- A pantoprazole intermediate 2 - chloromethyl - 3, 4 - dimethoxy pyridine hydrochloride preparation method
-
The invention belongs to the technical field of medicine, and particularly relates to a preparation method of a pantoprazole intermediate 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride. The preparation method comprises the following steps: using 3-hydroxyl-2-methyl-4-pyrone as a starting raw material, and then only performing five-step reaction to obtain the pantoprazole intermediate 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride. The preparation method reduces the reaction steps, shortens the reaction cycle, improves the working efficiency, and increases the yield coefficient.
- -
-
-
- Preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine
-
The invention discloses a preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine. The preparation method comprises the following steps: adding 20 to 30kg of 3,4-dimethoxy-2-methylpyridine-N-oxideinto 10 to 20kg of acetic acid to obtain a mixed solution; heating the mixed solution while stirring is mechanically carried out until the mixed solution is completely dissolved; weighing 50 to 70kgof acetic anhydride, and slowly adding the acetic anhydride into a system while stirring; then performing heat insulation for 15 to 16 hours at 85 to 95 DEG C; distilling out 80 to 90 percent of acetic anhydride under reduced pressure; cooling to 18 to 25 DEG C; slowly adding alkali to regulate pH value to 12 to 13; performing heating, stirring and hydrolyzation; adding 0.8 to 1.2kg of dichloromethane into the system and stirring for 1 hour; standing and performing liquid separation; respectively performing extraction by using equal amounts of dichloromethane for two times; adding anhydrous sodium sulfate into a merged extracting solution; stirring and drying the extracting solution; performing rotary evaporation and recycling dichloromethane to obtain a finished product. The preparation method of the 2-hydroxymethyl-3,4-dimethoxypyridine disclosed by the invention has the advantages that the yield is high, reaction conditions are mild, safety and reliability are achieved, a using amount of acetic anhydride is reduced, and the cost is reduced.
- -
-
Paragraph 0026; 0027-0030; 0032; 0033-0036; 0038; 0039-0042
(2018/07/30)
-
- Slow, spontaneous degradation of lansoprazole, omeprazole and pantoprazole tablets: Isolation and structural characterization of the toxic antioxidants 3H-benzimidazole-2-thiones
-
The spontaneous degradation of lansoprazole, omeprazole and pantoprazole tablets upon long-term and forced storage conditions was determined by high performance liquid chromatography (HPLC). The more abundant products could be isolated by liquid chromatography and their molecular weights determined by Mass Spectrometry (MS). Their structures, established according to their spectroscopic data, were compared to those of either the literature or of authentic samples. Thus lansoprazole led mainly to a mixture of 3H-benzimidazole-2-thione (2a) and 3H-benzimidazole-2-one (2c), omeprazole mainly to a mixture of 5-methoxy-3H-benzimidazole-2-thione (1a) and 2-hydroxymethyl-3, 5-dimethyl- 4-methoxypyridine (1b), and pantoprazole, to 5-difluoromethoxy-3H-benzimidazole-2-thione (3a) and 2-hydroxymethyl-3, 4-dimethoxypyridine (3b). Although some of the degradation products had already been observed under different conditions, the detection of benzimidazole-2- thiones is unprecedented and their involvement as possible physiological, yet toxic antioxidants must be emphasized. Plausible, unified mechanisms for the formation of the different degradation products observed herein and in previous papers from the literature are suggested.
- Rajab,Touma,Rudler,Afonso,Seuleiman
-
p. 749 - 754
(2013/10/08)
-
- Synthesis of a DOTA (Gd3+)-conjugate of proton-pump inhibitor pantoprazole for gastric wall imaging studies
-
Magnetic resonance imaging (MRI) is used to evaluate gastrointestinal (GI) structure and functions in humans. Despite filling the viscus lumen with a contrast agent, visualization of the viscus wall is limited. To overcome this limitation, we de novo synthesized a conjugate that covalently combines a Gd-based MRI contrast agent, encaged with a chelating agent (DOTA), with pantoprazole, which is a widely used proton pump inhibitor that binds to proton pumps in the stomach and colon. The DOTA linkage was installed at a mechanism-based strategic location in the pantoprazole molecule to minimize a possible negative effect of the structural modification on the drug. It is anticipated that by defining the wall of the stomach and colon, this compound will facilitate functional MRI of the GI tract in humans.
- Maharvi, Ghulam M.,Bharucha, Adil E.,Fauq, Abdul H.
-
p. 2808 - 2811
(2013/06/27)
-
- Structure-activity relationship of omeprazole and analogues as Helicobacter pylori urease inhibitors
-
Helicobacter pylori urease belongs to a family of highly conserved urea- hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K+-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal side of the H+/K+- ATPase of gastric parietal cells. Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in phosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pK(a)-value of the pyridine, the pK(a)-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide formation, in a quantitative structure-activity relationship. The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of β- mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 μmol/kg flurofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo, as a means of eradicating the infection, was tested and compared with the effect of 125 μmol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
- Kuhler,Fryklund,Bergman,Weilitz,Lee,Larsson
-
p. 4906 - 4916
(2007/10/03)
-
- (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
-
[(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
-
p. 1049 - 1057
(2007/10/02)
-
- 2--1H-thienoimidazoles. A Novel Class of Gastric H+/K+-ATPase Inhibitors
-
2-thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K+-ATPase.The isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo.Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thienoimidazole lead to highly active compounds with a favorable chemical stability.Various substitution patterns in the thienoimidazole moiety result in lower biological activity.The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation.Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H+/K+-ATPase blocker introduced on the market.
- Weidmann, Klaus,Herling, Andreas W.,Lang, Hans-Jochen,Scheunemann, Karl-Heinz,Rippel, Robert,et al.
-
p. 438 - 450
(2007/10/02)
-
- Fluoroalkoxy substituted benzimidazoles useful as gastric acid secretion inhibitors
-
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.
- -
-
-
- Picoline derivative useful as gastric acid secretion inhibitors
-
Picoline derivatives of the formula I STR1 wherein the substituents have the meanings given in the description, and their salts are new compounds having a pronounced protective action on the stomach.
- -
-
-
- 4-PYRIMIDONE COMPOUNDS
-
The compounds are substituted isocytosines which are histamine H 2-antagonists. Two specific compounds of the present invention are 2-2-(5-methyl-4-imidazolylmethylthio)-ethylamino!-5-(3-methoxybenzyl)-4-pyrim idone and 2-2-(5-methyl-4-imidazolylmethylthio)ethylamino!-5-benzyloxy-4-pyrimidone.
- -
-
-
