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Synthesis method of 3-aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene

A technology of oxo and aza, which is applied in the field of synthetic medicine and chemical industry, can solve the problems of difficult large-scale production, low product purity, cumbersome operation, etc., and achieve the effect of mild conditions, less side reactions, and easy operation

Inactive Publication Date: 2009-09-09
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the existing synthetic methods for 3-aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene are step-by-step reactions (1984, Tetrahedron, 40(12): 2385) , the use of a strong base will easily destroy the four-membered ring of the product, the yield is low, the product purity is not high, the operation is cumbersome, and it is not easy to produce on a large scale

Method used

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  • Synthesis method of 3-aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene
  • Synthesis method of 3-aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene

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Experimental program
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Effect test

Embodiment 1

[0014] Dissolve 10ml of 2,5-norbornadiene in 50ml of toluene, take an ice-salt bath to -10°C, add 9ml of chlorosulfonic acid isocyanate dropwise, and react at about 0°C for 10 hours after the addition is complete. Add 50ml of ice water and 37.5g of trisodium phosphate dodecahydrate to the system, and react at 50°C for 5 hours. The reaction system was suction-filtered, the filter cake was washed with 20 ml of dichloromethane, separated, the aqueous phase was extracted with 10 ml of dichloromethane, the organic phases were combined, washed with 20 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain a white solid. Recrystallize the white solid with petroleum ether: ethyl acetate = 1:5 to obtain 12.0 g of white needle-like solid, yield: 91.5%

Embodiment 2

[0016] Dissolve 10ml of 2,5-norbornadiene in 50ml of 1,2-dichloroethane, ice-bath to 0°C, add 14ml of chlorosulfonic acid isocyanate dropwise, and react for 3 hours at about 25°C after the dropwise addition. Add 50ml of ice water and 71g of disodium hydrogen phosphate dodecahydrate to the system, and react at 0°C for 48 hours. The reaction system was suction-filtered, the filter cake was washed with 20 ml of dichloromethane, separated, the aqueous phase was extracted with 10 ml of dichloromethane, the organic phases were combined, washed with 20 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain a white solid. Recrystallized with petroleum ether: ethyl acetate = 1:3 to obtain 11.5 g of white needle-like solid, yield: 87%

Embodiment 3

[0018] Dissolve 10ml of 2,5-norbornadiene in 50ml of dichloromethane at an internal temperature of 25°C, add 18ml of chlorosulfonic acid isocyanate dropwise, and react for 0.5 hours at about 25°C after the addition is complete. Add 50ml of ice water and 42g of sodium bicarbonate to the system, and react at 20°C for 24 hours. The reaction system was suction-filtered, the filter cake was washed with 20 ml of dichloromethane, separated, the aqueous phase was extracted with 10 ml of dichloromethane, the organic phases were combined, washed with 20 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain a white solid. Recrystallized from petroleum ether: ethyl acetate = 1:5 to obtain 10.9 g of white needle-like solid, yield: 81%.

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Abstract

A synthesis method of 3-aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene relates to a synthesis process of an important intermediate of 3-aminocarbonylbicycloheptenylpyridinediamine compound with anti-tumor active molecules. The method comprises the following steps: measuring off 2,5-norbornadiene, chlorosulfonyl isocyanate and weak-acid salt at a ratio of 1:1-2:1-5 (mol ratio); dissolving the 2,5-norbornadiene in an organic solvent, and adding the chlorosulfonyl isocyanate dropwise at the temperature of -10-25 DEG C; allowing reacting for 0.5-10h and then adding water of the same volume and the weak-acid salt; allowing reacting at the temperature of 0-50 DEG C for 5-48h; filtrating, separating, drying and eliminating the solvent by depressurized rotary evaporation to obtain a white solid; and recrystallizing with petroleum ether and ethyl acetate at a ratio of 1:5-1:2 to obtain the net product 3-aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene. The synthesis method has simple operation, high product yield up to 77-91% which is 15-30% higher than that of the existing method and purity above 98%, and can be widely used for synthesizing natural products.

Description

technical field [0001] A method for synthesizing 3-aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene, relating to the synthesis of 3-aminocarbonylbicycloheptenyl pyrimidine, a molecule with antitumor activity The invention discloses a process for an important intermediate of a diamine compound, belonging to the technical field of synthetic medicine and chemical industry. Background technique [0002] Four-membered cyclic lactam derivatives are a class of important skeleton structures that widely exist in the molecular skeletons of natural products and artificially synthesized drugs, such as penicillins and cephalosporins. It is also an important intermediate for the synthesis of some bioactive molecules (Tetrahedron 64 (2008) 8659-8667). 3-Aza-4-oxo-tricyclo[4.2.1.0(2,5)]non-7-ene is an important intermediate of 3-aminocarbonylbicycloheptylyrimidinediamine compounds (WO2006055561). Using it as a raw material to obtain its optically active chiral isomer (Tetrahedron 722 60 (2004) 7...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/12
Inventor 胡文浩戚浩强朱映光杨琍苹
Owner EAST CHINA NORMAL UNIV
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