CN103030574A - Cyano acidamide compound, and synthetic method and application of compound - Google Patents
Cyano acidamide compound, and synthetic method and application of compound Download PDFInfo
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Abstract
The invention discloses a cyano acidamide compound, and a synthetic method and an application of the compound, and belongs to the technical field of organic compound synthesis. A structural formula of the cyano acidamide compound is as follows as shown in the specification. The synthetic method of the compound comprises the steps that intermediates of alpha-substituted carboxylic acid and alpha-aminopheny-lacetonitrile are synthesized, and then condensed according to a conventional condensation method, and the cyano acidamide compound is obtained. The compound can be used for preventing and treating cucumber gray mold, downy mildew, powdery mildew, puccinia sorghi, rice blast, mosquito larvae and the like. The synthetic method is reasonable and easy to operate, and the synthetized compound is novel in structure and large in potential modification and transformation room, can serve as a pesticide activity precursor structure for in-depth study, can serve as an agricultural bactericide, and has potential production and application values.
Description
Technical field
The invention belongs to the organic compound synthesis technical field, particularly kind of cyanic amides and synthetic method thereof and application.
Background technology
There are grave danger in fungal diseases of plants and insect pest to agriculture production, and the generation of all kinds of disease and pests all causes huge loss every year.
Cyano group is common in the organic synthesis and has one of transformation of important practical value.Cyano group more and more is taken seriously in novel pesticide initiative field as an important functional group and an effective active group, such as efficient pesticides Frontline and bromothalonil, the weedicide cyhalofop-butyl, sterilant Guardian, zarilamid and Azoxystrobin etc. have all been brought into play vital role in agriculture production.Along with going deep into of research, cyano group is expected to obtain more new development at compound design and synthetic field, on its using value, be expected to formulate out performance more excellent have desinsection, a cyano derivative of mite, sterilization or weeding activity extremely.
Summary of the invention
The object of the present invention is to provide the kind of cyanic amides.
The present invention also aims to provide the preparation method of kind of cyanic amides.
The present invention also aims to provide the application of kind of cyanic amides aspect the control agricultural pest.
The kind of cyanic amides is characterized in that, described compound has the structure shown in the general formula I:
Wherein,
R
1Be C
1-4Alkyl in any; Be preferably methyl or sec.-propyl;
R
2Be in halogen, aryloxy and the arylthio any; Be preferably in bromine atoms, phenoxy group and the 2,4 dichloro benzene oxygen base any; Described aryloxy is phenoxy group or 2,4 dichloro benzene oxygen base;
R
3Be in alkyl, alkoxyl group, hydroxyl, amino, nitro and the halogen any; Be preferably in alkyl, alkoxyl group and the halogen any;
Described kind of cyanic amides is preferably:
N-(1-cyano group-1-phenylethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-tolyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-methoxyphenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(3-fluorophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(2, the 4-dichlorophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-phenylethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(3-fluorophenyl) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide, 2-bromo-N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-phenylethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-methoxyphenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(3-fluorophenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-bromophenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-fluorophenyl) ethyl)-3-methylbutyryl amine.
The preparation method of kind of cyanic amides comprises the steps:
(1) use the compound shown in the general formula I I to be raw material, obtain the compound shown in the general formula III by esterification, chloro:
R wherein
4Be methyl or ethyl;
(2) use the compound shown in the general formula IV to be raw material, obtain the compound shown in the general formula V with the potassium hydroxide aqueous solution reaction:
(3) use the compound shown in the general formula V and the compound condensation in DMF shown in the general formula III, then hydrolysis obtains the compound shown in the general formula VI:
Wherein, R
5Be halogen;
(4) use the compound shown in the general formula VII to be raw material, in the presence of nitrous acid, amino carried out diazotization, obtain the compound shown in the general formula VIII with the halogen substituted-amino:
(5) use the compound shown in the general formula VIII to be raw material, obtain the compound shown in the general formula I X with ammoniacal liquor, sodium cyanide effect:
(6) under the condition that methylene dichloride, DCC (dicyclohexylcarbodiimide) and DMAP (DMAP) exist, compound shown in general formula VI and the general formula VII and the compound shown in the general formula I X are carried out condensation, namely obtain the compound shown in the general formula I.
Kind of cyanic amides (compound shown in the general formula I), the application in control of agricultural pest: be used for control gray mold of cucumber, oidium, Powdery Mildew, corn rust, rice blast and mosquito larvae etc.
Beneficial effect of the present invention is:
The present invention proposes the cyano-containing compound of a class brand new, and found that this compound has preferably fungicidal activity and insecticidal activity; The synthetic method of this compounds provided by the invention is rationally easily gone, it is large that synthetic compound structure is novel, leeway is transformed in modification, can further investigate as the pesticide activity guide structure, and may be used as disinfectant use in agriculture, have potential production application and be worth.
Embodiment
The present invention will be further described in detail below in conjunction with specific embodiment:
Embodiment 1:N-(1-cyano group-1-phenylethyl)-2-phenoxy group propionic acid amide
(1) preparation R-2-hydroxy-propionic acid ethyl ester
In the 100mL there-necked flask of return line, water trap, thermometer is housed, add 24mL (0.27mol) dehydrated alcohol, 15g (0.11mol) D-ALPHA-Hydroxypropionic acid, 33mL benzene, 0.6mL the vitriol oil is heated to 70 ℃ and keep this temperature 4h, to no longer include moisture out till; Use NaHCO
3It is 7 that solution is adjusted the pH value; Filter, atmospheric distillation is removed benzene, ethanol, and 61 ℃ ~ 63 ℃ cuts are collected in then underpressure distillation under the 18mmHg, get colourless oil liquid, yield 88.4%.
1H-NMR：(300MHz，CDCl
3,ppm)：4.30-4.21(m，3H)，2.96(s，1H),1.42(d,3H,J＝6.93Hz),1.30(t，3H，J＝7.14Hz)。
(2) preparation S-2-chloropropionate
Be equipped with in the 100mL there-necked flask of dropping funnel, prolong, tail gas absorption, add R-2-hydroxy-propionic acid ethyl ester 10g (0.1mol) and the dry pyridine 0.1g that crosses, then be warming up to 60 ℃, drip SOCl
211.09g (0.11mol), reaction 9h; Then cooling is washed till neutrality with saturated sodium bicarbonate solution; Obtain organic phase after leaving standstill, with the organic phase washing, with dried over sodium sulfate, filtration, underpressure distillation, under the 45mmHg, collect 74 ℃ of cuts and get the 9.68g colourless liquid, yield 83.7%.
1H-NMR：(300MHz,CDCl
3,ppm)：4.39(q，1H，J＝6.93Hz)，4.24(q，2H，J=14.25Hz)，1.69(d，3H，J＝6.93Hz)，1.30(t，3H，J＝7.11Hz)。
(3) preparation potassium phenylate
With 31.1g (0.33mol) phenol and 50mL CCl
4Add in the 250mL four-hole bottle, stir the lower 18.48g (0.33mol) of dropping 20% potassium hydroxide aqueous solution, heat release is slightly arranged, solution is added and was continued at stirring at room 5 minutes by the red stain palm fibre, then leaves standstill minute water-yielding stratum; Water layer is concentrated into half of original volume, and brown crystallization is separated out in cooling, filters drying for standby in moisture eliminator.
(4) preparation R-2-phenoxy propionic acid ethyl ester
DMF makes solvent, and 5g (0.037mol) S-2-chloropropionate and 5.8g (0.044mol) potassium phenylate drop into 5 times 50 ℃ of reactions 5 hours in the water of DMF volume with reaction solution, then use ether extraction, drier, concentrated extracting solution; Use sherwood oil: the eluent of ethyl acetate=10:1 is crossed column chromatography, gets colourless liquid, productive rate 64.3%.
1H-NMR：(300MHz,CDCl
3,ppm)：7.29-6.86(m，5H)，4.74(q,1H,J＝7.12Hz)，4.21(q，2H,J＝7.12Hz)，1.64-1.60(m，3H)，1.24(t,3H,J＝7.12Hz)。
(5) preparation R-2-phenoxy propionic acid
Under the room temperature 3.3g (0.017mol) R-2-phenoxy propionic acid ethyl ester is dissolved in the mixed solution of 80mL tetrahydrofuran (THF) and 80mL water, stirs the lower 1.63g (0.068mol) of adding lithium hydroxide, 50 ℃ of lower reactions 5 hours.Steam except tetrahydrofuran (THF), aqueous phase as acidified to pH value is 1 ~ 2, separates out white solid, m.p.104 ~ 106 ℃ yield 84.6%.
1H-NMR：(300MHz,CDCl
3,ppm)：9.13(s，1H)，7.32-7.25(m，2H)，7.02-6.88(m，3H),4.79(q，1H，J＝6.84Hz)，1.65(d，3H，J＝6.84Hz)。
(6) preparation 2-amino-2-phenyl propionitrile
In the 250mL pressure bottle, with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), to the aqueous ethanolic solution that methyl phenyl ketone 18g (150mmol) is dissolved in 80mL50%, stir the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-phenyl propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-phenyl propionitrile hydrochloride 1.0g (5.4mmol) and be dissolved in the 20mL methylene dichloride, add the NaOH aqueous solution of 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours is filtered, get 2-amino-2-phenyl propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-phenylethyl)-2-phenoxy group propionic acid amide
Get 0.75g (4.5mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, under the ice bath, add the dichloromethane solution of dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), DMAP (DMAP) 0.604g (4.95mmol), dropping 2-amino-2-phenyl propionitrile, stirred lower normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, and solid is separated out in filtering, and filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.136 ~ 138 ℃, productive rate: 57.14%;
1H-NMR (300MHz, CDCl
3, ppm): 7.45-6.88 (m, 11H), 4.72 (m, 1H), 1.96,1.93 (ds, 3H), 1.61-1.55 (m, 3H); MS (FAB
+): 293.0 (M-H
+).
Embodiment 2:N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(4-aminomethyl phenyl) propionitrile
In the 250mL pressure bottle, the aqueous ethanolic solution with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), p-methyl aceto phenone 20g (150mmol) are dissolved in 80mL50% stirs the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(4-aminomethyl phenyl) propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-(4-aminomethyl phenyl) propionitrile hydrochloride 1.1g (5.4mmol) and be dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(4-aminomethyl phenyl) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-2-phenoxy group propionic acid amide
Get R-2-phenoxy propionic acid 0.75g (4.5mmol) and be dissolved in the 20mL methylene dichloride, under the ice bath, add the dichloromethane solution of dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), 0.604g (4.95mmol) DMAP (DMAP), dropping 2-amino-2-(4-aminomethyl phenyl) propionitrile, stirred lower normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, and refrigerator overnight is again filtered and is separated out solid, filtrate evaporating column Chromatographic purification (V sherwood oil: V ethyl acetate=5:1), get white solid, m.p.146 ~ 148 ℃, productive rate: 61.87%;
1H-NMR (300MHz, CDCl
3, ppm): 7.37-6.84 (m, 10H), 4.71 (m, 1H), 2.36,2.34 (ds, 3H), 1.96,1.93 (ds, 3H), 1.61-1.55 (m, 3H); MS (FAB
+): 331.0 (M+Na
+).
Embodiment 3:N-(1-cyano group 1-(4-p-methoxy-phenyl) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(4-p-methoxy-phenyl) propionitrile
In the 250mL pressure bottle, sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), p-methoxy-acetophenone 22.5g (150mmol) are dissolved in the aqueous ethanolic solution of 80mL50%, stir the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(4-p-methoxy-phenyl) propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-(4-p-methoxy-phenyl) propionitrile hydrochloride 1.3g (5.4mmol) and be dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(4-p-methoxy-phenyl) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(4-p-methoxy-phenyl) ethyl)-2-phenoxy group propionic acid amide
Get 0.66g (4mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, under the ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP 0.54g (4.4mmol) (DMAP), drip the dichloroethane solution of 2-amino-2-(4-p-methoxy-phenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, solid is separated out in filtering, and filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.158 ~ 160 ℃, productive rate: 68.5%;
1H-NMR (300MHz, CDCl
3, ppm): 7.38-5.82 (m, 11H), 4.73-4.67 (m, 1H), 3.81,3.80 (ds, 3H), 1.96,1.93 (ds, 3H), 1.60-1.54 (m, 3H); MS (FAB
+): 347.0 (M+Na
+).
Embodiment 4:N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(4-chloro-phenyl-) propionitrile
In the 250mL pressure bottle, the aqueous ethanolic solution with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), parachloroacetophenone 23g (150mmol) are dissolved in 80mL50% stirs the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(4-chloro-phenyl-) propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-(4-chloro-phenyl-) propionitrile hydrochloride 1.4g (5.4mmol) and be dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(4-chloro-phenyl-) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide
Get 0.66g (4mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, under the ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP 0.54g (DMAP) (4.4mmol), drip the dichloroethane solution of 2-amino-2-(4-chloro-phenyl-) propionitrile, stirred lower normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.154 ~ 156 ℃, productive rate: 51.30%;
1H-NMR (300MHz, CDCl
3, ppm): 7.39-6.90 (m, 10H), 4.74-4.70 (m, 1H), 1.91,1.90 (ds, 3H), 1.67-1.53 (m, 3H); MS (FAB
+): 327.0 (M-H
+).
Embodiment 5:N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(3-chloro-phenyl-) propionitrile
In the 250mL pressure bottle, the aqueous ethanolic solution with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), m chloroacetophenone 23g (150mmol) are dissolved in 80mL50% stirs the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(3-chloro-phenyl-) propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-(3-chloro-phenyl-) propionitrile hydrochloride 1.4g (5.4mmol) and be dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(3-chloro-phenyl-) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide
Get 0.66g (4mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), drip 2-amino-2-(3-chloro-phenyl-) propionitrile dichloroethane solution, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.158 ~ 160 ℃, productive rate: 63.4%;
1H-NMR (300MHz, CDCl
3, ppm): 7.42-6.91 (m, 10H), 4.75-4.71 (m, 1H), 1.90 (s, 3H), 1.62-1.54 (m, 3H); MS (FAB
+): 351.0 (M+Na
+).
Embodiment 6:N-(1-cyano group-1-(3-bromophenyl) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(3-bromophenyl) propionitrile
In the 250mL pressure bottle, the aqueous ethanolic solution with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), a bromoacetophenone 30g (150mmol) are dissolved in 80mL50% stirs the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(3-bromophenyl) propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-(3-bromophenyl) propionitrile hydrochloride 1.41g (5.4mmol) and be dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(3-bromophenyl) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(3-bromophenyl) ethyl)-2-phenoxy group propionic acid amide
Get 0.66g (4mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), drip 2-amino-2-(3-bromophenyl) propionitrile dichloromethane solution, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.150 ~ 152 ℃, productive rate: 69.4%;
1H-NMR (300MHz, CDCl
3, ppm): 7.57-6.90 (m, 10H), 4.75-4.68 (m, 1H), 1.90 (s, 3H), 1.64-1.52 (m, 3H); MS (FAB
+): 395 (M+Na
+).
Embodiment 7:N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(4-bromophenyl) propionitrile
In the 250mL pressure bottle, the aqueous ethanolic solution with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), parabromoacetophenone 30g (150mmol) are dissolved in 80mL50% stirs the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(4-bromophenyl) propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-(4-bromophenyl) propionitrile hydrochloride 1.41g (5.4mmol) and be dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(4-bromophenyl) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-phenoxy group propionic acid amide
Get 0.66g (4mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, under the ice bath, the dichloroethane solution that adds dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), dropping 2-amino-2-(4-bromophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.184 ~ 186 ℃, productive rate: 33.78%;
1H-NMR (300MHz, CDCl
3, ppm): 7.55-6.91 (m, 10H), 4.74-4.72 (m, 1H), 1.90 (s, 3H), 1.59-1.53 (m, 3H); MS (FAB
+): 394.9 (M+Na
+).
Embodiment 8:N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(4-fluorophenyl) propionitrile
In the 250mL pressure bottle, with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), to the aqueous ethanolic solution that fluoro acetophenone 20g (150mmol) is dissolved in 80mL50%, stir the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(4-fluorophenyl) propionitrile hydrochloride, filter, vacuum-drying, cryopreservation.
Get 2-amino-2-(4-fluorophenyl) propionitrile hydrochloride 1.1g (5.4mmol) and be dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(4-fluorophenyl) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-phenoxy group propionic acid amide
Get 0.66g (4mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, under the ice bath, the dichloromethane solution that adds dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), dropping 2-amino-2-(4-fluorophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.121 ~ 123 ℃, productive rate: 41.9%;
1H-NMR (300MHz, CDCl
3, ppm): 7.36-6.87 (m, 10H), 4.74-4.68 (m, 1H), 1.93,1.92 (ds, 3H), 1.61-1.53 (m, 3H); MS (FAB
+): 311.0 (M-H
+).
Embodiment 9:N-(1-cyano group-1-(2,4 dichloro benzene base) ethyl)-2-phenoxy group propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) S-2-chloropropionate; (3) potassium phenylate; (4) R-2-phenoxy propionic acid ethyl ester; (5) preparation of R-2-phenoxy propionic acid is all with embodiment 1;
(6) preparation 2-amino-2-(2,4 dichloro benzene base) propionitrile
In the 250mL pressure bottle, with sodium cyanide 8.5g (172mmol), ammonium chloride 9.2g (172mmol), 2,4-dichloroacetophenone 30g (150mmol) is dissolved in the aqueous ethanolic solution of 80mL50%, stirs the lower strong aqua 20mL that adds, 65 ℃ of lower reactions 8 hours.React complete, cooling is with reaction mixture impouring 300mL mixture of ice and water, the ethylene dichloride of 3 * 50mL extracts, the water washing organic phase of 4 * 50mL, anhydrous magnesium sulfate drying, filter, precipitation is dissolved in the 150mL anhydrous diethyl ether with resistates, pass into dry hydrogen chloride gas under 0 ℃, produce a large amount of pale precipitations, be 2-amino-2-(2, the 4-dichlorophenyl) propionitrile hydrochloride, filter vacuum-drying, cryopreservation.
Get 2-amino-2-(2, the 4-dichlorophenyl) propionitrile hydrochloride 1.41g (5.4mmol) is dissolved in the 20mL methylene dichloride, the NaOH aqueous solution that adds 10mL10%, stir 10min, separatory, anhydrous sodium sulfate drying organic phase 3 hours, filter, get 2-amino-2-(2,4 dichloro benzene base) propionitrile dichloromethane solution, for subsequent use;
(7) preparation N-(1-cyano group-1-(2,4 dichloro benzene base) ethyl)-2-phenoxy group propionic acid amide
Get 0.58g (3.5mmol) R-2-phenoxy propionic acid and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.85g (4mmol), DMAP (DMAP) 0.5g (4mmol), drip 2-amino-2-(2, the 4-dichlorophenyl) dichloromethane solution of propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column Chromatographic purification (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.142 ~ 144 ℃, productive rate: 54.33%;
1H-NMR (300MHz, CDCl
3, ppm): 7.81-6.90 (m, 9H), 4.73-4.67 (m, 1H), 2.15,2.09 (ds, 3H), 1.59-1.52 (m, 3H); MS (FAB
+): 385.1 (M+Na
+).
Embodiment 10:N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) preparation of S-2-chloropropionate is all with embodiment 1;
(3) preparation 2,4 dichloro phenol potassium
With 10g (0.06mol) 2,4 dichloro phenol and 20mL CCl
4Add in the 250mL four-hole bottle, 20% the aqueous solution that stirs that the lower 3.44g (0.33mol) of dropping potassium hydroxide is made into slightly has heat release, solution is by the red stain palm fibre, add and continued at stirring at room 5 minutes, static, minute water-yielding stratum, be concentrated into half of original volume, colourless crystallization is analysed in cooling, filters, and is dry in moisture eliminator, get the 12g colourless crystallization, productive rate 97.32%.
(4) preparation R-2-(2,4 dichloro benzene oxygen base) ethyl propionate
In 50 ℃ of reactions, the some plate detects in 20mL DMF for S-2-chloropropionate 5g (0.037mol) and 2,4 dichloro phenol potassium 8.1g (0.04mol), and reaction finishes afterreaction liquid and drops into 5 times in the water of DMF, ether extraction, and drying, concentrated; Use the petrol ether/ethyl acetate column chromatography, get weak yellow liquid, productive rate 92.7%.
(5) preparation R-2-(2,4 dichloro benzene oxygen base) propionic acid
R-2-(2,4 dichloro benzene oxygen base) ethyl propionate 0.88g (3.35mmol) is dissolved in the mixed solution of 10mL tetrahydrofuran (THF) and 10mL water, stirs the lower lithium hydroxide 0.32g (13.4mmol) of adding, 50 ℃ of lower reactions 5 hours.Steam except tetrahydrofuran (THF), aqueous phase as acidified to pH value is 1 ~ 2, separates out white solid, m.p.98 ~ 100 ℃, yield 80.77%.
1H-NMR：(300MHz,CDCl
3，ppm)：7.39-6.79(m,3H),4.74(q,1H,J＝6.86Hz),1.68(d，3H,J＝6.86Hz)。
(6) preparation of preparation 2-amino-2-(4-aminomethyl phenyl) propionitrile is with reference to embodiment 2.
(7) preparation N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
Get R-2-(2, the 4-dichlorophenoxy) propionic acid 1.06g (4.5mmol) is dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), DMAP (DMAP) 0.6g (4.95mmol), drip the dichloroethane solution of 2-amino-2-(4-aminomethyl phenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.166 ~ 168 ℃, productive rate: 65.3%;
1H-NMR (300MHz, CDCl
3, ppm): 7.44-6.84 (m, 8H), 4.74-4.68 (m, 1H), 2.37,2.35 (ds, 3H), 2.01,1.98 (ds, 3H), 1.66-1.57 (m, 3H); MS (FAB
+): 399.0 (M+Na
+).
Embodiment 11:N-(1-cyano group-1-phenylethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) preparation of S-2-chloropropionate is all with embodiment 1;
(3) 2,4 dichloro phenol potassium; (4) R-2-(2,4 dichloro benzene oxygen base) ethyl propionate; (5) preparation of R-2-(2,4 dichloro benzene oxygen base) propionic acid is all with embodiment 10;
(6) preparation of 2-amino-2-phenyl propionitrile is with embodiment 1;
(7) preparation N-(1-cyano group-1-phenylethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
Get R-2-(2, the 4-dichlorophenoxy) propionic acid 1.06g (4.5mmol) is dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), DMAP (DMAP) 0.6g (4.95mmol), drip the dichloroethane solution of 2-amino-2-phenyl propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.108 ~ 110 ℃, productive rate: 36%;
1H-NMR (300MHz, CDCl
3, ppm): 7.56-6.84 (m, 9H), 4.75-4.70 (m, 1H), 2.02,1.99 (ds, 3H), 1.67-1.56 (m, 3H); MS (FAB
+): 385.0 (M+Na
+).
Embodiment 12:N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) preparation of S-2-chloropropionate is all with embodiment 1;
(3) 2,4 dichloro phenol potassium; (4) R-2-(2,4 dichloro benzene oxygen base) ethyl propionate; (5) preparation of R-2-(2,4 dichloro benzene oxygen base) propionic acid is all with embodiment 10;
(6) preparation of 2-amino-2-(4-chloro-phenyl-) propionitrile is all with embodiment 4;
(7) preparation N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
Get R-2-(2, the 4-dichlorophenoxy) propionic acid 0.94g (4mmol) is dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), drip the dichloromethane solution of 2-amino-2-(4-chloro-phenyl-) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (petrol ether/ethyl acetate=5/1) gets white solid, m.p.102 ~ 104 ℃, productive rate: 49.7%;
1H-NMR (300MHz, CDCl
3, ppm): 7.50-6.84 (m, 8H), 4.77-4.66 (m, 1H), 1.98,1.97 (ds, 3H), 1.66-1.57 (m, 3H); MS (FAB
+): 419.0 (M+Na
+).
Embodiment 13:N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) preparation of S-2-chloropropionate is all with embodiment 1;
(3) 2,4 dichloro phenol potassium; (4) R-2-(2,4 dichloro benzene oxygen base) ethyl propionate; (5) preparation of R-2-(2,4 dichloro benzene oxygen base) propionic acid is all with embodiment 10;
(6) preparation of 2-amino-2-(3-chloro-phenyl-) propionitrile is all with embodiment 5;
(7) preparation N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
Get R-2-(2, the 4-dichlorophenoxy) propionic acid 0.94g (4mmol) is dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), drip the dichloromethane solution of 2-amino-2-(3-chloro-phenyl-) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.114 ~ 116 ℃, productive rate: 47.8%;
1H-NMR (300MHz, CDCl
3, ppm): 7.49-6.85 (m, 8H), 4.76-4.70 (m, 1H), 1.97,1.98 (ds, 3H), 1.67-1.56 (m, 3H); MS (FAB
+): 419.0 (M+Na
+).
Embodiment 14:N-(1-cyano group-1-(3-bromophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) preparation of S-2-chloropropionate is all with embodiment 1;
(3) 2,4 dichloro phenol potassium; (4) R-2-(2,4 dichloro benzene oxygen base) ethyl propionate; (5) preparation of R-2-(2,4 dichloro benzene oxygen base) propionic acid is all with embodiment 10;
(6) preparation of 2-amino-2-(3-bromophenyl) propionitrile is with embodiment 6;
(7) preparation N-(1-cyano group-1-(3-bromophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
Get R-2-(2, the 4-dichlorophenoxy) propionic acid 0.94g (4mmol) is dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), drip the dichloromethane solution of 2-amino-2-(3-bromophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.106 ~ 108 ℃, productive rate: 46.1%;
1H-NMR (300MHz, CDCl
3, ppm): 7.65-6.85 (m, 8H), 4.78-4.68 (m, 1H), 1.98,1.97 (ds, 3H), 1.68-1.56 (m, 3H); MS (FAB
+): 465 (M+Na
+).
Embodiment 15:N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) preparation of S-2-chloropropionate is all with embodiment 1;
(3) 2,4 dichloro phenol potassium; (4) R-2-(2,4 dichloro benzene oxygen base) ethyl propionate; (5) preparation of R-2-(2,4 dichloro benzene oxygen base) propionic acid is all with embodiment 10;
(6) preparation of 2-amino-2-(4-bromophenyl) propionitrile is all with embodiment 7;
(7) preparation N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
Get R-2-(2, the 4-dichlorophenoxy) propionic acid 0.82g (3.5mmol) is dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.8g (3.85mmol), DMAP (DMAP) 0.47g (3.85mmol), drip the dichloromethane solution of 2-amino-2-(4-bromophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.176 ~ 178 ℃, productive rate: 33.1%;
1H-NMR (300MHz, CDCl
3, ppm): 7.52-6.84 (m, 8H), 4.70-4.57 (m, 1H), 1.98 (s, 3H), 1.66-1.57 (d, 3H); MS (FAB
+): 464.9 (M+Na
+).
Embodiment 16:N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
(1) R-2-hydroxy-propionic acid ethyl ester; (2) preparation of S-2-chloropropionate is all with embodiment 1;
(3) 2,4 dichloro phenol potassium; (4) R-2-(2,4 dichloro benzene oxygen base) ethyl propionate; (5) preparation of R-2-(2,4 dichloro benzene oxygen base) propionic acid is all with embodiment 10;
(6) preparation of 2-amino-2-(4-fluorophenyl) propionitrile is all with embodiment 8;
(7) preparation N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide
Get R-2-(2, the 4-dichlorophenoxy) propionic acid 0.94g (4mmol) is dissolved in the 20mL methylene dichloride, under the ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), drip the dichloromethane solution of 2-amino-2-(4-fluorophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.106 ~ 108 ℃, productive rate: 68.4%;
1H-NMR (300MHz, CDCl
3, ppm): 7.55-6.84 (m, 8H), 4.75-4.68 (m, 1H), 2.00,1.98 (ds, 3H), 1.66-1.57 (dd, 3H); MS (FAB
+): 403.0 (M+Na
+).
Embodiment 17:2-bromo-N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-3-methylbutyryl amine
(1) preparation S-2-bromo-3 Methylbutanoic acid
In the four-hole bottle of 1L, add 75mL toluene, 75mL water, 40% HBr156mL (1.15mol) stirs and is down to 0 ℃; Once add Valine 48.1g (0.41mol), temperature can slowly rise to 3.5 ℃, is cooled to-5 ℃, drips 36.85g (0.54mol) NaNO
2Be dissolved in the aqueous solution of 80mL water, added in 6 hours, solution becomes is to dark-brown, and after dripping off ,-5 ℃ are continued reaction 3h, use the 125mL dilution with toluene, are warming up to 20 ℃ of reactions 12 hours.Separate organic phase, water merges organic phase with the extraction of 150mL toluene, uses 20%Na
2S
2O
3Solution 100mL lotion, rear with 20%NaCl solution 100mL lotion, the organic phase precipitation, oil pump is drained.The 52g faint yellow solid, m.p.32 ~ 34 ℃, productive rate 70%;
(2) preparation of 2-amino-2-(4-aminomethyl phenyl) propionitrile is with embodiment 2;
(3) preparation 2-bromo-N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.8g (4.4mmol) and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), DMAP (DMAP) 0.6g (4.95mmol), drip the dichloromethane solution of 2-amino-2-(4-aminomethyl phenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.188 ~ 190 ℃, productive rate: 58.04%;
1H-NMR (300MHz, CDCl
3, ppm): 7.45-6.96 (m, 5H), 4.34-4.28 (m, 1H), 2.40,2.39 (ds, 3H), 2.00,1.99 (ds, 3H), 1.08-1.01 (dd, 6H); MS (FAB
+): 347.0 (M+Na
+).
Embodiment 18:2-bromo-N-(1-cyano group-1-phenylethyl)-3-methylbutyryl amine
(1) preparation of S-2-bromo-3 Methylbutanoic acid is with embodiment 17;
(2) preparation of 2-amino-2-phenyl propionitrile is with embodiment 1;
(3) preparation 2-bromo-N-(1-cyano group-1-phenylethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.8g (4.4mmol) and be dissolved in the 20mL methylene dichloride, under the ice bath, add dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), DMAP (DMAP) 0.6g (4.95mmol), drip the dichloromethane solution of 2-amino-2-phenyl propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.184 ~ 185 ℃, productive rate: 60%;
1H-NMR (300MHz, CDCl
3, ppm): 7.55-7.05 (m, 6H), 4.34-4.27 (dd, 1H), 2.41-2.40 (m, 1H), 1.99,1.98 (ds, 3H), 1.08-1.02 (m, 6H); MS (FAB
+): 331.0 (M+Na
+).
Embodiment 19:2-bromo-N-(1-cyano group-1-(4-p-methoxy-phenyl) ethyl)-3-methylbutyryl amine
(1) preparation of S-2-bromo-3 Methylbutanoic acid is with embodiment 17;
(2) preparation of 2-amino-2-(4-p-methoxy-phenyl) propionitrile is with embodiment 3;
(3) preparation 2-bromo-N-(1-cyano group-1-(4-p-methoxy-phenyl) ethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.9g (5mmol) and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.13g (5.5mmol), DMAP (DMAP) 0.67g (5.5mmol), drip the dichloromethane solution of 2-amino-2-(4-p-methoxy-phenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.160 ~ 162 ℃, productive rate: 42.6%;
1H-NMR (300MHz, CDCl
3, ppm): 7.49-6.93 (m, 5H), 4.34-4.28 (dd, 1H), 2.30 (m, 1H), 2.00,1.99 (ds, 3H), 1.08-0.93 (m, 6H); MS (FAB
+): 339 (M+H
+).
Embodiment 20:2-bromo-N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-3-methylbutyryl amine
(1) preparation of S-2-bromo-3 Methylbutanoic acid is with embodiment 17;
(2) preparation of 2-amino-2-(4-chloro-phenyl-) propionitrile is with embodiment 4;
(3) 2-bromo-N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.9g (5mmol) and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.13g (5.5mmol), DMAP (DMAP) 0.67g (5.5mmol), drip the dichloromethane solution of 2-amino-2-(4-chloro-phenyl-) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.164 ~ 166 ℃, productive rate: 36.8%;
1H-NMR (300MHz, CDCl
3, ppm): 7.50-7.25 (m, 5H), 4.27-4.23 (m, 1H), 2.40-2.31 (m, 1H), 1.92,1.91 (ds, 3H), 1.05-0.95 (m, 6H); MS (FAB
+): 342.9 (M-H
+).
Embodiment 21:2-bromo-N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-3-methylbutyryl amine
(1) preparation of S-2-bromo-3 Methylbutanoic acid is with embodiment 17;
(2) preparation of 2-amino-2-(3-chloro-phenyl-) propionitrile is with embodiment 5;
(3) preparation 2-bromo-N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.72g (4mmol) and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 0.91g (4.4mmol), DMAP (DMAP) 0.54g (4.4mmol), drip the dichloromethane solution of 2-amino-2-(3-chloro-phenyl-) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.166 ~ 168 ℃, productive rate: 65%;
1H-NMR (300MHz, CDCl
3, ppm): 7.50-7.05 (m, 5H), 4.35-4.29 (dd, 1H), 2.44-2.36 (m, 1H), 1.97,1.96 (dd, 3H), 1.08-0.94 (m, 6H); MS (FAB
+): 342.9 (M-H
+).
Embodiment 22:2-bromo-N-(1-cyano group-1-(3-bromophenyl) ethyl)-3-methylbutyryl amine
(1) preparation of S-2-bromo-3 Methylbutanoic acid is with embodiment 17;
(2) preparation of 2-amino-2-(3-bromophenyl) propionitrile is with embodiment 6;
(3) 2-bromo-N-(1-cyano group-1-(3-bromophenyl) ethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.8g (4.5mmol) and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), DMAP (DMAP) 0.6g (4.95mmol), drip the dichloromethane solution of 2-amino-2-(3-bromophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (petrol ether/ethyl acetate=5/1) gets white solid, m.p.170 ~ 172 ℃, productive rate: 59.3%;
1H-NMR (300MHz, CDCl
3, ppm): 7.64-7.01 (m, 5H), 4.29-4.27 (dd, 1H), 2.43-2.37 (m, 1H), 1.96 (s, 3H), 1.08-0.95 (m, 6H); MS (FAB
+): 386.9 (M-H
+).
Embodiment 23:2-bromo-N-(1-cyano group-1-(4-bromophenyl) ethyl)-3-methylbutyryl amine
(1) preparation of S-2-bromo-3 Methylbutanoic acid is with embodiment 17;
(2) preparation of 2-amino-2-(4-bromophenyl) propionitrile is with embodiment 7;
(3) preparation 2-bromo-N-(1-cyano group-1-(4-bromophenyl) ethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.9g (5mmol) and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.13g (5.5mmol), DMAP (DMAP) 0.67g (5.5mmol), drip the dichloromethane solution of 2-amino-2-(4-bromophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.158 ~ 160 ℃, productive rate: 47.7%;
1H-NMR (300MHz, CDCl
3, ppm): 7.58-7.12 (m, 5H), 4.31-4.25 (dd, 1H), 2.43-2.31 (m, 1H), 1.95 (s, 3H), 1.17-0.93 (m, 6H); MS (FAB
+): 386.8 (M-H
+).
Embodiment 24:2-bromo-N-(1-cyano group-1-(4-fluorophenyl) ethyl)-3-methylbutyryl amine
(1) preparation of S-2-bromo-3 Methylbutanoic acid is with embodiment 17;
(2) preparation of 2-amino-2-(4-fluorophenyl) propionitrile is with embodiment 8;
(3) preparation 2-bromo-N-(1-cyano group-1-(4-fluorophenyl) ethyl)-3-methylbutyryl amine
Get S-2-bromo-3 Methylbutanoic acid 0.8g (4.5mmol) and be dissolved in the 20mL methylene dichloride, ice bath, add dicyclohexylcarbodiimide (DCC) 1.02g (4.95mmol), DMAP (DMAP) 0.6g (4.95mmol), drip the dichloromethane solution of 2-amino-2-(4-fluorophenyl) propionitrile, normal-temperature reaction 5 hours.Filter, removal of solvent under reduced pressure, resistates adds ethyl acetate, refrigerator overnight, the solid that filtering is separated out, filtrate evaporating column chromatography (V sherwood oil/V ethyl acetate=5/1) gets white solid, m.p.160 ~ 162 ℃, productive rate: 55.86%;
1H-NMR (300MHz, CDCl
3, ppm): 7.56-7.00 (m, 5H), 4.35-4.29 (dd, 1H), 2.44-2.36 (m, 1H), 1.99,1.98 (ds, 3H), 1.08-0.88 (m, 6H); MS (FAB
+): 349.0 (M+Na
+).
Embodiment 25: the fungicidal activity test of compound
According to People's Republic of China's agricultural industry criteria (NY/T1156.2-2006), adopt the mycelial growth rate method to measure.The inhibition of having measured the various plants pathogenic bacteria mycelial growth rates such as target compound apple wheel line bacterium, botrytis cinerea, Sclerotinia sclerotiorum, gibberella saubinetii, tomato early epidemic, potato late blight, rice banded sclerotial blight, Phytophthora capsici, cucumber wither, peanut Cercospora bacteria is active, result such as table 1; Part of compounds has been measured the live body fungicidal activity to oidium, Powdery Mildew, corn rust and rice blast, result such as table 2.
Table-1: the fungicidal activity data (Plating) of compound
Table-2: the live body fungicidal activity data of compound
Embodiment 26: the insecticidal activity test of compound
Choosing mythimna separata and larvae is tested object, target compound has been carried out active primary dcreening operation contrast, testing method is for coming treatment of selected examination worm take the target compound diluting soln: to the mythimna separata concentration for the treatment of as 600ppm, be 5ppm to the mosquito larvae concentration for the treatment of, testing method is tested according to national standard method.Under 600ppm concentration, process mythimna separata, under 5ppm concentration, process mosquito larvae, active as table-3:
The active lethality rate of desinsection primary dcreening operation when table-3:600ppm and 5ppm concentration
Can be found out by embodiment 25, kind of cyanic compound provided by the invention has preferably inhibition active to cucumber grey mold, rape sclerotium, apple wheel line aspect sterilization, inhibiting rate reaches as high as 67.2% when killing the cucumber grey mold when 50 μ g/mL, also has certain inhibition active to other tested bacterium; Embodiment 3 inhibiting rate to Powdery Mildew when 400 μ g/mL reaches 100%, inhibiting rate to corn rust reaches 85%, we are reduced to 100 μ g/mL, 25 μ g/mL to concentration in addition, the inhibiting rate of 3 pairs of Powdery Mildews of embodiment is respectively 65%, 60%, and concentration is reduced to 6.25 μ g/mL still 50% inhibiting rate; Embodiment 15 inhibiting rate to Powdery Mildew and corn rust when 400 μ g/mL all reaches 100%, when concentration is reduced to 100 μ g/mL and 25 μ g/mL, the inhibiting rate of Powdery Mildew is respectively 70% and 40%; Embodiment 14,16 pairs of rice blast inhibitions are better, and embodiment 12,16,24 pairs of oidium inhibitions are better; Insecticidal activity aspect, this compounds generally demonstrate under different concns has the activity of causing death to mosquito larvae, and its rate under 5ppm reaches as high as 70%.
Claims (7)
1. the kind of cyanic amides is characterized in that, described compound has the structure shown in the formula I:
Wherein,
R
1Be C
1-4Alkyl in any;
R
2Be in halogen, aryloxy and the arylthio any; Described aryloxy is phenoxy group or 2,4 dichloro benzene oxygen base;
R
3Be in alkyl, alkoxyl group, hydroxyl, amino, nitro and the halogen any.
2. kind of cyanic amides according to claim 1 is characterized in that R
1Be methyl or sec.-propyl.
3. kind of cyanic amides according to claim 1 is characterized in that R
2Be in bromine atoms, phenoxy group and the 2,4 dichloro benzene oxygen base any.
4. kind of cyanic amides according to claim 1 is characterized in that R
3Be in alkyl, alkoxyl group and the halogen any.
5. kind of cyanic amides according to claim 1 is characterized in that, described kind of cyanic amides is:
N-(1-cyano group-1-phenylethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-tolyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-methoxyphenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(3-fluorophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(2, the 4-dichlorophenyl) ethyl)-2-phenoxy group propionic acid amide, N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-phenylethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(3-fluorophenyl) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(4-bromophenyl) ethyl)-2-(2, the 4-dichlorophenoxy) propionic acid amide, N-(1-cyano group-1-(4-fluorophenyl) ethyl)-2-(2,4 dichloro benzene oxygen base) propionic acid amide, 2-bromo-N-(1-cyano group-1-(4-aminomethyl phenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-phenylethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-methoxyphenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-chloro-phenyl-) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(3-chloro-phenyl-) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(3-fluorophenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-bromophenyl) ethyl)-3-methylbutyryl amine, 2-bromo-N-(1-cyano group-1-(4-fluorophenyl) ethyl)-3-methylbutyryl amine.
6. the preparation method of kind of cyanic amides claimed in claim 1 is characterized in that, comprises the steps:
(1) use the compound shown in the general formula II to be raw material, obtain the compound shown in the general formula III by esterification, chloro:
R wherein
4Be methyl or ethyl;
(2) use the compound shown in the general formula IV to be raw material, obtain the compound shown in the general formula V with the potassium hydroxide aqueous solution reaction:
(3) use the compound shown in the general formula V and the compound condensation in DMF shown in the general formula III, then hydrolysis obtains the compound shown in the general formula VI:
Wherein, R
5Be halogen;
(4) use the compound shown in the general formula VII to be raw material, in the presence of nitrous acid, amino carried out diazotization, obtain the compound shown in the general formula VIII with the halogen substituted-amino:
(5) use the compound shown in the general formula VIII to be raw material, obtain the compound shown in the general formula IX with ammoniacal liquor, sodium cyanide effect:
(6) under the condition that methylene dichloride, DCC and DMAP exist, the compound shown in general formula VI and the general formula VII and the compound shown in the general formula IX are carried out condensation, namely obtain the compound shown in the formula I.
7. the application of kind of cyanic amides claimed in claim 1 in control of agricultural pest is characterized in that, is used for control gray mold of cucumber, oidium, Powdery Mildew, corn rust, rice blast and mosquito larvae.
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