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Preparation method of 2-hydroxymethyl-4-(methoxypropoxy)-3-methylpyridine hydrochloride

A technology of methylpyridine hydrochloride and methoxypropoxy, which is applied in the field of preparation of 2-hydroxymethyl-4--3-methylpyridine hydrochloride, can solve the problem that wastewater treatment is difficult and has not been mentioned. And, it is not suitable for industrial application, etc., to achieve the effect of good solid, improved purity and good stability

Inactive Publication Date: 2016-11-09
LIVZON GROUP CHANGZHOU KONY PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Patent WO2009 / 116072 introduces the preparation method of 2-hydroxymethyl-4-(methoxypropoxy)-3-picoline, the obtained 2-hydroxymethyl-4-(methoxypropoxy )-3-methylpyridine has a purity of about 80%. It does not mention how to prepare 2-hydroxymethyl-4-(methoxypropoxyl)-3-methylpyridine hydrochloride solid. At the same time, in the preparation of 2, When 3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide is used, dimethyl sulfoxide is used as a solvent. During post-treatment, all dimethyl sulfoxide enters the wastewater, and the wastewater treatment is difficult , not suitable for industrial application

Method used

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  • Preparation method of 2-hydroxymethyl-4-(methoxypropoxy)-3-methylpyridine hydrochloride

Examples

Experimental program
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Embodiment 1

[0027] Add 68g of 3-methoxypropanol into the reaction flask, add 90g of powdered sodium hydroxide under stirring, and react at 60-70°C for 30 minutes after the addition is complete. Then 2.5 g of tetrabutylammonium bromide and 105 g of 2,3-dimethyl-4-chloropyridine-N-oxide hydrochloride were added, and the stirring reaction was continued at 90-95°C for 6 hours. Cool down to room temperature, add 500ml of dichloromethane and 500ml of water, separate the phases, extract the water phase with dichloromethane three times, combine the organic phases, recover the dichloromethane, and obtain about 115g of a reddish-brown residue, which is 2,3-dichloromethane. Methyl-4-(methoxypropoxy)-pyridine-N-oxide was directly used in the next reaction.

[0028] Mix 110g of 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide with 12g of trifluoromethanesulfonic acid, slowly add 64g of acetyl chloride dropwise at room temperature, after the drop , keep warm at 15-35°C for 5 hours; slowly add 185ml of...

Embodiment 2

[0030] Referring to Example 1, 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide was prepared.

[0031]Mix 110g of 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide with 12g of trifluoromethanesulfonic acid, slowly add 64g of acetyl chloride dropwise at room temperature, after the drop , keep warm at 15-35°C for 5 hours; slowly add 185ml of water after the warm-keeping reaction, adjust the pH of the system to 13-14 with sodium hydroxide solution, then raise the temperature to 60-65°C and keep warm for 5 hours; keep warm After finishing, cool to room temperature, add 340ml of toluene, separate the phases, extract the water phase with toluene twice, combine the toluene phases, and concentrate to dryness under reduced pressure to obtain about 87g of the concentrate, which is dissolved in 150ml of ethyl acetate and cooled to below 5°C , then use saturated HCl ethyl acetate solution to adjust pH=3~4, stir and crystallize below 5°C for about 2 hours; filter with suction, wash the filt...

Embodiment 3

[0033] Referring to Example 1, 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide was prepared.

[0034] Mix 110g of 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide with 12g of trifluoromethanesulfonic acid, slowly add 64g of acetyl chloride dropwise at room temperature, after the drop , keep warm at 15-35°C for 5 hours; slowly add 185ml of water after the warm-keeping reaction, adjust the pH of the system to 13-14 with sodium hydroxide solution, then raise the temperature to 60-65°C and keep warm for 5 hours; keep warm After finishing, cool to room temperature, add 340ml of toluene, separate the phases, extract the water phase with toluene twice, combine the toluene phases, dry and dehydrate with anhydrous sodium sulfate, cool to below 5°C, and adjust the pH with saturated HCl ethyl acetate solution = 3 to 4, stirred and crystallized at below 5°C for about 2 hours; filtered with suction, washed the filter cake with cold acetone, and dried under reduced pressure at about 40°C t...

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Abstract

The invention relates to a preparation method of 2-hydroxymethyl-4-(methoxypropoxy)-3-methylpyridine hydrochloride. The method comprises the following steps: reacting an initial raw material 2,3-dimethyl-4-chloropyridine-N-oxide hydrochloride with 3-methoxypropanol under a solvent-free condition to obtain 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide, acetylizing the 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide, hydrolyzing the acetylized 2,3-dimethyl-4-(methoxypropoxy)-pyridine-N-oxide, and carrying out a salt formation reaction to obtain the 2-hydroxymethyl-4-(methoxypropoxy)-3-methylpyridine hydrochloride. The purity of 2-hydroxymethyl-4-(methoxypropoxy)-3-methylpyridine hydrochloride solid can reach 98% or above, and 2-chloromethyl-4-(methoxypropoxy)-3-methylpyridine obtained after a chlorination reaction of 2-hydroxymethyl-4-(methoxypropoxy)-3-methylpyridine hydrochloride can directly react with 2-mercaptobenzimidazole without a salt formation or purification process in order to prepare rabeprazole thioether; and the solid has good stability, has no strict requirements on transportation or storage conditions, can be stored for a long time, and is suitable for being used as a rabeprazole sodium intermediate.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of 2-hydroxymethyl-4-(methoxypropoxy)-3-methylpyridine hydrochloride. Background technique [0002] H2 receptor antagonists and proton pump inhibitors are the two most commonly used drugs to treat gastric acid-related digestive diseases. They both increase gastric pH, but proton pump inhibitors act on H+ / K+-ATPase and strongly inhibit gastric acid secretion. , and cause a large and lasting increase in gastric pH. Rabeprazole sodium is a new type of proton pump inhibitor, which can be used in the treatment of gastric acid-related diseases, such as peptic ulcer, gastroesophageal reflux disease, Zoller's syndrome and so on. Compared with omeprazole, rabeprazole sodium has a stronger inhibitory effect on H+ / K+-ATPase, and the inhibition can be restored; it has less effect on plasma gastrin levels; it has selective and strong inhibition of Helicobacter p...

Claims

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Application Information

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IPC IPC(8): C07D213/68
CPCC07D213/68
Inventor 陈敖李鸣海张耀华张之建巢向红
Owner LIVZON GROUP CHANGZHOU KONY PHARMA
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