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Synthetic method of isocoumarin ramification

A technique for synthesizing isocoumarin and its synthesis method, which is applied in the field of synthesis of isocoumarin derivatives, can solve the problems of insufficient mild reaction conditions, long reaction time, and low yield, and achieve short reaction time, ideal yield, and low raw material cheap effect

Active Publication Date: 2019-10-25
TIANJIN UNIV
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Problems solved by technology

[0008] However, in these methods for synthesizing 4-thioisocoumarin, Zeni et al. used methyl 2-ethynylbenzoate and disulfide compounds as raw materials, ferric chloride as additive, and ethylene dichloride as solvent , such compounds are obtained at room temperature ( A.; Godoi, B.; Pinton, S.; Back, D.F.; Menezes, P.H.; Zeni, G.J.Org.Chem.2011,76,6789.), but the reaction time of this method is long and the yield is low; Zhou et al. People use methyl 2-ethynylbenzoate and disulfide compounds as raw materials, ferric chloride as additive, and dichloroethane as solvent to obtain such compounds (Li, Z .; Hong, J.; Weng, L.; Zhou, X.Tetrahedron 2012,68,1552.), but the reaction time of this method is longer, the reaction conditions are not mild enough and the yield is not high
Ding et al. used methyl 2-ethynylbenzoate and N-phenyl-S-trifluoromethylthiolamine as raw materials, bismuth chloride and boron trifluoride ether as additives, and toluene as solvent to obtain this class compound, but the raw material of this method is more expensive, and the operation is more loaded down with trivial details

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preparation example Construction

[0023] The synthetic method of isocoumarin derivatives, comprises the steps: raw material 2-((2-R 2 )-ethynyl) methyl benzoate II is dissolved in dimethyl sulfoxide or deuterated dimethyl sulfoxide, dripped into thionyl chloride, and reacted to obtain isocoumarin derivatives I;

[0024]

[0025] In the formula:

[0026] R 1 are hydrogen atoms, methyl groups, fluorine atoms and bromine atoms;

[0027] R 2 hydrogen atom, phenyl, p-methoxyphenyl, p-nitrophenyl, p-chlorophenyl, 2-methoxycarbonylphenyl, 2-nitro-4-methylphenyl, 1-naphthyl, 2-thienyl, tert-butyl or trimethylsilyl;

[0028] R 3 is methyl or deuterated methyl.

[0029] Among them, 2-((2-R 2 The molar ratio of )-ethynyl)methyl benzoate II to thionyl chloride is preferably 3:1.

[0030] 2-((2-R 2 )-ethynyl)methyl benzoate II in dimethyl sulfoxide or deuterated dimethyl sulfoxide optimal reaction concentration of 1mmol / mL.

[0031] The reaction temperature was room temperature (25°C).

Embodiment 1

[0034] Preparation of 3-phenyl-4-methylthioisocoumarin l-a

[0035]

[0036] 2-((2-phenyl)-ethynyl)methyl benzoate ll-a (0.5mmol, 118mg) was dissolved in dimethylsulfoxide (0.5mL), and thionyl chloride (1.5mmol, 179mg), react at room temperature (25°C) until TLC shows that the substrate is completely reacted. Extract the reaction solution with water (20mL) and ethyl acetate (20mL×3), combine the organic phases, wash the organic phase with saturated brine, add anhydrous sodium sulfate to dry, add the organic phase to a column of silica gel and evaporate to dryness, column chromatography (acetic acid Ethyl ester:petroleum ether=5:95) to obtain 127 mg of white solid with a yield of 95% and a melting point of 127-128°C. 1 H NMR (600MHz, CDCl 3 )δ8.36(dd, J=7.8,1.2Hz,1H),8.24(d,J=7.8Hz,1H),7.88-7.85(m,1H),7.80-7.78(m,2H),7.59-7.56 (m,1H),7.48-7.46(m,3H),2.16(s,3H). 13 C NMR (150MHz, CDCl 3 )δ161.6, 158.0, 138.1, 135.3, 133.2, 130.0, 129.9, 129.8, 128.6, 127.9, 125.6, 120.9,...

Embodiment 2

[0038] Preparation of 3-(2-thienyl)-4-methylthioisocoumarin l-b

[0039]

[0040] Dissolve 2-(2-(2-thienyl)-ethynyl)methyl benzoate ll-b (0.5mmol, 121mg) in dimethyl sulfoxide (0.5mL), drop into thionyl chloride (1.5 mmol, 179mg), react at room temperature (25°C) until TLC shows that the substrate is completely reacted. Extract the reaction solution with water (20mL) and ethyl acetate (20mL×3), combine the organic phases, wash the organic phase with saturated brine, add anhydrous sodium sulfate to dry, add the organic phase to a column of silica gel and evaporate to dryness, column chromatography (acetic acid Ethyl ester:petroleum ether=5:95) to obtain 123 mg of a yellow-green solid with a yield of 90% and a melting point of 139-140°C. 1 H NMR (600MHz, CDCl 3 )δ8.32(dd, J=7.8,1.2Hz,1H),8.22(d,J=7.8Hz,1H),8.07(dd,J=3.6,1.2Hz,1H),7.85-7.82(m,1H ),7.55-7.51(m,2H),7.16(dd,J=5.4,4.8Hz,1H),2.32(s,3H). 13 C NMR (150MHz, CDCl 3 )δ160.8, 152.5, 138.6, 135.3, 134.0, 131.4, 131.3...

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Abstract

The invention discloses a synthetic method of isocoumarin ramification. The synthetic method comprises the following steps that a raw material 2-((2-R2)-ethynyl) methyl benzoate (II) is dissolved in dimethyl sulfoxide or deuterium dimethyl sulfoxide, and is dropped in thionyl chloride and reacts to obtain isocoumarin ramification (I). The synthetic method has the advantages that operation is easy,the raw material is cheap and easy to obtain, reaction condition is mild, reaction time is short, and the yield is ideal.

Description

technical field [0001] The invention relates to a synthesis method of isocoumarin derivatives. Background technique [0002] Isocoumarin derivatives are an important class of lactone compounds, which are widely distributed in nature and have been proved to have various pharmacological activities. For example, NM-3 containing the core structure of isocoumarin has entered clinical trials as an angiogenesis inhibitor. The structure A isolated from Polygonum hydroponica can exhibit obvious anti-inflammatory activity (see the following structural formula). [0003] [0004] The relevant research reports on the preparation of 4-thioisocoumarin derivatives using 2-alkynyl benzoate as raw materials are listed below: [0005] [1] A.; Godoi, B.; Pinton, S.; Back, D.F.; Menezes, P.H.; [0006] [2] Li, Z.; Hong, J.; Weng, L.; Zhou, X. Tetrahedron 2012, 68, 1552. [0007] [3] Li, Y.; Li, G.; Ding, Q.E.J.Org.Chem.2014, 23, 5017. [0008] However, in these methods for synthesizin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/76C07D409/04C07F7/08
CPCC07D311/76C07D409/04C07F7/0814C07F7/083
Inventor 杜云飞安雪婵赵康徐润瑶
Owner TIANJIN UNIV
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