Method for selective synthesis of alpha-narcotine with participation of blockage group

A noscapine and selective technology, applied in organic chemistry and other fields, can solve problems such as unsatisfactory yield

Inactive Publication Date: 2010-07-14
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is not ideal for the synthesis of other phthalide-3-carboxylic acids

Method used

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  • Method for selective synthesis of alpha-narcotine with participation of blockage group
  • Method for selective synthesis of alpha-narcotine with participation of blockage group
  • Method for selective synthesis of alpha-narcotine with participation of blockage group

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: N-(2-(2-bromo-3,4-methylenedioxy-5-methoxyphenyl)ethyl)-6,7-dimethoxy-1-oxo-isophenyl Preparation of furan-3-carboxamide

[0045] Under ice bath and stirring, 2-(2-bromo-3,4-methylenedioxy-5-methoxyphenyl)ethylamine hydrochloride 3.1g (10.0mmol), ether 20.0mL and 5.0% To a mixed solution of 42.0 mL of sodium carbonate solution, a mixed solution of 2.4 g (10.0 mmol) of acid chloride of 6,7-dimethoxyphthalide-3-carboxylic acid and 20.0 mL of ether was added dropwise, and a white solid gradually precipitated. After addition, continue to stir for 1.0h, and filter with suction to obtain some solids. The organic phase in the filtrate was separated, washed with saturated brine (40 mL), dried, filtered, and concentrated. The residue was combined with the white solid obtained by suction filtration, accumulatively 3.2 g, yield 65.5%.

[0046] MS(m / z): 493.0[M+H] + . 1 H NMR (CDCl 3 )δ2.86(t, 2H), 2.50(q, 2H), 3.84(s, 3H), 3.93(s, 3H), 4.10(s, 3H), 5.63(s, 1H), 6.0...

Embodiment 2

[0048] Example 2: 6,7-dimethoxy-3-(9-bromo-4-methoxy-5,6,7,8-tetrahydro-1',3'-dioxolane[4' , 5'-g]-5-isoquinolinyl)-1 (3H)-isobenzofuranone hydrochloride preparation

[0049] Under argon protection and stirring, N-(2-(2-bromo-3,4-methylenedioxy-5-methoxyphenyl)ethyl)-6,7-dimethoxy-1-oxo A mixture of 2.47 g (5 mmol) of oxo-isobenzofuran-3-carboxamide and 10.0 mL (10.0 mmol) of phosphorus oxychloride was heated at 100° C. for 1.5 h. After the excess phosphorus oxychloride was distilled off under reduced pressure, 20.0 mL of methanol was added to the residue to destroy the remaining phosphorus oxychloride, and the residue was concentrated to dryness under reduced pressure. The residue was dissolved by heating with 8.0 mL of methanol, and solid was precipitated by cooling. Suction filtration, drying to obtain light yellow solid.

[0050] Under stirring in an ice bath, the above light yellow solid was dissolved in 20 mL of methanol, and then 0.57 g (15 mmol) of sodium borohydrid...

Embodiment 3

[0052] Example 3: 6,7-dimethoxy-3-(9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-1',3'-diox Preparation of pentacyclo[4',5'-g]-5-isoquinolinyl)-1(3H)-isobenzofuranone hydrochloride

[0053]Under stirring, 6,7-dimethoxy-3-(9-bromo-4-methoxy-5,6,7,8-tetrahydro-1',3'-dioxolane[4 ', 5'-g]-5-isoquinolinyl)-1(3H)-isobenzofuranone hydrochloride 0.51g (1.0mmol) was added to 37% formaldehyde aqueous solution 0.50mL (7.0mmol) and 88% In a mixed solution of 0.5 mL (12.0 mmol) of formic acid, the temperature was gradually raised to 100° C., and the reaction was carried out for 8 h. Cool to room temperature, add 2.0 mL of 6.0 mol / L hydrochloric acid, and continue stirring for 2 h. Concentrate to dryness under reduced pressure, add 10.0 mL of water to the residue to adjust pH=9, and extract with ethyl acetate (10.0 mL×2). The organic layers were combined, washed with saturated brine (10 mL×2), and dried over anhydrous sodium sulfate. After filtration and concentration, the obtained crud...

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Abstract

The invention belongs to the technical field of drug synthesis, and relates to position selective synthesis of alpha-narcotine with participation of a blockage group, preparation of serial phthalide tetrahydroisoquinoline compounds and preparation of various phthalide-3-carboxylic acid compounds and various 3-oxo isochroman-1-carboxylic acid compounds through a universal mode. In the method, 2, 3-dimethoxy benzoic acid is used as a raw material and condensed with glyoxylate through the universal mode to obtain 6, 7-dimethoxy phthalide-3-carboxylic acid, the carboxylic acid and 2-(2-bromo-3, 4-methylenedioxy-5-methoxy-phenyl)-ethylamine hydrochloride are condensed to prepare amide, the amide reacts with Bischler-Napieralski to prepare bromo-alpha-narcotine through reaction, methylation and salt formation, and (-)-alpha-narcotine is then prepared through dehalogenation and resolution. Due to the positioning function of the blockage group, the invention effectively reduces the position selectivity of Bischler-Napieralski cyclization, and realizes the simple and efficient synthesis of alpha-narcotine through removal of the blockage group and the chiral resolution.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a selective synthesis method of α-narcotin with the participation of blocking groups and the synthesis of phthalide tetrahydroisoquinoline alkaloids. Background technique [0002] (-)-α-(3S, 5'R)-Narcotine is an opioid alkaloid, English name (-)-α-(3S, 5'P)-Noscapine or Narcotine, molecular formula C 22 h 23 NO 7 , chemical name (-)-α-(3S,5'R)-6,7-dimethoxy-3-(5,6,7,8-tetrahydro-4-methoxy-6-methyl -1',3'-dioxolane[4',5'-g]-5-isoquinolinyl)-1(3H)-isobenzofuranone is a classic antitussive drug with low toxicity and side effects , good tolerance, wide safety range and so on. At the same time, Narcidine can be used to treat stroke and edema. The latest pharmacodynamic experiments found that narcotin also has muscle relaxant and anti-anxiety effects. At the same time, norcidine has certain analgesic activity, but the activity is lower than that of morphine and codeine. In ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/056C07D307/88C07D311/76C07D317/64C07D405/04
Inventor 许佑君倪积智肖和平林禄清张青扬从俊杰曹新欣翁立鹏孙晓冬
Owner SHENYANG PHARMA UNIVERSITY
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