CN105837494A - Difluoroalky lindolone derivative and preparation method thereof - Google Patents

Difluoroalky lindolone derivative and preparation method thereof Download PDF

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CN105837494A
CN105837494A CN201610315274.9A CN201610315274A CN105837494A CN 105837494 A CN105837494 A CN 105837494A CN 201610315274 A CN201610315274 A CN 201610315274A CN 105837494 A CN105837494 A CN 105837494A
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ethyl
oxo
dihydro
potassium
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万文
王星禄
王勇
蒋海珍
郝健
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University of Shanghai for Science and Technology
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University of Shanghai for Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Abstract

The invention relates to a difluoroalky lindolone derivative and a preparation method thereof. The structure of the compound is shown in the description, wherein R1 is -I, -Br, -OMe, COOEt, CH3CO and the like, R2 is Ph, -CH2Ph, -CH3 and the like, and R3 is -CH3 -OAc and the like. According to the difluoroalky lindolone derivative and the preparation method thereof, on the condition of silver catalysis, difluoro ethyl acetate and methacrylamide are subjected to a free radical reaction, and synthesis of the difluoroalky lindolone compound is achieved.

Description

Fluoroalkyl indolone derivatives and preparation method thereof
Technical field
The present invention relates to a kind of fluoroalkyl indolone derivatives and preparation method thereof.
Background technology
Indolone is the heterocyclic compound that a class is important.Due to this compounds, there is potential biological activity and photoelectricity is special Property, its construction unit is widely present in some natural products, medicine and functional material molecule.Numerous studies show, at heterocycle Compound induces one after fluorine atom, its physical property, chemical property and physiological property (such as lipotropy, metabolic stability and Target proteins binding ability, cell membrane penetration and bioavailability) generally it is obviously improved than its parent molecule.5-fluorine Uracil is an anti-malignant tumor medicine being widely known by the people, and is to make its physiologically active be improved after introducing fluorine atom on heterocycle The strongest illustration.
Two fluorim carboxylic esters are cheap, easily prepare, convenient deposit and operation, and several years fluoroalkyls in past have obtained at a high speed Development, and by using two fluoro free radical reagent to realize the multiformity of structure.Current fluoroalkylization reaction is still faced with Several restrictions, such as, use costliness, poisonous fluorine-containing reagent, limited substrate spectrum, limited difluoro carboxylate compound Deng.Therefore, the fluoroalkylization reaction that two fluorim carboxylic esters participate in is still a big challenge.Up to the present, the two of silver catalysis Fluorim carboxylic ester reaction is seldom.
Summary of the invention
An object of the present invention is to provide a class fluoroalkyl indolone derivatives.
The two of the purpose of the present invention are the method providing difluoro carboxylate compound to prepare indolone derivatives, the method Achieve and use Methacrylamide to close with the reaction of difluoro carboxylate compound generation fluoroalkylization under conditions of silver is catalyzed The method becoming fluoroalkyl indole ketone compound.
For reaching above-mentioned purpose, present invention employs following reaction equation:
Wherein, R1For-I ,-Br ,-OMe, ester group or carbonyl etc.；R2For-Ph ,-CH2Ph ,-CH3Deng；R3For-CH3,-OAc etc..
According to above-mentioned reaction principle, the present invention adopts the following technical scheme that
One class fluoroalkyl indolone derivatives, it is characterised in that the structural formula of this derivant is:
Wherein R1For-I ,-Br ,-OMe, COOEt or CH3CO；R2For-Ph ,-CH2Ph or-CH3；R3For-CH3Or-OAc.
A kind of method preparing above-mentioned fluoroalkyl indolone, it is characterised in that the method has following steps: by first Base acrylamide, ethyl difluoro is dissolved in solvent, adds catalyst, oxidant and alkali, at room temperature reacts 24-48 Hour, after reaction terminates, remove solvent, purified obtain fluoroalkyl indole ketone compound；Described Methacrylamide, The mol ratio of ethyl difluoro, catalyst, oxidant and alkali is: (1 ~ 2.5): (1 ~ 5.0): (0.05 ~ 2.5): (0.5 ~ 2): (0.2 ~ 3.0)；Described catalyst is Disilver carbonate, perfluorinated sulfonic acid silver, Argentous fluoride or silver nitrate；Described oxidant is persulfuric acid Ammonium, potassium peroxydisulfate, Potassium metaperiodate. or iodobenzene diacetate ester；Described alkali is potassium hydroxide, potassium carbonate, sodium carbonate or bicarbonate Potassium；Described solvent is dimethyl sulfoxide, N, N-diformamide, dichloromethane, chloroform or N-Methyl pyrrolidone；Described The structural formula of Methacrylamide is:；The structure of described ethyl difluoro is:。
The present invention by various Methacrylamides and ethyl difluoro compound under silver nitrate is catalyzed, with N-methyl pyrrole Pyrrolidone makees solvent, and crossing iodobenzene diacetate ester is oxidant, and sodium acetate is alkali, uses a series of fluoroalkyls of one pot process Indolone derivatives.The method has gentle, easy and simple to handle, the substrate wide adaptability of reaction, productivity high.
Detailed description of the invention
Embodiment one:
5-carboxylic acid, ethyl ester-3-(2-carbethoxyl group-2,2-two fluoro ethyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1-hydrogen-Yin Diindyl uses following steps: be sequentially added into 0.492 gram of silver nitrate in the reaction bulb of 25 milliliters, 0.644 gram of iodobenzene diacetate ester, 0.246 gram of anhydrous sodium acetate, 0.247 gram to ester group Methacrylamide, 0.981 gram of trimethyl silane ethyl difluoro, so 10 milliliter of two N-Methyl pyrrolidone of rear addition, nitrogen is protected, is stirred at room temperature 48 hours, reacts and removes solvent after terminating, Separating with silica gel column chromatography, eluent is pure dichloromethane, obtains white solid 0.329 gram, yield 89%.
5-carboxylic acid, ethyl ester-3-(2-carbethoxyl group-2,2-two fluoro ethyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1- Hydrogen-indole, it is characterised in that the structure of this compound is:
Molecular formula: C18H21F2NO5
Chinese name: 5-carboxylic acid, ethyl ester-3-(2-carbethoxyl group-2,2-two fluoro ethyl)-1,3-dimethyl-2-oxo-2,3-two Hydrogen-1-hydrogen-indole
English name: 3-(2-Ethoxycarbonyl-2,2-difluoro-ethyl)-1,3-dimethyl-2-oxo-2,3- dihydro-1H-indole-5-carboxylic acid ethyl ester
Molecular weight: 396.14
Outward appearance: white solid
Proton nmr spectra (500MHz, CDCl3): δ 8.04 (dd, J=8.2,1.7Hz, 1H), 7.85 (d, J= 1.7Hz, 1H), 6.89 (d, J=8.2Hz, 1H), 4.36 (q, J=7.1Hz, 2H), 4.00 (q, J=7.2Hz, 2H), 3.25 (s,3H), 2.92-2.74 (m, 2H), 1.41 (s, 3H), 1.39 (t, J=7.1Hz, 3H), 1.22(t, J=7.2Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-99.19 ,-99.76 ,-105.39 ,-105.96.
Carbon-13 nmr spectra (125MHz, CDCl3): δ 179.08,166.22,163.13 (t, J=32.3Hz), 147.31, 131.20, 130.78, 124.77, 124.53, 107.93, 62.98, 60.95, 44.17 (d, J= 6.2Hz), 41.36 (t, J=22.6Hz), 29.65, 26.59, 25.41, 14.36, 13.65.
Embodiment two:
Preparation 7-carboxylic acid, ethyl ester-3-(2-carbethoxyl group-2,2-two fluoro ethyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1 Hydrogen-indole uses following steps: be sequentially added into 0.492 gram of silver nitrate, 0.644 gram of iodobenzene diacetate in the reaction bulb of 25 milliliters Ester, 0.246 gram of anhydrous sodium acetate, 0.247 gram of adjacent ester group Methacrylamide, 0.981 gram of trimethyl silane ethyl difluoro, Being subsequently adding 10 milliliter of two N-Methyl pyrrolidone, nitrogen is protected, and is stirred at room temperature 48 hours, and reaction is removed molten after terminating Agent, separates with silica gel column chromatography, and eluent is pure dichloromethane, obtains white solid 0.380 gram, yield 96%.
7-carboxylic acid, ethyl ester-3-(2-carbethoxyl group-2,2-two fluoro ethyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1 Hydrogen-indole is characterised by that the structure of this compound is:
Molecular formula: C18H21F2NO5
Chinese name: 7-carboxylic acid, ethyl ester-3-(2-carbethoxyl group-2,2-two fluoro ethyl)-1,3-dimethyl-2-oxo-2,3-two Hydrogen-1 hydrogen-indole
English name: 3-(2-Ethoxycarbonyl-2,2-difluoro-ethyl)-1,3-dimethyl-2-oxo-2,3- dihydro-1H-indole-7-carboxylic acid ethyl ester
Molecular weight: 396.14
Outward appearance: faint yellow oily
Proton nmr spectra (500MHz, CDCl3): δ 7.54 (dd, J=8.0,1.3Hz, 1H), 7.29 (dd, J= 7.3,1.3Hz, 1H), 7.05(dd, J=7.9, 7.4Hz, 1H), 4.39 (q, J=7.1Hz, 2H), 4.10-3.92 (m, 2H),3.29 (s, 3H), 2.89-2.69 (m, 2H), 1.40 (t, J=3.6Hz, 6H),1.21(t, J= 7.2Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-99.46 ,-100.03 ,-104.56 ,-105.13.
Carbon-13 nmr spectra (125MHz, CDCl3): δ 179.77,166.74,163.43 (t, J=33.3Hz), 142.01, 132.78, 129.61, 126.28, 121.43, 116.36, 63.00, 61.59, 43.30 (d, J= 5.1Hz),41.19 (t, J=56.6Hz), 30.26, 29.67, 25.66, 14.21, 13.64.
Embodiment three:
Preparation 2,2-bis-fluoro-3-(7-methoxyl group-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) ethyl propionate employing Following steps: be sequentially added into 0.492 gram of silver nitrate in the reaction bulb of 25 milliliters, 0.644 gram of iodobenzene diacetate ester, 0.246 gram Anhydrous sodium acetate, 0.205 gram of O-methoxy Methacrylamide, 0.981 gram of trimethyl silane ethyl difluoro, it is subsequently adding 10 milliliter of two N-Methyl pyrrolidone, nitrogen is protected, is stirred at room temperature 48 hours, reacts and removes solvent after terminating, uses silica gel Column chromatography for separation, eluent is pure dichloromethane, obtains white solid 0.291 gram, yield 89%.
2,2-bis-fluoro-3-(7-methoxyl group-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) ethyl propionate feature The structure being this compound is:
Molecular formula: C16H19F2NO4
Chinese name: 2,2-bis-fluoro-3-(7-methoxyl group-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) propanoic acid second Ester
English name: 2,2-Difluoro-3-(7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H- indol-3-yl)-propionic acid ethyl ester
Molecular weight: 327.13
Outward appearance: faint yellow oily
Proton nmr spectra (500MHz, CDCl3): δ 7.35-7.28 (m, 1H), 7.18 (d, J=8.4Hz, 1H), 7.14(d, J=7.4Hz, 1H), 4.43-4.26(m, 2H), 4.19(s, 3H), 3.5 (S, 3H), 3.21-3.00 (m, 2H), 1.70 (s, 3H), 1.56 (t, J=7.1Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-98.58 ,-99.15 ,-105.76 ,-106.32.
Carbon-13 nmr spectra (125MHz, CDCl3) δ 178.68, 163.25 (t, J=33.3Hz), 145.11, 132.14, 123.64, 123.11 (d, J=23.5Hz), 122.32, 115.73 (dd, J=247.7Hz, J= 253.6Hz), 111.73, 62.45, 55.51, 44.10 (d, J =5.1Hz), 41.0 (t, J=23.4Hz), 31.24, 25.40, 13.31.
Embodiment four:
3-(5,7-dimethoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) the fluoro-ethyl propionate of-2,2-two adopts By following steps: be sequentially added into 0.492 gram of silver nitrate in the reaction bulb of 25 milliliters, 0.644 gram of iodobenzene diacetate ester, 0.246 Gram anhydrous sodium acetate, 0.235 gram 5,7-dimethoxy-methyl acrylamide, 0.981 gram of trimethyl silane ethyl difluoro, so 10 milliliter of two N-Methyl pyrrolidone of rear addition, nitrogen is protected, is stirred at room temperature 48 hours, reacts and removes solvent after terminating, Separating with silica gel column chromatography, eluent is pure dichloromethane, obtains white solid 0.296 gram, yield 83%.
3-(5,7-dimethoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole)-2,2-two fluoro-propanoic acid second Ester, it is characterised in that the structure of this compound is:
Molecular formula: C17H21F2NO5
Chinese name: 3-(5,7-dimethoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole)-2,2-two fluoro-third Acetoacetic ester
English name: 3-(5,7-Dimethoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)- 2,2-difluoro-propionic acid ethyl ester
Molecular weight: 357.14
Outward appearance: faint yellow solid
Proton nmr spectra (500MHz, CDCl3): δ 6.42 (d, J=2.3Hz, 1H), 6.38 (d, J=2.3Hz, 1H), 4.03 (ddq, J=43.2, 10.7, 7.2Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.45 (s, 3H), 2.86-2.63 (m, 2H), 1.35 (s, 3H), 1.22 (t, J=7.2Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-98.67 ,-99.24 ,-105.63 ,-106.20.
Carbon-13 nmr spectra (125MHz, CDCl3): δ 178.75,163.83 (t, J=32.3Hz), 156.30, 146.05, 133.06, 129.58, 124.84, 101.46, 99.45, 62.83, 55.82 (d, J=10.8Hz), 44.99 (d, J=5.1Hz), 41.19 (t, J=21.7Hz), 29.69, 27.40, 25.78, 13.69.
Embodiment five:
3-(7-bromo-1,3,5-trimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) the fluoro-ethyl propionate of-2,2-two use as follows Step: being sequentially added into 0.492 gram of silver nitrate, 0.644 gram of iodobenzene diacetate ester in the reaction bulb of 25 milliliters, 0.246 gram anhydrous Sodium acetate, 0.268 gram of 5-methyl-7-bromomethyl acrylamide, 0.981 gram of trimethyl silane ethyl difluoro, it is subsequently adding 10 milliliter of two N-Methyl pyrrolidone, nitrogen is protected, is stirred at room temperature 48 hours, reacts and removes solvent after terminating, uses silica gel Column chromatography for separation, eluent is pure dichloromethane, obtains white solid 0.300 gram, yield 77%.
Bromo-1,3,5-trimethyl-2-oxo-2 of 3-(7-, 3-dihydro-1 hydrogen-indole)-2, the fluoro-ethyl propionate of 2-bis-, it is special Levy and be that the structure of this compound is:
Molecular formula: C16H18BrF2NO3
Chinese name: 3-(7-bromo-1,3,5-trimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) the fluoro-ethyl propionate of-2,2-two
English name: 3-(7-Bromo-1,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-2,2- difluoro-propionic acid ethyl ester
Molecular weight: 389.04
Outward appearance: white solid
Proton nmr spectra (500MHz, CDCl3): δ 7.16 (d, J=1.1Hz, 1H), 7.09 (d, J=2.0Hz, 1H), 4.07(qd, J=7.2, 4.3Hz, 2H), 3.48 (s, 3H), 2.89-2.63 (m, 2H), 2.55(s, 3H), 1.35(s, 3H), 1.26(t, J=7.2Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-98.19 ,-98.76 ,-106.10 ,-106.67.
Carbon-13 nmr spectra (125MHz, CDCl3): δ 178.97,163.23 (t, J=31.5Hz), 140.36, 134.59, 133.37, 124.59, 122.05, 114.34 (dd, J=246.8Hz, J=252.9Hz), 112.33, 63.11, 43.91 (d, J= 6.6Hz), 41.41 (t, J=21.7Hz), 29.74, 25.78, 18.81, 13.75.
Embodiment six:
3-(5-acetyl group-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) employing of-2,2-two fluoro-ethyl propionate is such as Lower step: be sequentially added into 0.492 gram of silver nitrate, 0.644 gram of iodobenzene diacetate ester, 0.246 gram of nothing in the reaction bulb of 25 milliliters Water acetic acid sodium, 0.217 gram, to methyl ketone Methacrylamide, 0.981 gram of trimethyl silane ethyl difluoro, is subsequently adding 10 Milliliter two N-Methyl pyrrolidone, nitrogen is protected, is stirred at room temperature 48 hours, reacts and removes solvent after terminating, uses silicagel column Chromatography, eluent is pure dichloromethane, obtains white solid 0.251 gram, yield 74%.
3-(5-acetyl group-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole)-2, the fluoro-ethyl propionate of 2-bis-, its The structure being characterised by this compound is:
Molecular formula: C17H19F2NO4
Chinese name: 3-(5-acetyl group-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole)-2,2-two fluoro-propanoic acid second Ester
English name: 3-(5-Acetyl-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-2,2- difluoro-propionic acid ethyl ester
Molecular weight: 339.13
Outward appearance: yellow oily
Proton nmr spectra (500MHz, CDCl3): δ 7.95 (dd, J=8.2,1.8Hz, 1H), 7.84 (d, J= 1.7Hz, 1H), 6.91 (d, J=8.1Hz, 1H), 4.00 (qd, J=7.2, 3.0Hz, 2H), 3.27 (s, 3H), 2.93-2.74 (m, 2H), 2.58(s, 3H), 1.42 (s, 3H), 1.22(t, J=7.2Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-99.42 ,-99.99 ,-105.22 ,-105.79.
Carbon-13 nmr spectra (125MHz, CDCl3): δ 196.71,179.13,163.13 (t, J=32.3Hz), 147.60, 131.79, 131.21, 130.56, 123.52, 107.81, 63.03, 44.17 (d, J=3.7Hz), 41.06 (t, J=22.6Hz), 29.66, 26.63, 26.37, 25.42, 13.67.
Embodiment seven:
3-(7-bromo-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) the following step of-2,2-two fluoro-ethyl propionate employing Rapid: in the reaction bulb of 25 milliliters, to be sequentially added into 0.492 gram of silver nitrate, 0.644 gram of iodobenzene diacetate ester, 0.246 gram of anhydrous vinegar Acid sodium, 0.254 gram, to methyl ketone Methacrylamide, 0.981 gram of trimethyl silane ethyl difluoro, is subsequently adding 10 milliliters Two N-Methyl pyrrolidone, nitrogen is protected, is stirred at room temperature 48 hours, reacts and removes solvent after terminating, uses silica gel column chromatography Separating, eluent is pure dichloromethane, obtains white solid 0.285 gram, yield 76%.
3-(7-bromo-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole)-2, the fluoro-ethyl propionate of 2-bis-, its feature The structure being this compound is:
Molecular formula: C15H16F2BrNO3
Chinese name: 3-(7-bromo-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) the fluoro-ethyl propionate of-2,2-two
English name: 3-(7-Bromo-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-2,2- difluoro-propionic acid ethyl ester
Molecular weight: 375.03
Outward appearance: yellow oily
Proton nmr spectra (500MHz, CDCl3): δ 7.39 (dd, J=8.2,1.2Hz, 1H), 7.11 (d, J= 6.2Hz, 1H), 6.88 (dd, J=8.2, 7.3Hz, 1H), 4.10-3.94 (m, 2H), 3.60 (s, 3H), 2.89-2.66 (m, 2H), 1.38 (s, 3H), 1.23 (t, J=7.2Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-99.18 ,-99.75 ,-105.02 ,-105.59.
Carbon-13 nmr spectra (125MHz, CDCl3): δ 179.17,163.23 (t, J=31.5Hz), 140.66, 134.13, 134.02, 123.34, 122.80, 114.39 (dd, J=248.2Hz, J=253.0Hz), 102.64, 63.02, 44.13 (d, J=4.5Hz), 41.30 (t, J=23.1Hz), 30.02, 25.90, 13.69.
Embodiment eight:
The fluoro-3-(5-of 2,2-bis-iodo-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole) the following step of-ethyl propionate employing Rapid: in the reaction bulb of 25 milliliters, to be sequentially added into 0.492 gram of silver nitrate, 0.644 gram of iodobenzene diacetate ester, 0.246 gram of anhydrous vinegar Acid sodium, 0.301 gram, to methyl ketone Methacrylamide, 0.981 gram of trimethyl silane ethyl difluoro, is subsequently adding 10 milliliters Two N-Methyl pyrrolidone, nitrogen is protected, is stirred at room temperature 48 hours, reacts and removes solvent after terminating, uses silica gel column chromatography Separating, eluent is pure dichloromethane, obtains white solid 0.347 gram, yield 82%.
2,2-bis-fluoro-3-(5-iodo-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole)-ethyl propionate, its feature The structure being this compound is:
Molecular formula: C15H16F2INO3
Chinese name: the fluoro-3-(5-of 2,2-bis-iodo-1,3-dimethyl-2-oxo-2,3-dihydro-1 hydrogen-indole)-ethyl propionate
English name: 2,2-Difluoro-3-(5-iodo-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol- 3-yl)-propionic acid ethyl ester
Molecular weight: 423.01
Outward appearance: white solid
Proton nmr spectra (500MHz, CDCl3): δ 7.60 (dd, J=8.2,1.7Hz, 1H), 7.44 (d, J= 1.7Hz, 1H), 6.64 (d, J=8.2Hz, 1H), 4.07 (ddp, J=14.0, 7.1, 3.6Hz, 2H), 3.19 (s, 3H), 2.87-2.67 (m, 2H), 1.37(s, 3H), 1.25 (t, J=7.1Hz, 3H).
Enantiomeric excess (470MHz, CDCl3, internal standard: C6F6): δ-98.33 ,-98.90 ,-106.14 ,-106.71.
Carbon-13 nmr spectra (125MHz, CDCl3): δ 177.98,163.23 (t, J=31.5Hz), 143.09, 137.33, 132.6 (d, J=8.7Hz), 114.3 (dd, J=248.5Hz, J=252.7Hz), 110.43, 84.53, 63.20, 44.36, 44.31, 41.9(dd, J=21.7, 23.6Hz), 26.40, 25.34, 13.76。
Application prospect: indolone is the heterocyclic compound that a class is important, its construction unit is widely present in some natural products Thing, SARS drug design, exploitation.After introducing fluorine atom in such indolone heterocyclic compound, the lipotropy of its compound, generation Thank the physical property such as stability and target proteins binding ability, cell membrane penetration and bioavailability, chemical property and Physiological property, is generally obviously improved than its parent molecule.Fluorine-containing new drug development will be widely used in.

Claims (2)

1. a class fluoroalkyl indolone derivatives, it is characterised in that the structural formula of this derivant is:
Wherein R1For-I ,-Br ,-OMe, COOEt or CH3CO；R2For-Ph ,-CH2Ph or-CH3；R3For-CH3Or-OAc.
2. the method preparing fluoroalkyl indolone according to claim 1, it is characterised in that the method have as Lower step: by Methacrylamide, ethyl difluoro is dissolved in solvent, adds catalyst, oxidant and alkali, in room temperature Lower reaction 24-48 hour, after reaction terminates, removes solvent, purified obtains fluoroalkyl indole ketone compound；Described first The mol ratio of base acrylamide, ethyl difluoro, catalyst, oxidant and alkali is: (1 ~ 2.5): (1 ~ 5.0): (0.05 ~ 2.5): (0.5 ~ 2): (0.2 ~ 3.0)；Described catalyst is Disilver carbonate, perfluorinated sulfonic acid silver, Argentous fluoride or silver nitrate；Described Oxidant is Ammonium persulfate., potassium peroxydisulfate, Potassium metaperiodate. or iodobenzene diacetate ester；Described alkali is potassium hydroxide, potassium carbonate, carbon Acid sodium or potassium bicarbonate；Described solvent is dimethyl sulfoxide, N, N-diformamide, dichloromethane, chloroform or N-methyl pyrrole Pyrrolidone；The structural formula of described Methacrylamide is:；The structure of described ethyl difluoro is:。
CN201610315274.9A 2016-05-14 2016-05-14 Difluoroalky lindolone derivative and preparation method thereof Pending CN105837494A (en)

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CN112194608A (en) * 2020-09-25 2021-01-08 湖南生物机电职业技术学院 Synthesis method of visible light promoted 3-methyl-3-difluoroethyl-2-oxindole compound

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Publication number Priority date Publication date Assignee Title
CN108467391A (en) * 2018-06-08 2018-08-31 上海大学 3-（1,3- benzodiazole -2- difluoromethyls）3-hydroxyindole quinoline ketone compounds and preparation method thereof
CN109734564A (en) * 2019-01-31 2019-05-10 南京理工大学 A method of synthesis trifluoroethyl aromatic compound
CN110194733A (en) * 2019-06-25 2019-09-03 上海应用技术大学 A kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound
CN110194733B (en) * 2019-06-25 2022-11-15 上海应用技术大学 Preparation method of 3-difluoroalkyl-3-hydroxyindolone compound
CN112194608A (en) * 2020-09-25 2021-01-08 湖南生物机电职业技术学院 Synthesis method of visible light promoted 3-methyl-3-difluoroethyl-2-oxindole compound
CN112194608B (en) * 2020-09-25 2022-05-06 湖南生物机电职业技术学院 Synthesis method of visible light promoted 3-methyl-3-difluoroethyl-2-oxindole compound

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