrate form-I.
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Page/Page column 17-20
(2008/06/13)
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- A NOVEL ONE POT PROCESS FOR PREPARATION OF PANTOPRAZOLE SODIUM SESQUIHYDRATE
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The present invention provides a novel one-pot process for preparation of Pantoprazole sodium sesquihydrate Form-I in the pure form without isolating the pantoprazole base.
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Page/Page column 8-9
(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 13; 14
(2010/11/30)
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- PYRIDINE BENZIMIDAZOLE SULFOXIDES WITH HIGH PURITY
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A method for preparing a pyridine benzimidazole sulfoxide compound having the formula (I) with the step of oxidizing a pyridine benzimidazole thioether compound with an oxidation agent, during that oxidation step a pyridine benzimidazole sulfone compound is formed as an undesired by-product. It is proposed to stop the oxidation step prior the amount of undesired pyridine benzimidazole sulfone product exceeds 1,0 %-by weight based on the entire amounts of compounds.
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Page/Page column 16-17
(2008/06/13)
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- (H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate
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[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.
- Kohl,Sturm,Senn-Bilfinger,Simon,Kruger,Schaefer,Rainer,Figala,Klemm
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p. 1049 - 1057
(2007/10/02)
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- Fluoroalkoxy substituted benzimidazoles useful as gastric acid secretion inhibitors
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Dialkoxypyridines of formula I STR1 wherein R1 is 1-3C-alkyl which is completely or predominantly substituted by fluorine, or a chlorodifluoromethyl radical and R1' is hydrogen, halo, trifluoromethyl, 1-3C-alkyl, or 1-3C-alkoxy which is optionally completely or predominantly substituted by fluorine, or R1 and R1', together with the oxygen atom to which R1 is bonded, are 1-2C-alkylenedioxy, which is optionally completely or partly substituted by fluorine, or chlorotrifluoroethylenedioxy, R3 is 1-3C-alkoxy, one of R2 and R4 is 1-3C-alkoxy and the other is a hydrogen atom or 1-3C-alkyl and n is 0 or 1, and salts thereof are new compounds with a pronounced protective action on the stomach. Processes for preparing these compounds, medicaments containing them and their use, as well as intermediate compounds and their use for preparing the subject dialkoxypyridines, are disclosed.
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