CN103554074B - Preparation method of 3-trifluoromethyl coumarin derivative - Google Patents

Preparation method of 3-trifluoromethyl coumarin derivative Download PDF

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CN103554074B
CN103554074B CN201310540718.5A CN201310540718A CN103554074B CN 103554074 B CN103554074 B CN 103554074B CN 201310540718 A CN201310540718 A CN 201310540718A CN 103554074 B CN103554074 B CN 103554074B
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chromen
methyl
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arh
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CN103554074A (en
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邹建平
曹晓慧
李大鹏
潘向强
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Weng Houke
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Suzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3

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Abstract

The invention discloses a preparation method of a 3-trifluoromethyl coumarin derivative, which is characterized by comprising the following steps of dissolving the coumarin derivative, sodium trifluoromethanesulfonate and manganese acetate in a solvent, and reacting at 20-100 DEG C to obtain the 3-trifluoromethyl coumarin derivative. According to the method disclosed by the invention, the coumarin derivative is used as an initiator, and the raw materials are easily available in multiple varieties; multiple types of products obtained by the method can be directly used or can be further used for other reactions; meanwhile, the synthesis path is simple and short, the reaction conditions are mild, the reaction operation and after-treatment process are simple, the yield is relatively high, and the method is suitable for large-scale production.

Description

A kind of preparation method of 3-trifluoromethyl coumarin derivatives
Technical field
The present invention relates to a kind of coumarin derivatives, be specifically related to a kind of preparation method of 3-trifluoromethyl coumarin derivatives.
Background technology
Coumarin derivatives is the very important natural product of a class, organofluorine compound and biological phenomena closely related, therefore synthesize 3-trifluoromethyl coumarin derivatives and there is important value.In prior art, only has the synthesis of little bibliographical information several 3-trifluoromethyl tonka bean camphor.Such as, document 1. John Kallikat Augustine, Agnes Bombrun, Balakrishna Ramappa, Chandrakantha Boodappa, Tetrahedron Letters, 2012,53 (33), 4422-4425; With document 2. Wojciech Dmowski and Krystyna Piasecka-Maciejewska, Organic Preparations and Procedures International, 2002,34 (5), 514-517, individually discloses a kind of synthetic method of 3-trifluoromethyl coumarin derivatives.Synthetic route is as follows:
In technique scheme, reaction 1 needs to use excessive phosphonic acid anhydride reagent, and the scope of application that the substrate of a lot of reaction is difficult to obtain causing reacting is little.Reaction 2 needs to use toxic gas sulfur tetrafluoride, and productive rate all very low (32-36%).Therefore reaction conditions synthetic method that is gentle, applied widely, that meet Green Chemistry requirement is developed extremely important.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of 3-trifluoromethyl coumarin derivatives and preparation method thereof.
To achieve the above object of the invention, the technical solution used in the present invention is: a kind of preparation method of 3-trifluoromethyl coumarin derivatives, coumarin derivatives, Sodium trifluoromethanesulfinate and manganese acetate are dissolved in solvent, react at 20 ~ 100 DEG C, obtain 3-trifluoromethyl coumarin derivatives;
Described coumarin derivatives is as shown in having structure general formula:
；
Wherein R 1, R 2, R 3, R 4, Z selection take one of following scheme:
(1) Z is hydrogen, methyl, methoxyl group, chlorine or phenyl, R 1, R 2, R 3and R 4be all hydrogen;
(2) Z is hydrogen, methyl, methoxyl group, chlorine or phenyl, R 1, R 2, R 3or R 4in any one be selected from: the one in C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, halogen, nitro, cyano group, ethanoyl and methyl ester group, other 3 is hydrogen;
(3) Z is hydrogen, R 1, R 2, R 3, R 4in any two be selected from respectively: C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, halogen, nitro, cyano group, ethanoyl or methyl ester group, other 2 is hydrogen;
(4) Z is hydrogen, R 1, R 2, R 3, R 4in wantonly three kinds of substituting groups be selected from respectively: C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, halogen, nitro, cyano group, ethanoyl or methyl ester group, the 4th is hydrogen;
Described solvent is selected from: the one in methyl alcohol, ethanol, acetonitrile, formic acid, acetic acid, propionic acid, chloroform, methylene dichloride, 1,2-ethylene dichloride or toluene.
In technique scheme, the 3-trifluoromethyl coumarin derivatives general formula of acquisition is as follows:
。
In technique scheme, described coumarin derivatives is selected from 2H-chromen-2-one, 4-methyl-2H-chromen-2-one, 4-methoxyl group-2H-chromen-2-one, the chloro-2H-chromen-2-one of 4-, 4-phenyl-2H-chromen-2-one, the fluoro-2H-chromen-2-one of 5-, 5-cyano group-2H-chromen-2-one, 6-methyl-2H-chromen-2-one, 6-propoxy--2H-chromen-2-one, the bromo-2H-chromen-2-one of 6-, 6-nitro-2H-chromen-2-one, 6-ethanoyl-2H-chromen-2-one, 7-methoxyl group-2H-chromen-2-one, 7-ethyl-2H-chromen-2-one, the chloro-2H-chromen-2-one of 7-, 7-methoxycarbonyl-2H-chromen-2-one, 7-acetoxyl group-2H-chromen-2-one, 8-methyl-2H-chromen-2-one, the iodo-2H-chromen-2-one of 8-, 4,6-dimethyl-2H-chromen-2-one, the bromo-2H-chromen-2-one of 4-methyl-6-, 4-methyl-7-methoxyl group-2H-chromen-2-one, the chloro-2H-chromen-2-one of 4-methyl-7-, the iodo-2H-chromen-2-one of 4-methyl-7-, 4-methyl-7-nitro-2H-chromen-2-one, 4-methyl-7-acetoxyl group-2H-chromen-2-one, 5,8-dimethyl-2H-chromen-2-one, 5-methoxyl group-6-nitro-2H-chromen-2-one, the bromo-2H-chromen-2-one of the chloro-7-of 6-, 7-methyl-8-cyano group-2H-chromen-2-one, one in the chloro-8-methoxycarbonyl of 5-methyl-6--2H-chromen-2-one.
The reaction process of technique scheme can be expressed as:
Due to the utilization of technique scheme, the present invention compared with prior art has following advantages:
1. the present invention uses coumarin derivatives for initiator, and raw material is easy to get, kind is a lot; The product types utilizing method of the present invention to obtain is various, not only directly can use, but also may be used for other and further react.
2. reaction conditions gentleness of the present invention, operation and last handling process are simple, and productive rate is higher, is suitable for scale production.
Embodiment
Below in conjunction with embodiment, the invention will be further described:
The synthesis of embodiment one: 3-trifluoromethyl-2H-chromen-2-one
Using 2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
2H-chromen-2-one 0.073 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.078 gram (0.5 mmol), manganese acetate 0.135 gram (0.5 mmol) and 30 ml methanol are added, 25 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 54%).
1H NMR (CDCl 3): δ8.17 (s, 1H, C 4-H),7.69 (t, J= 7.8 Hz, 1H, ArH), 7.63 (d, J= 7.8 Hz, 1H, ArH), 7.46-7.30 (m, 2H, ArH), 13C NMR (CDCl 3): δ155.9, 154.6, 143.4 (q, J= 4.8 Hz), 134.4, 129.5, 125.3, 121.3 (q, J= 272.1 Hz), 117.6 (q, J= 33.2 Hz), 116.7, 115.9. 19F NMR (CDCl 3): δ-66.2(s, 3F).
The synthesis of embodiment two: 3-trifluoromethyl-4-methyl-2H-chromen-2-one
Using 4-methyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
4-methyl-2H-chromen-2-one 0.080 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 ml methanol are added, 40 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ7.84 (d, J= 7.5 Hz, 1H, ArH), 7.70 (t, J= 7.8 Hz, 1H, ArH), 7.39-7.42 (m, 2H, ArH), 2.33 (s, 3H)。
The synthesis of embodiment three: 3-trifluoromethyl-4-methoxyl group-2H-chromen-2-one
Using 4-methoxyl group-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
4-methoxyl group-2H-chromen-2-one 0.090 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of ethanol are added, 50 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 71%).
1H NMR (CDCl 3): δ 7.84 (d, J= 8.2 Hz, 1H, ArH), 7.67 (t, J= 7.8 Hz, 1H, ArH), 7.44-7.31 (m, 2H, ArH), 4.18 (s, 3H, 4-OCH 3). 13C NMR (CDCl 3): δ169.6, 157.8, 153.7, 134.6, 127.3, 121.8 (q, J= 273.5 Hz), 117.1, 116.1, 105.7 (q, J= 31.9 Hz), 64.7 (d, J= 2.8 Hz). 19F NMR (CDCl 3): δ-58.8(s, 3F).
The synthesis of the chloro-2H-chromen-2-one of embodiment four: 3-trifluoromethyl-4-
Using the chloro-2H-chromen-2-one of 4-, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the chloro-2H-chromen-2-one of 4-0.090 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of ethanol are added, 70 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ7.85 (d, J= 7.6 Hz, 1H, ArH), 7.70 (t, J= 7.8 Hz, 1H, ArH), 7.39-7.42 (m, 2H, ArH)。
The synthesis of embodiment five: 3-trifluoromethyl-4-phenyl-2H-chromen-2-one
Using 4-phenyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
4-phenyl-2H-chromen-2-one 0.111 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of ethanol are added, 70 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 82%).
1H NMR (CDCl 3): δ7.59?7.39 (m, 8H), 7.24 (dd, J= 13.9, 6.4 Hz, 1H)。
The synthesis of the fluoro-2H-chromen-2-one of embodiment six: 3-trifluoromethyl-5-
Using the fluoro-2H-chromen-2-one of 5-, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the fluoro-2H-chromen-2-one of 5-0.082 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of acetonitriles are added, 50 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 82%).
1H NMR (CDCl 3): δ7.94 (s, 1H, ArH), 7.60 (t, J= 7.5 Hz, 1H, ArH), 6.93-7.16 (m, 2H, ArH)。
The synthesis of embodiment seven: 3-trifluoromethyl-5-cyano group-2H-chromen-2-one
Using 5-cyano group-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
5-cyano group-2H-chromen-2-one 0.086 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of acetonitriles are added, 40 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 81%).
1H NMR (CDCl 3): δ7.94 (s, 1H, 1H, ArH), 7.83 (t, J= 7.5 Hz, 1H, ArH), 7.47-7.67 (m, 2H, ArH)。
The synthesis of embodiment eight: 3-trifluoromethyl-6-methyl-2H-chromen-2-one
Using 6-methyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
6-methyl-2H-chromen-2-one 0.080 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of acetonitriles are added, 30 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ8.09 (s, 1H, C 4-H), 7.48 (d, J= 8.6 Hz, 1H, ArH), 7.39 (s, 1H, ArH), 7.29 (d, J= 8.6 Hz, 1H, ArH), 2.44 (s, 3H, 6-CH 3). 13C NMR (CDCl 3): δ156.2, 152.8, 143.3 (q, J= 4.8 Hz), 135.5, 135.2, 129.1, 121.4 (q, J= 272.0 Hz), 117.5 (q, J= 33.1 Hz), 116.8, 116.5, 20.7. 19F NMR (CDCl 3): δ-65.9(s, 3F).
The synthesis of embodiment nine: 3-trifluoromethyl-6-propoxy--2H-chromen-2-one
Using 6-propoxy--2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
6-propoxy--2H-chromen-2-one 0.102 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 20 milliliters of formic acid are added, 20 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 70%).
1H NMR (CDCl 3): δ7.94 (s, 1H, 1H, ArH), 7.68 (d, J= 7.5 Hz, 1H, ArH), 6.78-6.83 (m, 2H, ArH), 3.93 (t, J= 10.5 Hz, 2H), 2.43 (m, 2H), 1.91 (t, J= 8.5 Hz, 3H)。
The synthesis of the bromo-2H-chromen-2-one of embodiment ten: 3-trifluoromethyl-6-
Using the bromo-2H-chromen-2-one of 6-, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the bromo-2H-chromen-2-one of 6-0.102 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 20 milliliters of formic acid are added, 30 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 78%).
1H NMR (CDCl 3): δ8.07 (s, 1H, ArH), 7.94 (s, 1H, 1H, ArH), 7.62 (d, J= 7.5 Hz, 1H, ArH), 7.25 (d, J= 7.5 Hz, 1H, ArH)。
The synthesis of embodiment 11: 3-trifluoromethyl-6-nitro-2H-chromen-2-one
Using 6-nitro-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
6-nitro-2H-chromen-2-one 0.095 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 20 milliliters of formic acid are added, 40 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 88%).
1H NMR (CDCl 3): δ8.58 (s, 1H, ArH), 8.54 (d, J= 9.1 Hz, 1H, ArH), 8.26 (s, 1H, C 4-H), 7.56 (d, J= 9.1 Hz, 1H, ArH). 13C NMR (CDCl 3): δ157.8, 154.1, 144.4, 142.1 (q, J= 4.7 Hz), 128.8, 125.2, 120.7 (q, J= 273.2 Hz), 120.0 (q, J= 34.7 Hz), 118.4, 116.8. 19F NMR (CDCl 3): δ-66.6(s, 3F).
The synthesis of embodiment 12: 3-trifluoromethyl-6-ethanoyl-2H-chromen-2-one
Using 6-ethanoyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
6-ethanoyl-2H-chromen-2-one 0.094 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 10 milliliters of acetic acid are added, 80 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 81%).
1H NMR (CDCl 3): δ8.26 (d, J= 7.5 Hz, 1H, ArH), 8.23 (s, 1H, ArH), 7.94 (s, 1H, ArH), 7.47 (d, J= 7.5 Hz, 1H, ArH), 2.54 (s, 3H)。
The synthesis of embodiment 13: 3-trifluoromethyl-7-methoxyl group-2H-chromen-2-one
Using 7-methoxyl group-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
7-methoxyl group-2H-chromen-2-one 0.088 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 10 milliliters of acetic acid are added, 90 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 76%).
1H NMR (CDCl 3): δ8.08 (s, 1H, C 4-H), 7.50 (d, J= 8.7 Hz, 1H, ArH), 6.92 (d, J= 8.7 Hz, 1H, ArH), 6.85 (s, 1H, ArH), 3.91 (s, 3H, 7-OCH 3), 13C NMR (CDCl 3): δ164.9, 156.8, 156.4, 143.2 (q, J= 4.7 Hz), 130.5, 121.7 (q, J= 271.3 Hz), 113.8, 113.8 (q, J= 33.2 Hz), 110.3, 100.7, 56.0. 19F NMR (CDCl 3): δ-65.7(s, 3F).
The synthesis of embodiment 14: 3-trifluoromethyl-7-ethyl-2H-chromen-2-one
Using 7-ethyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
7-ethyl-2H-chromen-2-one 0.088 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 20 milliliters of propionic acid are added, 100 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 71%).
1H NMR (CDCl 3): δ7.88 (s, 1H, ArH), 7.84 (d, J= 7.5 Hz, 1H, ArH), 7.12-7.14 (m, 2H, ArH), 2.72 (m, 2H), 1.22 (t, J= 8.5 Hz, 3H)。
The synthesis of the chloro-2H-chromen-2-one of embodiment 15: 3-trifluoromethyl-7-
Using the chloro-2H-chromen-2-one of 7-, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the chloro-2H-chromen-2-one of 7-0.090 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 20 milliliters of propionic acid are added, 20 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 87%).
1H NMR (CDCl 3): δ8.12 (s, 1H, C 4-H), 7.56 (d, J= 8.4 Hz, 1H, ArH), 7.42 (s, 1H, ArH), 7.36 (d, J= 8.4 Hz, 1H, ArH). 13C NMR (CDCl 3): δ150.4, 150.1, 137.7 (q, J= 4.7 Hz), 136.0, 125.5, 121.3, 116.4 (q, J= 272.1 Hz), 113.3 (q, J= 33.9 Hz), 112.6, 100.6. 19F NMR (CDCl 3): δ-66.3(s, 3F).
The synthesis of embodiment 16: 3-trifluoromethyl-7-methoxycarbonyl-2H-chromen-2-one
Using 7-methoxycarbonyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
7-methoxycarbonyl-2H-chromen-2-one 0.102 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 20 milliliters of propionic acid are added, 50 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 82%).
1H NMR (CDCl 3): δ8.14 (d, J= 7.5 Hz, 1H, ArH), 7.95 (d, J= 7.5 Hz, 1H, ArH),7.88 (s, 1H, ArH), 7.64 (s, 1H, ArH), 3.89 (s, 3H)。
The synthesis of embodiment 17: 3-trifluoromethyl-7-acetoxyl group-2H-chromen-2-one
Using 7-acetoxyl group-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
7-acetoxyl group-2H-chromen-2-one 0.102 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of chloroforms are added, 40 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 74%).
1H NMR (CDCl 3): δ8.14 (s, 1H, C 4-H), 7.62 (d, J= 8.5 Hz, 1H, ArH), 7.20 (s, 1H, ArH), 7.16 (d, J= 8.5 Hz, 1H, ArH), 2.34 (s, 3H), 13C NMR (CDCl 3): δ168.3, 155.5, 155.4, 155.2, 142.7 (q, J= 4.8 Hz), 130.3, 124.9 (q, J= 271.9 Hz), 119.3, 117.0 (q, J= 33.3 Hz), 114.4, 100.5, 21.1. 19F NMR (CDCl 3): δ-66.2(s, 3F).
The synthesis of embodiment 18: 3-trifluoromethyl-8-methyl-2H-chromen-2-one
Using 8-methyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
8-methyl-2H-chromen-2-one 0.080 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of methylene dichloride are added, 20 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 71%).
1H NMR (CDCl 3): δ8.14 (s, 1H, ArH), 7.53 (d, J= 7.4 Hz, 1H, ArH), 7.45 (d, J= 7.4 Hz, 1H, ArH), 7.28 (m, 1H, ArH)，2.48（s, 3H, 8-CH 3）. 13C NMR (CDCl 3): δ156.1, 153.0, 143.6 (q, J= 4.7 Hz), 135.7, 127.1, 126.7, 124.8, 121.4 (q, J= 272.0 Hz), 117.3 (q, J= 33.2 Hz), 116.5, 15.4. 19F NMR (CDCl 3): δ-66.1(s, 3F).
The synthesis of the iodo-2H-chromen-2-one of embodiment 19: 3-trifluoromethyl-8-
Using the iodo-2H-chromen-2-one of 8-, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the iodo-2H-chromen-2-one of 8-0.136 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of chloroforms are added, 40 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ7.94 (s, 1H, ArH), 7.22-7.80 (m, 3H, ArH)。
The synthesis of embodiment 20: 3-trifluoromethyl-4,6-dimethyl-2H-chromen-2-one
With 4,6-dimethyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
4,6-dimethyl-2H-chromen-2-one 0.087 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of methylene dichloride are added, 30 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 75%).
1H NMR (CDCl 3): δ7.58 (s, 1H, ArH), 7.45 (d, J= 8.4 Hz, 1H, ArH), 7.25 (d, J= 8.4 Hz, 1H, ArH), 2.67 (s, 3H, 4-CH 3), 2.46 (s, 3H, 6-CH 3). 13C NMR (CDCl 3): δ156.0, 154.9, 151.1, 135.0, 134.6, 125.6, 122.8 (q, J= 275.3 Hz), 118.6, 116.8, 115.1 (q, J= 30.2 Hz), 21.1, 15.6 (q, J= 3.9 Hz). 19F NMR (CDCl 3): δ-56.7(s, 3F).
The synthesis of embodiment 21: 3-trifluoromethyl-4-methyl-7-methoxyl group-2H-chromen-2-one
Using 4-methyl-7-methoxyl group-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
4-methyl-7-methoxyl group-2H-chromen-2-one 0.095 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of toluene are added, 20 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 81%).
1H NMR (CDCl 3): δ7.70 (d, J= 9.0 Hz, 1H, ArH), 6.92(d, J= 9.0 Hz, 1H, ArH), 6.80 (s, 1H, ArH), 3.90 (s, 3H, 7-OCH 3), 2.63 (s, 3H, 4-CH 3), 13C NMR (CDCl 3): δ164.4, 156.4, 155.1, 127.1, 123.1 (q, J= 274.8 Hz), 113.4, 112.4, 120.0 (q, J= 30.3 Hz), 100.4, 56.0, 15.7 (q, J= 3.7 Hz). 19F NMR (CDCl 3): δ-56.4(s, 3F).
The synthesis of the chloro-2H-chromen-2-one of embodiment 22: 3-trifluoromethyl-4-methyl-7-
Using the chloro-2H-chromen-2-one of 4-methyl-7-, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the chloro-2H-chromen-2-one of 4-methyl-7-0.096 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.234 gram (1.5 mmol), manganese acetate 0.54 gram (2.0 mmol) and 30 milliliters of toluene are added, 50 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 85%).
1H NMR (CDCl 3): δ7.74 (d, J= 8.5 Hz, 1H, ArH), 7.47-7.29 (m, 2H, ArH), 2.67 (q, J= 2.1 Hz, 3H, 4-CH 3). 13C NMR (CDCl 3): δ155.4, 154.6, 153.5, 140.4, 127.2, 125.8, 122.8 (q, J= 275.4 Hz), 117.9, 117.5, 115.6 (q, J= 30.6 Hz), 21.1, 16.0 (q, J= 4.0 Hz). 19F NMR (CDCl 3): δ-56.9(s, 3F).
The synthesis of embodiment 23: 3-trifluoromethyl-4-methyl-7-acetoxyl group-2H-chromen-2-one
Using 4-methyl-7-acetoxyl group-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
4-methyl-7-acetoxyl group-2H-chromen-2-one 0.110 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.234 gram (1.5 mmol), manganese acetate 0.54 gram (2.0 mmol) and 30 milliliters of toluene are added, 100 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 80%).
1H NMR (CDCl 3): δ7.81 (d, J= 9.4 Hz, 1H, ArH), 7.17-7.15 (m, 2H, ArH), 2.67 (d, J= 2.0 Hz, 3H, 4-CH 3), 2.35 (s, 3H). 13C NMR (CDCl 3): δ168.3, 155.5, 154.7, 154.5, 153.7, 127.0, 122.7 (q, J= 275.2 Hz), 118.8, 116.7, 114.7 (q, J= 29.6 Hz), 110.3, 21.1, 15.8 (q, J= 4.0 Hz). 19F NMR (CDCl 3): δ-56.8(s, 3F).
The synthesis of embodiment 24: 3-trifluoromethyl-5,8-dimethyl-2H-chromen-2-one
With 5,8-dimethyl-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
5,8-dimethyl-2H-chromen-2-one 0.087 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of toluene are added, 40 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ8.33 (s, 1H, C 4-H), 7.39 (d, J= 7.5 Hz, 1H, ArH), 7.08 (d, J= 7.5 Hz, 1H, ArH), 2.55 (s, 3H, 5-CH 3), 2.43 (s, 3H, 8-CH 3). 13C NMR (CDCl 3): δ156.0, 153.6, 140.5 (q, J= 4.8 Hz), 135.5, 135.3, 126.0, 124.2, 121.6 (q, J= 272.0 Hz), 116.3 (q, J= 33.0 Hz), 115.5, 18.1, 15.3. 19F NMR (CDCl 3): δ-65.9(s, 3F).
The synthesis of embodiment 25: 3-trifluoromethyl-5-methoxyl group-6-nitro-2H-chromen-2-one
Using 5-methoxyl group-6-nitro-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
5-methoxyl group-6-nitro-2H-chromen-2-one 0.111 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 ml methanol are added, 40 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 74%).
1H NMR (CDCl 3): δ8.38 (d, J= 7.5 Hz, 1H, ArH), 7.94 (s, 1H, ArH), 7.30 (d, J= 7.5 Hz, 1H, ArH), 3.83 (s, 3H)。
The synthesis of the bromo-2H-chromen-2-one of the chloro-7-of embodiment 26: 3-trifluoromethyl-6-
Using the bromo-2H-chromen-2-one of the chloro-7-of 6-, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the bromo-2H-chromen-2-one of the chloro-7-of 6-0.130 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of ethanol are added, 50 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ7.94 (s, 1H, ArH), 7.91 (s, 1H, ArH), 7.68 (s, 1H, ArH)。
The synthesis of embodiment 27: 3-trifluoromethyl-7-methyl-8-cyano group-2H-chromen-2-one
Using 7-methyl-8-cyano group-2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
7-methyl-8-cyano group-2H-chromen-2-one 0.093 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 10 milliliters of acetic acid are added, 80 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ8.07 (d, J= 7.5 Hz, 1H, ArH), 7.94 (s, 1H, ArH), 7.28 (d, J= 7.5 Hz, 1H, ArH), 2.47 (s, 3H)。
The synthesis of the chloro-8-methoxycarbonyl of embodiment 28: 3-trifluoromethyl-5-methyl-6--2H-chromen-2-one
Using the chloro-8-methoxycarbonyl of 5-methyl-6--2H-chromen-2-one, Sodium trifluoromethanesulfinate as raw material, its reaction formula is as follows:
the chloro-8-methoxycarbonyl of 5-methyl-6--2H-chromen-2-one 0.126 gram (0.5 mmol), Sodium trifluoromethanesulfinate 0.156 gram (1.0 mmol), manganese acetate 0.27 gram (1.0 mmol) and 30 milliliters of acetonitriles are added, 60 DEG C of reactions in reaction flask;
tLC follows the tracks of reaction until terminate completely;
the crude by column chromatography obtained after reaction terminates is separated (sherwood oil: ethyl acetate=50:1), obtains target product (productive rate 72%).
1H NMR (CDCl 3): δ8.50 (s, ArH), 7.94 (s, 1H, ArH), 3.95 (s, 3H), 2.33 (s, 3H)。
Embodiment 29: tumor cell in vitro increment inhibit activities test
Coumarin derivatives has significant pharmacologically active, as antitumor, anti-vascular disease etc., is confirm These characteristics, has carried out the test of tumor cell in vitro increment inhibit activities to the part of compounds in the embodiment of the present invention.
1, laboratory sample and experimental technique
The preparation of sample solution: test sample is the compound obtained in above-described embodiment.Precision takes appropriate amount of sample, is mixed with the solution of desired concn with methyl alcohol, active for survey.
The succeeding transfer culture of clone and cell: adopt human leukemia HL60 cell and typeⅡ pneumocyte.Various cell all with containing 10% FBS RPMI-1640 substratum, at 37 DEG C of succeeding transfer culture in the incubator passing into 5% carbonic acid gas.
Tumor cell proliferation inhibition activity testing method: with the inhibit activities of tetrazolium (MTT) method test to human leukemia HL60 cell; With the inhibit activities of Sulforhodamine B (SRB) method test to typeⅡ pneumocyte.
2, experimental result
In mtt assay or srb assay test, the Proliferation Ability of compound to human leukemia HL60 cell and typeⅡ pneumocyte of different concns the results are shown in Table 1.
The compound of table 1 different concns is to the inhibiting rate (%) of cancer cell multiplication
3, conclusion
From above table, the compound tested in the embodiment of the present invention 2, 5, 6, 11, 22with 27to human leukemia HL60 cell and typeⅡ pneumocyte, all there is obvious cell inhibitory effect effect, can be used as inhibition of cell proliferation or antineoplastic agent, carry out further antineoplastic research.

Claims (2)

1. a preparation method for 3-trifluoromethyl coumarin derivatives, is characterized in that: be dissolved in solvent by coumarin derivatives, Sodium trifluoromethanesulfinate and manganese acetate, reacts at 20 ~ 100 DEG C, obtains 3-trifluoromethyl coumarin derivatives;
Described coumarin derivatives is as shown in having structure general formula:
；
Wherein R 1, R 2, R 3, R 4, Z selection take one of following scheme:
(1) Z is hydrogen, methyl, methoxyl group, chlorine or phenyl, R 1, R 2, R 3and R 4be all hydrogen;
(2) Z is hydrogen, methyl, methoxyl group, chlorine or phenyl, R 1, R 2, R 3or R 4in any one be selected from: the one in C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, halogen, nitro, cyano group, ethanoyl and methyl ester group, other 3 is hydrogen;
(3) Z is hydrogen, R 1, R 2, R 3, R 4in any two be selected from respectively: C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, halogen, nitro, cyano group, ethanoyl or methyl ester group, other 2 is hydrogen;
(4) Z is hydrogen, R 1, R 2, R 3, R 4in wantonly three kinds of substituting groups be selected from respectively: C1 ~ C4 alkyl, C1 ~ C4 alkoxyl group, halogen, nitro, cyano group, ethanoyl or methyl ester group, the 4th is hydrogen;
Described solvent is selected from: the one in methyl alcohol, ethanol, acetonitrile, formic acid, acetic acid, propionic acid, chloroform, methylene dichloride, 1,2-ethylene dichloride or toluene.
2. the preparation method of 3-trifluoromethyl coumarin derivatives according to claim 1, is characterized in that: described coumarin derivatives is selected from 2H-chromen-2-one, 4-methyl-2H-chromen-2-one, 4-methoxyl group-2H-chromen-2-one, the chloro-2H-chromen-2-one of 4-, 4-phenyl-2H-chromen-2-one, the fluoro-2H-chromen-2-one of 5-, 5-cyano group-2H-chromen-2-one, 6-methyl-2H-chromen-2-one, 6-propoxy--2H-chromen-2-one, the bromo-2H-chromen-2-one of 6-, 6-nitro-2H-chromen-2-one, 6-ethanoyl-2H-chromen-2-one, 7-methoxyl group-2H-chromen-2-one, 7-ethyl-2H-chromen-2-one, the chloro-2H-chromen-2-one of 7-, 7-methoxycarbonyl-2H-chromen-2-one, 8-methyl-2H-chromen-2-one, the iodo-2H-chromen-2-one of 8-, 4,6-dimethyl-2H-chromen-2-one, the bromo-2H-chromen-2-one of 4-methyl-6-, 4-methyl-7-methoxyl group-2H-chromen-2-one, the chloro-2H-chromen-2-one of 4-methyl-7-, the iodo-2H-chromen-2-one of 4-methyl-7-, 4-methyl-7-nitro-2H-chromen-2-one, 5,8-dimethyl-2H-chromen-2-one, 5-methoxyl group-6-nitro-2H-chromen-2-one, the bromo-2H-chromen-2-one of the chloro-7-of 6-, 7-methyl-8-cyano group-2H-chromen-2-one, one in the chloro-8-methoxycarbonyl of 5-methyl-6--2H-chromen-2-one.
CN201310540718.5A 2013-11-05 2013-11-05 Preparation method of 3-trifluoromethyl coumarin derivative Expired - Fee Related CN103554074B (en)

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