CN101024619B - Method for synthesizing N-substituted O-bromobenzylacidamide - Google Patents
Method for synthesizing N-substituted O-bromobenzylacidamide Download PDFInfo
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- CN101024619B CN101024619B CN2007100387921A CN200710038792A CN101024619B CN 101024619 B CN101024619 B CN 101024619B CN 2007100387921 A CN2007100387921 A CN 2007100387921A CN 200710038792 A CN200710038792 A CN 200710038792A CN 101024619 B CN101024619 B CN 101024619B
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- benzene
- bromobenzylacidamide
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- bromine
- bromo
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Abstract
The invention relates to a compound method for N-replaced ortho-bromine amide compound that includes the following steps: adopting dimethyl sulphoxide and water as mixing solvent, NaOH as alkali, 1-bromine-2-(2, 2- dibrom vinyl), heating benzene and amine compound to 70-100 degree centigrade, using TLC method to take tracing reaction until reacting raw material 1-bromine-2-(2, 2-dibrom vinyl dispearing); adding distilled water into reaction system, using ethyl acetate extracting for three times, combining organic phase, washing by vaporized water and saturation salt water once, drying by anhydrous magnesium sulfate for half hour, filtering, rotating to remove solvent; taking column chromatography to raw material to gain N- replaced ortho-bromine amide compound. The invention uses 1-bromine-2-(2, 2-dibrom vinyl) benzene and primary amine as raw material, has low toxin solvent. It is simple to process, environment protection, high yield, etc.
Description
Technical field
The present invention relates to a kind of synthetic method of O-bromobenzylacidamide, particularly a kind of synthetic method of N-substituted O-bromobenzylacidamide.
Background technology
N-substituted O-bromobenzylacidamide compounds is the very important synthetic intermediate of a class in organic chemistry, has the important as precursors of physiologically active substance as synthesis of indole-2-ketone (Oxindole) etc., and it more and more obtains people's attention in recent years.Indol-2-one and derivative thereof are because the singularity of its structure is obtaining very extensive and important use aspect biological and the medical science.For example, the SU5416 and the SU6668 that contain the indol-2-one structure can be used as growth factor receptor inhibitor, are the important drugs of treatment and somatomedin diseases associated, particularly angiokeratoma; Tenidap (Tenidap) is the novel anti-inflammatory medicine with anti-inflammatory and illness alleviation dual function; Ropinirole (Ropinirole) is main medicine for the treatment of at present parkinsonism or the like.
The preparation method of N-substituted O-bromobenzylacidamide has a lot, generally is to be obtained by the bromobenzene compounds reaction that aliphatic amide and functional group replace, and these functional groups comprise: halogen, cyano group, carboxyl, acyl chlorides and diazo or the like.Also can under special reaction reagent effect, obtain in addition from adjacent bromophenylacetonitril and starting bromide through low-temp reaction.
The main method of the preparation N-substituted O-bromobenzylacidamide of having reported at present is listed below:
(1) from adjacent bromobenzyl bromine, under the effect of potassium cyanide, obtain, specifically react as follows by three-step reaction:
(2) from adjacent bromophenylacetonitril, obtain through two-step reaction, specifically react as follows:
(3) after adjacent bromobenzyl acid was at room temperature reacted with aliphatic amide, low temperature (0 ℃) obtained after handling, and specifically reacts as follows:
(4) diazonium compound and aliphatic amide react under the condition of microwave and obtain, and specifically react as follows:
(5) with the Nitromethane 99Min. be solvent, adjacent bromophenylacetonitril and bromide obtain with the effect of nitro tetrafluoride phosphine under the reaction conditions of low temperature (15 ℃), specifically react as follows:
In sum, the method for preparing N-replacement benzyl acid amides has a lot, but the raw material of these reactions is difficult to obtain, and needs synthesizing through more complicated; The reagent toxicity of using in some reaction is bigger, easily causes environmental pollution; The productivity ratio of partial reaction is lower or need react at low temperatures, and condition is relatively harsher or the like.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of N-substituted O-bromobenzylacidamide.
For achieving the above object, the reaction mechanism that the inventive method adopts is:
According to above-mentioned reaction mechanism, the present invention has adopted following technical scheme:
A kind of synthetic method of N-substituted O-bromobenzylacidamide is characterized in that this method has following steps:
A. with volume ratio be 3: 1 dimethyl sulfoxide (DMSO) and water as mixed solvent, sodium hydroxide is done alkali, and 1-bromo-2-(2, the 2-dibromo vinyl) benzene and primary amine are heated to 70～100 ℃; Reinforced mol ratio is: alkali: 1-bromo-2-(2, the 2-dibromo vinyl) benzene: primary amine=2～5: 1: 2～5, follow the tracks of reaction with the thin-layer chromatography method, and disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene;
B. reaction adds distilled water after finishing in system, uses ethyl acetate extraction, merges organic phase; Use distilled water and saturated common salt water washing organic phase again, use anhydrous magnesium sulfate drying then, filter, remove solvent, get crude product with Rotary Evaporators;
C. crude product column chromatography purification, developping agent are sherwood oil and the ethyl acetate mixed solution by 5: 1 volume ratio, and the solid that obtains is the N-substituted O-bromobenzylacidamide, and its structural formula is:
Wherein R is C
4～C
18Straight or branched alkyl or C
5～C
8Cycloalkyl or replacement or unsubstituted benzyl.
The structural formula of above-mentioned primary amine is: R-NH
2, wherein R is C
4～C
18Straight or branched alkyl or C
5～C
8Cycloalkyl or replacement or unsubstituted benzyl.
The present invention compared with prior art, have following conspicuous high-lighting characteristics and remarkable advantage: raw material of the present invention is easy to get, and uses conventional reaction solvent, operate very simply, mild condition is reacted environmental protection, productive rate is up to 64-83% etc.
Embodiment
Example one: the preparation of N-benzyl O-bromobenzylacidamide
Preparation N-benzyl O-bromobenzylacidamide adopts following step: 1. add 10 gram 1-bromo-2-(2 in 250 milliliters of round-bottomed flasks, the 2-dibromo vinyl) benzene, 15.68 gram benzylamine, 5.52 gram sodium hydroxide, 120 milliliters of dimethyl sulfoxide (DMSO), 40 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 7.44 gram N-benzyl O-bromobenzylacidamides, productive rate is 83%.Fusing point: 67-68 ℃.
Proton nmr spectra (CDCl
3): 8.01 (s, 1H), 7.18 (m, 7H), 7.00 (t, J=7.63Hz, 1H), 6.60 (br, 1H), 4.80 (s, 2H), 3.50 (s, 2H).
Carbon-13 nmr spectra (CDCl
3): 174.97,144.14,135.71,128.58,127.62,127.43,127.18,124.30,124.23,122.20,108.90,43.55,35.59.
Example two: the preparation of N-normal-butyl O-bromobenzylacidamide
Preparation N-normal-butyl O-bromobenzylacidamide adopts following step: 1. add 8 gram 1-bromo-2-(2 in 150 milliliters of round-bottomed flasks, the 2-dibromo vinyl) benzene, 8.56 gram n-Butyl Amine 99,4.7 gram sodium hydroxide, 48 milliliters of dimethyl sulfoxide (DMSO), 16 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 4.08 gram N-normal-butyl O-bromobenzylacidamides, productive rate is 64%.
Proton nmr spectra (CDCl
3): 8.01 (s, 1H), 7.18 (m, 2H), 6.94 (t, J=7.48Hz, 1H), 6.75 (br, 1H), 3.65 (q, J=7.32Hz, 2H), 3.43 (s, 2H), 1.58 (m, 2H), 1.31 (m, 2H), 0.88 (t, J=7.29Hz, 3H).
Carbon-13 nmr spectra (CDCl
3): 174.82,144.53,127.60,124.54,124.26,121.90,108.17,39.61,35.63,29.35,20.06,13.61.
Example three: the preparation of N-isobutyl-O-bromobenzylacidamide
Preparation N-isobutyl-O-bromobenzylacidamide adopts following step: 1. add 8 gram 1-bromo-2-(2 in 150 milliliters of round-bottomed flasks, the 2-dibromo vinyl) benzene, 8.56 gram isobutylamine, 4.7 gram sodium hydroxide, 48 milliliters of dimethyl sulfoxide (DMSO), 16 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 4.46 gram N-isobutyl-O-bromobenzylacidamides, productive rate is 70%.
Proton nmr spectra (CDCl
3): 7.92 (s, 1H), 7.15 (m, 2H), 6.94 (t, J=7.48Hz, 1H), 6.74 (d, J=7.50Hz, 1H), 3.45 (s, 2H), 3.43 (d, J=7.70Hz, 2H), 2.06 (m, 1H), 0.88 (d, J=6.70,6H).
Carbon-13 nmr spectra (CDCl
3): 175.12,144.88,127.55,124.41,124.20,121.88,108.45,47.39,35.57,26.85,20.08.
The preparation of example four: N-ring octyl group O-bromobenzylacidamide
Preparation N-ring octyl group O-bromobenzylacidamide adopts following step: 1. add 5 gram 1-bromo-2-(2 in 150 milliliters of round-bottomed flasks, the 2-dibromo vinyl) benzene, 9.3 gram cyclooctylamine, 2.9 gram sodium hydroxide, 30 milliliters of dimethyl sulfoxide (DMSO), 10 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 2.6 gram N-ring octyl group O-bromobenzylacidamides, productive rate is 72%.Fusing point: 53-54 ℃.
Proton nmr spectra (CDCl
3): 7.59 (s, 1H), 7.17 (m, 2H), 6.90 (m, 2H), 4.44 (t, J=9.0Hz, 1H), 3.41 (s, 2H), 2.19 (m, 2H), 1.62 (m, 12H).
Carbon-13 nmr spectra (CDCl
3): 173.97,143.43,127.20,124.89,124.34,121.51,110.12,51.75,35.87,31.10,26.02,25.38.
Example five: the preparation of N-cyclopentyl base O-bromobenzylacidamide
Preparation N-cyclopentyl O-bromobenzylacidamide adopts following step: 1. add 20 gram 1-bromo-2-(2 in 500 milliliters of round-bottomed flasks, the 2-dibromo vinyl) benzene, 25 gram cyclopentamine, 11.7 gram sodium hydroxide, 240 milliliters of dimethyl sulfoxide (DMSO), 80 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 8.8 gram N-cyclopentyl O-bromobenzylacidamides, productive rate is 75%.Fusing point: 56-57 ℃.
Proton nmr spectra (CDCl
3): 7.59 (s, 1H), 7.19 (t, J=7.92Hz, 2H), 6.96 (t, J=7.50Hz, 1H), 6.85 (d, J=7.92Hz, 1H), 4.78 (p, J=8.88Hz, 1H), 3.44 (s, 2H), 1.98 (m, 2H), 1.85 (m, 4H), 1.65 (m, 3H).
Carbon-13 nmr spectra (CDCl
3): 174.93,143.30,128.20,127.27,124.84,124.40,121.64,109.68,51.75.27.14,25.05.
Example six: N-is to the preparation of xylyl O-bromobenzylacidamide
Preparation N-adopts following step to the xylyl O-bromobenzylacidamide: 1. add 10 gram 1-bromo-2-(2 in 250 milliliters of round-bottomed flasks, the 2-dibromo vinyl) benzene, 17.74 gram is to xylylamine, 5.52 gram sodium hydroxide, 120 milliliters of dimethyl sulfoxide (DMSO), 40 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 7.27 the gram N-to the xylyl O-bromobenzylacidamide, productive rate is 78%.
Proton nmr spectra (CDCl
3): 7.31 (d, J=7.88Hz, 1H), 7.16 (AA ' BB ', 4H), 7.08 (t, J=7.9Hz, 1H), 6.95 (m, 2H), 6.50 (br, 1H), 4.80 (s, 2H), 3.50 (s, 2H), 2.20 (s, 3H).
Carbon-13 nmr spectra (CDCl
3): 168.25,137.79,134.630,130.87,129.47,128.78,128.53,126.04,125.29,122.76,120.98,44.43,37.61,21.10.
The preparation of example seven: N-(3,5-two trifluoromethyls) benzyl O-bromobenzylacidamide
Preparation N-(3,5-two trifluoromethyls) the benzyl O-bromobenzylacidamide adopts following step: 1. add 10 gram 1-bromo-2-(2, the 2-dibromo vinyl) benzene in 250 milliliters of round-bottomed flasks, 35.78 grams 3,5-two trifluoromethyl benzylamines, 5.52 gram sodium hydroxide, 120 milliliters of dimethyl sulfoxide (DMSO), 40 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 9.69 gram N-(3,5-two trifluoromethyls) benzyl O-bromobenzylacidamides, productive rate is 75%.
Proton nmr spectra (CDCl
3): 7.82 (s, 1H), 7.31 (d, J=7.88Hz, 1H), 7.25 (s, 2H), 7.08 (t, J=7.9Hz, 1H), 6.95 (m, 2H), 6.40 (br, 1H), 4.46 (s, 2H), 3.54 (s, 2H), 2.35 (s, 6H).
Carbon-13 nmr spectra (CDCl
3): 168.25,140.35,140.22,140.15,140.08,140.01,137.22,134.60,134.01,133.94,133.87,133.80,133.31,133.24,133.71,133.10,132.60,132.53,132.47,132.40,131.90,131.83,131.76,131.69,130.08,129.47,128.78,126.52,126.35,126.17,126.00,125.29,123.02,122.95,122.76,122.49,122.32,122.14,121.97,120.98,115.82,44.44,38.43.
Example eight: the preparation of N-Octadecane base O-bromobenzylacidamide
Preparation N-Octadecane base O-bromobenzylacidamide adopts following step: 1. add 5 gram 1-bromo-2-(2 in 150 milliliters of round-bottomed flasks, the 2-dibromo vinyl) benzene, 19.72 gram Octadecane base amine, 2.9 gram sodium hydroxide, 30 milliliters of dimethyl sulfoxide (DMSO), 10 ml waters, be heated to 100 ℃, follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene; 2. stopped reaction adds distilled water in system, with ethyl acetate extraction three times, merges organic phase, and organic phase is respectively washed once with distilled water and saturated aqueous common salt, and anhydrous magnesium sulfate drying half an hour, filtration spins off solvent; 3. crude product with column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, obtain 4.8 gram N-Octadecane base O-bromobenzylacidamides, productive rate is 70%.
Proton nmr spectra (CDCl
3): 7.31 (d, J=7.88Hz, 1H), 7.08 (t, J=7.9Hz, 1H), 6.95 (m, 2H), 6.40 (br, 1H), 3.44 (s, 2H), 3.20 (m, 2H), 1.55 (m, 2H), 1.25 (m, 30H), 0.86 (t, 3H).
Carbon-13 nmr spectra (CDCl
3): 168.44,134.17,129.47,129.02,125.29,123.00,120.98,44.28,39.51,32.01,29.73,29.68,29.62,29.71,29.40,29.38,29.36,29.29,26.33,26.29,19.77,13.10.
Claims (1)
1. the synthetic method of a N-substituted O-bromobenzylacidamide is characterized in that this method has following steps:
A. with volume ratio be 3: 1 dimethyl sulfoxide (DMSO) and water as mixed solvent, sodium hydroxide is done alkali, and 1-bromo-2-(2, the 2-dibromo vinyl) benzene and primary amine are heated to 70～100 ℃; Reinforced mol ratio is: alkali: 1-bromo-2-(2, the 2-dibromo vinyl) benzene: primary amine=2～5: 1: 2～5; Follow the tracks of reaction with the thin-layer chromatography method, disappear to reaction raw materials 1-bromo-2-(2, the 2-dibromo vinyl) benzene;
B. reaction adds distilled water after finishing in system, uses ethyl acetate extraction, merges organic phase; Use distilled water and saturated common salt water washing organic phase again, use anhydrous magnesium sulfate drying then, filter, remove solvent, get crude product with Rotary Evaporators;
C. crude product column chromatography purification, developping agent are sherwood oil and the ethyl acetate mixed solution by 5: 1 volume ratio, and the solid that obtains is the N-substituted O-bromobenzylacidamide, and its structural formula is:
The structural formula of described primary amine is: R-NH
2, wherein R is C
4～C
18Straight or branched alkyl or C
5～C
8Cycloalkyl or replacement or unsubstituted benzyl.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688550A (en) * | 2002-08-27 | 2005-10-26 | 阿斯利康(瑞典)有限公司 | 2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1688550A (en) * | 2002-08-27 | 2005-10-26 | 阿斯利康(瑞典)有限公司 | 2,5-dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12 |
Non-Patent Citations (2)
| Title |
|---|
| 王先恒摘.S35-09 N-苄基酰胺的新合成法.中国医药工业杂志35 1.2004,35(1),48. |
| 王先恒摘.S35-09 N-苄基酰胺的新合成法.中国医药工业杂志35 1.2004,35(1),48. * |
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