Asymmetric synthesis method for anti-allergy drug carbinoxamine

A synthesis method and technology of carbisamin, applied in the direction of organic chemistry, etc., can solve the problems of limited industrial application, difficult to obtain, expensive catalyst, etc., and achieve the effects of mild conditions, convenient operation and low price.

Active Publication Date: 2017-06-13
CHINA THREE GORGES UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The catalysts used in the reported methods are expensive and

Method used

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  • Asymmetric synthesis method for anti-allergy drug carbinoxamine
  • Asymmetric synthesis method for anti-allergy drug carbinoxamine
  • Asymmetric synthesis method for anti-allergy drug carbinoxamine

Examples

Experimental program
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Embodiment 1

[0028] Embodiment 1: Synthesis of (4-chlorophenyl) (2-pyridyl) ketone-N-oxide (formula (III))

[0029] Dissolve 2.0g of (4-chlorophenyl)(2-pyridyl)methanone in 15mL of hydrogen peroxide (30% aqueous solution), add 5mL of acetic acid, heat to 85°C for 12h, and check the progress of the reaction by TLC until the raw materials react Complete, add saturated sodium bicarbonate solution, extract with dichloromethane, wash, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain 2.1 g of white solid with a yield of 95%. 1 H NMR (400MHz, CDCl 3 ):δ=7.46-7.50(m,5H),7.82(dt,J 1 =4.4Hz,J 2 =2.4Hz, 2H), 8.27-8.29 (m, 1H)ppm.

Embodiment 2-5

[0030] The catalyst structure used in embodiment 2-5:

[0031]

Embodiment 2

[0032] Embodiment 2: Synthesis of (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide (formula (IV))

[0033]

[0034] In a 20 mL Schlenk test tube, add 38 mg of catalyst 1a, 0.23 g of (4-chlorophenyl)(2-pyridyl)methanone-N-oxide, 1.6 g of sodium formate, seal the test tube, replace the gas with nitrogen 3 times, and add by syringe 5mL DMSO / H 2 O (1:1) mixed solvent, reacted for 24 hours at 50 DEG C, added water after the completion of the reaction, extracted 3 times with ethyl acetate, combined and concentrated to dryness, purified to obtain a white solid 0.208g, yield 90%, HPLC assay product ( The enantiomeric excess ee of S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide was 95%. HPLC separation conditions: OD-H chiral column, mobile phase: n-hexane / isopropanol=90:10 (volume ratio), flow rate: 1.0mL / min, wavelength: 220nm, column temperature: 30°C, retention time: t R =9.0min,t S = 11.5min; 1 H NMR (400MHz, CDCl 3 ): δ=6.08(d, J=4.4Hz, 1H), 6.42(d, J=4.8Hz, 1H), 7.00(t, J=...

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PUM

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Abstract

The invention relates to an asymmetric synthesis method for an anti-allergy drug carbinoxamine. The method specifically comprises the following steps: oxidizing (4-chlorophenyl)(2-pyridyl)ketone to obtain (4-chlorophenyl)(2-pyridyl)ketone-N-oxide; by taking monosulfonylated chiral diamine and metal ruthenium/rhodium/iridium complex as catalysts and sodium formate or a formic acid and triethylamine mixture or isopropanol as a hydrogen source, reducing the (4-chlorophenyl)(2-pyridyl)ketone-N-oxide through asymmetry transfer hydrogenation to prepare (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide; reducing the (S)-(4-chlorophenyl)(2-pyridyl)methanol-N-oxide to obtain (S)-(4-chlorophenyl)(2-pyridyl)methanol; and performing etherification reaction on the (S)-(4-chlorophenyl)(2-pyridyl)methanol and 2-chloro-N,N-dimethylethylamine to obtain the product, wherein the overall yield is 74.6%.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a novel method for asymmetric synthesis of an antiallergic drug carbinoxamine. Background technique [0002] Carbinoxamine (formula (I)), also known as chlorpheniramine, the chemical name is 2-[(4-chlorophenyl)(2-pyridyl)methoxy]-N,N-dimethylethyl amine. It is an ethanolamine H1 receptor antagonist, an antihistamine drug, and has a mild sedative effect. In April 2013, the US FDA approved carbinoxamine maleate sustained-release formulation for the treatment of seasonal and perennial allergic rhinitis in children. Studies have shown that the activity of carbinoxamine in the S configuration is far superior to that of its racemate. [0003] [0004] The S-configuration carbinoxamine is mainly through the resolution of the racemate, which causes waste of another enantiomer. The key to the asymmetric synthesis of carbinoxamine lies in the preparation of the ch...

Claims

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Application Information

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IPC IPC(8): C07D213/30
CPCC07D213/30
Inventor 周海峰王百贵刘祈星江小兰
Owner CHINA THREE GORGES UNIV
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