- Method for preparing chiral sulfoxide drugs in water phase
-
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.
- -
-
Paragraph 0056-0058
(2020/09/09)
-
- Method for producing proton pump inhibitor compound having optical activity
-
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.
- -
-
Page/Page column 16
(2019/06/15)
-
- INHIBITORS OF SARM1 NADase ACTIVITY AND USES THEREOF
-
The present disclosure provides compounds useful as inhibitors of SARM1 NADase activity, compositions thereof, and methods of using the same. The present disclosure provides compounds useful for treating a neurodegenerative or neurological disease or disorder, compositions thereof, and methods of using the same.
- -
-
-
- Method for preparing benzimidazole proton pump inhibitor
-
The invention provides a novel method for preparing a benzimidazole proton pump inhibitor, and belongs to the field of medicine synthesis. According to the method provided by the invention, a complexformed by using graphene oxide and a transition metal salt is used as a catalyst, and the corresponding benzimidazole proton pump inhibitor is obtained through oxidizing a thioether by an oxidizing agent under an alkaline condition in an organic solvent. The method has the advantages of mild reaction condition, high yield, environmental friendliness, and less impurity, the catalyst can be recycled, and the method is suitable for industrial production.
- -
-
Paragraph 0042; 0043; 0044; 0046; 0047; 0048; 0078; 0079
(2018/09/08)
-
- Synthesis of Esomeprazole and Related Proton Pump Inhibitors through Iron-Catalyzed Enantioselective Sulfoxidation
-
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
-
p. 9738 - 9743
(2018/10/09)
-
- A catalytic asymmetric oxidizing thioether preparation of chiral pharmaceutical method
-
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.
- -
-
Paragraph 0038-0044; 0053-0055
(2020/02/07)
-
- Rabeprazole analogue preparation method
-
The invention discloses a rabeprazole analogue preparation method, and particularly relates to a (R)-rabeprazole preparation method. According to the method, under the co-action of a vanadium metal and a tetradentate organic ligand, a prochiral thioether compound is oxidized with an oxidizing agent to generate (R)-rabeprazole. The method of the present invention has advantages of high enantioselectivity, high product purity and high yield, and is suitable for industrial production.
- -
-
Paragraph 0037-0051
(2018/10/27)
-
- Preparation method for key intermediate rabeprazole thioether
-
The invention discloses a preparation method for rabeprazole thioether 2-[[[4-(3- methoxypropoxy)-3-methylpyridin-2-yl] methyl] sulfo]-1H-benzimidazole. By using Mitsunobu reaction, the rabeprazole thioether is prepared from rabeprazole oxhydryl in one-step synthesis way without chlorination reaction. In the reaction process, the high-corrosive chloride agent, such as, thionyl chloride, is not used, so that the violent corrosion of the reaction to the device is obviously reduced, and meanwhile, the reaction yield is obviously increased due to the shortened reaction step. According to the invention, the process is simple, the reaction condition is mild, the corrosion to the device is small, the yield is higher (70%-80%) and the method is suitable for industrial production.
- -
-
-
- Method for preparing optically-pure Rabeprazole
-
The invention discloses a method for preparing optically-pure Rabeprazole. The method is used for preparing a chiral 2-[[4-(3-methoxypropoxy)-3-methylpyrid-2-yl]methylsulfinyl]-1H-benzimidazole compound (Rabeprazole), which is present in a single-enantiomer form or rich-enantiomer form, in an enantioselective manner. The same effects, i.e., identical enantioselectivity and conversion ratio can be achieved through complexing a tartaric acid diamide ligand and titanium and adding an organic-base additive or not in the presence of water. The invention further provides a method for preparing a sodium salt from the obtained Rabeprazole.
- -
-
Paragraph 0070; 0071; 0072; 0073; 0074
(2017/08/28)
-
- A optically pure and its sodium salt preparation method
-
The invention discloses preparation methods of optically pure rabeprazole and a sodium salt thereof. The preparation method of optically pure rabeprazole specifically comprises the steps of dissolving an S-(-)-rabeprazole or R-(+)-rabeprazole crude product in an organic solvent, extracting by using ammonium hydroxide, removing an organic layer, adjusting a pH value of the ammonium hydroxide extract to be 8.5-10.5 by using acetic acid, extracting by using a ketone type solvent, washing the obtained organic layer by using a buffering solution with the pH value of 9-11, and cooling and crystallizing to obtain optically pure rabeprazole. According to the preparation method of optically pure rabeprazole, the chiral rabeprazole solids can be obtained at lower temperature without being subjected to high-temperature concentration; the obtained chiral rabeprazole has good crystal form, high chemical purity and high chiral purity.
- -
-
Paragraph 0047; 0048
(2017/08/10)
-
- Amorphous dexrabeprazole sodium and preparation method thereof
-
The invention relates to amorphous dexrabeprazole sodium and a preparation method thereof. The preparation method of the amorphous dexrabeprazole sodium comprises the following steps: 1) taking a chiral ligand, a titanium type catalyst, an organic alkali, water and a reaction solvent; after mixing, heating and stirring to form a chiral catalyst; then adding rabeprazole thioether and adding an oxidant to carry out an asymmetric oxidation reaction, so as to obtain dexrabeprazole; 2) dissolving the dexrabeprazole into an alcohol type solvent, and adding sodium salt and carrying out a salt forming reaction; after finishing the reaction, carrying out concentration treatment to obtain an oily product of dexrabeprazole sodium; 3) adding an extracting solvent into the oily product of the dexrabeprazole sodium to obtain a dexrabeprazole sodium extracting solution; adding the dexrabeprazole sodium extracting solution into an ether type solvent and carrying out crystallization treatment; carrying out drying treatment to obtain the amorphous dexrabeprazole sodium. The amorphous dexrabeprazole sodium provided by the invention has the advantages of low moisture content, high stability and easiness of being absorbed.
- -
-
Paragraph 0039-0041
(2017/08/29)
-
- Chiral sulfoxide compound and its salt new method and the preparation of crystalline forms
-
The invention discloses a novel preparation method for a chirality sulfoxide type compound and salt of the chirality sulfoxide type compound and a crystal form. The preparation method is used for preparing a chirality sulfoxide compound which exists in a single enantiomer form or in a rich enantiomer form in an enantioselective mode. Under the conditions that tartaric acid diamide ligand, titanium complexation and water exist, the same effect that when alkali is added can be achieved without adding the alkali, namely the same enantioselectivity and percent conversion can be achieved. Besides, the invention further provides a novel crystal form of S - ( - ) - omeprazole sodium salt.
- -
-
Paragraph 0134; 0135
(2017/02/24)
-
- A right-handed sodium rebeilazole for method for the synthesis of
-
The invention relates to a method for synthesizing rabeprazole sodium. The method comprises the following steps: performing asymmetric oxidation on raw materials with cumyl hydroperoxide, extracting through a sodium hydroxide solution, neutralizing to the pH value of 9.7 by using acid, separating out high-purity white rabeprazole sodium solids, filtering without drying, directly adding a wet sample into a mixed system of sodium hydroxide and dichloromethane and alkane solvent while stirring for reacting at the temperature of 0-30 DEG C for 3-5 hours, filtering, and drying, thereby obtaining the white rabeprazole sodium solids. According to the method disclosed by the invention, the operating steps are simplified, the yield is improved, the rabeprazole is prevented from being dried and heated, unknown impurities generated by heat instability are reduced, and use of an organic solvent is reduced.
- -
-
Paragraph 0039-0040
(2017/04/11)
-
- An electronic circular dichroism study for the structurechiroptical relationship of chiral proton pump inhibitors
-
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
-
p. 110 - 112
(2016/03/01)
-
- Synthesis of prazole compounds
-
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.
- -
-
Page/Page column 92-94
(2016/02/03)
-
- PROCESS FOR THE PREPARATION OF RABEPRAZOLE
-
The present invention provides a compound of Formula III, process of its preparation and its use as a reference marker or as a reference standard. The present invention further provides a process for the preparation of rabeprazole, a salt or a solvate thereof. The invention also provides a chromatographic method for testing the purity of rabeprazole, a salt or a solvate thereof.
- -
-
-
- Application of continuous flow micromixing reactor technology for synthesis of benzimidazole drugs
-
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
-
p. 1272 - 1276
(2013/11/06)
-
- Catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide catalyzed by a titanium complex with (S,S)-N,N′-dibenzyl tartramide ligand
-
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
-
experimental part
p. 457 - 460
(2012/07/28)
-
- OPTICAL RESOLUTION OF SUBSTITUTED 2-(2- PYRIDINYLMETHYLSULPHINYL)-1H-BENZIMIDAZOLES
-
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)
-
- SALTS AND POLYMORPHS OF DEXRABEPRAZOLE
-
The present invention provides dexrabeprazole magnesium hydrate and a process for its preparation. The present invention also provides a magnesium, calcium or potassium salt of dexrabeprazole, optionally in amorphous form, and processes for its preparation.
- -
-
Page/Page column 16-17
(2012/01/13)
-
- NEW CRYSTALLINE FORMS OF RABEPRAZOLE SODIUM
-
The present invention relates to crystalline forms of rabeprazole sodium and processes for their preparation. The invention also relates to pharmaceutical compositions comprising rabeprazole sodium.
- -
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Page/Page column 26-27
(2010/04/03)
-
- PROCESS FOR PURIFICATION OF RABEPRAZOLE SODIUM
-
There is provided a process for preparing amorphous rabeprazole sodium. Thus, for example, sodium hydroxide was dissolved in methanol. Rabeprazole was added to the solution and stirred at 25 - 35°C for 1 hour. Methanol was distilled off from the reaction mass, dichloromethane was added to the residual mass and the contents were stirred to obtain solution. The solution was added to cyclohexane. The contents were stirred at 25 - 35°C for 30 minutes, centrifuged the material and washed at 60 - 65°C to obtain amorphous rabeprazole sodium.
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Page/Page column 3-4
(2010/04/03)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF RABEPRAZOLE
-
The present invention provides a purification process for Rabeprazole compound of formula (I) or its sodium salt. Formula (I)
- -
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Page/Page column 8
(2010/12/31)
-
- Process for the preparation of pyridine-methylsulfinyl compounds
-
A process for the preparation of a compound of formula (I), or a salt thereof, wherein Q is ═CR8— or ═N—; and R1-R8 are as herein defined; comprising the reaction of a compound of formula (II), or a salt thereof, wherein Q, R1-R7 are as herein defined; with a reducing agent selected from a trivalent phosphorous compound, an oxidizable solvent and a sulfonic acid chloride; and, if desired, the conversion of a compound of formula (I) to another compound of formula (I) or a salt thereof.
- -
-
Page/Page column 6
(2009/04/24)
-
- Process for the preparation of a gastric acid secretion inhibitor
-
The present process comprises the preparation of rabeprazole or a pharmaceutically acceptable salt thereof by oxidation in an acidic media of a N-oxide sulfide derivative compound, followed by a further selective reduction of the N-oxide obtained to afford rabeprazole.
- -
-
-
- Method for preparing 2- (2-pyridinylmethylsulfinyl) benzimidazoles
-
The present invention provides a method for preparing an antiulcer agent, 2-(2-pyridinylmethylsulfinyl)benzimidazoles, such as Omeprazole, Lansoprazole, Pantoprazole and Rabeprazole, which includes oxidizing an intermediate having a linkage of methylthio group (—CH2S—) to methylsulfinyl (—CH2S(O)—) in the presence of an oxidation catalyst of an alkali metal salt of tungstate at a temperature of 10-50° C.
- -
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Page/Page column 3-4
(2009/01/24)
-
- PROCESS FOR PREPARATION OF PYRIDINYLMETHYLSULPHINYL BENZIMIDAZOLE COMPOUNDS AND PYRIDINE INTERMEDIATES
-
Process for preparing 4-chloro-substituted pyridine intermediates of Formula (I), useful for preparation of pyridinylmethylsulphinyl benzimidazole compounds, especially Rabeprazole is disclosed herein. The invention, further describes process for preparation of stable Rabeprazole sodium of high purity in a reproducible and consistent manner.
- -
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Page/Page column 14-15
(2009/10/22)
-
- Synthesis of metabolites and related substances of rabeprazole, an anti-ulcerative drug
-
Rabeprazole sodium (Aciphex) is a gastric proton pump inhibitor used for the prevention and treatment of gastric acid-related diseases. During the synthesis of bulk drug of rabeprazole sodium, we have observed metabolites rabeprazole sulfide and rabeprazole sulfone and related substances rabeprazole-N-oxide, rabeprazole sulfone-N-oxide, N-aralkyl rabeprazole, chloro rabeprazole, and methoxy rabeprazole as impurities in the drug substance. The present work describes the synthesis and characterization of these compounds. Copyright Taylor & Francis Group, LLC.
- Reddy, Ganta Madhusudhan,Mukkanti, Kaga,Bhaskar, Boluggodu Vijaya,Reddy, Padi Pratap
-
body text
p. 278 - 290
(2009/04/11)
-
- SELECTIVE PRODUCTION OF SULPHOXIDES
-
The invention pertains to a process for producing a sulphoxide compound, comprising oxidizing a thioether compound with an ozonide formed from a olefin and ozone, to obtain the corresponding sulphoxide compound, provided that the olefin is not ethene. The ozonide converts thio - ether compounds selectively, unlike its art - known oxidizing counterparts. The milder ozonide does not require manipulation of the stoichiometric amount of available oxidizing agent during the reaction, to prevent the formation of sulphones.
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Page/Page column 12
(2009/03/07)
-
- An improved process for the production of rabeprazole sodium substantially free from the impurities
-
The present work details the journey towards development of a simple and cost-viable process for large-scale synthesis of rabeprazole sodium substantially free from the impurities. The detailed study of different parameters affecting the quality and yield percentage of the compound has been presented. Yield is increased from 40% (reported process) to 75% with the improved process at sulfoxidation stage.
- Reddy, Pingili Ramchandra,Himabindu, Vurimidi,Jaydeepkumar, Lilakar,Reddy, Ganta Madhusudhan,Kumar, Jonnalagadda Vijaya,Reddy, Ghanta Mahesh
-
experimental part
p. 896 - 899
(2010/04/22)
-
- 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
-
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
-
experimental part
p. 987 - 991
(2009/07/19)
-
- Process for preparing 2-(2-pyridylmethyl)-sulfinyl-1H-benzimidazoles and the intermediate compounds used therein
-
The present invention relates to a process for preparing 2-(2-pyridylmethyl)sulphinyl-1H-benzimidazoles that are proton pump inhibitors, using as intermediates 2-benzimidazolylsulphinic acid derivatives. The present invention also relates to said intermediate compounds, their use and a process for the preparation thereof. These novel intermediate compounds are 2-benzimidazolylsulphinic acid esters that are obtained from their corresponding alkaline salts, which are in turn obtained by oxidation of substituted 2-mercaptobenzimidazoles. The intermediate compounds of the invention are converted into 2-(2-pyridylmethyl)sulphinyl-1H-benzimidazoles by reaction with substituted 2-methylpyridines.
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Page/Page column 16
(2008/12/09)
-
- A process for the preparation of pyridine-methylsulfinyl compounds
-
A process for the preparation of a compound of formula (I), or a salt thereof, wherein Q is =CR8- or =N-; and R1-R8 are as herein defined; comprising the reaction of a compound of formula (II), or a salt thereof, wherein Q, R1-R7 are as herein defined; with a reducing agent selected from a trivalent phosphorous compound, an oxidizable solvent and a sulfonic acid chloride; and, if desired, the conversion of a compound of formula (I) to another compound of formula (I) or a salt thereof.
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Page/Page column 9
(2008/12/05)
-
- A PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVES AND THEIR SALTS
-
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 30-32
(2008/06/13)
-
- PROCESS FOR PREPARING PROTON PUMP INHIBITORS
-
The present application relates to a process for the preparation of proton pump inhibitors of the benzimidazole-type represented by the general Formula I, Formula I wherein R1 and R2 are the same as or different from each other and are selected from hydrogen, methoxy or difluoromethoxy, R3, R4 and R5 are the same as or different from each other and are selected from hydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy, and their pharmaceutically acceptable salts.
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Page/Page column 19-21
(2008/06/13)
-
- IMPROVED PROCESS FOR THE PREPARATION OF PURE RABEPRAZOLE
-
The present invention relates to a process for the preparation of pure Rabeprazole sulfoxide using the solvent mixture for the extraction steps and this invention further relates to the process for the preparation of amorphous Rabeprazole sodium using pure rabeprazole base in presence of aqueous NaOH and water miscible solvent and adding an anti-solvent.
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Page/Page column 10
(2009/01/23)
-
- A PROCESS OF SULFOXIDATION OF BIOLOGICALLY ACTIVE COMPOUNDS
-
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 13
(2009/01/24)
-
- Process for the preparation of 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole substantially free of sulfone impurity
-
A process for the preparation of rabeprazole substantially free of sulfone impurity is disclosed. The method comprises reacting 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-1H-benzimidazole with an oxidizing agent and removing the unreacted sulfide compounds and sulfone impurities from the medium by means of an extraction and two additional crystallization steps. The unreacted compounds are removed with the organic layer of said extraction step whereas the impurities are removed with the additional crystallization steps wherein rabeprazole free base and impurities are treated in the same phase. Preparation of rabeprazole sodium salt is also covered within the scope of the present invention. Product of the previous crystallization steps is dissolved in methanolic sodium hydroxide and obtained solution is concentrated. Sodium salt of rabeprazole is precipitated by way of adding the residue into diethyl ether. Both rabeprazole and its sodium salt are obtained with sulfone impurity percentage around 0.08 %.
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Page/Page column 6
(2008/06/13)
-
- SALTS OF BENZIMIDAZOLE DERIVATIVE WITH AMINES AND PROCESS FOR PRODUCTION THEREOF
-
It is an object of the present invention to provide (1) a process for manufacturing alkali metal salts of 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1 H -benzimidazole which are useful as gastric acid secretion inhibitors, anti-ulcer agents and other drugs and (2) salts of 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1 H -benzimidazole with amines which are intermediates for the production of the alkali metal salts, and a process for manufacturing the same. According to the present invention, disclosed are salts represented by the following formula (I): (wherein A + represents an isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion).
- -
-
Page/Page column 15 -17
(2008/06/13)
-
- Process for Production of Benzimidazole Derivative Salt Precipitate
-
The present invention provides a process for the production of a 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1 H-benzimidazole alkali metal salt (1), which is a drug or an intermediate for the production of a drug, the process not requiring large-scale equipment and being excellent in terms of workability, operability and energy conservation. According to the present invention, there is disclosed a process for the production of a salt precipitate represented by formula (1) (wherein B represents an alkali metal ion), the process comprising the steps of: dissolving the compound represented by formula (2) in a first organic solvent and adding an alkali metal hydroxide, or dissolving the alkali metal hydroxide in the first organic solvent and adding the compound represented by formula (2); and further adding a second organic solvent to a reaction mixture obtained.
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Page/Page column 3; 7-8
(2008/06/13)
-
- PROCESS FOR THE PREPARATION OF 2-(2-PYRIDYLMETHYL)-SULFINYL-1H-BENZIMIDAZOLES
-
The present invention relates to an improved process for the preparation of substituted. 2-(2-pyridylmethyl)-sulfinyl-1H-benzimidazoles or its derivatives, which are useful for a medicament such as an inhibitor of gastric acid secretion or an anti-ulcer agent or an intermediate to produce medicaments in good yield and high purity. More particularly, the present invention relates to a process for preparing a sulfoxide compound of the formula (I) in good yield and relatively high purity and pharmaceutically acceptable salt, hydrate and solvate thereof. (I) wherein R1 and R3 are selected from the group consisting of hydrogen, methyl or C1-4 alkoxy, R2 is selected from the group consisting of substituted or unsubstituted C1-4 alkoxy, R4 is selected from the group consisting of hydrogen or substituted or unsubstituted C1-4 alkoxy. Comprising the step of oxidizing a sulfide compound of formula (II) with Peroxyacetic acid or its derivatives necessarily at the pH 5-7 using aqueous sodium carbonate solution. (II) wherein R1 R2 R3 and R4 are as defined above.
- -
-
Page/Page column 9
(2008/06/13)
-
- PROCESS FOR THE PREPARATION OF PYRIDINE COMPOUNDS
-
A process for preparation of a compound of formula (I), both as the isomeric mixture and individual isomers, wherein Q is ═CR8— or ═N—; each R1, R2, R3, R4 is independently selected from hydrogen, halogen, hydroxy; nitro; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen or C1-C6 alkoxy; phenyl-C1-C6 alkyl; phenyl-C1-C6 alkoxy; and —N(RaRb) wherein each Ra and Rb is independently hydrogen or C1-C6 alkyl or Ra and Rb, taken together with the nitrogen atom they are linked to, form a saturated heterocyclic ring; and each R5, R6, R7, R8 is independently selected from hydrogen, halogen, hydroxy; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen; C1-C6 alkyl-carbonyl, C1-C6 alkoxy-carbonyl, and oxazol-2-yl; comprising converting a compound of formula (IV), to said compound of formula (I), in the presence of a catalyst, if necessary in an organic solvent.
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Page/Page column 5
(2008/06/13)
-
- A process for the preparation of pyridine compounds
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A process for the preparation of a compound of formula (I) or a salt thereof, both as the isomeric mixture and the individual isomers, wherein Q is =CR8- or =N-; each R1, R2, R3 and R4 is independently selected from hydrogen, halogen, hydroxy; nitro; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen or C1-C6 alkoxy; phenyl-C1-C6 alkyl; phenyl-C1-C6 alkoxy; and - N(RaRb) wherein each Ra and Rb is independently hydrogen or C1-C6 alkyl or Ra and Rb, taken together with the nitrogen atom they are linked to, form a saturated heterocyclic ring; and each R5, R6, R7 and R8 is independently selected from hydrogen, halogen, hydroxy; C1-C6 alkyl optionally substituted with hydroxy; alkylthio C1-C6; C1-C6 alkoxy optionally substituted with halogen; C1-C6 alkyl-carbonyl, C1-C6 alkoxy-carbonyl, and oxazol-2-yl; comprising converting a compound of formula (IV), or a salt thereof, wherein Q, R1, R2, R3, R4, R5, R6 and R7 are as defined above, to said compound of formula (I), or a salt thereof, in the presence of a catalyst, if necessary in an organic solvent; and, if desired, converting a compound of formula (I) to a salt thereof to another compound of formula (I); and/or, if desired, resolving an isomeric mixture of a compound of formula (I) in the individual isomers.
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Page/Page column 7
(2008/06/13)
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- MORPHINE SULPHATE FORMULATIONS
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Described is a pellet composition comprising a core element comprising morphine sulfate, a filler and a binder, wherein the morphine sulfate, calculated as the anhydrous form, comprises about 50 wt% to about 85 wt% of the total weight of the core element; and a coating disposed on at least a portion of the core element, the coating comprising an insoluble matrix polymer which is insoluble at pH 1 to 7.5; an enteric polymer which is insoluble at pH 1 to 4 and soluble at pH 6 to 7.5; and an acid soluble polymer which is soluble at a pH of 1 to 4, wherein the ratio of the acid soluble polymer to the enteric polymer is 1.45:1 to 2.5:1 on a weight basis. Also described are dosage forms comprising the disclosed pellets.
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Page/Page column 6-7
(2008/06/13)
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- A PREPARATION METHOD FOR SUBSTITUTED 2-(2-PYRIDYLMETHOYLSULPHINYL)-l-H-BENZIMID AZOLES
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The invention relates to a process for the preparation of a substituted 2-(2-pyridylmethylsulphinyl)-l-H-benzimidazole involving the reaction of a corresponding 2-(2-pyridylrnethylthio)-l-H-benzirnidazole compound with a hypohalite oxidation agent in the presence of a phase transfer catalyst, wherein the reaction involves a biphasic reaction mixture containing an aqueous and an organic phase. The reaction can immediately succeed the formation of said 2-(2-pyridylmethylthio)-l-H-benzimidazole compound in a one pot synthesis, in order to avoid time-consuming and costly purification steps. Overoxidation, leading to sulphone impurities, is thus avoided and yields improved. Hence, the invention also relates to a substituted 2-(2-pyridylmethylsulphinyl)-l-H-benzimidazole containing less than 0.2 wt% sulphone impurities.
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Page/Page column 11; 12
(2010/11/30)
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- Identification and synthesis of potential impurities of rabeprazole sodium
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Rabeprazole sodium (1, Achiphex) is a gastric proton pump inhibitor. It causes dose-dependent inhibition of acid secretion and is useful as an anti-ulcer agent. In the process for the preparation of 1, two potential unknown impurities were identified in HPLC at levels ranging from 0.05-0.8%. Based on mass spectral data vide LC-MS, the two impurities were characterized as 2-{[(4-chloro-3-methyl-2-pyridinyl) methyl] sulfinyl}-1H-bezimidazole (2, chloro analogue of rabeprazole) and 2-[{(4-methoxy-3-methyl-2-pyridinyl)methyl} sulfinyl]-1H-benzimidazole (3, methoxy analogue of rabeprazole). The structures were unambiguously established by independently synthesizing them and co-injecting in HPLC. To our knowledge, the compounds 2 and 3 have not been reported as process impurities elsewhere.
- Pingili, R. Reddy,Jambula, M. Reddy,Ganta, M. Reddy,Ghanta, M. Reddy,Sajja,Sundaram,Boluggdu, V. Bhaskar
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p. 814 - 818
(2007/10/03)
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- PROCESS FOR THE PREPARATION OF SULPHINYL DERIVATIVES BY OXIDATION OF THE CORRESPONDING SULFIDES
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The present invention relates to a mild and industrially applicable process for preparing sulfinyl derivatives of Formula (II), useful as inhibitors of gastric acid secretion, comprising the selective oxidation of the corresponding sulfides of Formula (I), as represented in scheme (I) and (II) in which said oxidation is performed with hydrogen peroxide in the presence of low amounts of a rhenium compound as catalyst, at a temperature from 0° C to room temperature.
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- Process for the preparation of organic compounds containing a sulfinyl or sulfonyl group in the presence of epsilon-phthalimidoperhexanoic acid
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A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.
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- Process for the preparation of organic compounds containing a sulfinyl or sulfonyl group
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A process for the oxidation of thioethers to sulfoxides or sulfones or for the oxidation of sulfoxides to sulfones by treatment of thioethers or sulfoxides with an oxidizing amount of ε-phthalimidoperhexanoic acid is particularly useful for the preparation of compounds of industrial interest, in particular pharmaceuticals for human or veterinary use.
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- Processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles
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Improved processes for preparing substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles are disclosed.
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