CN1314660C - Cinnamide compound synthesizing process - Google Patents
Cinnamide compound synthesizing process Download PDFInfo
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- CN1314660C CN1314660C CNB2005100602079A CN200510060207A CN1314660C CN 1314660 C CN1314660 C CN 1314660C CN B2005100602079 A CNB2005100602079 A CN B2005100602079A CN 200510060207 A CN200510060207 A CN 200510060207A CN 1314660 C CN1314660 C CN 1314660C
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Abstract
The present invention discloses a method for synthesizing a cinnamamide compound. The cinnamamide compound is prepared from bromoacetamide and aromatic aldehyde at the temperature of the room temperature to the return temperature under the condition of the existence of triphenylphosphine, inorganic base and inorganic salt in aqueous phase. The method used in the organic synthesis is a convergent synthetic method. In the reaction, the bromoacetamide reacts with the triphenylphosphine to obtain the intermediate body of phosphonium salt which then reacts with alkali to obtain ylide correspondingly, and the product cinnamamide is prepared from the ylide and the aromatic aldehyde. The intermediate body in the two-step reaction of the synthetic method has no need to be separated, which decreases the working procedure, saves the time and the energy source and reduces the waste effluent, and the yield is high. The reaction in the method of the present invention processes in the water phase system, thereby the poisonous and harmful organic solvents or the expensive organic solvents such as benzene, toluene, tetrahydrofuran, dimethylformamide, etc. in the traditional synthetic method can be avoided.
Description
Technical field
The present invention relates to the method for cinnamide compound synthesizing.Especially under aqueous phase triphenylphosphine, mineral alkali and inorganic salt existence condition, alpha-brominated ethanamide and aromatic aldehyde react the method for cinnamide compound synthesizing.
Background technology
Cinnamide compound is as the medicine existing history for a long time that is applied clinically.Osmanthus piperazine propylamine (cinpropazide) has retardance Ca
2+Carrier function is used for coronary heart disease and bronchospasm asthma, also can stop the Ca of mast cell membrane
2+Carrier prevents threshing allergy.Cinepazet (cinepazet) has the antianginal effect, and cinepazide (cinepazide) has the vasodilation effect, is used for the treatment of hypertension.BW-122U (cinromide) compounds has anticonvulsant action, can be used for treating insane ravine.Cinmetacin (cinmetacin) then has good anti-inflammatory effect.
Have at some in recent years and find all to contain cinnamide compound in the plant of pharmacologic action.The compound of some Wheat Proteins has the protection microbial film, prevents effects such as aging, heart trouble, cancer.Long ago, people recognize that oat is a good anti-oxidant source, the nearest cinnamide compound that also contains its exclusive avenanthramide by name with strong antioxidant action in the oat except that abundant vitamins C and vitamin-E are arranged of discovering.The Cortex Bulbus Allii extract has very strong DPPH free radical scavenging effect, and it is its main active compounds that two cinnamide compounds (N-trans-coumaroyloctopamine and N-trans-feruloyloctopamine) are wherein arranged.
Acting in inflammation and the immune response between leukocyte function antigen (LFA-1) and the intercellular adhesion molecule (ICAM-1) plays important effect.Right-arylthio cinnamide compound is the anti-agent of knot of the newfound LFA-1/ICFA-1 effect of a class, discovers that through mouse models can reduce cardiac muscle blocks scope.
Clinical some that are used for pain management tie anti-agent medicine (as capsaicin and RTX) because the anti-effect of knot, the a large amount of use can produce the Neurotoxic side effect of cumulative bad, and newfound N-aryl then has stronger analgesic effect can obviously reduce neurotoxicity to tertiary butyl cinnamide compound.
In sum; cinnamide compound has not only obtained application clinically as medicine; and much be the compound with medicinal function that is present in plant and the food, cinnamide compound is also being played the part of very active role in new drug development research recently.
The synthetic method of existing cinnamide compound has:
1) aromatic aldehyde compound generates cinnamic acid compound (Knoevenagel reaction) with propanedioic acid condensation and decarboxylation earlier, generate cinnamyl chloride with thionyl chloride or oxalyl chloride reaction then, in the presence of alkali, generate cinnamide compound (formula A) again with the amine effect.
Formula A
2) aromatic aldehyde compound carries out the Wittig reaction or carries out the Horner-Emmons-Wittig reaction with carbalkoxy methylene radical phosphinate generating the laurate compounds with ylide earlier, generate the corresponding cinnamic acid compounds through the alkaline condition hydrolysis then, generate cinnamyl chloride with thionyl chloride or oxalyl chloride reaction again, in the presence of alkali, generate cinnamide compound (formula B) at last with the amine effect.Perhaps some cinnamide compound can carry out aminolysis by laurate and amine and obtains.
Formula B
3) aromatic aldehyde compound and malonic acid monoester condensation and decarboxylation generate the laurate compounds, carry out aminolysis by laurate and amine again and obtain cinnamide compound, or, in the presence of alkali, generate cinnamide compound at last with the amine effect by hydrolysis, chloride.
Above building-up reactions method is referred to as the line style synthetic method in organic synthesis, its reaction is by adding the synthetic final product of molecule segment gradually, be referred to as convergence type synthetic method (formula C) with another kind in organic synthesis and compare, its total recovery is lower, and combined coefficient is also low.And the institute in the above-mentioned synthetic method responds and all need carry out in organic solvent, and almost per step reaction product all needs to separate purifies, and therefore exists complex procedures, energy consumption to reach the big problem of environmental pollution greatly.
Formula C
Summary of the invention
The present invention aims to provide a kind of method of cinnamide compound synthesizing, to realize simplifying technology, improves combined coefficient and synthesis yield, reduces the purpose of environmental pollution.
The method of cinnamide compound synthesizing of the present invention (formula I),
ArCH＝CHCONR
1R
2 I)
In the formula, Ar is the monoalkyl phenyl that is substituted in different positions, dialkyl phenyl organic, the polyalkylbenzene base, the monohydroxy phenyl, dihydroxy phenyl, the poly-hydroxy phenyl, the monoalkoxy phenyl, the dialkoxy phenyl, many alkoxyl phenyls, the alkoxyl group hydroxy phenyl, the dialkoxy hydroxy phenyl, the phenyl that single or multiple identical or different halogens replace, single nitrophenyl, dinitrophenyl, the mono amino phenyl that the N-alkyl replaces, the diamino-phenyl that the N-alkyl replaces, N, mono amino phenyl or N that the N-dialkyl group replaces, the diamino-phenyl that the N-dialkyl group replaces, or for replacing or unsubstituted furans-2-base, thiophene phenol-2-base or thiazol-2-yl; R
1Be hydrogen, R
2For methyl, ethyl, n-propyl, normal-butyl or be less than positive alkyl, aryl, arylmethyl or the 2-aryl ethyl of 8 carbon atoms; Aryl wherein is the monohydroxy phenyl that is substituted in different positions, dihydroxy phenyl, poly-hydroxy phenyl, monoalkoxy phenyl, dialkoxy phenyl, many alkoxyl phenyls, alkoxyl group hydroxy phenyl, dialkoxy hydroxy phenyl, phenyl, single nitrophenyl or the dinitrophenyl that single or multiple identical or different halogen replaces, the mono amino phenyl that the N-alkyl replaces, diamino-phenyl, the N that the N-alkyl replaces, mono amino phenyl or N that the N-dialkyl group replaces, the diamino-phenyl that the N-dialkyl group replaces; Perhaps R
1, R
2All be methyl, ethyl, n-propyl, normal-butyl or the positive alkyl that is less than 8 carbon atoms; Perhaps R
1, R
2Be respectively methylethyl, methyl n-propyl, methyl normal-butyl, ethyl n-propyl, ethyl normal-butyl or n-propyl normal-butyl; It is characterized in that alpha-brominated ethanamide (formula II) and aromatic aldehyde (formula III) under aqueous phase triphenylphosphine, mineral alkali and inorganic salt existence condition, react under in room temperature to reflux temperature,
BrCH
2CONR
1R
2 II)
R in the formula
1, R
2Definition cotype I)
ArCHO III)
The definition cotype I of Ar in the formula)
Triphenylphosphine: alpha-brominated ethanamide: aromatic aldehyde: the equivalence ratio of mineral alkali is 1: 1: 1: 1～3: 3: 1: 3, the equivalent concentration of aromatic aldehyde was 0.05～1.0, and the volumetric molar concentration of inorganic salt is 0.5～4.0, and the reaction times is 5 minutes to 2 hours; The gained reaction solution is used ethyl acetate extraction with the reaction solution equal volume amounts earlier, after the water washing of the organic phase of extraction with the saturated aqueous common salt of 1/2 volume and 1/2 volume, use anhydrous sodium sulfate drying again, the elimination siccative is purified.
The inventive method can be represented with following reaction formula:
Among the present invention, the expression formula of used alpha-brominated ethanamide is BrCH
2CONR
1R
2, in the formula, R
1Be hydrogen, R
2For methyl, ethyl, n-propyl, normal-butyl or be less than positive alkyl, aryl, arylmethyl or the 2-aryl ethyl of 8 carbon atoms; Aryl wherein is the monohydroxy phenyl, dihydroxy phenyl or the poly-hydroxy phenyl that are substituted in different positions, monoalkoxy phenyl, dialkoxy phenyl, many alkoxyl phenyls, alkoxyl group hydroxy phenyl, dialkoxy hydroxy phenyl, phenyl, single nitrophenyl or the dinitrophenyl that single or multiple identical or different halogen replaces, the mono amino phenyl that the N-alkyl replaces, diamino-phenyl, the N that the N-alkyl replaces, mono amino phenyl or N that the N-dialkyl group replaces, the diamino-phenyl that the N-dialkyl group replaces; Perhaps R
1, R
2All be methyl, ethyl, n-propyl, normal-butyl or the positive alkyl that is less than 8 carbon atoms; Perhaps R
1, R
2Be respectively methylethyl, methyl n-propyl, methyl normal-butyl, ethyl n-propyl, ethyl normal-butyl or n-propyl normal-butyl.
Substituent difference can demonstrate different reactive behavioies on the alpha-brominated ethanamide nitrogen-atoms, and its reactive behavior of acid amides that general single fatty group replaces is the strongest, is the acid amides that divalent aliphatic group replaces then, and relatively poor is the acid amides that single aromatic base replaces.
Among the present invention, but used aromatic aldehyde can be to pass through just synthetic compound of classical reaction at commercially available general chemistry product or some.Its expression formula is ArCHO, in the formula, Ar is the monoalkyl phenyl that is substituted in different positions, dialkyl phenyl organic, the polyalkylbenzene base, the monohydroxy phenyl, dihydroxy phenyl, the poly-hydroxy phenyl, the monoalkoxy phenyl, the dialkoxy phenyl, many alkoxyl phenyls, the alkoxyl group hydroxy phenyl, the dialkoxy hydroxy phenyl, the phenyl that single or multiple identical or different halogens replace, single nitrophenyl, dinitrophenyl, the mono amino phenyl that the N-alkyl replaces, the diamino-phenyl that the N-alkyl replaces, N, mono amino phenyl or N that the N-dialkyl group replaces, the diamino-phenyl that the N-dialkyl group replaces, or for replacing or unsubstituted furans-2-base, thiophene phenol-2-base or thiazol-2-yl.
The difference of substituent difference and the position of substitution also demonstrates different reactive behavioies to reactive behavior on the aromatic aldehyde aromatic ring.General electron-withdrawing group have a reactive behavior height, and electron donating group exist reactive behavior just low.Contain active hydrogen group (as hydroxyl) and then can reduce reactive behavior.Adjacent hydroxyl substitution reaction is active high, and just low to hydroxyl substitution reaction activity.
Among the present invention, the adding of inorganic salt has tangible booster action to reaction.Inorganic salt can be lithium chloride, sodium-chlor or Repone K, and are the best with the effect of lithium chloride.Its preferred volumetric molar concentration is 1.0～3.0.
Among the present invention, used mineral alkali is preferential with the lithium hydroxide for for lithium hydroxide, sodium hydroxide, potassium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, lithium bicarbonate, sodium bicarbonate or saleratus especially.
Among the present invention, the preferred equivalent concentration of aromatic aldehyde in reaction solution is 0.07～0.12.
Among the present invention, triphenylphosphine: alpha-brominated ethanamide: aromatic aldehyde: the preferred equivalence ratio of mineral alkali is 1.8: 1.8: 1.0: 2.1.
Among the present invention, the temperature of reaction of employing be room temperature to reflux temperature, be preferential especially with the reflux temperature.Reaction times generally can finish in several minutes to 20 minutes, even also can finish in 2 hours some aromatic aldehyde substrates that contain active hydrogen group, had very high reaction efficiency.
The present invention adopts by alpha-brominated ethanamide and aromatic aldehyde compound under triphenylphosphine, mineral alkali and inorganic salt effect, the method of directly synthesizing cinnamide, alpha-brominated ethanamide generates the quaternary alkylphosphonium salt intermediate with the triphenylphosphine reaction earlier in reaction, and then this salt generate corresponding ylide with the alkali effect, and ylide generates product cinnamide (suc as formula C) with the aromatic aldehyde reaction again.The intermediate of its two-step reaction need not to separate in this synthetic method, has reduced reaction process, has both saved the time, has also saved the energy, and the yield height, has also significantly reduced waste discharge.The inventive method places reaction aqueous phase system to carry out, and has avoided prior synthesizing method to use poisonous and harmful or expensive organic solvent such as benzene, toluene, tetrahydrofuran (THF), dimethyl formamide.
Embodiment
Embodiment 1
104.7 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.5 equivalent) and 37 milligrams of (0.35mmol of phenyl aldehyde, 1.0 equivalent), 142 milligrams of (0.54mmol of triphenylphosphine, 1.5 equivalent) be suspended in and contain 26 milligrams of (0.65mmol of lithium hydroxide, 1.8 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes, then the reaction solution cool to room temperature, with ethyl acetate extraction (10ml * 3), the saturated common salt water washing of organic phase after the merging, with behind the anhydrous sodium sulfate drying, also concentrating under reduced pressure obtains crude product after filtration again.(sherwood oil: ethyl acetate=5: 1) separate purification and obtain a yellow oil, 69 milligrams of N-normal-butyl cinnamides, productive rate are 96% to this crude product, and the E/Z ratio is 86/14 through silica gel column chromatography.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.61(d，J＝15.6Hz，1H)，7.48-7.46(m，2H)，7.34-7.30(m，3H)，6.45(d，J＝15.6Hz，1H)，6.09(bs，1H)，3.38(q，J＝6.4Hz，2H)，1.59-1.51(m，2H)，1.42-1.35(m，2H)，0.92(t，J＝6.4Hz，3H).(Z-isomer)
1HNMR(400MHz，CDCl
3)δ7.43-7.41(m，2H)，7.34-7.30(m，3H)，6.75(d，J＝12.4Hz，1H)，5.99(d，J＝12.8Hz，1H)，5.69(bs，1H)，3.22(q，J＝6.4Hz，2H)，1.42-1.35(m，2H)，1.15-1.25(m，2H)，0.84(t，J＝6.4Hz，3H).
Embodiment 2
194 milligrams of (1.00mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.8 equivalent) and 78 milligrams of (0.56mmol of 4-chlorobenzaldehyde, 1.0 262 milligrams of (1.00mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 52 milligrams of (1.23mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography (sherwood oil: ethyl acetate=3: 1) separate to purify and to obtain white solid (mp.118-120 ℃), 132 milligrams of N-normal-butyls-3-Phenyl Acrylamide, productive rate is 100%, the E/Z ratio is 86/14.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.57(d，J＝16.0Hz，1H)，7.41(d，J＝7.6Hz，2H)，7.32(d，J＝7.6Hz，2H)，6.37(d，J＝16.0Hz，1H)，5.77(bs，1H)，3.41-3.36(m，2H)，1.59-1.51(m，2H)，1.43-1.34(m，2H)，0.96-0.92(t，J＝7.2Hz，3H).(Z-isomer)
1HNMR(400MHz，CDCl
3)δ7.41(d，J＝8.4Hz，2H)，7.29(d，J＝8.4Hz，2H)，6.65(d，J＝12.4Hz，1H)，5.97(d，J＝12.4Hz，1H)，5.77(bs，1H)，3.23(q，J＝6.4Hz，2H)，1.42-1.37(m，2H)，1.27-1.20(m，2H)，0.89-0.85(t，J＝7.2Hz，3H).
Embodiment 3
194 milligrams of (1.00mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.8 equivalent) and 84 milligrams of (0.56mmol of 4-nitrobenzaldehyde, 1.0 262 milligrams of (1.00mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 52 milligrams of (1.23mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 5 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography (sherwood oil: ethyl acetate=3: 1) separate to purify and to obtain yellow solid (mp.126-128 ℃), 112 milligrams of N-normal-butyl-3-(4-nitrophenyl) acrylamides, productive rate is 80.5%, the E/Z ratio is 95/5.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ8.19(d，J＝8.4Hz，2H)，7.65(d，J＝15.6Hz，1H)，7.63(d，J＝8.4Hz，1H)，6.55(d，J＝15.6Hz，1H)，5.98(bs，1H)，3.42-3.37(m，2H)，1.58-1.52(m，2H)，1.41-1.36(m，2H)，0.96-0.91(t，J＝7.2Hz，3H).
Embodiment 4
194 milligrams of (1.00mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.8 equivalent) and 76 milligrams of (0.56mmol of 4-methoxybenzaldehyde, 1.0 262 milligrams of (1.00mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 52 milligrams of (1.23mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 20 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography (sherwood oil: ethyl acetate=3: 1) separate to purify and to obtain white solid (mp.78-80 ℃), 125 milligrams of N-normal-butyl-3-(4-p-methoxy-phenyl) acrylamides, productive rate is 96%, the E/Z ratio is 82/18.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.56(d，J＝15.2Hz，1H)，7.41(d，J＝8.6Hz，2H)，6.84(d，J＝8.6Hz，2H)，6.31(d，J＝15.2Hz，1H)，6.02(bs，1H)，3.79(s，3H)，3.39-3.34(m，2H)，1.56-1.50(m，2H)，1.41-1.34(m，2H)，0.95-0.85(t，J＝7.2Hz，3H).
Embodiment 5
194 milligrams of (1.00mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.8 equivalent) and 68 milligrams of (0.56mmol of 2-hydroxy benzaldehyde, 1.0 262 milligrams of (1.00mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 52 milligrams of (1.23mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 80 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography (sherwood oil: ethyl acetate=1: 1) separate to purify and to obtain yellow oil, 85 milligrams of N-normal-butyl-3-(2-hydroxy phenyl) acrylamides, productive rate is 70%, the E/Z ratio is 99/1.
(E-isomer)
1H?NMR(400MHz，Acetone)δ9.38(bs，1H)，7.96(d，J＝15.6Hz，1H)，7.59(s，1H)，7.48(d，J＝7.2Hz，1H)，7.20-7.16(m，1H)，6.99(d，J＝8.0Hz，1H)，6.85-6.81(m，1H)，6.81(d，J＝15.6Hz，1H)，3.36(q，J＝6.4Hz，2H)，1.59-1.51(m，2H)，1.42-1.33(m，2H)，0.91(t，J＝7.2Hz，3H).
Embodiment 6
194 milligrams of (1.00mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.8 equivalent) and 68 milligrams of (0.56mmol of 3-hydroxy benzaldehyde, 1.0 262 milligrams of (1.00mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 52 milligrams of (1.23mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 65 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography (sherwood oil: ethyl acetate=1: 1) separate to purify and to obtain yellow oil, 86 milligrams of N-normal-butyl-3-(3-hydroxy phenyl) acrylamides, productive rate is 71%, the E/Z ratio is 75/25.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.52(d，J＝15.2Hz，1H)，7.12-7.08(m，1H)，7.03(s，1H)，6.91-6.81(m，3H)，6.53(bs，1H)，6.38(d，J＝15.2Hz，1H)，3.32-3.27(m，2H)，1.50-1.35(m，2H)，1.35-1.25(m，2H)，0.84(t，J＝7.2Hz，4H)(Z-isomer)
1H?NMR(400MHz，CDCl
3)(selected?peaks)δ6.96(s，1H)，6.66(d，J＝12.4Hz，1H)，6.02(bs，1H)，5.93(d，J＝12.4Hz，1H)，3.21-3.16(m，2H)，1.15-1.10(m，2H)，0.78(t，J＝7.2Hz，4H)E/Z＝1∶0.34
Embodiment 7
194 milligrams of (1.00mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.8 equivalent) and 55 milligrams of (0.56mmol of 2 furan carboxyaldehyde, 1.0 262 milligrams of (1.00mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 52 milligrams of (1.23mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography separate (sherwood oil: ethyl acetate=3: 1) purify and obtain yellow oil, 110 milligrams of N-normal-butyl-3-(2-furyl) acrylamides, productive rate is 99%, the E/Z ratio is 30/70.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.40(s，1H)，7.38(d，J＝15.2Hz，1H)，6.50(d，J＝3.2Hz，1H)，6.43-6.41(m，1H)，6.31(d，J＝15.2Hz，1H)，5.89(bs，1H)，3.36(q，J＝6.4Hz，2H)，1.57-1.49(m，2H)，1.41-1.32(m，2H)，0.92(t，J＝7.2Hz，3H).
(Z-isomer)
1H?NMR(400MHz，CDCl
3)δ7.40(d，J＝1.6Hz，1H)，7.20(d，J＝3.2Hz，1H)，6.50(d，J＝12.8Hz，1H)，6.44-6.43(m，1H)，6.10(bs，1H)，5.70(d，J＝12.8Hz，1H)，3.35-3.30(m，2H)，1.54-1.48(m，2H)1.39-1.33(m，2H)，0.93(t，J＝7.2Hz，3H).
Embodiment 8
N, 135 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-di-n-butyl, 1.8 equivalent) and 32 milligrams of (0.30mmol of phenyl aldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 26 milligrams of (0.65mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 8 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography (sherwood oil: ethyl acetate=3: 1) separate to purify and to obtain yellow oil, N, 74 milligrams of N-di-n-butyl cinnamides, productive rate are 95%, the E/Z ratio is 98/2.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.69(d，J＝15.2Hz，1H)，7.50(d，J＝7.2Hz，1H)，7.37-7.30(m，3H)，6.82(d，J＝15.2Hz，1H)，3.43-3.35(m，4H)，1.65-1.53(m，4H)，1.41-1.29(m，4H)，0.98-0.91(m，6H).
Embodiment 9
N, 135 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-di-n-butyl, 1.8 equivalent) and 44 milligrams of (0.30mmol of 4-chlorobenzaldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 26 milligrams of (0.65mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography separate (sherwood oil: ethyl acetate=3: 1) purify and obtain yellow oil, N, 90 milligrams of N-di-n-butyl-3-(4-chloro-phenyl-) acrylamides, productive rate is 98%, the E/Z ratio is 96/4.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.60(d，J＝15.6Hz，1H)，7.40(d，J＝8.0Hz，2H)，7.29(d，J＝8.0Hz，2H)，6.77(d，J＝15.6Hz，1H)，3.41-3.33(m，4H)，1.60-1.50(m，4H)，1.37-1.26(m，4H)0.95-0.89(m，6H).
Embodiment 10
N, 135 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-di-n-butyl, 1.9 equivalent) and 42 milligrams of (0.28mmol of 4-nitrobenzaldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.9 equivalent) be suspended in and contain 26 milligrams of (0.65mmol of lithium hydroxide, 2.3 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 5 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography separate (sherwood oil: ethyl acetate=3: 1) purify and obtain gray solid (72-74 ℃), N, 78 milligrams of N-normal-butyl cinnamides, productive rate are 92%, the E/Z ratio is 99/1.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ8.23(d，J＝8.8Hz，2H)，7.71(d，J＝15.6Hz，1H)，7.64(d，J＝8.8Hz，2H)，6.95(d，J＝15.6Hz，1H)，3.46-3.38(m，4H)，1.67-1.56(m，4H)1.41-1.32(m，4H)，1.00-0.93(m，6H).
Embodiment 11
116 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-phenyl, 1.8 equivalent) and 32 milligrams of (0.30mmol of phenyl aldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 26 milligrams of (0.65mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes.Aftertreatment is with embodiment 1.(sherwood oil: ethyl acetate=3: 1) purification obtains white solid (mp.142-146 ℃) to crude product, and 64 milligrams of N-phenyl cinnamides, productive rate are 96%, and the E/Z ratio is 87/13 through the silica gel column chromatography separation.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ8.09(bs，1H)，7.67(d，J＝15.6Hz，1H)，7.60(d，J＝7.2Hz，2H)，7.37(d，J＝7.2Hz，2H)，7.27-7.24(m，5H)，7.06-7.03(m，1H)，6.58(d，J＝15.6Hz，1H).E/Z＝1.00∶0.16
Embodiment 12
116 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-phenyl, 1.8 equivalent) and 42 milligrams of (0.30mmol of 4-chlorobenzaldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 26 milligrams of (0.65mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography separate (sherwood oil: ethyl acetate=3: 1) purify and obtain white solid (161-165 ℃), 75 milligrams of N-phenyl-3-(4-chloro-phenyl-) acrylamides, productive rate is 97%, the E/Z ratio is 99/1.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.69(d，J＝15.6Hz，1H)，7.63(d，J＝7.6Hz，2H)，7.41(d，J＝8.0Hz，2H)，7.36-7.31(m，4H)，7.16-7.12(m，1H)，6.55(d，J＝15.6Hz，1H)
Embodiment 13
116 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-phenyl, 1.8 equivalent) and 45 milligrams of (0.30mmol of 4-nitrobenzaldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 26 milligrams of (0.65mmol of lithium hydroxide, 2.1 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography (sherwood oil: ethyl acetate=3: 1) separate to purify and to obtain yellow solid (mp.119-123 ℃), 77 milligrams of N-phenyl-3-(4-nitrophenyl) acrylamides, productive rate is 96%, the E/Z ratio is 93/7.
(E-isomer)
1H?NMR(400MHz，DMSO-d
6)δ10.36(s，1H)，8.28(d，J＝8.8Hz，2H)，7.89(d，J＝8.8Hz，2H)，7.72-7.67(m，3H)，7.37-7.31(m，3H)，7.10-7.07(m，1H)，7.02(d，J＝16.0Hz，1H)
Embodiment 14
218 milligrams of (0.90mmol of the alpha-brominated ethanamide of N-(2-phenyl) ethyl, 1.8 equivalent) and 53 milligrams of (0.50mmol of phenyl aldehyde, 1.0 236 milligrams of (0.90mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 44 milligrams of (1.10mmol of lithium hydroxide, 2.2 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 10 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography separate (sherwood oil: ethyl acetate=3: 1) purify and obtain white solid (mp.93-95 ℃), 120 milligrams of N-(2-phenyl) ethyl cinnamides, productive rate is 96%, the E/Z ratio is 90/10.
(E-isomer)
1H?NMR(400MHz，CDCl
3)δ7.61(d，J＝15.6Hz，1H)，7.47-7.45(m，2H)，7.33-7.28(m，5H)，7.25-7.20(m，3H)，6.36(d，J＝15.6Hz，1H)，5.98(bs，1H)，3.67-3.62(m，2H)，2.88(t，J＝7.2Hz，2H)
Embodiment 15
218 milligrams of (0.90mmol of the alpha-brominated ethanamide of N-(2-phenyl) ethyl, 1.8 equivalent) and 61 milligrams of (0.50mmol of 2-hydroxy benzaldehyde, 1.0 236 milligrams of (0.90mmol of triphenylphosphine equivalent),, 1.8 equivalent) be suspended in and contain 44 milligrams of (1.10mmol of lithium hydroxide, 2.2 equivalent) and in lithium chloride water (5ml) solution of 1.2 volumetric molar concentrations, back flow reaction 5 minutes.Aftertreatment is with embodiment 1.Crude product through silica gel column chromatography separate (sherwood oil: ethyl acetate=1: 1) purify yellow oil, 69 milligrams of N-(2-phenyl) ethyl-3-(2-hydroxy phenyl) acrylamides, productive rate is 52%, the E/Z ratio is 99/1.
(E-isomer)
1H?NMR(400MHz，DMSO-d
6)δ10.00(s，1H)，8.15-8.13(m，1H)，7.65(d，J＝16.0Hz，1H)，7.43(d，J＝7.2Hz，1H)，7.34-7.18(m，6H)，7.91(d，J＝8.4Hz，1H)，6.86-6.82(m，1H)，6.66(d，J＝16.0Hz，1H)，3.43-3.40(m，2H)，2.82-2.78(m，2H)。
Embodiment 16
104.7 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.0 equivalent) and 57 milligrams of (0.54mmol of phenyl aldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.0 equivalent) be suspended in lithium chloride water (5ml) solution that contains 26 milligrams of lithium hydroxides (0.65mmol, 1.2 equivalents) and 1.2 volumetric molar concentrations back flow reaction 30 minutes, aftertreatment is with embodiment 1, get 47 milligrams of N-normal-butyl cinnamides, productive rate is 65%, and the E/Z ratio is 87/13.
Embodiment 17
209.4 milligrams of (1.08mmol of the alpha-brominated ethanamide of N-normal-butyl, 3.0 equivalent) and 37 milligrams of (0.35mmol of phenyl aldehyde, 1.0 284 milligrams of (1.08mmol of triphenylphosphine equivalent),, 3.0 equivalent) be suspended in lithium chloride water (10ml) solution that contains 52 milligrams of lithium hydroxides (1.30mmol, 3.7 equivalents) and 1.2 volumetric molar concentrations back flow reaction 5 minutes, aftertreatment is with embodiment 1, get 70 milligrams of N-normal-butyl cinnamides, productive rate is 98%, and the E/Z ratio is 87/13.
Embodiment 18
104.7 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.5 equivalent) and 37 milligrams of (0.35mmol of phenyl aldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.5 equivalent) be suspended in lithium chloride water (5ml) solution that contains 26 milligrams of lithium hydroxides (0.65mmol, 1.8 equivalents) and 1.2 volumetric molar concentrations room temperature reaction 2 hours, aftertreatment is with embodiment 1, get 32 milligrams of N-normal-butyl cinnamides, productive rate is 45%, and the E/Z ratio is 91/9.
Embodiment 19
104.7 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.5 equivalent) and 37 milligrams of (0.35mmol of phenyl aldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.5 equivalent) be suspended in lithium chloride water (5ml) solution that contains 26 milligrams of lithium hydroxides (0.65mmol, 1.8 equivalents) and 1.2 volumetric molar concentrations, 70 ℃ were reacted 45 minutes, aftertreatment is with embodiment 1, get 53 milligrams of N-normal-butyl cinnamides, productive rate is 74%, and the E/Z ratio is 90/10.
Embodiment 20
104.7 milligrams of (0.54mmol of the alpha-brominated ethanamide of N-normal-butyl, 1.5 equivalent) and 37 milligrams of (0.35mmol of phenyl aldehyde, 1.0 142 milligrams of (0.54mmol of triphenylphosphine equivalent),, 1.5 equivalent) be suspended in lithium chloride water (5ml) solution that contains 26 milligrams of lithium hydroxides (0.65mmol, 1.8 equivalents) and 2.5 volumetric molar concentrations back flow reaction 5 minutes, aftertreatment is with embodiment 1, get 69 milligrams of N-normal-butyl cinnamides, productive rate is 96%, and the E/Z ratio is 86/14.
Embodiment 21
In the two neck bottles of 100ml, add 50ml exsiccant CH
2Cl
2Add 1.9ml (24mmol then, 1.2 pyridine equivalent) and 2ml (20mmol, 1.0 n-Butyl Amine 99 equivalent), the bromoacetyl bromide that in 0 ℃, adds 2.1ml (24mmol, 1.2 equivalents), rise to stirring at room 2h then after, add saturated sodium hydrogen carbonate solution termination reaction, with the CH of 2 * 20ml
2Cl
2Extraction. the organic phase anhydrous sodium sulfate drying after the merging, filter, underpressure distillation, crude product separates (sherwood oil: ethyl acetate=1: 3) obtain a yellow oil, alpha-brominated ethanamide 3.8 grams of N-normal-butyl, productive rate 99%. through silica gel column chromatography
1H?NMR(400MHz，CDCl3)δ6.56(s，1H)，3.88(s，2H)，3.29(q，J＝5.2Hz，2H)，1.55-1.51(m，2H)，1.39-1.34(m，2H)，0.94(t，J＝6.0Hz，3H)
Embodiment 22
In the two neck bottles of 50ml, add 25ml exsiccant CH
2Cl
2Add 0.95ml (12mmol then, 1.2 pyridine equivalent) and 1.7ml (10mmol, 1.0 N equivalent), the N-dibutylamine adds 1.05ml (12mmol in 0 ℃, 1.2 bromoacetyl bromide equivalent), after rising to stirring at room 2h then, add saturated sodium hydrogen carbonate solution termination reaction, with the CH of 2 * 20ml
2Cl
2Extraction. the organic phase anhydrous sodium sulfate drying after the merging, filter, underpressure distillation, crude product separates (sherwood oil: ethyl acetate=1: 3) obtain yellow oil, N, alpha-brominated ethanamide 2.4 grams of N-di-n-butyl, productive rate 96%. through silica gel column chromatography
1H?NMR(400MHz，CDCl3)δ3.85(s，2H)，3.33-3.25(m，4H)，1.63-1.47(m，4H)，1.36-1.23(m，4H)，0.96-0.88(m，6H)
Embodiment 23
In the two neck bottles of 50ml, add 25ml exsiccant CH
2Cl
2Add 0.95ml (12mmol then, 1.2 pyridine equivalent) and 1.7ml (10mmol, 1.0 aniline equivalent), the bromoacetyl bromide that in 0 ℃, adds 1.05ml (12mmol, 1.2 equivalents), rise to stirring at room 3h then after, add saturated sodium hydrogen carbonate solution termination reaction, with the CH of 2 * 20ml
2Cl
2Extraction, the organic phase anhydrous sodium sulfate drying after the merging filters, and underpressure distillation obtains white solid (mp.132-134 ℃) behind the crude product recrystallization, alpha-brominated ethanamide 1.9 grams of N-phenyl, productive rate 89%.
1H?NMR(400MHz，DMSO-d
6)δ9.64(s，1H)，6.84(d，J＝8.4Hz，2H)，6.60-6.56(m，2H)，6.35-6.32(m，1H)，3.29(s，2H)
Embodiment 24
In the two neck bottles of 50ml, add 25ml exsiccant CH
2Cl
2Add 0.95ml (12mmol then, 1.2 pyridine equivalent) and 1.25ml (10mmol, 1.0 2-phenyl-ethyl amine equivalent), the bromoacetyl bromide that in 0 ℃, adds 1.05ml (12mmol, 1.2 equivalents), rise to stirring at room 2h then after, add saturated sodium hydrogen carbonate solution termination reaction, with the CH of 2 * 20ml
2Cl
2Extraction. the organic phase anhydrous sodium sulfate drying after the merging, filter, underpressure distillation, crude product separates (sherwood oil: ethyl acetate=1: 3) obtain white solid (mp.70-72 ℃) through silica gel column chromatography, alpha-brominated ethanamide 2.18 grams of N-(2-phenyl) ethyl, productive rate 90%.
1H?NMR(400MHz，CDCl3)δ7.35-7.31(m，2H)，7.26(d，J＝5.6Hz，1H)，7.21(d，J＝7.2Hz，2H)，6.54(bs，1H)，3.58-3.53(m，2H)，2.85(d，J＝7.2Hz，2H)。
Claims (6)
1. the method for the cinnamide compound of a synthesis type I,
ArCH＝CHCONR
1R
2 I
In the formula, Ar is the mono amino phenyl that replaces of phenyl, single nitrophenyl, dinitrophenyl, N-alkyl that the monoalkyl phenyl that is substituted in different positions, polyalkylbenzene base, monohydroxy phenyl, poly-hydroxy phenyl, monoalkoxy phenyl, many alkoxyl phenyls, alkoxyl group hydroxy phenyl, dialkoxy hydroxy phenyl, single or multiple identical or different halogen replace, diamino-phenyl, the N that the N-alkyl replaces, mono amino phenyl or N that the N-dialkyl group replaces, the diamino-phenyl that the N-dialkyl group replaces, or be furans-2-base, thiophene-2-base or thiazol-2-yl; R1 is a hydrogen, and R2 is positive alkyl or aryl or arylmethyl or the 2-aryl ethyl that is less than 8 carbon atoms; Aryl wherein is the monohydroxy phenyl that is substituted in different positions, poly-hydroxy phenyl, monoalkoxy phenyl, many alkoxyl phenyls, alkoxyl group hydroxy phenyl, dialkoxy hydroxy phenyl, phenyl, single nitrophenyl or the dinitrophenyl that single or multiple identical or different halogen replaces, the mono amino phenyl that the N-alkyl replaces, diamino-phenyl, the N that the N-alkyl replaces, mono amino phenyl or N that the N-dialkyl group replaces, the diamino-phenyl that the N-dialkyl group replaces; Perhaps R
1, R
2It all is the positive alkyl that is less than 8 carbon atoms; Perhaps R
1, R
2Be respectively methylethyl, methyl n-propyl, methyl normal-butyl, ethyl n-propyl, ethyl normal-butyl or n-propyl normal-butyl;
It is characterized in that α with formula II--the aromatic aldehyde of bromo ethanamide and formula III reacts under in room temperature to reflux temperature under aqueous phase triphenylphosphine, mineral alkali and inorganic salt existence condition,
BrCH
2CONR
1R
2 II
R in the formula
1, R
2Definition cotype I
ArCHO III
The definition cotype I of Ar in the formula
Triphenylphosphine: alpha-brominated ethanamide: aromatic aldehyde: the equivalence ratio of mineral alkali is 1: 1: 1: 1～3: 3: 1: 3, the equivalent concentration of aromatic aldehyde was 0.05～1.0N, and the volumetric molar concentration of inorganic salt is 0.5～4.0M, and the reaction times is 5 minutes to 2 hours; The gained reaction solution is used ethyl acetate extraction with the reaction solution equal volume amounts earlier, after the water washing of the organic phase of extraction with the saturated aqueous common salt of 1/2 volume and 1/2 volume, use anhydrous sodium sulfate drying again, the elimination siccative is purified.
2. the method for cinnamide compound synthesizing according to claim 1 is characterized in that inorganic salt are lithium chloride, sodium-chlor or Repone K.
3. the method for cinnamide compound synthesizing according to claim 1 is characterized in that mineral alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, lithium bicarbonate, sodium bicarbonate or saleratus.
4. the method for cinnamide compound synthesizing according to claim 1, it is characterized in that triphenylphosphine: alpha-brominated ethanamide: aromatic aldehyde: the equivalence ratio of mineral alkali is 1.8: 1.8: 1.0: 2.1.
5. the method for cinnamide compound synthesizing according to claim 1, the volumetric molar concentration that it is characterized in that inorganic salt is 1.0～3.0M.
6. the method for cinnamide compound synthesizing according to claim 1, the equivalent concentration that it is characterized in that aromatic aldehyde is 0.07～0.12N.
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| CN101979386A (en) * | 2009-12-17 | 2011-02-23 | 海南康虹医药科技开发有限公司 | Method for preparing cinepazide free alkali |
| CN102515996B (en) * | 2011-11-14 | 2015-11-25 | 南开大学 | A kind of method of synthesizing beta-aromatic acrylamides |
| CN102701924B (en) * | 2012-05-25 | 2016-02-10 | 湖北远成赛创科技有限公司 | The preparation method of cinnamaldehyde diethylacetal |
| CN103910759B (en) * | 2012-12-29 | 2016-05-11 | 安徽贝克生物制药有限公司 | The preparation method of ethoxycarbonyl ethylidene triphenylphosphine |
| CN103719082B (en) * | 2014-01-22 | 2015-11-18 | 杭州宇龙化工有限公司 | A kind of cinnamide compound is as the application of plant growth regulator |
| CN109180515B (en) * | 2018-08-17 | 2021-04-06 | 苏利制药科技江阴有限公司 | Synthetic method of N- [ 2-hydroxy-2- (4-methoxyphenyl) ethyl ] cinnamamide |
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