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The preparation method of 4-[4-(1-piperidinylmethyl)pyridine-2-oxygen]-cis-2-butene-1-ol

A technology of -cis-2-, piperidinylmethyl, applied in the field of preparation of 4-[4-(1-piperidinylmethyl)pyridine-2-oxygen]-cis-2-butene-1-ol , to achieve the effect of high yield, less acid consumption and reasonable purification and separation method

Active Publication Date: 2012-02-22
浙江东亚药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, it is found through experiments that when the dereaction THP reaction is carried out with 2 times the molar amount of hydrochloric acid, the ether bond at the pyridine-2 position will be broken and the impurity 4-(1-piperidylmethyl)-2-hydroxypyridine (5) will be generated. The reaction yield is generally only 70-75%

Method used

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  • The preparation method of 4-[4-(1-piperidinylmethyl)pyridine-2-oxygen]-cis-2-butene-1-ol
  • The preparation method of 4-[4-(1-piperidinylmethyl)pyridine-2-oxygen]-cis-2-butene-1-ol
  • The preparation method of 4-[4-(1-piperidinylmethyl)pyridine-2-oxygen]-cis-2-butene-1-ol

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Experimental program
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Effect test

Embodiment 1

[0038] Add 1000 mL of water to 200 g of 2-[4-(2-tetrahydropyranyl)-cis-2-butene-1-oxo]-4-(1-piperidinyl) pyridine and adjust the pH to about 2 with hydrochloric acid , Stirring 20h at 0 degrees. The aqueous layer was adjusted to pH 13 with solid NaOH, extracted with butyl acetate, and the butyl acetate extract was washed with water and saturated brine, respectively. After recovering butyl acetate, 136 g of light brown oil was obtained, yield: 90.4%.

[0039] MS (ESI): 262.3 (M + +H + )

[0040] 1 H-NMR (CDCl 3 ): 8.00(d, 1H), 6.90(d, 1H), 6.70(s, 1H), 5.8(m, 1H), 5.7(m, 1H), 4.99(d, 2H), 4.30(d, 2H) , 3.82 (br, 1H), 3.42 (d, 2H), 2.42 (s, 4H), 1.65 (m, 4H), 1.42 (s, 2H).

Embodiment 2

[0042] Add 400 mL of water to 200 g of 2-[4-(2-tetrahydropyranyl)-cis-2-butene-1-oxo]-4-(1-piperidinyl) pyridine and adjust the pH to about 1 with sulfuric acid , Stir at -10 degrees for 24h. The aqueous layer was treated with any weight concentration of Na 2 CO 3 The aqueous solution was adjusted to pH 9, extracted with methyl isobutyl ketone, and the methyl isobutyl ketone extract was washed with water and saturated brine respectively. After recovering methyl isobutyl ketone, 133 g of light brown oil was obtained, yield: 88.4%.

Embodiment 3

[0044] Add 5000L of water to 252g of 2-[4-(2-tetrahydropyranyl)-cis-2-butene-1-oxygen]-4-(1-piperidinyl)pyridine, adjust with p-toluenesulfonic acid The pH was about 3, and stirred for 15 hours at 50 degrees. The aqueous layer was adjusted to pH 14 with KOH solid, extracted with toluene, and the toluene extract was washed with water and saturated brine, respectively. After recovering toluene, 162 g of light brown oil was obtained, yield: 85.1%.

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Abstract

The invention discloses a preparation method of 4-[4-(1-piperidinemethyl)pyridine-2-oxygen]-cis-2-buten-1-ol, which comprises the following steps: adjusting 2- The pH of (4-substituted oxy-cis-2-butene-1-oxygen)-4-(1-piperidinyl)pyridine aqueous solution is 1<pH<7, then reacts, in the aqueous solution of reaction product, add Adjust the pH to 7.5-14 with an inorganic base, and then extract with an organic solvent to collect the target product. Significant advantages of the present invention: water replaces organic solvents methanol and toluene, reducing cost and pollution; the amount of acid is small, greatly reducing the three wastes, which is beneficial to environmental protection; the purification and separation method of the product is reasonable, easy to operate, and the yield is as high as 90%, suitable for large-scale industrial production, and has great value in the preparation of a new generation of H2 receptor inhibitor lavutidine.

Description

technical field [0001] The invention discloses a method for industrially preparing 4-[4-(1-piperidinylmethyl)pyridine-2-oxygen]-cis-2-buten-1-ol. Background technique [0002] Peptic ulcer is a common disease. According to reports, one fifth of men and one tenth of women sometimes suffer from gastric ulcer or duodenal ulcer, which seriously endangers human health. There are many drugs used to treat peptic ulcer, such as antacids, anticholinergic drugs, H2 receptor antagonists, proglumide, prostaglandin E2 synthetic agents, proton pump inhibitors, etc. Among them, H2 receptor antagonists are an important class of drugs used to reduce ulcer-causing factors, such as cimetidine, ranitidine, famotidine, roctidine, and nizatidine. Laftidine (3) is a new generation of H2 receptor antagonist developed by Japan's Fuji and Dapeng Company, which was first listed in Japan in April 2000. Because of its unique pharmacological characteristics and good clinical use reports, it is consider...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/64
Inventor 赵建宏刘娜刘强池正明
Owner 浙江东亚药业股份有限公司