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Asymmetric synthetic method of (-)-huperzine key intermediate

A synthesis method and intermediate technology are applied in the field of asymmetric synthesis for synthesizing huperzine key intermediates, which can solve problems such as uneconomical, and achieve the effects of high yield and simple post-processing.

Inactive Publication Date: 2011-01-05
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] It is not economical to use expensive metal palladium and chiral phosphorus ligands (Tetrahedron: Asymmetry, 2001, 12, 3213-3216) in the reaction

Method used

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  • Asymmetric synthetic method of (-)-huperzine key intermediate
  • Asymmetric synthetic method of (-)-huperzine key intermediate
  • Asymmetric synthetic method of (-)-huperzine key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 7,8,9,10-tetrahydro-8-hydroxy-2-methoxy-7-methyl-11-oxo-5,9-methylenecyclooctane[b]pyridine-5(6H )-methyl carboxylate

[0038] Methyl 5,6,7,8-tetrahydro-2-methyl-6-oxo-5-quinolinecarboxylate (940mg, 4mmol), 2-methyl-acrolein (140mg, 8mmol), catalyst (316mg, 1.2mmmol), additive NaOAc (336mg, 4mmol), added in THF, stirred, refluxed for 4 to 5 days, the reaction solution was cooled, washed three times with saturated sodium bicarbonate solution, washed twice with saturated sodium chloride, The crude product was subjected to column chromatography to obtain 2a (660 mg) and 2b (340 mg), wherein 2b was subjected to sodium hydroxide / dichloromethane at room temperature for 6 hours, and the crude product was subjected to column chromatography to obtain 2a (306 mg). Or use the enantiomer of the optically active catalyst to do the opposite configuration of 2a. The main configuration of 2a 1 HNMR (CDCl 3): 7.06(d, 1H, J=7.1Hz), 6.62(d, 1H, J=7.1Hz), 3.91(s, 3H), 3.81(s, 3H), 3...

Embodiment 2

[0043] 7,8,9,10-tetrahydro-8-hydroxy-2-methoxy-7-methyl-11-oxo-5,9-methylenecyclooctane[b]pyridine-5(6H )-methyl carboxylate

[0044] Methyl 5,6,7,8-tetrahydro-2-methyl-6-oxo-5-quinolinecarboxylate (940mg, 4mmol), 2-methyl-acrolein (140mg, 8mmol), catalyst (388mg, 1.2mmmol), additive trifluoroacetic acid (456mg, 4mmol), added to tetrahydrofuran, stirred, refluxed for 4 to 5 days, the reaction solution was cooled, washed three times with saturated sodium bicarbonate solution, washed two times with saturated sodium chloride The second time, the crude product was subjected to column chromatography to obtain 2a (620 mg) and 2b (320 mg), wherein 2b was subjected to sodium hydroxide / dichloromethane at room temperature for 6 hours, and the crude product was subjected to column chromatography to obtain 2a (290 mg). Or use the enantiomer of the optically active catalyst to do the opposite configuration of 2a. The main configuration of 2a 1 HNMR (CDCl 3 ): 7.06(d, 1H, J=7.1Hz), 6...

Embodiment 3

[0049] 7,8,9,10-tetrahydro-8-hydroxy-2-methoxy-7-phenyl-11-oxo-5,9-methylenecyclooctane[b]pyridine-5(6H )-methyl carboxylate

[0050] Methyl 5,6,7,8-tetrahydro-2-methyl-6-oxo-5-quinolinecarboxylate (940mg, 4mmol), 2-phenyl-propenal (140mg, 8mmol), catalyst (328mg, 1.3mmmol), additive sodium methoxide (189mg, 3.5mmol), added to tetrahydrofuran, stirred, refluxed for 4 to 5 days, the reaction solution was cooled, washed with saturated sodium bicarbonate solution three times, washed with saturated sodium chloride for two Once, the crude product was subjected to column chromatography to obtain 2a-1 (600mg) and 2b-1 (300mg), wherein 2b-1 was subjected to sodium hydroxide / methylene chloride at room temperature for 6 hours, and the crude product was obtained by column chromatography to obtain 2a-1 ( 280mg). Or use the enantiomer of the optically active catalyst to do the opposite configuration of 2a-1.

[0051] (-)-(5S,9R)-9,10-dihydro-2-methoxy-7-phenyl-11-oxo-5,9-methylenecyc...

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Abstract

The invention belongs to the field of asymmetric catalysis of organic chemistry, and in particular relates to an asymmetric synthetic method of a (-)-huperzine key intermediate, comprising the following step of: synthesizing a huperzine key intermediate by using an asymmetric Michael / Adol cascade reaction of organic micromolecule catalysis. The asymmetric Michael / Adol cascade reaction is characterized in that the key intermediate (-)-(5S, 9R)-9,10-dihydro-2-methoxyl-7-methyl-11-oxo-5,9-methylene cyclooctane [b] pyridine-5(6H)-methyl carbonate is prepared by using high yield, high optical purity in a gram level.

Description

technical field [0001] The invention relates to an asymmetric synthesis method for synthesizing key intermediates of huperzines Background technique [0002] Huperzine [Huperzine] is an alkaloid extracted from Huperzina serrata (Thumb.) Trev, which is a class of potent reversible inhibitors of cholinesterase Esterase has a selective inhibitory effect, because it can easily pass through the blood-brain barrier, and has the effect of promoting memory reproduction and enhancing memory retention, and is suitable for benign memory disorders. For example, (-)-Huperzine A (Huperzine A) has a significant effect on the treatment of Alzheimer's disease (AD). Therefore, since the successful separation of huperzine [Huperzine], it has attracted great interest of synthetic chemists. In many processes of synthesizing Huperzine A, there is an important intermediate whose structure is as follows: (-)- (5S,9R)-9,10-dihydro-2-methoxy-7-methyl-11-oxo-5,9-methylenecyclooctane[b]pyridine-5(6H)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/22C07B53/00B01J31/02
Inventor 马大为于芳张晓菁
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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