CN105801571A - Heterocyclic difluoromethylated oxirane compound and preparation method thereof - Google Patents

Heterocyclic difluoromethylated oxirane compound and preparation method thereof Download PDF

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CN105801571A
CN105801571A CN201610230557.3A CN201610230557A CN105801571A CN 105801571 A CN105801571 A CN 105801571A CN 201610230557 A CN201610230557 A CN 201610230557A CN 105801571 A CN105801571 A CN 105801571A
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mmol
cdcl
methyl
heterocycle
difluoromethyl
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郝健
田文枫
蒋海珍
陈运荣
万文
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University of Shanghai for Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention relates to a heterocyclic difluoromethylated oxirane compound and a preparation method thereof.The structural general formula is shown in the description, wherein R1 is hydrogen or methyl, X is oxygen or sulfur atoms, and R2 is phenyl with a 4-bromo or 3-bromo or 4-fluoro or 4-chloro or 4-methyl or 3-methoxyl or 2-methoxyl or 4-nitryl or 3-nitryl or 4-cyano substituent, 3-naphthalene, and 2-thiophene or 2-furan.The preparation method of the heterocyclic difluoromethylated oxirane compound is simple and efficient.2-bromoaromatic ethyl ketone and heterocyclic fluorine-containing slices are subjected to a reaction, and the heterocyclic difluoromethylated oxirane compound is prepared in one step.The advantages that raw materials are easy to obtain, toxicity is low, reaction conditions are mild, and operation is simple are achieved.The epoxy compound prepared through the reaction can further react to generate other valuable derivatives.

Description

Oxirane compound of heterocycle difluoromethyl and preparation method thereof
Technical field
The present invention relates to oxirane compound of a kind of heterocycle difluoromethyl and preparation method thereof.
Background technology
Due to the special nature of fluorine atom, as electronegativity is maximum and atomic radius is less close with the radius of hydrogen atom, will Fluorine atom or fluoro-containing group introduce molecule generally can change its physicochemical property (such as lipotropy, metabolic stability and target egg White binding ability, cell membrane penetration and bioavailability).Therefore fluorochemical is in medicine, the field such as pesticide and material It is widely used.Develop new method and become more and more important to prepare fluorochemical.
Epoxyethane derivative is the organic synthesis intermediate that a class is important, occupies critical role in organic synthesis.Cause This uses fluorine-containing epoxyethane derivative to prepare fluorochemical as intermediate is one of its potential application.Such as, pass through Trinitrogenazole alcohol fluorochemical prepared by the oxirane compound of heterocycle difluoromethyl has shown the strongest antifungal Activity (Eto H.; Kaneko Y.;Sakamoto T. Chem. Pharm. Bull.2000,48,982.).Its reaction Formula is as follows:
The method synthesizing this epoxyethane derivative at present is the substituted 1-Phenylethanone. of heterocycle difluoromethyl and diazomethane reaction, Wherein the substituted 1-Phenylethanone. of heterocycle difluoromethyl needs a point multistep to prepare, and affects reaction efficiency；Azimethylene. toxicity is relatively big and has The danger of blast.Its reaction equation is as follows:
Therefore develop a kind of low toxicity and dangerous low method is prepared the substituted oxirane compound of heterocycle difluoromethyl and carries High reaction efficiency is necessary.
Summary of the invention
An object of the present invention is to provide the oxirane of a kind of heterocycle difluoromethyl.
The two of the purpose of the present invention are to provide the preparation method of this compound, and the method uses 2-bromo fragrance ethyl ketone and heterocycle Fluorine-containing stripping and slicing is reacted, and a step has prepared the substituted oxirane compound of heterocycle difluoromethyl, has efficiently, and raw material is easy to get and poison The advantage such as property is low.
The compou nd synthesis of the present invention have employed following reaction equation:
Wherein, R1For hydrogen or methyl, X is oxygen or sulphur atom, R2For phenyl, there is fluorine, chlorine, bromine, methyl, methoxyl group, nitro or The phenyl of cyano substituent, naphthalene, thiophene or furan.
The present invention adopts the following technical scheme that
The oxirane of a kind of heterocycle difluoromethyl, it is characterised in that the structural formula of this compound is:
Wherein, R1For hydrogen or methyl, X is oxygen or sulphur atom, R2For phenyl ,-bromine ,-fluorine ,-chlorine, -methyl ,-methoxyl group ,-nitro or the phenyl of-cyano substituent ,-naphthalene ,-thiophene or-furan.
A kind of method of oxirane preparing above-mentioned heterocycle difluoromethyl, is characterized in that the concrete steps of the method For: under inert gas shielding, 2-bromo aromatic ketone, heterocycle fluoro-building block, copper powder, catalyst are pressed 1:1 ~ 8:2 ~ 16:0.1 ~ The mol ratio of 0.5 is dissolved in dimethyl sulfoxide, reacts 2～10 hours at 20～80 DEG C, and separated purification prepares heterocycle difluoro first The oxirane of base；The structural formula of described 2-bromo aromatic ketone is:Wherein, R2For phenyl, there is fluorine, chlorine, The phenyl of bromine, methyl, methoxyl group, nitro or cyano substituent, naphthalene, thiophene or furan；The structure of described heterocycle fluoro-building block Formula is:Wherein, R1For hydrogen or methyl, X is oxygen or sulphur atom, and its source is reference literature (F. Ge, Z. Wang, W. Wan, W. Lu, J. Hao, Tetrahedron Lett.2007,48,3251) prepare
The present invention uses 2-bromo fragrance ethyl ketone and heterocycle fluorine-containing stripping and slicing reaction, and a step has prepared the substituted ring of heterocycle difluoromethyl Oxidative ethane compound, has raw material and is easy to get, and toxicity is low, reaction condition gentleness simple operation and other advantages.The epoxidation that reaction prepares Compound can react other valuable derivants of generation further.
Detailed description of the invention
Embodiment one:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-phenyloxirane compounds uses following steps: in blanket of nitrogen Under enclosing, being sequentially added into 2-bromoacetophenone (1.98g, 10 mmol) in the reaction bulb of 100 mL, 2-mono-bromine difluoro methyl takes For benzo 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), p-methyl benzenesulfonic acid (0.17g, 1 Mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature after terminating, kieselguhr filters, water Removing solvent with ethyl acetate extraction, organic layer concentrates and uses silica gel column chromatography to separate, and obtains colourless oil liquid 1.81 grams, receives Rate is 63%.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.80 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.54 – 7.51 (m, 2H), 7.44 – 7.37 (m, 2H), 7.32 – 7.30 (m, 3H), 3.60 (d, J = 5.2 Hz, 1H), 3.02 – 2.99 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.64 (d, J=277.9 Hz, 1F), -105.24 (d, J = 277.9 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.9 (t, JC-F= 33.7 Hz), 150.4, 139.7, 131.9, 129.2, 128.2, 128.0, 126.8, 125.2, 121.2, 114.4 (t, JC-F= 248.8 Hz), 111.3, 60.2 (t, JC-F= 30.7 Hz), 50.7 (t, JC-F= 3.4 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3067, 1611, 1451, 1359, 1285, 1125, 1002, 751。
High resolution mass spectrum (ESI): calcd for C16H12F2NO2 [M+H+] 288.0831, found: 288.0830。
Embodiment two:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(4-bromophenyl) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(4-bromophenyl) ethyl ketone (2.76g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), to toluene sulphur Acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature after terminating, Kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white solid 2.59 grams, yield is 71%.Fusing point is 90 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.79 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.46 – 7.36 (m, 6H), 3.59 (d, J = 5.2 Hz, 1H), 2.98 – 2.96 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.40 (d, J=279.8 Hz, 1F), -105.05 (d, J = 279.8 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.5 (t, JC-F= 33.5 Hz), 150.4, 139.7, 131.5, 131.0, 129.6, 126.9, 125.3, 123.5, 121.3, 114.1 (t, JC-F= 248.9 Hz), 111.3, 59.7 (t, JC-F= 30.9 Hz), 50。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3084, 1621, 1362, 1280, 1087, 993, 747。
High resolution mass spectrum (ESI): calcd for C16H11BrF2NO2 [M+H+] 365.9936, found 365.9934。
Embodiment three:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(3-bromophenyl) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(3-bromophenyl) ethyl ketone (2.76g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), to toluene sulphur Acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature after terminating, Kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white solid 2.59 grams, yield is 71%.Fusing point is 59 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.78 (d, J=7.7 Hz, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.47 – 7.33 (m, 4H), 7.15 (t, J = 7.9, 1H), 3.57 (d, J = 5.1 Hz, 1H), 2.96 – 2.94 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-103.80 (d, J=278.7 Hz, 1F), -104.43 (d, J = 280.3 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.3 (t,1JC-F = 33.5 Hz), 150.3, 139.6, 134.2, 132.3, 130.9, 129.7, 126.9, 126.5, 125.2, 122.2, 121.2, 114.2 (t, 1JC-F= 248.8 Hz), 111.2, 59.5 (t, 1JC-F= 31.2 Hz), 50.7 (t, JC-F= 3.2 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3058, 1567, 1356, 1277, 1117, 996, 750。
High resolution mass spectrum (ESI): calcd for C16H11BrF2NO2 [M+H+] 365.9936, found: 365.9932。
Embodiment four:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(4-chlorphenyl) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(4-chlorphenyl) ethyl ketone (2.32g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), to toluene sulphur Acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature after terminating, Kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white solid 2.18 grams, yield is 68%.Fusing point is 91 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.79 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.47 (d, J = 8.4 Hz, 3H), 7.42 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 3.59 (d, J = 5.1 Hz, 1H), 2.98 – 2.96 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.48 (d, J=278.7 Hz, 1F), -105.14 (d, J = 278.7 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.6 (t, JC-F= 33.7 Hz), 150.4, 139.7, 135.3, 130.5, 129.4, 128.5, 126.9, 125.3, 121.3, 114.2 (d, JC-F=248.5), 111.3, 59.7 (JC-F, J=30.9), 50.8 (t, JC-F=3.4)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3086, 1611, 1362, 1281, 1090, 995, 749。
High resolution mass spectrum (ESI): calcd for C16H11ClF2NO2 [M+H+] 322.0441, found: 322.0439。
Embodiment five:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(4-fluorophenyl) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(4-fluorophenyl) ethyl ketone (2.16g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), to toluene sulphur Acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature after terminating, Kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white solid 2.32 grams, yield is 76%.Fusing point is 60 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.79 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.51 (dd, J = 8.5 Hz, 5.4, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 3.58 (s, 1H), 3.00 – 2.97 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.74 (d, J=278.4 Hz, 1F), -105.44 (d, J = 278.4 Hz, 1F), -111.42 – -111.49 (m, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=163.0 (d, JC-F= 248.8 Hz), 155.7 (t, JC-F=33.6), 150.4, 139.7, 130.1 (d, JC-F= 8.5 Hz), 127.9 (d, JC-F= 3.5 Hz), 126.9, 125.3, 121.3, 115.4 (d, JC-F= 21.7 Hz), 114.2 (t, J = 248.7 Hz), 111.3, 59.7 (t, JC-F= 30.7 Hz), 50.7 (t, JC-F= 3.3 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3074, 1608, 1512 1360, 1284, 1087, 997, 746。
High resolution mass spectrum (ESI): calcd for C16H11F3NO2 [M+H+] 306.0736, found: 306.0730。
Embodiment six:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(4-nitrobenzophenone) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(4-nitrobenzophenone) and ethyl ketone (2.43g, 10 Mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), right Toluenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to after terminating Room temperature, kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white Color solid 1.59 grams, yield is 48%.Fusing point is 120 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=8.19 (d, J=8.8 Hz, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 3.67 (d, J = 5.0 Hz, 1H), 3.02 – 3.00 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-103.66 (d, J=281.7 Hz, 1F), -104.34 (d, J = 281.2 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.1 (t, JC-F= 33.2 Hz), 150.5, 148.3, 139.7, 139.1, 129.0, 127.2, 125.5, 123.5, 121.4, 114.0 (t, JC-F= 248.5 Hz), 111.4, 59.6 (t, JC-F= 31.4 Hz), 51.1 (t, JC-F= 3.2 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3104, 1606, 1568, 1516, 1347, 1174, 1092, 998, 753。
High resolution mass spectrum (ESI): calcd for C16H11F2N2O4 [M+H+] 333.0681, found: 333.0680。
Embodiment seven:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(3-nitrobenzophenone) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(3-nitrobenzophenone) and ethyl ketone (2.43g, 10 Mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), right Toluenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to after terminating Room temperature, kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white Color solid 1.99 grams, yield is 60%.Fusing point is 91 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=8.44 (s, 1H), 8.20 (d, J=9.1 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 3.66 (d, J = 4.9 Hz, 1H), 3.08 – 3.00 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-103.71 (d, J=281.7 Hz, 1F), -104.35 (d, J = 281.7 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.1 (t, JC-F= 33.3 Hz), 150.4, 148.0, 139.6, 134.3, 134.0, 129.5, 127.2, 125.5, 124.2, 123.2, 121.4, 114.0 (t, JC-F= 248.8 Hz), 111.4, 59.5 (t, JC-F= 31.4 Hz), 51.0 (t, JC-F= 3.2 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3081, 1615, 1528, 1444, 1348, 1174, 1083, 993, 750。
High resolution mass spectrum (ESI): calcd for C16H11F2N2O4 [M+H+] 333.0681, found: 333.0679。
Embodiment eight:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(4-cyano-phenyl) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(4-cyano-phenyl) and ethyl ketone (2.23g, 10 Mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), right Toluenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to after terminating Room temperature, kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white Color solid 2.5 grams, yield is 80%.Fusing point is 93 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.78 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 3.63 (d, J = 5.0 Hz, 1H), 2.99 – 2.97 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-103.74 (d, J=281.2 Hz, 1F), -104.38 (d, J = 281.2 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.1 (t, JC-F=33.3 Hz), 150.4, 139.6, 137.2, 132.1, 128.6, 127.1, 125.5, 121.3, 118.0, 114.0 (t, JC-F=249.0 Hz), 113.2, 111.4, 59.6 (t, JC-F=31.3 Hz), 51.0 (t, JC-F=3.2 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3004, 2224, 1611, 1446, 1278, 1112, 992, 752。
High resolution mass spectrum (ESI): calcd for C17H11F2N2O2 [M+H+] 313.0783, found: 313.0780。
Embodiment nine:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(4-aminomethyl phenyl) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(4-aminomethyl phenyl) and ethyl ketone (2.12g, 10 Mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), right Toluenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to after terminating Room temperature, kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white Color solid 1.87 grams, yield is 62%.Fusing point is 53 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.81 (d, J=7.4 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.45 – 7.37 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 3.58 (d, J = 5.2 Hz, 1H), 3.00 – 2.98 (m, 1H), 2.30 (s, 2H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.84 (d, J=276.9 Hz, 1F), -105.48 (d, J = 276.9 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=156.0 (t, JC-F= 33.7 Hz), 150.4, 139.8, 139.1, 129.0, 128.9, 127.9, 126.8, 125.2, 121.2, 114.4 (t, JC-F= 249.4 Hz), 111.3, 60.1 (t, JC-F= 30.5 Hz), 50.7 (t, JC-F= 3.4 Hz), 21.1。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3033, 2972, 2927, 1611, 1445, 1362, 1281, 1175, 1118, 996, 748。
High resolution mass spectrum (ESI): calcd for C17H14F2NO2 [M+H+] 302.0987, found: 302.1001。
Embodiment ten:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(3-methoxyphenyl) the following step of oxirane compound employing Rapid: under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(3-methoxyphenyl) ethyl ketone (2.28g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), P-methyl benzenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction cools down after terminating To room temperature, kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains Colourless oil liquid 2.60 grams, yield is 82%.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.79 (d, J=7.4,1H), 7.56 (d, J=7.0, 1H), 7.43 – 7.36 (m, 2H), 7.21 (t, J = 7.7, 1H), 7.08 (d, J = 7.6, 1H), 7.05 (s, 1H), 6.87 – 6.84 (m, 1H), 3.70 (s, 3H), 3.58 (d, J = 5.0, 1H), 3.01 – 2.99 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.73 (d, J=277.4 Hz, 1F), -105.66 (d, J = 277.4 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=159.3,155.8 (t, JC-F=33.6 Hz), 150.4, 139.7, 133.3, 129.4, 126.8, 125.2, 121.2, 120.1, 115.1, 114.3 (t, JC-F=248.9 Hz), 113.2, 111.3, 60.1 (t, JC-F=30.6 Hz), 55.0, 50.7 (t, JC-F=3.2 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3072, 3005, 2950, 2840, 1601, 1359, 1289, 1124, 1007, 752。
High resolution mass spectrum (ESI): calcd for C17H14F2NO3 [M+H+] 318.0936, found: 318.0933。
Embodiment 11:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(2-methoxyphenyl) the following step of oxirane compound employing Rapid: under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(2-methoxyphenyl) ethyl ketone (2.28g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), P-methyl benzenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction cools down after terminating To room temperature, kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains White solid 2.22 grams, yield is 70%, and fusing point is 60 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.80 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 3.62 (d, J = 5.1 Hz, 1H), 3.24 (s, 3H), 2.97 (s, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-108.98 (d, J=266.2 Hz, 1F), -110.79 (d, J = 266.1 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=157.6,156.6 (t, JC-F= 33.8 Hz), 150.7, 140.1, 130.9, 126.6, 125.1, 121.1, 120.4, 120.2, 113.7 (t, JC-F= 250.1 Hz), 111.12, 110.1, 58.2 (t, JC-F= 30.2 Hz), 54.9, 50.5 (t, JC-F= 3.8 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3076, 3009, 2928, 2833, 1604, 1497, 1461, 1364, 1243, 1124, 1010, 757。
High resolution mass spectrum (ESI): calcd for C17H14F2NO3 [M+H+] 318.0936, found:318.0936。
Embodiment 12:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(2-naphthalene) oxirane compound employing following steps: at nitrogen Under atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(2-naphthalene) ethyl ketone (2.48g, 10 mmol), 2-monobromo two Methyl fluoride replacement benzo 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), p-methyl benzenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature after terminating, kieselguhr filters, Solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white solid 2.23 grams, yield Being 66%, fusing point is 60 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=8.05 (s, 1H), 7.81 (d, J=8.9 Hz, 4H), 7.63 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.51 – 7.46 (m, 2H), 7.45 – 7.37 (m, 2H), 3.69 (d, J = 5.2 Hz, 1H), 3.11 – 3.09 (m, 1H);Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.44 Hz.
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.93 (t, JC-F= 33.7 Hz), 150.5, 139.8, 133.4, 132.7, 129.4, 128.2, 128.1, 127.9, 127.6, 126.9, 126.8, 126.4, 125.3, 124.8, 121.3, 114.6 (t, JC-F= 248.9 Hz), 111.4, 60.4 (t, JC-F= 30.9 Hz), 51.0 (t, JC-F= 3.3 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3061, 1607, 1447, 1352, 1279, 1239, 1117, 1000, 820, 753。
High resolution mass spectrum (ESI): calcd for C20H14F2NO2 [M+H+] 338.0987, found: 338.0988。
Embodiment 13:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(2-furan) oxirane compound employing following steps: at nitrogen Under atmosphere is enclosed, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(2-furan) ethyl ketone (1.88g, 10 mmol), 2-mono- Bromine difluoro methyl replaces benzo 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), p-methyl benzenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature, silicon after terminating Diatomaceous earth filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains colorless oil liquid Body 0.64 gram, yield is 23%.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.82 (d, J=7.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.34 (s, 1H), 6.64 (d, J = 3.0 Hz, 1H), 6.32 (dd, J = 3.2 Hz, 1.7, 1H), 3.62 (d, J = 5.2 Hz, 1H), 3.58 – 3.56 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-105.98 (d, J=279.4 Hz, 1F), -107.78 (d, J = 279.5 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.8 (t, JC-F= 33.3 Hz), 150.5, 145.1 (d, JC-F= 1.7 Hz), 143.5, 139.9, 127.0, 125.4, 121.4, 113.0 (t, JC-F= 250.4 Hz), 112.7, 111.4, 110.9, 55.1 (t, JC-F= 30.1 Hz), 50.2 (t, JC-F= 3.8 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3131, 1731, 1613, 1451, 1352, 1293, 1128, 1013, 930, 752。
High resolution mass spectrum (ESI): calcd for C14H10F2NO3 [M+H+] 278.0623, found: 278.0620。
Embodiment 14:
Preparation 2-[1-(2-benzothiazole) difluoromethyl]-2-(2-thiophene) oxirane compound employing following steps: at nitrogen Under atmosphere is enclosed, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(2-thiophene) ethyl ketone (2.04g, 10 mmol), 2-mono- Bromine difluoro methyl replaces benzo 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), p-methyl benzenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature, silicon after terminating Diatomaceous earth filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains colorless oil liquid Body 1.58 grams, yield is 54%.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.80 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 4.9 Hz, 2H), 6.96 – 6.88 (m, 1H), 3.65 (d, J = 5.2 Hz, 1H), 3.27 – 3.07 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-105.32 (d, J=277.1 Hz, 1F), -106.87 (d, J = 277.1 Hz,1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.6 (t, JC-F= 33.5 Hz), 150.4, 139.7, 134.2, 128.6, 127.0, 126.9, 126.8, 125.3, 121.3, 113.4 (t, JC-F= 250.5 Hz), 111.3, 57.3 (t, JC-F= 31.0 Hz), 52.4 (t, JC-F= 3.5 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3101, 1727, 1613, 1571, 1445, 1357, 1282, 1126, 1045, 995, 753。
High resolution mass spectrum (ESI): calcd for C14H10F2NO2S [M+H+] 294.0395, found: 294.0395。
Embodiment 15:
Preparation 2-[1-(2-[4-morpholinodithio) difluoromethyl]-2-(4-bromophenyl) oxirane compound employing following steps: Under nitrogen atmosphere, in the reaction bulb of 100 mL, it is sequentially added into 2-bromo-1-(4-bromophenyl) ethyl ketone (2.76g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-thiazoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), to toluene sulphur Acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction is cooled to room temperature after terminating, Kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains white solid 2.13 grams, yield is 56%, and fusing point is 93 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=8.15 (d, J=8.2 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 3.65 (d, J = 5.2 Hz, 1H), 3.00 – 2.97 (m, 1H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-97.53 (d, J=269.0 Hz, 1F), -99.03 (d, J = 269.0 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=161.2 (t, JC-F=33.2 Hz), 152.3, 135.1, 131.6, 131.4, 130.0, 126.8, 126.7, 124.4, 123.4, 121.8, 116.7 (d, JC-F=247.4 Hz), 60.2 (t, JC-F= 30.6 Hz), 51.2 (t, JC-F= 3.4 Hz)。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 3060, 1588, 1364, 1230, 1074, 943, 766。
High resolution mass spectrum (ESI): calcd for (M+) C16H11BrF2NOS: 381.9707, found: 381.9701。
Embodiment 16:
Preparation 2-[1-(5-methyl benzothiazole-2-base) difluoromethyl]-2-(4-bromophenyl) oxirane compound employing is such as Lower step: under nitrogen atmosphere, is sequentially added into 2-bromo-1-(4-bromophenyl in the reaction bulb of 100 mL) ethyl ketone (2.76g, 10 mmol), 2-mono-bromine difluoro methyl substituted benzene 1,3-azoles (7.4 g, 30 mmol), copper powder (4.3 g, 66 mmol), P-methyl benzenesulfonic acid (0.17g, 1 mmol), 50 mL dimethyl sulfoxides, at 50 c stirring 2 hours, reaction cools down after terminating To room temperature, kieselguhr filters, and solvent is removed in water and ethyl acetate extraction, and organic layer concentrates and uses silica gel column chromatography to separate, and obtains White solid 2.47 grams, yield is 65%, and fusing point is 95 degrees Celsius.The structure of this compound is:
Proton nmr spectra (500MHz, CDCl3): δ=7.56 (s, 1H), 7.44 (d, J=8.2 Hz, 3H), 7.38 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 3.58 (d, J = 5.2 Hz, 2H), 2.97 – 2.95 (m, 1H), 2.45 (s, 3H)。
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ=-104.64 (d, J=278.4 Hz, 1F), -105.34 (d, J = 278.4 Hz, 1F)。
Carbon-13 nmr spectra (125MHz, CDCl3): δ=155.5 (t, JC-F= 33.4 Hz), 148.7, 139.9, 135.4, 131.5, 131.1, 129.7, 128.2, 123.5, 121.0, 114.1 (t, JC-F=248.9 Hz), 110.7, 59.8 (t, JC-F= 30.8 Hz), 50.8 (t, JC-F= 3.3 Hz), 21.3。
Infrared spectrum (uses Perkin-Elmer983G infrared spectrometer, KBr pressed disc method, unit cm-1): 2922, 1583, 1483, 1356, 1280, 1076, 1008, 936, 790。
High resolution mass spectrum (ESI): calcd for C17H13BrF2NO2 [M+H+] 380.0092, found: 380.0088。

Claims (2)

1. the oxirane of a heterocycle difluoromethyl, it is characterised in that the structural formula of this compound is:
Wherein, R1For hydrogen or methyl, X is oxygen or sulphur atom, R2For phenyl ,-bromine ,-fluorine ,-chlorine ,- Methyl ,-methoxyl group ,-nitro or the phenyl of-cyano substituent ,-naphthyl ,-thienyl or-furyl.
2. the method preparing the oxirane of heterocycle difluoromethyl according to claim 1, is characterized in that the party Concretely comprising the following steps of method: under inert gas shielding, 2-bromo aromatic ketone, heterocycle fluoro-building block, copper powder, catalyst are pressed 1:1 ~ The mol ratio of 8:2 ~ 16:0.1 ~ 0.5 is dissolved in dimethyl sulfoxide, reacts 2～10 hours at 20～80 DEG C, and separated purification prepares The oxirane of heterocycle difluoromethyl；The structural formula of described 2-bromo aromatic ketone is:Wherein, R2For phenyl, Having the phenyl of fluorine, chlorine, bromine, methyl, methoxyl group, nitro or cyano substituent, naphthalene, thiophene or furan, its source is purchased for market Buy；The structural formula of described heterocycle fluoro-building block is:Wherein, R1For hydrogen or methyl, X is oxygen or sulfur Atom.
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