Method for preparing sulfur ether intermediates of proton pump inhibitor

A thioether and proton pump technology, applied to thioether intermediates 2-[S-arylmethyl]thio-1H-benzimidazole compound, 2-[S-arylmethyl]thio-1H-imidazo In the field of [4,5-b]pyridine compounds, it can solve the problems of unfavorable cost and cumbersome operation, and achieve the effects of avoiding oxidative deterioration, simple reaction steps and low production cost

Active Publication Date: 2014-07-16
WUTONG AROMA CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The route restores 16 After filtering off the catalyst, the 17 Direct ring closure reaction reduces separation loss to a certain extent, but it also uses expensive Pd / C catalyst
Also in preparation 18 When using potassium ethyl xanthate for cyclization and strong acid acidification, it brings disadvantages in cost and complicated operation

Method used

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  • Method for preparing sulfur ether intermediates of proton pump inhibitor
  • Method for preparing sulfur ether intermediates of proton pump inhibitor
  • Method for preparing sulfur ether intermediates of proton pump inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Proton pump inhibitor temoprazole sulfide intermediate 2-[ S -(pyridin-2-yl)methyl]thio-1 H - the preparation of benzimidazole

[0066]

[0067] 150 mL of water was added to the reaction flask, and 2-nitroaniline (13.8 g, 0.1 mol), Na 2 S·9H 2 O (72 g, 0.3 mol) and PEG-400 (2.0 mL), heated to reflux, reacted for 4 hours, then cooled the reaction system to 40 °C, directly added CS without separation 2 (9.0 mL, 0.15 mol), after continuing to reflux for 7 hours, add 70 mL methanol, 2-chloromethylpyridine (15.3 g, 0.12 mol), KOH (13.2 g, 85%, 0.2 mol) , heated to reflux again, and reacted for 4 hours. The reaction solution was evaporated under reduced pressure to remove methanol, poured into 100 mL of ice water, a large amount of solids were precipitated, and the yellow crude product was obtained by suction filtration, which was recrystallized with petroleum ether to obtain 15.3 g of light yellow solid, yield 64.6%, mp 105~108 ℃.

[0068] Spectral data: EI-MS ( m...

Embodiment 2

[0071] Proton pump inhibitor Lansoprazole sulfide intermediate 2-[ S -(3-Methyl-4-(2,2,2-trifluoro)ethoxypyridin-2-yl)methyl]thio-1 H - the preparation of benzimidazole

[0072]

[0073] 150 mL of water was added to the reaction flask, and 2-nitroaniline (13.8 g, 0.1 mol), Na 2 S·9H 2 O (72 g, 0.3 mol) and PEG-400 (2.0 mL), heated to reflux, reacted for 4 hours, then cooled the reaction system to 40 °C, directly added CS without separation 2 (9.0 mL, 0.15 mol), after continuing to reflux for 7 hours, add 70 mL methanol, 2-chloromethyl-3-methyl-4-(2,2,2-trifluoro)ethoxy Basepyridine (28.8 g, 0.12 mol), KOH (13.2 g, 85%, 0.2 mol), heated to reflux again, and reacted for 4 hours. The reaction solution was evaporated under reduced pressure to remove methanol, poured into 100 mL of ice water, a large amount of solids precipitated, and the yellow crude product was obtained by suction filtration, which was recrystallized with petroleum ether to obtain 26.5 g of light yellow so...

Embodiment 3

[0078] 150 mL of water was added to the reaction flask, and 2-nitro-4-methoxyaniline (16.8 g, 0.1 mol), Na 2 S·9H 2 O (72 g, 0.3 mol) and PEG-400 (2.0 mL), heated to reflux, reacted for 5 hours, then cooled the reaction system to 40 °C, directly added CS 2 (9.0 mL, 0.15 mol), after continuing to reflux for 5.5 hours, 70 mL of methanol, 2-chloromethyl-3,5-dimethyl-4-methoxypyridine (22.3 g, 0.12 mol), KOH (13.2 g, 85%, 0.2 mol), heated to reflux again, and reacted for 4 hours. The reaction liquid was evaporated to remove methanol under reduced pressure, poured into 100 mL of ice water, a large amount of solids precipitated, and the yellow crude product was obtained by suction filtration, which was recrystallized with petroleum ether to obtain 23.7 g of light yellow solid, yield 71.9%, mp 118~119 ℃.

[0079] Spectral data: EI-MS ( m / z ): 329 [M + ];

[0080] 1 H-NMR (400 MHz, CDCl 3 , ppm), 8.21 (1H, s, pyridine), 7.42 (1H, d, J = 8.8 Hz, ArH), 7.10 (1H, d, J = 2....

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Abstract

The invention relates to a method for preparing a proton pump inhibitor sulfide intermediate of a drug for treating stomach diseases. The o-nitroaniline compound undergoes a continuous reduction-cyclization-condensation three-step process using water and lower alcohols as solvents under alkaline conditions. A series of proton pump inhibitor thioether intermediates (I) can be prepared with high efficiency through a one-pot reaction procedure, wherein X and Y are nitrogen atoms or carbon atoms, and R1 is selected from hydrogen, methoxy, pyrrol-1-yl and One of difluoromethoxy; R2, R3 and R4 are respectively selected from hydrogen, methyl, methoxy, 3-methoxy n-propoxy, 2,2,2-trifluoroethoxy and methyl One of the base sec-butylamine groups. The invention has the advantages of adopting a one-pot cooking synthesis process, reasonable process route design, simple and convenient operation, environment-friendly, avoiding separation loss in the synthesis process, and high yield of the target product. The general structural formula of (I) is:.

Description

technical field [0001] The present invention relates to the technical field of medicine manufacture, specifically, the sulfide intermediate 2-[ S -(hetero)arylmethyl]thio-1 H -benzimidazole compound and 2-[ S -(hetero)arylmethyl]thio-1 H -imidazo[4,5- b ] A one-pot preparation process for pyridine compounds. Background technique [0002] Proton pump inhibitors (PPIs), also known as H + / K + -ATPase inhibitors are mainly used to treat gastric ulcer, duodenal ulcer, reflux esophagitis and other diseases related to gastric acid secretion disorders, and are the first choice for clinical treatment of gastric acid-related diseases. Its most important structural skeleton is a benzimidazole-substituted (hetero)arylmethyl sulfoxide compound (Scheme 1, Ⅱa). Such compounds include temoprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, leminoprazole, ilaprazole, and the like. [0003] [0004] Scheme 1 [0005] In addition, imidazo[4,5- b ] Pyridine compounds (Sc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D235/28C07D401/14
Inventor 卫洁刘倩丁涛王树华冀亚飞
Owner WUTONG AROMA CHEM CO LTD
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