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Synthetic method for Lafutidine oxide impurities

A technology for oxidizing impurities and synthesis methods, applied in the chemical field, can solve problems affecting product quality, etc., and achieve the effects of improving product purity and content, improving quality, and high yield

Active Publication Date: 2017-04-26
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Compound I is a common impurity in the production of lafutidine, which will affect the quality of the final product
After searching, there is currently no method for synthesizing this impurity, so synthesizing this impurity and confirming its structure, synthesizing this impurity to study its physical and chemical properties to control it, and choosing a suitable method to effectively remove it is of great significance to improve the quality of lafutidine

Method used

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  • Synthetic method for Lafutidine oxide impurities
  • Synthetic method for Lafutidine oxide impurities
  • Synthetic method for Lafutidine oxide impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 (2-(2-furyl methylsulfonyl) acetate-(4-nitrophenol) ester synthesis

[0031] Add 6.02g of 2-(2-furylmethylmercapto)acetic acid-(4-nitrophenol)ester (compound II, 0.02mol), 40mL of DMSO into a four-necked flask, stir at 20°C under temperature control, and add 6.16g of 2 - Iodosobenzoic acid (IBX, 0.22mol), temperature-controlled reaction for 12 hours. After the reaction was complete, 120 mL of water and 80 mL of dichloromethane were added, stirred for 0.5 minutes, and then separated. The organic layer was washed with water and saturated brine successively, the layers were separated, and the organic layer was spin-dried to obtain 5.2 g of an oil, which was recrystallized by adding acetone 26 mL, filtered, and dried to obtain (2-(2-furanmethylsulfonyl)acetic acid-( 4-nitrophenol) ester (compound III) 4.66g, yield 68.3%.

Embodiment 2

[0032] Example 2 2-[(2-furylmethyl)thionyl]-N-[4-[4-(1-piperidylmethyl)-2-pyridyl]oxygen-(Z)-2- Synthesis of butenyl]acetamide

[0033] 3.14g 4-[4-(N-piperidylmethyl)pyridine-2-oxygen]cis-2-butene-1-amine docking (compound IV, 0.012mol, 1eq), was added to 30mL ethyl acetate and 20mL5 %NaHCO 3 In the mixed solution, cool down to 0-5°C, add (2-(2-furanmethylsulfonyl)acetic acid-(4-nitrophenol) ester (compound III) 4.3g (0.0126mol, 1.05eq) and keep stirring 2h. After the reaction, the layers were separated, and the organic layer was washed with 2% NaHCO 3 , saturated saline, and water, and spin-dried the organic layer after washing to obtain 5.5 g of light green oil, add 50 mL of methyl tert-butyl ether, stir for 1 h at 30-40 ° C, cool to 0-5 ° C, stir for 1 h, and filter. Dry under reduced pressure to get 2-[(2-furylmethyl)sulfinyl]-N-[4-[4-(1-piperidylmethyl)-2-pyridyl]oxygen-(Z) -2-butenyl]acetamide (Compound I) crude product 4.35g, yield 81.3%.

Embodiment 3

[0034] Example 3 2-[(2-furylmethyl)thionyl]-N-[4-[4-(1-piperidylmethyl)-2-pyridyl]oxygen-(Z)-2- Purification of butenyl]acetamide

[0035] Add 4.2 g of the crude product to 30 mL of isopropanol, raise the temperature to 35-40 °C, and then gradually cool down to 5-10 °C after 0.5 h, keep stirring for 2 h, filter, and dry under reduced pressure to obtain the fine compound I 3.3 with a yield of 78.6%. Purity >99.5%.

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Abstract

The invention belongs to the technical field of chemistry and in particular relates to a synthetic method of Lafutidine oxide impurities, namely -2-[(2- furyl methyl) sulfonyl]-N-[4-[4-(1-piperidyl methyl)-2-pyridyl]oxygen-(Z)-2-butenyl] acetamide (formula I). The synthetic method mainly comprises the following steps: 2-(2-furfuryl sulfydryl)acetic acid-(4-nitrophenol) ester, namely the compound II is oxidized and then docked and refined with 4-[4-(N-piperidine methyl) pyridine-2-oxygen] cis-2-butene-1-amine, namely the compound IV to obtain oxide impurities of which the purity is more than 99.5%. The synthesized high-purity Lafutidine oxide impurities are taken as impurity standards for product inspection, thereby being beneficial to strengthening location and qualitativeness of the impurities so as to improve the quality control of Lafutidine active pharmaceutical ingredients.

Description

technical field [0001] The invention belongs to the technical field of chemistry, and in particular relates to a method for synthesizing lafutidine oxidized impurities. Background technique [0002] The chemical name of lafutidine is -2-[(2-furylmethyl)sulfinyl]-N-[4-[4-(1-piperidylmethyl)-2-pyridyl]oxygen-( Z)-2-butenyl]acetamide, is a new type of long-acting, powerful H 2 Receptor antagonists (Histamine H 2 -receptor antagonists), its basic pharmacophore contains furan ring, basic piperidine picoline ether group, flexible azetene-containing plane and sulfoxide-sulfur four-atom bond, with the second-generation furan ring and the fourth Substituted benzylic piperidine group and proton pump inhibitor basic aromatic ring pyridine ring and other key pharmacodynamic structures, so it has two functions at the same time, that is, more sustained and powerful anti-acid effect and strong mucosal protection effect. [0003] Compound I is a common impurity in the production of lafut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/38
CPCC07D307/38
Inventor 李晓曦唐金龙
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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