- A practical one pot synthesis of 2-[2-(pridylmethyl)-thio]-1H-benzimidazoles
-
A combination of Et3N and pTSCl was found to be far superior than pTSCl or benzene sulfonyl chloride alone in convert ing substituted 2-picoline-N-oxides to the corresponding 2-chloromethylpyridines and has been exploited for the synthesis of a variety of 2-[2-(pyridylmethyl)-thio]-1H-benzimidazoles, key intermediates in the manufacture of H+/K+-ATPase inhibitors in a single pot.
- Rane,Pathak,Kaushik,Prasad Rao,Kumar, Ashok
-
-
Read Online
- An improved process for the production of lansoprazole: Investigation of key parameters that influence the water content in final API
-
An improved large-scale synthesis of lansoprazole 1 an anti-ulcer drug is described. The synthesis commences with condensation of 2-mercaptobenzimadazole 3 with 2-chloromethyl-3methyl4-(2,2, 2-trifluoro ethoxy) pyridine hydrochloride 2 using water as a solvent to yield thioether 4. Subsequently, 4 was selectively oxidized to 1 by using sodium hypochlorite, a mild, economic, and eco- friendly oxidizing agent. A systematic investigation of crystallization parameters in the final stage, which enabled us to control the water content in the final API to 0.10%, were also discussed. (As recommended by USP 28 monograph (The United States Pharmacopeia: USP 28: NF 23, 28th rev. of The Pharmacopeia of the U.S., 23rd ed. of The National Formulary; United States Pharmacopeial Convention; Rockville, MD, 2005; p 1110.).
- Gangula, Srinivas,Elati, Chandrasekhar R.,Neredla, Anitha,Baddam, Sudhakar R.,Neelam, Uday Kumar,Bandichhor, Rakeshwar,Dongamanti, Ashok
-
-
Read Online
- Preparation method of thioether
-
The preparation method comprises the following steps: (a) reacting a halogenated alkyl pyridine derivative or a salt thereof with 2 -mercaptobenzimidazole derivative in a water-soluble organic solvent under basic conditions. (b) The reaction solution obtained in step (a) was subjected to first devitrification step and second devitrification step, and purified. The prepared thioether is low in water content, uniform in water content and high in thioether purity, facilitates control of the water content of a reaction system in a subsequent thioether asymmetric oxidation reaction, and ensures high selectivity and reproducibility of asymmetric oxidation reaction. In addition, the preparation method of the thioether provided by the invention is simple in process and good in repeatability, and is more conducive to large-scale production.
- -
-
Paragraph 0053; 0058
(2021/11/03)
-
- Electrophilic Chlorine from Chlorosulfonium Salts: A Highly Chemoselective Reduction of Sulfoxides
-
Herein, we describe a selective late-stage deoxygenation of sulfoxides based on a novel application of chlorosulfonium salts and demonstrate a new process using these species generated in situ from sulfoxides as the source of electrophilic chlorine. The use of highly nucleophilic 1,3,5-trimethoxybenzene (TMB) as the reducing agent is described for the first time and applied in the deoxygenation of simple and functionalized sulfoxides. The method is easy to handle, economic, suitable for gram-scale operations, and readily applied for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial medicines and analogues. We also report the results of competition experiments that define the more reactive sulfoxide and we present a mechanistic proposal based on substrate and product observations.
- Acosta-Guzmán, Paola,Mahecha-Mahecha, Camilo,Gamba-Sánchez, Diego
-
supporting information
p. 10348 - 10354
(2020/07/13)
-
- Enhanced Antigiardial Effect of Omeprazole Analog Benzimidazole Compounds
-
Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating the need to find new alternative treatments. In this study, we synthesized a series of 2-mercaptobenzimidazoles that are derivatives of omeprazole, and the chemical structures were confirmed through mass, 1H NMR, and 13C NMR techniques. The in vitro efficacy compounds against Giardia, as well as its effect on the inhibition of triosephosphate isomerase (TPI) recombinant, were investigated, the inactivation assays were performed with 0.2 mg/mL of the enzyme incubating for 2 h at 37 ?C in TE buffer, pH 7.4 with increasing concentrations of the compounds. Among the target compounds, H-BZM2, O2N-BZM7, and O2N-BZM9 had greater antigiardial activity (IC50: 36, 14, and 17 μM on trophozoites), and inhibited the TPI enzyme (K2: 2.3, 3.2, and 2.8 M?1 s?1) respectively, loading alterations on the secondary structure, global stability, and tertiary structure of the TPI protein. Finally, we demonstrated that it had low toxicity on Caco-2 and HT29 cells. This finding makes it an attractive potential starting point for new antigiardial drugs.
- Arreguin-Espinosa, Roberto,Calderón-Jaimes, Ernesto,Cuevas-Cruz, Miguel,Gómez-Manzo, Saúl,Hernández-Ochoa, Beatriz,Méndez-Tenorio, Alfonso,Marcial-Quino, Jaime,Ramírez-Nava, Edson Jiovany,Rocha-Ramírez, Luz María,Sánchez-Carrillo, Adrián,Santos-Segura, Araceli
-
-
- Method for preparing high-purity razole intermediate and medicine by using green technology instead of phosgene, thionyl chloride and other toxic and harmful substances
-
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.
- -
-
-
- Preparation method for dexlansoprazole
-
The invention discloses a preparation method for dexlansoprazole, belonging to the field of organic synthesis. The method comprises the following steps: (1) carrying out reaction on 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine and thionyl chloride, and compounding 2-chloromethyl-3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine; (2) putting 2-chloromethyl-3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine acquired in the step (1) and 2-sulfydryl-1H-benzimidazole into an aqueous liquid, and then adding a phase transfer catalyst and sodium hydroxide, thereby acquiring 2-[[3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine-2-group] methylmercapto]-1H-benzimidazole; (3) taking L-ethyl tartrate as a chiral assistant agent, titanium isopropoxide and diisopropylethylamine as a catalyst and cumyl hydroperoxide as an oxidizing agent and reacting with 2-[[3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine-2-group] methylmercapto]-1H-benzimidazole acquired in the step (2) at low temperature, thereby acquiring dexlansoprazole. The preparation method for dexlansoprazole disclosed by the invention is simple and efficient, is capable of obviously shortening the reaction time under the condition of guaranteeing the product yield and is capable of improving the product quality.
- -
-
-
- Refining method for lansoprazole crude product
-
The invention discloses a refining method for a lansoprazole crude product. The method includes: firstly dissolving the crude product, performing decoloration, then conducting cooling and filtration to obtain a solid, and subjecting the obtained solid to refrigeration crystallization treatment in a mixed solvent of propylene oxide/tetrahydrocarbon furan/dichloromethane, and carrying out filtering, washing and drying on the obtained crystal so as to obtain a refined lansoprazole product. According to the method, a refined lansoprazole product with extremely high yield and low impurities can be obtained by one treatment, and the prepared refined lansoprazole product does not contain water or solvate of ethanol, has yield up to 83%-88%, purity of not less than 99.76%, and the content of impurities sulfide and sulfone respectively lower than 0.07% and 0.14%.
- -
-
Paragraph 0031; 0033
(2017/09/02)
-
- Preparation method of Dexlansoprazole
-
The invention discloses a preparation method of Dexlansoprazole. The preparation method comprises: 1, preparing a compound III; 2, preparing crude Dexlansoprazole; and 3, purifying the crude Dexlansoprazole. The method is characterized in that a compound 2 processed with active carbon is added in 1-1.5 h in step 1 to make the reaction completely carried out in order to increase the yield; and isopropyl titanate (IV) or titanium tert-butoxide is added in 10-15 min at 60-65 DEG C to form an enough complex in order to reduce the isomer content and improve the yield and the purity. The method has the advantages of simplicity in operation, high yield and high purity of the above product, and facilitation of commercial production.
- -
-
Paragraph 0032; 0033; 0034; 0035; 0038
(2017/07/21)
-
- Preparation method of (R)-lansoprazole
-
The invention provides a preparation method of (R)-lansoprazole. Through a condensation reaction and an asymmetric oxidation reaction of thioether, the (R)-lansoprazole is prepared. The preparation method comprises refining a (R)-lansoprazole finished product. In the first reaction step, cheap sodium hydroxide replaces sodium methylate, a reaction temperature is reduced to the room temperature from a return temperature, ethanol is used as a solvent and a high yield of 99.5% is realized. In the second asymmetric oxidation step, a yield is 80% or more. The preparation method has simple processes, is free of multiple complex extraction and separation processes and is suitable for industrial production. In the third step, through reaction condition optimization, a reaction conversion rate is greater than 85% and enantioselectivity is greater than 97%. Through purification, the product quality satisfies the FDA same-type product standards, optical purity and chemical purity are greater than 99.5%, the content of thioether is less than 0.1% and sulphone content is less than 0.1%. The preparation method has stable processes and an industrialization prospect.
- -
-
Paragraph 0018; 0022; 0026
(2017/10/27)
-
- Preparation technology of lansoprazole
-
The invention provides a preparation technology of lansoprazole. The preparation technology comprises the following steps that 1, a raw material A 2-mercapto benzimidazole is dissolved into methanol in the presence of alkali, a raw material B 2-chloromethyl-3-methyl-4-(2,2,2,-trifluoroethoxyl)pyridine hydrochloride is added for a reaction, filtering is conducted by adding water, obtained precipitates are washed and dried, and then an intermediate C [[[3-methyl-4-(2,2,2,-trifluoroethoxyl)-2-pyridyl]methyl]sulfydryl]-H-benzimidazole is obtained; the intermediate C is dissolved into ethanol, a mixed solution of hydrogen peroxide, a catalyst and ethanol is added for a reaction, filtering is conducted by adding water, obtained precipitates are washed, and then the lansoprazole is obtained. According to the preparation technology, the yield is increased, the cost is reduced, the production cycle is shortened, and the preparation technology is more suitable for industrialized production.
- -
-
Paragraph 0041
(2017/08/30)
-
- Dexlansoprazole and its preparation method and use
-
The invention provides a dexlansoprazole and its preparation method and use. The preparation method of dexlansoprazole comprises synthesizing a dexlansoprazole crude product through a simple process and carrying out further optical purity refinement and purification to obtain a dexlansoprazole product having optical purity close to 100%. The dexlansoprazole product has optical purity close to 100%, has high purity, can be used as a medicinal component and has a better effect.
- -
-
Paragraph 0177-0181
(2017/08/31)
-
- ION PAIR CATALYSIS OF TUNGSTATE AND MOLYBDATE
-
D The present invention relates to ion pair catalysts (I) comprising the cationic bisguanidinium ligand (A) and diperoxomolybdate anion (B). The present invention also relates to ion pair catalysts (III) comprising the cationic bisguanidinium ligand (C) and peroxotungstate anion (D). It further relates to the use of the said catalysts in the manufacture of enantiomerically enriched sulfoxides.
- -
-
Page/Page column 29
(2017/10/30)
-
- Easy removal of N-carboxybenzyl (Cbz) protective group by low-carbon alcohol
-
Background: A new method for the removal of Cbz protective group was established. It is accomplished by using methanol, ethanol or t-butanol as a deprotective reagent, and the scope and limitations of this method were also preliminarily investigated. These results broaden utility of N-Cbz protective group in synthetic chemistry, especially in synthesis or use of imidazole, benzimidazole, pyrazole or their derivatives. Methods: Using N-Cbz-imidazole as a model compound, the feasibility of the deprotection method was investigated. We studied various reaction conditions including solvent, reaction temperature and catalyst on the influence of the deprotection reaction. Typical experimental procedure, N-Cbz-imidazole (0.40 g, 2.0 mmol) was added to a solution of methanol (30 mL), and the reaction mixture was stirred at room temperature. Hourly tracking and detection by HPLC analysis. Results: These results indicate that the deprotection method effectiveness is closely related with the substrate structure. In the explored scope, it is valid for some heterocyclic compounds, such as N-Cbz-protected imidazole, pyrazole compound, benzimidazole and benzimidazole derivatives, but possibly not for other amino chemicals. Further application of the method to other types of heterocyclic amine compounds is in progress in our labs. The novel deprotection approach can widen use of N-Cbz protective group in synthetic chemistry. There currently are many active pharmaceutical ingredients containing azole structures, for example: omeprazole, esomeprazole, lansoprazole, dexlansoprazole and pantoprazole etc. It has potential to be utilized in pharmaceutical industries and fine chemicals. Conclusion: In summary, this new method of removal of Cbz protective group using low-carbon alcohols of methanol, ethanol or tert-butanol as deprotective reagents is feasible and effective in the kind of heterocyclic amino compounds of imidazoles, pyrazoles and their derivatives. This new approach is simple and mild. Furthermore, removal of Cbz protective group does not affect other functional groups on the molecule, i.e., the structure remains unchanged.
- Song, Guo-Qiang,Qin, Feng,Huang, Xian-Feng,Lv, Xiao-Bing,Yang, Bei
-
p. 177 - 180
(2016/02/26)
-
- 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
-
supporting information
p. 110 - 112
(2016/03/01)
-
- Enantioselective Sulfoxidation Catalyzed by a Bisguanidinium Diphosphatobisperoxotungstate Ion Pair
-
The first enantioselective tungstate-catalyzed oxidation reaction is presented. High enantioselectivities were achieved for a variety of drug-like phenyl and heterocyclic sulfides under mild conditions with H2O2, a cheap and environmentally friendly oxidant. Synthetic utility was demonstrated through the preparation of (S)-Lansoprazole, a commercial proton-pump inhibitor. The active ion-pair catalyst was identified to be bisguanidinium diphosphatobisperoxotungstate using Raman spectroscopy and computational studies.
- Ye, Xinyi,Moeljadi, Adhitya Mangala Putra,Chin, Kek Foo,Hirao, Hajime,Zong, Lili,Tan, Choon-Hong
-
supporting information
p. 7101 - 7105
(2016/07/06)
-
- NOVEL SOLVATE OF DEXLANSOPRAZOLE
-
The present invention provides novel solvate of dexlansoprazole (or R-lansoprazole), particularly diol solvate and its hydrate form of dexlansoprazole (or R-lansoprazole) which is chemically known as (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole compound of the formula (I), as well as processes for the preparation thereof. The said solvates are useful in the preparation of dexlansoprazole with enhanced chiral purity and better HPLC purity with less sulphone impurity content.
- -
-
Paragraph 0072
(2013/03/26)
-
- 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)
-
- NOVEL SOLVATE OF DEXLANSOPRAZOLE
-
The present invention provides novel solvate of dexlansoprazole (or R- lansoprazole), particularly diol solvate and its hydrate form of dexlansoprazole (or R-lansoprazole) which is chemically known as (R)-2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl] methyl] sulfmyl]-lH-benzimidazole compound of the formula (I), as well as processes for the preparation thereof. The said solvates are useful in the preparation of dexlansoprazole with enhanced chiral purity and better HPLC purity with less sulphone impurity content.
- -
-
Page/Page column 17
(2011/09/15)
-
- PROCESS FOR THE PREPARATION OF PROTON PUMP INHIBITORS
-
The present invention relates to novel and improved processes for the preparation of Proton Pump Inhibitors such as 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole and pharmaceutically acceptable salts thereof.
- -
-
Page/Page column 27
(2010/09/17)
-
- Microwave synthesis of lansoprazole drug intermediate
-
The sulfide intermediate, (′2-[[[3-Methyl-4- (2,2,2-trifluoroethoxy)- 2-pyridinyl] methyl] thio]-1H-benzimidazole) (3), required for the industrial synthesis of the anti-ulcer drug Lansoprazole, has been prepared in excellent yields by microwave irradiation of a dry mixture of 2-chloromethyl-3-methyl-4- (2,2,2-trifluoroethoxy)pyridine hydrochloride (1) and 2-mercaptobenzimidazole (2) in the presence of Na2CO3.
- Sailu,Ramakrishna,Komaraiah,Reddy
-
experimental part
p. 363 - 366
(2009/05/31)
-
- Synthesis and characterization of metabolites and potential impurities of lansoprazole, an antiulcerative drug
-
Lansoprazole (Prevacid) is an antiulcerative drug used for the treatment of duodenal and gastric ulcers, reflux oesophagitis, and Zollinger-Ellison syndrome. During the bulk synthesis of lansoprazole, we have observed five impurities: lansoprazole N-oxide, lansoprazole sulfone N-oxide, lansoprazole sulfide, lansoprazole sulfone and N-aralkyl lansoprazole. The present work describes the synthesis and characterization of these impurities. Copyright Taylor & Francis Group, LLC.
- Reddy, Ganta Madhusudhan,Mukkanti,Kumar, T. Laxmi,Babu, J. Moses,Reddy, Padi Pratap
-
p. 3477 - 3489
(2008/12/23)
-
- METHOD AND APPARATUS FOR PRODUCING OXIDIZED COMPOUND
-
There is provided a method and an apparatus for producing an oxidized compound, which includes measuring an electric potential of an oxidation reaction solution for producing an oxidized compound by an oxidation reaction, and determining an end point of the oxidation reaction on the basis of a predefined decrease of the electric potential, thereby simply determining the end point of the oxidation reaction to swiftly move on to the next step. For example, the apparatus for producing an oxidized compound has a reactor (1) for carrying out an oxidation reaction; an oxidation reduction potential detection means (5) for detecting the value of an oxidation reduction potential of an oxidation reaction solution in the reactor; and a determination means (6) for monitoring at all time the detected values of the oxidation reduction potential detected by the oxidation reduction potential detection means and determining a point where the amount of an electric potential dropped from a highest electric potential of the oxidation reduction potential reaches the predefined amount of an electric potential, as an end point of the oxidation reaction, in which the apparatus allows to carry out the method of the invention at an industrial production level.
- -
-
Page/Page column 14; 15
(2008/06/13)
-
- PROCESSES FOR THE PREPARATION OF LANSOPRAZOLE
-
The invention relates to processes for the preparation of benzimidazole sulphinyl compounds. More particularly, it relates to the preparation of pure lansoprazole and pharmaceutical compositions that include the pure lansoprazole.
- -
-
Page/Page column 12
(2008/06/13)
-
- Process for preparing lansoprazole
-
The invention relates to a process for preparing lansoprazole. It is also directed to lansoprazole having a specific surface area and a pharmaceutical composition comprising lansoprazole.
- -
-
Page/Page column 9
(2008/06/13)
-
- METHOD FOR PREPARING 2- (2-PYRIDYLMETHYLSULPHINYL) BENZIMIDAZOLES
-
The present invention provides a method for preparing an antiulcer agent, 2-(2-pyridylmethylsulphinyl)benzimidazoles, such as Omeprazole, Lansoprazole and Pantoprazole, which includes oxidizing an intermediate having a linkage of methylthio group (—CH2S—) to methylsulfinyl (—CH2S(O)—) in the presence of an oxidation catalyst of acetyl acetonate of molybdenium (II) [(CH3C(O)CH2C(O)CH2)2Mo].
- -
-
Page/Page column 3
(2008/06/13)
-
- PROCESS FOR THE PREPARATION OF SULPHINYL DERIVATIVES BY OXIDATION OF THE CORRESPONDING SULFIDES
-
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.
- -
-
-
- Crystals of benzimidazole derivatives and their production
-
A substantially solvent-free and stable crystal of the compound of the formula: STR1 wherein the ring A may optionally be substituted, R1 represents hydrogen or an N-protecting group, each of R2, R3 and R4 (1) a hydrogen atom, (2) an alkyl group which may optionally be substituted with halogen atom(s) or (3) an alkoxy group which may optionally be substituted with halogen atom(s) or alkoxy; or its salt, is produced by subjecting a solvate of the compound (I) or its salt to de-solvent treatment, in an industrially advantageous method.
- -
-
-