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Method for preparing 4-(3-methoxy propoxy)-2,3-dimethyl pyridine-N-oxide

A technology of methoxypropoxy and lutidine, applied in the field of organic chemical synthesis, can solve the problems of shortening reaction steps, many side reactions unfavorable to industrialization, long reaction time, etc.

Inactive Publication Date: 2013-02-13
SHOUGUANG FUKANG PHARMA
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method shortens the reaction steps, does not need to go through the chlorination reaction step, but still needs one step of nitration, and directly obtains 4-(3 -methoxypropoxy)-2,3-lutidine-N-oxide reaction temperature is higher, the required reaction time is longer, more side reactions are not conducive to industrialization

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  • Method for preparing 4-(3-methoxy propoxy)-2,3-dimethyl pyridine-N-oxide
  • Method for preparing 4-(3-methoxy propoxy)-2,3-dimethyl pyridine-N-oxide
  • Method for preparing 4-(3-methoxy propoxy)-2,3-dimethyl pyridine-N-oxide

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[0032] The invention provides a preparation method of 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide, comprising the following steps: A) 2,3-dimethyl Pyridine-N-oxide, bromine source and solvent are mixed, heated and reacted to obtain 2,3-dimethyl-4-bromopyridine-N-oxide; B) the 2,3-dimethyl-4- Bromopyridine-N-oxide is mixed with 3-methoxypropanol and reacted with heating to obtain 4-(3-methoxypropoxy)-2,3-dimethylpyridine-N-oxide.

[0033] The 2,3-lutidine-N-oxide can be purchased from the market or self-made, and there is no special limitation. The 2,3-lutidine-N-oxide described in the present invention is preferably prepared according to the following steps: 2,3-lutidine, glacial acetic acid and hydrogen peroxide are mixed, heated and reacted to obtain 2,3-di Pyridine-N-oxide. The molar ratio of the 2,3-lutidine to hydrogen peroxide is 1:1.5~3, preferably 1:2~2.5, and the molar ratio of the 2,3-lutidine to glacial acetic acid is 1:1.5 ~2.5, preferably 1:1.8~2.2.

[0...

Embodiment 1

[0059] 1.1 Add 60g of glacial acetic acid to a 500ml four-neck flask, control the temperature not higher than 50°C, add 53.5g (0.5mol) 2,3-lutidine, stir for 30min, slowly raise the temperature to 80°C, add 85g within 2h (1.25mol) hydrogen peroxide (50%), then heated up to 93°C, reacted for 5h, distilled off water and unreacted glacial acetic acid under reduced pressure (the temperature should not exceed 100°C), and obtained wine red liquid 2,3-lutidine -N-oxide 60.3g, calculated yield is 98%.

[0060] 1.2 Mix 60.3g (0.49mol) of 2,3-lutidine-N-oxide obtained in 1.1, 112g (0.81mol) of potassium carbonate and 500ml of carbon tetrachloride, raise the temperature to reflux and drop slowly within 5h Add 116g (0.73mol) of bromine, continue to reflux for 2 hours after addition, and cool down to room temperature, add a small amount of 10% sodium bisulfite solution until the dyeing of the reaction solution becomes lighter, filter, recover potassium bromide, and distill the filtrate to ...

Embodiment 2

[0070] 2.1 Add 60g of glacial acetic acid to a 500ml four-necked flask, control the temperature not higher than 50°C, add 53.5g (0.5mol) 2,3-lutidine, stir for 30min, slowly raise the temperature to 80°C, add 68g within 2h (1.0mol) hydrogen peroxide (50%), then heat up to 93°C, react for 5h, cool down to 80°C, add 17g (0.25mol) hydrogen peroxide (50%) dropwise, heat up to 93°C, continue to react for 3h, and remove by distillation under reduced pressure Water and unreacted glacial acetic acid (the temperature must not exceed 100°C) gave 60.3 g of wine-red liquid 2,3-lutidine-N-oxide, and the calculated yield was 98%.

[0071] 2.2 Mix 60.3g (0.49mol) of 2,3-lutidine-N-oxide obtained in 2.1, 130g (0.94mol) of potassium carbonate and 500ml of dichloroethane, raise the temperature to reflux and drop slowly within 5h Add 150g (0.94mol) of bromine, continue to reflux for 8 hours after adding, cool down to room temperature, add a small amount of 10% sodium bisulfite solution until the...

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Abstract

The invention provides a method for preparing 4-(3-methoxy propoxy)-2,3-dimethyl pyridine-N-oxide, comprising the following steps: mixing 2,3-dimethyl pyridine-N-oxide (a), a bromine source and a solvent, carrying out heating reaction to obtain 2,3-dimethyl-4-bromo pyridine-N-oxide; mixing the 2,3-dimethyl-4-bromo pyridine-N-oxide with 3-methoxy propanol, and carrying out heating reaction to obtain a target compound. Compared with the method of nitrifying the 2,3-dimethyl pyridine-N-oxide (a) and then directly subjecting the 2,3-dimethyl pyridine-N-oxide (a) to react with the 3-methoxy propanol and potassium carbonate to obtain the target compound in the prior art, the method provided by the invention has the advantages that: the nitration is omitted, the use and consumption of the mixed nitric acid and sulfuric acid are avoided, and the pollution of a large amount of waste acid to the environment is reduced. In addition, the reaction activity of the bromide is higher than that of the corresponding chloride, and thus the 3-methoxy propoxy is easier to react in one step with a short reaction time. Moreover, the bromine containing wastewater generated from the reaction can be reutilized.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a preparation method of 4-(3-methoxypropoxy)-2,3-lutidine-N-oxide. Background technique [0002] 4-(3-methoxypropoxy)-2,3-lutidine-N-oxide is an intermediate of proton pump inhibitor-rabeprazole, which is the successor of Ogilvy It is the fourth proton pump inhibitor on the market after prazole, lansoprazole and pantoprazole, and it has good curative effect on gastroesophageal reflux disease, gastric ulcer and duodenal ulcer. [0003] The traditional production process for preparing 4-(3-methoxypropoxy)-2,3-lutidine-N-oxide is divided into four steps: [0004] (1) Using 2,3-lutidine (a) as raw material, 2,3-lutidine-N-oxide (b) was prepared by nitric oxidation with acetic acid and hydrogen peroxide; [0005] (2) Add 2,3-dimethylpyridine-N-oxide (b) to nitric acid to obtain 2,3-dimethyl-4-nitropyridine-N-oxide (c); [0006] (3) Reaction of 2,3-dim...

Claims

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Application Information

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IPC IPC(8): C07D213/89
Inventor 宋伟国甲宗青高东圣董良军刘杰夏艳田梅吕伟香
Owner SHOUGUANG FUKANG PHARMA
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