Method for preparing sulfur ether intermediates of proton pump inhibitor

A technology of agent sulfide and intermediate, applied in the field of pharmaceutical manufacturing, can solve problems such as unfavorable cost and complicated operation, and achieve the effects of avoiding oxidative deterioration, concise reaction steps and reasonable process route design.

Active Publication Date: 2012-10-03
WUTONG AROMA CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This route reduces 16 and filters out the catalyst, and then directly carries out the ring closure reaction of 17, which reduces the separation loss to a certain extent, but it also uses expensive Pd / C catalyst
In addition, when preparing 18, potassium ethyl xanthate was used for cyclization and strong acid acidification, which brought 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 sulfur ether intermediates of a proton pump inhibitor. According to the method, an ortho-nitroaniline compound is subjected to a continuous three-step and one-pot reaction process of reduction, cyclization and condensation by taking water and low alcohols as solvents under the alkaline condition to prepare a series of sulfur ether intermediates of the proton pump inhibitor () in high efficiency, wherein X and Y are nitrogen atoms or carbon atoms, and R1 is selected from one of hydrogen, methoxyl, pyrrole-1-yl and difluoro methoxyl; and R2, R3 and R4 are selected from one of hydrogen, methyl, methoxyl, 3-methoxyl n-propoxy, 2,2,2-trifluoro-ethyoxyl and methyl sec-butylamino respectively. The method has the advantages that a one-pot synthetic process is reasonable in design, easy and convenient to operate and environment-friendly, separation loss in the synthetic process is avoided, and target products are high in yield. A structural general formula is shown in the specification.

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 Applications(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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