CN104016886A - N-1,2-disubstituted ethyl valinamide carbamate derivative and application thereof - Google Patents
N-1,2-disubstituted ethyl valinamide carbamate derivative and application thereof Download PDFInfo
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- CN104016886A CN104016886A CN201410280228.0A CN201410280228A CN104016886A CN 104016886 A CN104016886 A CN 104016886A CN 201410280228 A CN201410280228 A CN 201410280228A CN 104016886 A CN104016886 A CN 104016886A
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- DNLOZHQIICYKBJ-YSYXNDDBSA-N CCCC(c(cc1)cc(OC)c1OC)NC([C@H](C(C)C)NC(OC(C)C)=C=C)=O Chemical compound CCCC(c(cc1)cc(OC)c1OC)NC([C@H](C(C)C)NC(OC(C)C)=C=C)=O DNLOZHQIICYKBJ-YSYXNDDBSA-N 0.000 description 1
Abstract
The invention belongs to the field of plant bactericides, and relates to a N-1,2-disubstituted ethyl valinamide carbamate derivative as shown in formula (I) and a pharmaceutically acceptable salt thereof, wherein substituent groups R<1>, R<2> and Rn are defined in the specification. The invention further relates to a preparation method for the compound with the formula (I), an intermediate specially developed for preparing the compound and application of the compound in preventing and controlling plant diseases.
Description
Technical field
The invention belongs to pesticide field, particularly N-1,2-bis-replaces ethyl valine amide carbamate derivatives and applies as sterilant.
Background technology
In agriculture production, be often subject to the harm of the harmful organisms such as worm, grass, bacterium and cause that grain drop in production even has no harvest.Oomycete pathogenic bacteria is the important pathogenic bacteria of the upper class of agricultural, and host range is wide, comprises vegetables, fruit, flowers, forest, cotton, fiber crops, the various crops of wet goods.Oomycetes phytopathogen is strong to the destructiveness of host plant, hazardness is large, short incubation period, infect frequently again, thereby within a season of growth for plant, germ can blaze about infects, and is difficult to control, thereby causes the serious loss in agroforestry.
Valine amide carbamate fungicide is the sterilant of the novel structure of one class preventing and control plant Oomycete disease, and its mechanism of action is different from the phenyl amide series bactericidal agent of original treatment Oomycete.This series bactericidal agent is developed by Beyer Co., Ltd the end of the nineties in last century and is come into operation, and with widely used sterilant in the market without mutual resistance.Raw material is simple, and cost is low, is easy to suitability for industrialized production, and its degraded product is environmentally friendly.The use of this sterilant has been played vital role to administering all multiresistance pathogenic bacterias that caused by the unreasonable use of benzamides sterilant.Therefore, valine amide carbamate derivatives has caused showing great attention to of world Ge great Nong Hua company in recent years, drops into one after another huge fund for the research and development of this series bactericidal agent.The valine amide carbamate fungicide of recent development development mainly comprises iprovalicarb (Dutzmann, Pflanzenschutz Nachrichten Bayer, 1999,52 (1): 15-32), benzene metsulfovax (Reuveni, Eur J Plant Pathol, 2003,109:243-251), different benzene metsulfovax (Miyakeetal, JP 08325235,2005) and Valiphenal (Gisietal, Modern Crop Protection Compounds, 2007:651-671).
The present invention is optimized the amino part of valine amide amino formate compounds, and a series of valine amide compounds have been synthesized in design, and through the fungicidal activity test to various plants pathogenic bacterium, result shows that the compounds of this invention has good fungicidal activity.
Summary of the invention
The object of the present invention is to provide a kind of N-1,2-bis-replaces ethyl valine amide carbamate derivatives.This compounds has excellent fungicidal activity, prepares medicine and has a extensive future.
N-1 provided by the invention, it is compound or its pharmacy acceptable salt with following general formula (I) that 2-bis-replaces ethyl valine amide carbamate derivatives:
Wherein, R
1hydrogen, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6alkynyl, benzyl, described benzyl benzene ring hydrogen is optionally selected from halogen, hydroxyl, cyano group, C by 1-5
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6the substituting group of alkynyl replaces, R
1be preferably hydrogen, methyl, ethyl, propargyl;
R
2be an optional 1-5 substituting group, be selected from hydrogen, hydroxyl, cyano group, halogen, C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6alkynyl, benzyloxy, phenyl, described benzyloxy and phenyl benzene ring hydrogen are optionally selected from halogen, hydroxyl, C by 1-5
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6the substituting group of alkynyl replaces, R
2be preferably hydrogen, methyl, ethyl, halogen, methoxyl group;
N is 0 to 5 integer, preferentially selects 0,1.
In addition, the present invention relates to the purposes as bactericide suc as formula (I) defined compound.
In the present invention, term " alkyl " refers to the stable hydrocarbon of straight or branched.This type of substituent example includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl.
Equally, term " alkoxyl group " refers to the saturated alkoxyl group of straight or branched.This type of substituent example includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy.
Term " thiazolinyl " refers to the thiazolinyl of straight or branched, and this type of substituent example includes but not limited to vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1-pentenyl, 1-hexenyl.
Term " alkynyl " refers to the alkynyl of straight or branched, and this type of substituent example includes but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, 1-hexin base.
Term " haloalkyl " is straight or branched alkyl, and on these alkyl, hydrogen atom can partly or entirely be replaced by halogen atom; Definition and the term " haloalkyl " of term " halogenated alkoxy ", " haloalkenyl group ", " halo alkynyl " are similar.
Term " halogen " refers to fluorine, chlorine, bromine, iodine.
The present invention further provides pesticide composition, its formula that comprises significant quantity (I) compound and carrier.The present invention also provides pesticide composition, one of disclosed particular compound of embodiment part that it comprises significant quantity and carrier.
The compounds of this invention (I) syntheti c route is as follows, prepared by the method that all raw materials are all methods by describing in these signal formulas, know by organic chemistry filed those of ordinary skill or can business buy.All final compounds of the present invention are all the methods by describing in these signal formulas or prepare by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.
According to general formula of the present invention (I) compound, R
1, R
2, n defines as summary of the invention.
Work as R
1for methyl, during n=0, the synthetic route of general formula compound 10 is:
In synthetic route, compound 1 methyl is turned to compound 2, compound 2 passes through bromo-reaction, obtain compound 3, compound 3 obtains compound 4 with the phenol reactant replacing, compound 4 obtains compound 5 with oxammonium hydrochloride, and compound 5 reduction obtain compound 6, and compound 6 obtains the compound shown in general formula 10 with compound 9.
The present invention also provides the preparation method of described general formula 10 compounds, and the method comprises the steps:
1) Acetovanillone is dissolved in to methylene dichloride, adds sodium hydroxide, water, add Tetrabutyl amonium bromide to cook phase-transfer catalyst, mechanical stirring.Drip methyl-sulfate, drip off, room temperature continues to stir 2h.After raw material point disappears, stop stirring standing separatory, organic solvent extraction water layer, by after strong aqua dilution, backwash organic layer twice, dried over mgso organic layer, precipitation, obtain yellow oil, the standing white solid that becomes, obtains compound 2, and said organic solvent refers to ether, isopropyl ether, ethyl acetate, ethylene dichloride, chloroform or toluene.
2) 3,4-dimethoxy-acetophenone 2 is dissolved in to ethyl acetate, refluxes, add cupric bromide in batches.Add rear continuation backflow 2h.Filter ethyl acetate rinse filter residue.Saturated NaHCO
3solution is washed organic layer, and saturated common salt is washed once.Anhydrous MgSO
4dry organic layer, precipitation.Ethyl alcohol recrystallization, obtains compound 3.
3) fortified phenol is dissolved in to acetone, adds Anhydrous potassium carbonate, stirring at room 1h.Add compound 3, continue to stir 6h.After raw material point disappears, precipitation, organic solvent dissolves again, and sodium hydroxide solution is washed organic layer twice, dried over mgso organic layer, precipitation.Ethyl alcohol recrystallization, obtains compound 4.
4) compound 4 is dissolved in to ethanol, adds oxammonium hydrochloride, add sodium hydroxide, stirring at room 8h in batches.After raw material point disappears, precipitation, dissolves raffinate again with organic solvent, washes organic layer with water, and organic solvent backwash water layer twice merges organic layer, dried over mgso organic layer, precipitation.Product recrystallization obtains compound 5.
5) compound 5 is dissolved in to ethanol, adds 10%Pd/C, concentrated hydrochloric acid.To inflated with nitrogen in autoclave, drive air away, fill hydrogen exchange nitrogen.Fill hydrogen, stirring at room 24h.After having reacted, cross filtering Pd/C, add appropriate concentrated hydrochloric acid, product is converted into ammonium salt completely, precipitation, product recrystallization precipitation being obtained with ethanol.The salt that recrystallization obtains, in ethanol, adds sodium hydrate solid, stirring at room 1h.Precipitation is removed ethanol, and product is dissolved in organic solvent, washing organic layer, anhydrous MgSO
4dry organic layer, precipitation obtains compound 6.
6) by sodium hydroxide water dissolution, add Valine, stir, under low temperature, under condition, isopropyl chlorocarbonate is added drop-wise in reaction solution, drip Bi Shengzhi room temperature, continue to be stirred to and react completely, once, diluted acid adjusts pH to acid to organic solvent washing, organic solvent extraction, dry, precipitation obtains compound 9.
7) compound 6 use THF are dissolved, under cold condition, add alkali and Vinyl chloroformate, under this condition, be stirred to and react completely, compound 9 use THF are dissolved, be added drop-wise in reaction solution, drip Bi Shengzhi room temperature, continue to stir 3h, precipitation, ethyl alcohol recrystallization obtains compound 10, and said alkali refers to sodium carbonate, sodium bicarbonate, salt of wormwood, triethylamine, N-methylmorpholine or pyridine.
Work as R
1for H, during n=0, take Acetovanillone as raw material, directly bromo obtains product 11, then carries out nucleophilic substitution reaction with phenol sodium, obtains product 12, is then made oxime 13, is reduced with hydrogen to amine 14, by mixed anhydride method, obtains target compound 15.Synthetic route is as follows:
Work as R
1during for propargyl, synthetic route is as follows:
This route specific experiment step is as follows:
1) Acetovanillone 1 is dissolved in to ethyl acetate, refluxes, add cupric bromide in batches.1h adds, and continues backflow 2h.Filter ethyl acetate rinse filter residue.Saturated NaHCO
3solution is washed organic layer, and saturated common salt is washed once.MgSO
4dry organic layer, precipitation.The chromatography that reduces pressure, obtains compound 11.
2) fortified phenol sodium is dissolved in DMF, stirs lower temperature control 85-90 ℃, drips the DMF solution of bromo-4-hydroxy 3-methoxybenzene ethyl ketone 11, and add half an hour.Drip off and continue reaction five minutes, stop heating, by the reaction solution frozen water that to pour into salt acid for adjusting pH be 3, organic solvent extraction repeatedly, merging organic layer, water backwash organic layer.Anhydrous magnesium sulfate drying organic layer, filters, precipitation, and product column chromatography, obtains compound 12.
3) compound 12 is added to the water, and adds sodium acetate and oxammonium hydrochloride, stirs backflow 3h.After completion of the reaction, be chilled to room temperature, organic solvent extraction three times, merges organic layer, and anhydrous magnesium sulfate drying organic layer filters precipitation.Product column chromatography, obtains compound 13.
4) compound 13 heating are dissolved in to ethanol, are chilled to room temperature, add Pd/C, concentrated hydrochloric acid.To inflated with nitrogen in autoclave, drive air away, hydrogen exchange nitrogen repeatedly.Fill hydrogen, stirring at room 24h.After completion of the reaction, filter, precipitation, product recrystallization obtains the hydrochloride of compound 14.
5), at-10 ℃, the THF solution of isopropyl chlorocarbonate is dropped in the THF solution of 3-methyl-2-isopropyl oxygen formamido group butyric acid 9 and N-methylmorpholine.1h drips off, and continues to stir two hours.Drip the THF solution of 1-(4-hydroxy 3-methoxybenzene base)-2-substituent phenoxy ethamine.Add half an hour, adds rear room temperature reaction 10h.Filter, precipitation, organic solvent dissolves again, sodium carbonate washing organic layer, dilute hydrochloric acid salt acid elution organic layer, dried over mgso organic layer, precipitation.Ethyl alcohol recrystallization, obtains compound 15.
6) compound 15 is dissolved in to acetone, adds Anhydrous potassium carbonate, stirring at room 1h, the acetone soln of dropping propargyl bromide, drip off half an hour, drips off and change backflow into, backflow 30h.After raw material point no longer changes, precipitation, organic solvent dissolution resistates, sodium hydroxide solution is washed organic layer, washing organic layer, anhydrous magnesium sulfate drying organic layer, precipitation, with ethyl alcohol recrystallization, obtains compound 16.
General formula intermediate 12:
General formula 12 intermediates are for preparing general formula 15 compounds, to develop specially, wherein R
2according to the definition in above-mentioned general formula 15, determine.
General formula intermediate 13:
General formula 13 intermediates are for preparing general formula 15 compounds, to develop specially, wherein R
2according to the definition in above-mentioned general formula 15, determine.
General formula intermediate 14:
General formula 14 intermediates are for preparing general formula 15 compounds, to develop specially, wherein R
2according to the definition in above-mentioned general formula 15, determine.
Work as R
1for methyl, during n=1, by bromo-3,4-dimethoxy-acetophenone 3 is hydrolyzed to 2-hydroxyl-(3,4-Dimethoxyphenyl) ethyl ketone 17, then makes oxime 18, through high pressure, is reduced to amine 19.Through mixed anhydride method, make acid amides 20 again, finally by over hydrogenation sodium, pull out hydroxyl hydrogen, obtain target compound 21 with replacement benzyl bromine reaction.Synthetic route is as follows:
This route concrete steps are as follows:
1) compound 3 is dissolved in ethanol, adds water, adds alkali, backflow 6h.After completion of the reaction, precipitation is removed ethanol, and resistates adds water, is extracted with ethyl acetate, and merges organic layer, and anhydrous magnesium sulfate drying organic layer filters, precipitation, and thick product reduced pressure chromatography, obtains compound 17.
2) compound 17 is dissolved in ethanol, adds oxammonium hydrochloride, and stirring at room adds sodium hydrate solid in batches, and add half an hour, adds rear backflow 4h.Precipitation is removed ethanol, adds water, and ethyl acetate extraction three times, merges organic layer, and anhydrous magnesium sulfate drying filters, precipitation, and recrystallization, obtains compound 18.
3) compound 18 is dissolved in ethanol, adds Pd/C, and concentrated hydrochloric acid is driven air away to inflated with nitrogen in autoclave, fills hydrogen exchange nitrogen three times.Fill hydrogen, stirring at room 24h.After having reacted, cross filtering Pd/C, precipitation, product recrystallization precipitation being obtained with ethanol.The salt that recrystallization obtains, in ethanol, adds sodium hydrate solid, stirring at room.Precipitation is removed ethanol, and product is dissolved in organic solvent, washing organic layer, and dry organic layer, precipitation obtains compound 19.
4), at-10 ℃, the THF solution of isopropyl chlorocarbonate is dropped in the THF solution of 3-methyl-2-isopropoxy carbonyl aminobutyric acid 9 and N-methylmorpholine.Dripping off rear continuation stirs two hours.Drip the THF solution of 2-(3,4-Dimethoxyphenyl)-2-monoethanolamine 19.Add half an hour, adds rear room temperature reaction 10h.Filter precipitation.Recrystallization, obtains compound 20.
5) low-temp reaction device is adjusted to-10 ℃, compound 20 is added to the DMF suspension liquid of sodium hydride, stirs, and dissolves.The DMF solution that drips benzyl bromine, drip off half an hour, drips off and continue to stir 6h.After completion of the reaction, by product impouring frozen water, standing, separate out white solid, filter, solid is dried and is obtained compound 21.
General formula intermediate 20:
General formula 20 intermediates are for preparing general formula 21 compounds, to develop specially.
Structural formula provided by the invention (I) compound is the compound with excellent fungicidal activity, can be for preventing and treating disease that Oomycete pathogenic bacteria produces as oidium, late blight, white epidemic disease etc., concrete as cucumber downy mildew, downy mildew of garpe, Chinese cabbage downy mildew, tomato late blight, the late blight of potato, capsicum late blight, peronophythora litchi, soybean phytophthora root rot etc.The compounds of this invention also can be applicable to sclerotium disease, ring spot, gray mold, banded sclerotial blight etc.The compounds of this invention can directly be used, and also can add that the upper carrier of accepting of agricultural is used, also can with other bactericide compounded use.
Embodiment
The compounds of this invention and preparation method thereof is further illustrated and illustrated to the embodiment hereinafter providing and preparation example.Should be appreciated that the scope of following embodiment and preparation example and limit the scope of the invention never in any form.
Embodiment 1: the preparation of dimethoxy-acetophenone 2
Acetovanillone 1 (50.0g, 300.9mmol) is dissolved in to 200mLCH
2cl
2, add sodium hydroxide (31.3g, 782.3mmol), 200mLH
2o, adds 4.0g Tetrabutyl amonium bromide to cook phase-transfer catalyst, mechanical stirring.Drip methyl-sulfate (49.4g, 391.2mmol), 1h drips off, and room temperature continues to stir 2h.After raw material point disappears, stop stirring standing separatory, twice of 100mL dichloromethane extraction water layer, 200mL strong aqua is diluted to after 400mL, backwash organic layer twice, 300mL washes organic layer twice, dried over mgso organic layer, precipitation, obtain yellow oil 53.7g, the standing white solid that becomes, fusing point: 45-46 ℃.Yield: 99%.
1H?NMR(300MHz,CDCl
3)δ7.53(m,2H,Ar-H),6.89(d,J＝8.3Hz,1H,Ar-H),4.09–3.85(m,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.57(s,3H,COCH
3).
Synthesizing of the bromo-1-of embodiment 2:2-(3,4-Dimethoxyphenyl) ethyl ketone 3
3,4-dimethoxy-acetophenone 2 (50.0g, 277.5mmol) is dissolved in to 700mL ethyl acetate, refluxes, add cupric bromide (123.9g, 554.9mmol) in batches.1h adds, and continues backflow 2h.Filter a small amount of ethyl acetate rinse filter residue.The saturated NaHCO of 200mL
3solution is washed organic layer 3 times, and 200mL saturated common salt is washed once.Anhydrous MgSO
4dry organic layer, precipitation.Ethyl alcohol recrystallization, obtains light brown solid 36.0g.Fusing point: 75-76 ℃, productive rate: 50.2%.
1H?NMR(300MHz,CDCl
3)δ7.75–7.43(m,2H,Ar-H),6.92(d,J＝8.4Hz,1H,Ar-H),4.42(s,2H,CH
2),3.96-3.98(d,J＝6.6Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3).
Embodiment 3:1-(3,4-Dimethoxyphenyl)-2-is synthetic to fluorophenoxy ethyl ketone 4a's
Phenol (20.0g, 212.8mmol) is dissolved in to 200mL acetone, adds K
2cO
3(30.8g, 223.4mmol) powder, stirring at room 1h.Add the bromo-1-of 2-(3,4-Dimethoxyphenyl) ethyl ketone 3 (57.8g, 223.4mmol), continue to stir 6h.After raw material point disappears, precipitation, 200mL methylene dichloride dissolves again, and 100mL1mol/L sodium hydroxide solution is washed organic layer twice, dried over mgso organic layer, precipitation.Ethyl alcohol recrystallization, obtains white solid 49.4g, fusing point: 83-85 ℃, yield 85.3%.
1HNMR(400MHz,CDCl
3))δ7.77–7.51(m,2H,Ar-H),7.26(s,2H,Ar-H),7.05–6.83(m,4H,Ar-H),3.95(d,J＝9.1Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3).
According to the method for embodiment 3, select suitable raw material and reagent, make respectively the compound of 4b to 4h.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 4:1-(3,4-Dimethoxyphenyl)-2-is synthetic to fluorophenoxy ethyl ketone 4b's
White solid, fusing point: 125-126 ℃.
1H?NMR(400MHz,CDCl
3)δ7.59(d,J＝1.7Hz,2H,Ar-H),7.06–6.72(m,5H,Ar-H),5.24(s,2H,CH
2),3.98(d,J＝9.2Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3).
The adjacent fluorophenoxy ethyl ketone of embodiment: 1-(3,4-Dimethoxyphenyl)-2-4c's is synthetic
White solid, fusing point: 110-111 ℃.
1H?NMR(300MHz,CDCl
3)δ7.79–7.47(m,2H,Ar-H),7.15–6.71(m,5H,Ar-H),5.32(s,2H,CH
2),3.97(d,J＝6.3Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3).
Embodiment 6:1-(3,4-Dimethoxyphenyl)-2-is synthetic to chlorophenoxy ethyl ketone 4d's
White solid, fusing point: 106-107 ℃.
1H?NMR(400MHz,CDCl
3)δ7.72–7.51(m,2H,Ar-H),7.34–7.17(m,2H,Ar-H),6.92(dd,J＝17.5,8.7Hz,3H,Ar-H),5.25(s,2H,CH
2),3.98(d,J＝10.1Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3).
Embodiment 7:1-(3,4-Dimethoxyphenyl)-2-is synthetic to methylphenoxy ethyl ketone 4e's
White solid, fusing point: 89-91 ℃.
1H?NMR(400MHz,CDCl
3)δ7.69(dd,J＝8.4,1.9Hz,1H,Ar-H),7.60(d,J＝1.9Hz,1H,Ar-H),7.11(d,J＝8.3Hz,2H,Ar-H),6.93(d,J＝8.4Hz,1H,Ar-H),6.87(d,J＝8.6Hz,2H,Ar-H),5.23(s,2H,CH
2),3.98(d,J＝8.7Hz,6H,Ar-m-OCH3+Ar-p-OCH
3),2.31(s,3H,CH
3).
Between embodiment 8:1-(3,4-Dimethoxyphenyl)-2-, methylphenoxy ethyl ketone 4f's is synthetic
White solid, fusing point: 73-74 ℃.
1H?NMR(400MHz,CDCl
3)δδ7.69(dd,J＝8.4,1.9Hz,1H,Ar-H),7.60(d,J＝1.9Hz,1H,Ar-H),7.18(t,J＝7.8Hz,1H,Ar-H),6.93(d,J＝8.4Hz,1H,Ar-H),6.85–6.69(m,3H,Ar-H),5.23(s,2H,CH
2),3.97(d,J＝8.4Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.34(s,3H,CH
3).
Embodiment 9:1-(3,4-Dimethoxyphenyl)-2-is synthetic to methoxyphenoxy ethyl ketone 4g's
White solid, fusing point: 96-98 ℃.
1H?NMR(400MHz,CDCl
3))δ7.65(dd,J＝8.4,1.8Hz,1H,Ar-H),7.57(d,J＝1.8Hz,1H,Ar-H),6.90(dt,J＝5.9,2.5Hz,3H,Ar-H),6.85–6.76(m,2H,Ar-H),5.19(s,2H,CH
2),3.95(d,J＝8.0Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.76(s,3H,C
6H
4OCH
3).
Embodiment 10:1-(3,4-Dimethoxyphenyl)-2-O-methoxy phenoxy group ethyl ketone 4h's is synthetic
White solid, fusing point: 89-90 ℃.
1H?NMR(400MHz,CDCl
3)δ7.70(dd,J＝8.4,1.9Hz,1H,Ar-H),7.63(d,J＝1.8Hz,1H,Ar-H),7.04–6.82(m,5H,Ar-H),5.32(s,2H,CH
2),3.97(d,J＝7.2Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.91(s,1H,C
6H
4OCH
3).
Embodiment 11:1-(3,4-Dimethoxyphenyl)-2-phenoxy group ethyl ketone oxime 5a's is synthetic
1-(3,4-Dimethoxyphenyl)-2-phenoxy group ethyl ketone 4a (20.0g, 69.7mmol) is dissolved in to 500mL ethanol, adds oxammonium hydrochloride (7.3g, 104.5mmol), add sodium hydroxide (4.2g, 104.5mmol) in batches, 0.5h adds.Stirring at room 8h.After raw material point disappears, precipitation, dissolves raffinate again with 400mL methylene dichloride, and 200mL washes organic layer, and 100mL methylene dichloride backwash water layer twice merges organic layer, dried over mgso organic layer, precipitation.Product obtains white solid 16.8g with ethyl alcohol recrystallization.Fusing point: 85-87 ℃, yield 84.1%.
1H?NMR(400MHz,CDCl
3)δ7.57(dt,J＝21.4,10.7Hz,1H,Ar-H),7.50(d,J＝1.9Hz,1H,Ar-H),7.27–7.17(m,1H,Ar-H),6.94–6.78(m,4H,Ar-H),5.16(s,2H,CH
2),3.87(d,J＝8.9Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3).
According to the method for embodiment 11, select suitable raw material and reagent, make respectively the compound of 5b to 5h.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 12:1-(3,4-Dimethoxyphenyl)-2-is synthetic to fluorophenoxy ethyl ketone oxime 5b's
White solid, fusing point: 81-85 ℃,
1h NMR (300MHz, CDCl
3) δ 7.64 (dd, J=8.4,1.9Hz, 1H, Ar-H), 7.56 (d, J=1.8Hz, 1H, Ar-H), 6.93 (tdd, J=9.6,8.0,3.4Hz, 5H, Ar-H), 5.21 (s, 2H, CH
2), 3.95 (d, J=6.9Hz, 6H, Ar-m-OCH
3+ Ar-p-OCH
3).
The adjacent fluorophenoxy ethyl ketone of embodiment 13:1-(3,4-Dimethoxyphenyl)-2-oxime 5c's is synthetic
White solid, fusing point: 96-99 ℃.
1H?NMR(400MHz,CDCl
3)δ7.74–7.20(m,2H,Ar-H),7.10–6.70(m,5H,Ar-H),5.34–4.84(m,2H,CH
2),3.94–3.76(m,6H,Ar-m-OCH
3+Ar-p-OCH
3).
Embodiment 14:1-(3,4-Dimethoxyphenyl)-2-is synthetic to chlorophenoxy ethyl ketone oxime 5d's
White solid, fusing point: 132-134 ℃.
1H?NMR(400MHz,CDCl
3)δ7.40–7.05(m,4H,Ar-H),6.86(t,J＝8.4Hz,3H,Ar-H),5.24(s,2H,CH
2),3.88(d,J＝8.7Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3).
Embodiment 15:1-(3,4-Dimethoxyphenyl)-2-is synthetic to methylphenoxy ethyl ketone oxime 5e's
White solid, fusing point: 80-83 ℃.
1H?NMR(400MHz,CDCl
3)δ7.28(dd,J＝5.9,4.0Hz,2H,Ar-H),7.09(d,J＝8.2Hz,2H,Ar-H),6.92–6.80(m,3H,Ar-H),5.29(s,2H,CH
2),4.11–3.64(d,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.30(s,3H,CH
3).
Between embodiment 16:1-(3,4-Dimethoxyphenyl)-2-, methylphenoxy ethyl ketone oxime 5f's is synthetic
White solid, fusing point: 91-92 ℃.
1H?NMR(300MHz,CDCl
3)δ7.34–6.95(m,3H,Ar-H),6.89–6.37(m,4H,Ar-H),5.21–4.66(s,2H,CH
2),3.83–3.65(d,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.21(s,J＝6.7Hz,3H,CH
3).
Embodiment 17:1-(3,4-Dimethoxyphenyl)-2-is synthetic to methoxyphenoxy ethyl ketone oxime 5g's
White solid, fusing point: 97-98 ℃.
1H?NMR(400MHz,CDCl
3)δ7.57(dd,J＝8.4,1.5Hz,1H,Ar-H),7.49(d,J＝1.5Hz,1H,Ar-H),6.82(dt,J＝10.3,3.1Hz,3H,Ar-H),6.75(dd,J＝9.7,2.7Hz,2H,Ar-H),5.11(s,2H,CH
2),3.87(d,J＝8.2Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.68(s,3H,OCH
3).
Embodiment 18:1-(3,4-Dimethoxyphenyl)-2-O-methoxy phenoxy group ethyl ketone oxime 5h's is synthetic
White solid, fusing point: 116-117 ℃.
1H?NMR(400MHz,CDCl
3)δ7.40–7.15(m,3H,?Ar-H),6.97–6.55(m,4H,Ar-H),5.27(s,2H,CH
2),3.82–3.77(d,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.72(s,3H,OCH
3).
Embodiment 19:1-(3,4-Dimethoxyphenyl)-2-phenoxyethylamine 6a's is synthetic
1-(3,4-Dimethoxyphenyl)-2-phenoxy group ethyl ketone oxime 5a (10.0g, 34.8mmol) heating is dissolved in to 500mL ethanol, is chilled to room temperature, add 1.0g Pd/C, 3mL concentrated hydrochloric acid.To inflated with nitrogen in autoclave, drive air away, fill hydrogen exchange nitrogen three times.Fill hydrogen 20atm, stirring at room 24h.After having reacted, cross filtering Pd/C, add appropriate concentrated hydrochloric acid, product is converted into ammonium salt completely, precipitation, product recrystallization precipitation being obtained with ethanol.The salt that recrystallization obtains, in ethanol, adds 1.2eq sodium hydrate solid, and stirring at room 1h neutralizes.Precipitation is removed ethanol, and product is dissolved in 100mL methylene dichloride, and 50mL washes organic layer, MgSO
4dry organic layer, precipitation obtains 7.5g faint yellow solid.Fusing point: 77-78 ℃; Yield: 78.7%.
1H?NMR(300MHz,CDCl
3)δ7.29(dd,J＝9.5,6.3Hz,2H,Ar-H),7.10–6.78(m,6H,Ar-H),4.41(dd,J＝8.9,3.5Hz,1H,CHCH
2),4.07(dd,J＝9.0,3.6Hz,1H,CHCH
2),3.91(d,J＝7.3Hz,7H,Ar-m-OCH
3+Ar-p-OCH
3+NH
2CH),2.26–1.71(m,2H,NH
2).
According to the method for embodiment 19, select suitable raw material and reagent, make respectively the compound of 6b to 6h.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 20:1-(3,4-Dimethoxyphenyl)-2-is synthetic to fluorophenoxy ethamine 6b's
Faint yellow solid, fusing point: 96-99 ℃;
1h NMR (400MHz, CDCl
3) δ 7.09 – 6.91 (m, 4H, Ar-H), 6.91 – 6.76 (m, 3H, Ar-H), 4.50 (s, 1H, CHCH
2), 4.10 (d, J=7.7Hz, 1H, CHCH
2), 3.92 (d, J=7.7Hz, 7H, Ar-m-OCH
3+ Ar-p-OCH
3+ NH
2cH).
The adjacent fluorophenoxy ethamine of embodiment 21:1-(3,4-Dimethoxyphenyl)-2-6c's is synthetic
Faint yellow solid, fusing point: 65-68 ℃.
1H?NMR(300MHz,CDCl
3)δ7.11–6.63(m,7H,Ar-H),4.36(dd,J＝8.8,3.5Hz,1H,CHCH
2),4.04(dd,J＝9.0,3.5Hz,1H,CHCH
2),3.88(t,J＝7.0Hz,1H+NH
2CH),3.82(d,J＝8.1Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),1.82(s,2H,NH
2).
Embodiment 22:1-(3,4-Dimethoxyphenyl)-2-is synthetic to chlorophenoxy ethamine 6d's
Faint yellow solid, fusing point: 94-97 ℃.
1H?NMR(400MHz,CDCl
3)δ7.26–7.21(m,2H,Ar-H),7.08–7.01(m,1H,Ar-H),6.98(dt,J＝12.0,6.0Hz,1H,Ar-H),6.86(dt,J＝12.3,5.8Hz,3H,Ar-H),4.40(dd,J＝9.0,3.6Hz,1H,CHCH
2),4.03(dd,J＝8.9,3.7Hz,1H,CHCH
2),3.90(dd,J＝15.6,9.0Hz,7H,Ar-m-OCH
3+Ar-p-OCH
3+NH
2CH),1.85(s,2H,NH
2).
Embodiment 23:1-(3,4-Dimethoxyphenyl)-2-is synthetic to methylphenoxy ethamine 6e's
Faint yellow solid, fusing point: 68-72 ℃.
1H?NMR(400MHz,CDCl
3)δ7.19–6.95(m,4H,Ar-H),6.86(dd,J＝18.9,8.1Hz,3H,Ar-H),4.40(d,J＝6.1Hz,1H,CHCH
2),4.04(t,J＝13.0Hz,1H,?CHCH
2),3.88(t,J＝22.4Hz,7H,Ar-m-OCH
3+Ar-p-OCH
3+NH
2CH),2.31(s,5H,Ar-CH
3+NH
2).
Between embodiment 24:1-(3,4-Dimethoxyphenyl)-2-, methylphenoxy ethamine 6f's is synthetic
Faint yellow solid, fusing point: 64-66 ℃.
1H?NMR(300MHz,CDCl
3)δ7.12–6.36(m,7H,Ar-H),4.30(dd,J＝8.5,3.8Hz,1H,CHCH
2),4.02–3.87(m,1H,CHCH
2),3.81(t,J＝8.8Hz,7H,NH
2CH+Ar-m-OCH
3+Ar-p-OCH
3),2.25(s,3H,CH
3),2.14(s,2H,NH
2).
Embodiment 25:1-(3,4-Dimethoxyphenyl)-2-is synthetic to methoxyphenoxy ethamine 6g's
Faint yellow solid, fusing point: 57-60 ℃.
1H?NMR(300MHz,CDCl
3)δ7.09–6.95(m,2H,Ar-H),6.92–6.76(m,5H,Ar-H),4.38(dd,J＝8.9,3.4Hz,1H,CHCH
2),4.01(m,1H,CHCH
2),3.91(d,J＝6.3Hz,7H,NH
2CH+Ar-m-OCH
3+Ar-p-OCH
3),3.78(s,3H,C
6H
4OCH
3),2.14(s,2H,NH
2).
Embodiment 26:1-(3,4-Dimethoxyphenyl)-2-O-methoxy phenoxyethylamine 6h's is synthetic
Faint yellow solid, fusing point: 90-94 ℃.
1H?NMR(400MHz,CDCl
3)δ7.09–6.75(m,7H,Ar-H),4.44(dd,J＝9.3,3.4Hz,1H,CHCH
2),4.12(dd,J＝9.3,3.4Hz,1H,CHCH
2),3.91(s,4H,NH
2CH+C
6H
4OCH
3),3.87(d,J＝5.4Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),1.83(s,2H,NH
2).
Synthesizing of embodiment 27:3-methyl-2-isopropoxy carbonyl aminobutyric acid 9
By sodium hydroxide (12.0g, 0.3mol) 150ml water dissolution, add α-amino-isovaleric acid (17.5g, 0.15mol), stir.Cryosel is chilled to-10 ℃ of left and right under bathing, and drips isopropyl chlorocarbonate (20.3g, 0.18mol), drips and finishes, and removes cryosel and bathes, stirring at room 1h, stopped reaction.Once, water is adjusted pH to 2～3, extracted with diethyl ether (50mL * 4), anhydrous MgSO with 1M dilute hydrochloric acid to the washing of 50ml ether
4dry, precipitation obtains colorless oil 22.3g, and refrigerator freezing obtains white solid.Productive rate 73.1%.
1H?NMR(400MHz,CDCl
3)δ10.90(s,1H,COOH),5.22(s,1H,CHNHCO),5.04–4.84(m,1H,(CH
3)
2CHO),4.34(dd,J＝8.9,4.3Hz,1H,COCHNH),2.24(dd,J＝12.0,6.1Hz,1H,(CH
3)
2CHCH),1.25(s,6H,(CH
3)
2CHO),1.07–0.83(m,6H,(CH
3)
2CHCH).
Embodiment 28:N-(1-(3,4-Dimethoxyphenyl)-2-phenoxy group ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10a's is synthetic
At-10 ℃, by isopropyl chlorocarbonate (2.11g, 60mL THF solution 18.7mmol) drops in the 80mLTHF solution of 3-methyl-2-isopropoxy carbonyl aminobutyric acid 9 (3.80g, 18.7mmol) and N-methylmorpholine (1.88g, 18.7mmol).1h drips off, and continues to stir two hours.Drip the 60mLTHF solution of 1-(3,4-Dimethoxyphenyl)-2-phenoxyethylamine 6a (5.0g, 18.3mmol).Add half an hour, adds rear room temperature reaction 10h.Filter, precipitation, 200mL methylene dichloride dissolves again, 100mL 1mol/L sodium carbonate washed twice, 100mL 1mol/L hydrochloric acid washed twice, dried over mgso organic layer, precipitation.Ethyl alcohol recrystallization, obtains white solid 6.7g.Fusing point: 138-140 ℃, yield 80.4%.
1H?NMR(400MHz,CDCl
3)δ7.37–7.20(m,2H,Ar-H),7.02–6.75(m,6H,Ar-H),6.67(s,1H,CHCONH),5.32(s,1H,OCONH),?5.16(s,1H,Ar-CH),4.86(td,J＝12.1,5.9Hz,1H,OCH(CH
3)
2),4.34–4.10(m,2H,OCH
2),4.00(dd,J＝17.6,11.0Hz,1H,OCONHCH),3.86(s,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.17(d,J＝5.9Hz,1H,CHCH(CH
3)
2),1.25–1.10(m,6H,OCH(CH
3)
2),1.05–0.83(m,6H,CHCH(CH
3)
2).
According to the method for embodiment 28, select suitable raw material and reagent, make respectively the compound of 10b to 10h.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 29:N-(1-(3,4-Dimethoxyphenyl)-2-is to fluorophenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10b's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.02–6.87(m,4H,Ar-H),6.87–6.78(m,3H,Ar-H),6.62(s,1H,CHCONH),5.29(s,1H,OCONH),5.13(s,1H,Ar-CH),4.88(dd,J＝12.6,6.3Hz,1H,OCH(CH
3)
2),4.27–4.10(m,2H,OCH
2),3.98(dd,J＝15.3,8.6Hz,1H,OCONHCH),3.86(s,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.15(s,1H,CHCH(CH
3)
2),1.29–1.09(m,6H,OCH(CH
3)
2),1.05–0.84(m,6H,CHCH(CH
3)
2).
Embodiment 30:N-(the adjacent fluorophenoxy ethyl of 1-(3,4-Dimethoxyphenyl)-2-)-3-methyl-2-isopropoxy carbonyl amido butyramide 10c's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.16–6.82(m,7H,Ar-H),6.75(dd,J＝19.7,7.5Hz,1H,CHCONH),5.38–5.27(m,1H,OCONH),5.15(s,1H,Ar-CH),4.90(dt,J＝12.4,6.2Hz,1H,OCH(CH
3)
2),4.31(ddd,J＝35.6,9.6,4.4Hz,2H,OCH
2),4.04(d,J＝6.5Hz,OCONHCH),3.89(d,J＝7.2Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.20(dd,J＝13.1,6.5Hz,1H,CHCH(CH
3)
2),1.30–1.10(m,6H,OCH(CH
3)
2),1.02–0.79(m,6H,CHCH(CH
3)
2).
Embodiment 31:N-(1-(3,4-Dimethoxyphenyl)-2-is to chlorophenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10d's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.24–7.10(m,2H,Ar-H),6.86–6.71(m,5H,Ar-H),6.53(d,J＝6.0Hz,1H,CHCONH),5.24(d,J＝4.5Hz,1H,OCONH),5.05(s,1H,Ar-CH),4.80(dt,J＝12.7,5.0Hz,1H,OCH(CH
3)
2),4.23–4.03(m,2H,OCH
2),3.99–3.85(m,1H,OCONHCH),3.79(s,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.08(s,1H,CHCH(CH
3)
2),1.21–1.04(m,6H,OCH(CH
3)
2),0.97–0.76(m,6H,CHCH(CH
3)
2).
Embodiment 32:N-(1-(3,4-Dimethoxyphenyl)-2-is to methylphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10e's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.07(d,J＝8.4Hz,2H,Ar-H),6.92(d,J＝7.3Hz,2H,Ar-H),6.84–6.75(m,3H,Ar-H),6.64(d,J＝7.4Hz,1H,CHCONH),5.29(s,1H,OCONH),5.15(s,1H,Ar-CH),4.87(dq,J＝11.6,5.9Hz,1H,OCH(CH
3)
2),4.27–4.06(m,2H,OCH
2),3.98?(dd,J＝14.8,8.1Hz,1H,OCONHCH),3.86(s,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.28(s,3H,Ar-CH3),2.17(d,J＝6.3Hz,1H,CHCH(CH
3)
2),1.34–1.14(m,6H,OCH(CH
3)
2),1.02–0.78(m,6H,CHCH(CH
3)
2).
Embodiment 33:N-(methylphenoxy ethyl between 1-(3,4-Dimethoxyphenyl)-2-)-3-methyl-2-isopropoxy carbonyl amido butyramide 10f's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.18(t,J＝7.6Hz,1H,Ar-H),6.94(s,2H,Ar-H),6.83(dd,J＝15.3,7.4Hz,3H,Ar-H),6.72(s,1H,Ar-H),6.70(s,1H,CHCONH),5.34(s,1H,OCONH),5.26(dd,J＝18.4,8.3Hz,1H,Ar-CH),4.88(dd,J＝12.9,6.5Hz,1H,OCH(CH
3)
2),4.19(dd,J＝17.5,7.7Hz,2H,OCH
2),4.06(d,J＝6.5Hz,1H,OCONHCH),3.88(s,6H,Ar-m-OCH
3+Ar-p-OCH
3),2.34(s,3H,Ar-CH
3),2.21–2.11(m,1H,CHCH(CH
3)
2),1.34–1.12(m,6H,OCH(CH
3)
2),1.08–0.82(m,6H,CHCH(CH
3)
2).
Embodiment 34:N-(1-(3,4-Dimethoxyphenyl)-2-is to methoxyphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10g's is synthetic
1H?NMR(400MHz,CDCl
3)δ6.84(s,2H,Ar-H),6.76(d,J＝6.6Hz,5H,Ar-H),6.60(s,1H,CHCONH),5.22(s,1H,OCONH),5.07(s,1H,Ar-CH),4.90–4.73(m,1H,OCH(CH
3)
2),4.16–4.01(m,2H,OCH
2),3.96(d,J＝7.3Hz,1H,OCONHCH),3.80(d,J＝6.3Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.69(s,3H,C
6H
4-o-OCH
3),2.09(s,1H,CHCH(CH
3)
2),1.19–1.08(m,6H,OCH(CH
3)
2),0.93–0.76(m,6H,CHCH(CH
3)
2).
Embodiment 35:N-(1-(3,4-Dimethoxyphenyl)-2-O-methoxy phenoxy group ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10h's is synthetic
1H?NMR(400MHz,CDCl
3)δ6.98(dd,J＝13.7,7.9Hz,4H,Ar-H),6.90(dd,J＝11.3,4.3Hz,3H,Ar-H),6.82(d,J＝8.2Hz,1H,CHCONH),5.24(s,2H,OCONH+Ar-CH),4.97–4.73(m,1H,OCH(CH
3)
2),4.31–4.13(m,2H,OCH
2),4.02(dd,J＝17.1,8.4Hz,1H,OCONHCH),3.90–3.80(m,9H,Ar-m-OCH
3+Ar-p-OCH
3+C
6H
4-o-OCH
3),2.26–2.02(m,1H,CHCH(CH
3)
2),1.29–1.12(m,6H,OCH(CH
3)
2),1.00–0.74(m,6H,CHCH(CH
3)
2).
The physical and chemical parameter table of compound 10
Synthesizing of embodiment 36:2-bromo-1-(4-hydroxy 3-methoxybenzene base) ethyl ketone 11
Acetovanillone 1 (40.0g, 240.7mmol) is dissolved in to 600mL ethyl acetate, refluxes, add cupric bromide (105.4g, 471.8mmol) in batches.1h adds, and continues backflow 2h.Filter, with ethyl acetate rinse filter residue.The saturated NaHCO of 200mL
3solution is washed organic layer 3 times, and 200mL saturated common salt is washed once.MgSO
4dry organic layer, precipitation.Reduced pressure chromatography (sherwood oil: ethyl acetate=10:1; Sherwood oil: ethyl acetate=4:1), obtain light yellow solid 27.5g, fusing point: 59-60 ℃, yield 46.8%.
1H?NMR(400MHz,CDCl
3)δ7.56–7.31(m,2H，Ar-H),6.89(t,J＝8.9Hz,1H,Ar-H),6.11(s,1H,OH),4.34(s,2H,CH
2),3.98–3.74(s,3H,CH
3).
Embodiment 37:1-(4-hydroxy 3-methoxybenzene base)-2-phenoxy group ethyl ketone 12a's is synthetic
Sodium phenylate (5.7g, 60.6mmol) is dissolved in 60mL DMF, stirs lower temperature control 85-90 ℃, drips the DMF solution of bromo-4-hydroxy 3-methoxybenzene ethyl ketone 11 (5.0g, 20.4mmol), and add half an hour.Drip off and continue reaction five minutes, stop heating, reaction solution is poured in the frozen water that 500mL is 3 with salt acid for adjusting pH, 50mL dichloromethane extraction 6 times, merges organic layer, 500mL water backwash organic layer 3 times.Anhydrous magnesium sulfate drying organic layer, filters precipitation, product reduced pressure chromatography (sherwood oil: ethyl acetate=10:1; Sherwood oil: ethyl acetate=5:1) obtain white solid 4.4g, fusing point: 80-81 ℃, yield: 84.1%.
1H?NMR(300MHz,CDCl
3)δ7.54(d,J＝10.0Hz,2H,Ar-H),7.23(d,J＝7.7Hz,2H,Ar-H),6.90(dd,J＝15.3,7.1Hz,4H,Ar-H),6.05(s,1H,OH),5.16(s,2H,CH
2),3.89(s,3H,CH
3).
According to the method for embodiment 37, select suitable raw material and reagent, make respectively the compound of 12b to 12g.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 38:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to fluorophenoxy ethyl ketone 12b's
White solid, fusing point: 96-97 ℃,
1h NMR (400MHz, CDCl
3) δ 7.67 – 7.53 (m, 2H, Ar-H), 7.05 – 6.95 (m, 3H, Ar-H), 6.94 – 6.86 (m, 2H, Ar-H), 6.17 (d, J=2.7Hz, 1H, OH), 5.23 (s, 2H, CH
2), 3.99 (s, 3H, OCH
3).
The adjacent fluorophenoxy ethyl ketone of embodiment 39:1-(4-hydroxy 3-methoxybenzene base)-2-12c's is synthetic
White solid, fusing point: 77-79 ℃.
1H?NMR(400MHz,CDCl
3)δ7.53(dd,J＝5.8,1.8Hz,2H,Ar-H),7.08–6.72(m,5H,Ar-H),6.09(s,1H,OH),5.23(s,2H,CH
2),3.90(s,3H,CH
3).
Embodiment 40:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to chlorophenoxy ethyl ketone 12d's
White solid, fusing point: 86-87 ℃.
1H?NMR(400MHz,CDCl
3)δ7.64–7.56(m,2H,Ar-H),7.28–7.20(m,2H,Ar-H),6.97(t,J＝14.9Hz,1H,Ar-H),6.91–6.83(m,2H,Ar-H),6.20(s,1H,OH),5.24(s,2H,CH
2),3.98(s,3H,CH
3).
Embodiment 41:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to methylphenoxy ethyl ketone 12e's
White solid, fusing point: 85-87 ℃.
1H?NMR(400MHz,CDCl
3)δ7.70–7.52(m,2H,Ar-H),7.16–7.05(m,2H,Ar-H),7.00(d,J＝8.1Hz,1H,Ar-H),6.91–6.79(m,2H,Ar-H),6.28(s,1H,OH),5.23(s,2H,CH
2),3.97(d,J＝2.1Hz,3H,OCH
3),2.31(s,3H,CH
3).
Embodiment 42:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to methoxyphenoxy ethyl ketone 12f's
White solid, fusing point: 93-94 ℃.
1H?NMR(400MHz,CDCl
3)δ7.61(d,J＝9.9Hz,2H,Ar-H),6.98(d,J＝8.0Hz,1H,Ar-H),6.91(d,J＝9.1Hz,2H,Ar-H),6.84(d,J＝9.0Hz,2H,Ar-H),6.32(d,J＝40.4Hz,1H,OH),5.19(s,2H,CH
2),4.01–3.90(m,3H,C
6H
3OCH
3),3.77(s,3H,C6H
4OCH
3).
Embodiment 43:1-(4-hydroxy 3-methoxybenzene base)-2-O-methoxy phenoxy group ethyl ketone 12g's is synthetic
White solid, fusing point: 84-85 ℃.
1H?NMR(400MHz,CDCl
3)δ7.68–7.59(m,2H,Ar-H),7.00–?6.91(m,3H,Ar-H),6.88–6.84(m,2H,Ar-H),6.20(s,1H,OH),5.31(s,2H,CH
2),3.96(s,3H,C
6H
3OCH
3),3.91(s,3H,C
6H
4OCH
3).
Embodiment 44:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to fluorophenoxy ethyl ketone oxime 13a's
1-(4-hydroxy 3-methoxybenzene base)-2-phenoxy group ethyl ketone 12a (5.0g, 19.4mmol) adds in 40mL water, adds sodium acetate (8.5g, 103.2mmol) and oxammonium hydrochloride (4.3g, 61.5mmol), stirs backflow 3h.After completion of the reaction, be chilled to room temperature, 50mL ethyl acetate extraction three times, merges organic layer, and anhydrous magnesium sulfate drying organic layer filters precipitation.Product reduced pressure chromatography (sherwood oil: ethyl acetate=10:1; Sherwood oil: ethyl acetate=4:1), obtain white crystal 4.3g, fusing point: 67-68 ℃.
1H?NMR(400MHz,CDCl
3)δ7.26(m,4H,Ar-H),7.03–6.77(m,4H,Ar-H),5.41–4.81(m,2H,CH
2),3.90(d,J＝4.8Hz,3H,CH
3).
According to the method for embodiment 44, select suitable raw material and reagent, make respectively the compound of 13b to 13g.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 45:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to fluorophenoxy ethyl ketone oxime 13b's
Clear crystal, fusing point: 118-119 ℃,
1h NMR (400MHz, CDCl
3) δ 7.27 – 7.18 (m, 2H, Ar-H), 7.01 – 6.85 (m, 5H, Ar-H), 5.25 (s, 2H, CH
2), 3.91 (d, J=4.6Hz, 3H, CH
3).
The adjacent chlorophenoxy ethyl ketone of embodiment 46:1-(4-hydroxy 3-methoxybenzene base)-2-oxime 13c's is synthetic
Clear crystal, fusing point: 77-79 ℃.
1H?NMR(400MHz,CDCl
3)δ7.34(d,J＝2.0Hz,1H,Ar-H),7.12–7.03(m,4H,Ar-H),6.95–6.87(m,2H,Ar-H),5.36–5.32(m,2H,CH
2),3.93(s,3H,CH
3).
Embodiment 47:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to chlorophenoxy ethyl ketone oxime 13d's
Off-white color solid, fusing point: 93-95 ℃.
1H?NMR(400MHz,CDCl
3)δ7.31–7.17(m,4H,Ar-H),6.91(dd,J＝13.9,8.5Hz,3H,Ar-H),5.30–4.75(m,2H，CH
2),3.89(d,J＝4.8Hz,3H,CH
3).
Embodiment 48:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to methylphenoxy ethyl ketone oxime 13e's
White solid, fusing point: 112-115 ℃.
1H?NMR(300MHz,CDCl
3)δ7.30–7.18(m,2H,Ar-H),7.14–7.00(m,2H,Ar-H),6.96–6.81(m,3H,Ar-H),5.35–4.83(m,2H，CH
2),3.88(s,3H,C
6H
3OCH
3),2.30(d,J＝3.1Hz,3H,CH
3).
Embodiment 49:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to methoxyphenoxy ethyl ketone oxime 13f's
White solid, fusing point: 105-107 ℃.
1H?NMR(400MHz,CDCl
3)δ7.27–7.16(m,2H,Ar-H),6.97–6.74(m,5H,Ar-H),5.33–4.86(m,2H,CH
2),3.91(s,3H,C
6H
3OCH
3),3.78(s,3H,C
6H
4OCH
3).
Embodiment 50:1-(4-hydroxy 3-methoxybenzene base)-2-O-methoxy phenoxy group ethyl ketone oxime 13g's is synthetic
White solid, fusing point: 114-115 ℃.
1H?NMR(300MHz,CDCl
3)δ7.21(d,J＝12.0Hz,2H,?Ar-H),6.94–6.73(m,5H,Ar-H),5.33–4.84(m,2H,CH
2),3.78(s,3H,C
6H
3OCH
3),3.68(s,3H,C
6H
4OCH
3).
Synthesizing of embodiment 51:1-(4-hydroxy 3-methoxybenzene base)-2-phenoxyethylamine 14a hydrochloride
1-(4-hydroxy 3-methoxybenzene base)-2-phenoxy group ethyl ketone oxime 13a (2.0g, 7.3mmol) heating is dissolved in to 100mL ethanol, is chilled to room temperature, add 0.2g Pd/C, 0.6mL concentrated hydrochloric acid.To inflated with nitrogen in autoclave, drive air away, hydrogen exchange nitrogen three times.Fill hydrogen 20atm, stirring at room 24h.After completion of the reaction, filter, precipitation, product recrystallization obtains white solid 1.2g.Yield 63.8%.
1H?NMR(300MHz,DMSO)δ9.29(s,1H,OH),8.76(s,3H,NH
3 +),7.42–7.22(m,3H,Ar-H),6.99(dd,J＝15.4,7.7Hz,4H,Ar-H),6.83(d,J＝8.1Hz,1H,Ar-H),4.58(s,1H,Ar-CH),4.38–4.16(m,2H,CHCH
2),3.80(s,3H,OCH
3).
According to the method for embodiment 51, select suitable raw material and reagent, make respectively the compound of 14b to 14g.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 52:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to fluorophenoxy ethamine 14b hydrochloride
1H?NMR(300MHz,DMSO)δ9.20(s,1H,OH),7.85(s,3H,NH
3 +),7.22(s,1H,Ar-H),7.14(t,J＝8.7Hz,2H,Ar-H),7.03(dd,J＝9.1,4.4Hz,2H,Ar-H),6.94(d,J＝8.3Hz,1H,Ar-H),6.81(d,J＝8.0Hz,1H,Ar-H),4.51(s,1H,Ar-CH),4.18(s,2H,CHCH
2),3.79(s,3H,OCH
3).
Synthesizing of the adjacent fluorophenoxy ethamine of embodiment 53:1-(4-hydroxy 3-methoxybenzene base)-2-14c hydrochloride
1H?NMR(400MHz,DMSO)δ9.30(s,1H,OH),8.84(s,3H,NH
3 +),7.37(s,1H,Ar-H),7.31–7.19(m,2H,Ar-H),7.14(t,J＝7.8Hz,1H,Ar-H),7.05–6.95(m,2H,Ar-H),6.84(d,J＝8.1Hz,1H,Ar-H),4.61(s,1H,Ar-CH),4.50–4.27(m,2H,CHCH
2),3.80(s,3H,OCH
3).
Embodiment 54:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to chlorophenoxy ethamine 14d hydrochloride
1H?NMR(400MHz,DMSO)δ9.29(s,1H,OH),8.70(s,3H,NH
3 +),7.37(d,J＝8.7Hz,2H,Ar-H),7.31(s,1H,Ar-H),7.06(d,J＝8.7Hz,2H,Ar-H),6.98(d,J＝7.7Hz,1H,Ar-H),6.80(dd,J＝20.6,8.4Hz,1H,Ar-H),4.59(s,1H,Ar-CH),4.32–4.20(m,2H,CHCH
2),3.80(s,3H,OCH
3).
Embodiment 55:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to methylphenoxy ethamine 14e's
1H?NMR(400MHz,CDCl
3)δ7.04–6.87(m,3H,Ar-H),6.87–6.64(m,4H,Ar-H),4.37–4.11(m,1H,Ar-CH),3.93(s,1H,CHCH
2),3.82(s,4H,CHCH
2+OCH
3),2.21(s,3H,CH
3),1.67(s,2H,NH
2).
Embodiment 56:1-(4-hydroxy 3-methoxybenzene base)-2-is synthetic to methoxyphenoxy ethamine 14f hydrochloride
1H?NMR(400MHz,DMSO)δ9.30(s,1H,OH),8.73(s,3H,NH
3 +),7.33(s,1H,Ar-H),6.98(d,J＝9.1Hz,3H,Ar-H),6.86(dd,J＝18.8,8.5Hz,3H,Ar-H),4.56(s,1H,Ar-CH),4.33–4.13(m,2H,CHCH
2),3.81(s,3H,C
6H
3OCH
3),3.71(s,3H,C
6H
4OCH
3).
Synthesizing of embodiment 57:1-(4-hydroxy 3-methoxybenzene base)-2-O-methoxy phenoxyethylamine 14g hydrochloride
1H?NMR(400MHz,DMSO)δ9.28(s,1H,OH),8.71(s,3H,NH
3 +),7.34(s,1H,Ar-H),7.10(d,J＝7.0Hz,1H,Ar-H),7.01(dt,J＝15.2,7.3Hz,3H,Ar-H),6.91(dd,J＝10.6,4.4Hz,1H,Ar-H),6.83(d,J＝8.1Hz,1H,Ar-H),4.56(s,1H,Ar-CH),4.39–4.18(m,2H,CHCH
2),3.81(s,3H,C
6H
3OCH
3),3.78(s,3H,C
6H
4OCH
3).
Embodiment 58:N-(1-(4-hydroxy 3-methoxybenzene base-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15a's is synthetic
At-10 ℃, by isopropyl chlorocarbonate (0.44g, 12mL THF solution 3.94mmol) drops in the 20mLTHF solution of 3-methyl-2-isopropyl oxygen formamido group butyric acid 9 (0.80g, 3.94mmol) and N-methylmorpholine (0.40g, 3.94mmol).1h drips off, and continues to stir two hours.Drip the 60mLTHF solution of 1-(4-hydroxy 3-methoxybenzene base)-2-phenoxyethylamine (1.0g, 3.86mmol).Add half an hour, adds rear room temperature reaction 10h.Filter, precipitation, 40mL methylene dichloride dissolves again, 20mL 1mol/L sodium carbonate washed twice, 20mL1mol/L hydrochloric acid washed twice, dried over mgso organic layer, precipitation.Ethyl alcohol recrystallization, obtains khaki color solid 1.32g, yield 75.6%, fusing point: 137-140 ℃.
1H?NMR(400MHz,CDCl
3)δ7.29(dd,J＝9.7,5.4Hz,3H,Ar-H),6.99(t,J＝7.3Hz,1H,Ar-H),6.94–6.84(m,4H,Ar-H),6.75(d,J＝7.4Hz,1H,CHCONH),5.72(s,1H,OH),5.32(s,1H,OCONH),5.23(dd,J＝22.8,8.6Hz,1H,Ar-CH),4.88(dt,J＝19.3,6.4Hz,1H,OCH(CH
3)
2),4.22(ddd,J＝14.9,9.5,5.2Hz,2H,OCH
2),4.10–3.96(m,1H,OCONHCH),3.87(d,J＝6.1Hz,3H,C
6H
3OCH
3),2.14(dd,J＝24.9,18.5Hz,1H,CHCH(CH
3)
2),1.34–1.10(m,6H,OCH(CH
3)
2),1.08–0.75(m,6H,CHCH(CH
3)
2).
According to the method for embodiment 58, select suitable raw material and reagent, make respectively the compound of 15b to 15g.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 59:N-(1-(4-hydroxy 3-methoxybenzene base-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15b's is synthetic
1H?NMR(400MHz,CDCl
3)δ6.89(t,J＝8.6Hz,2H,Ar-H),6.84–6.67(m,5H,Ar-H),6.52(s,1H,CHCONH),5.54(s,1H,OH),5.20(s,1H,OCONH),5.06(s,1H,Ar-CH),4.89–4.64(m,1H,OCH(CH
3)
2),4.22–4.01(m,2H,OCH
2),3.91(dd,J＝17.1,8.7Hz,1H,OCONHCH),3.80(d,J＝1.9Hz,3H,C
6H
3OCH
3),2.09(s,1H,CHCH(CH
3)
2),1.18–1.05(m,6H,OCH(CH
3)
2),0.95–0.74(m,6H,CHCH(CH
3)
2).
Embodiment 60:N-(1-(the adjacent fluorophenoxy of 4-hydroxy 3-methoxybenzene base-2-) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15c's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.16–6.87(m,7H,Ar-H),6.83(s,1H,CHCONH),5.76(s,1H,OH),5.32(s,1H,OCONH),5.24(s,1H,Ar-CH),4.89(dd,J＝12.2,6.1Hz,1H,OCH(CH
3)
2),4.41–4.18(m,2H,OCH
2),4.04(s,1H,OCONHCH),3.90(d,J＝5.7Hz,3H,C
6H
3OCH
3),2.18(d,J＝6.9Hz,1H,CHCH(CH
3)
2),1.21(dd,J＝13.7,5.8Hz,6H,OCH(CH
3)
2),1.04–0.80(m,6H,CHCH(CH
3)
2).
Embodiment 61:N-(1-(4-hydroxy 3-methoxybenzene base-2-is to chlorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15d's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.27–7.15(m,2H,Ar-H),6.86(dd,J＝19.5,7.7Hz,5H,Ar-H),6.75(s,1H,CHCONH),5.75(s,1H,OH),5.31(s,1H,OCONH),5.22(s,1H,Ar-CH),4.96–4.76(m,1H,OCH(CH
3)
2),4.33–4.07(m,2H,OCH
2),4.10–3.95(m,1H,OCONHCH),3.88(d,J＝7.5Hz,3H,C
6H
3OCH
3),2.16(d,J＝6.0Hz,1H,CHCH(CH
3)
2),1.32–1.12(m,6H,OCH(CH
3)
2),1.03–0.88(m,6H,CHCH(CH
3)
2).
Embodiment 62:N-(1-(4-hydroxy 3-methoxybenzene base-2-is to methylphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15e's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.09(d,J＝8.3Hz,1H,Ar-H),6.89(dd,J＝13.4,4.4Hz,3H,Ar-H),6.80(dd,J＝8.6,2.3Hz,2H,Ar-H),6.73(d,J＝7.7Hz,1H,CHCONH),5.74(d,J＝9.8Hz,1H,OH),5.29(dt,J＝13.5,7.2Hz,1H,OCONH),5.20(d,J＝7.2Hz,1H,Ar-CH),4.99–4.79(m,1H,OCH(CH
3)
2),4.28–4.07(m,2H,OCH
2),4.07–3.94(m,1H,OCONHCH),3.87(d,J＝6.6Hz,3H,C
6H
3OCH
3),2.30(s,3H,C
6H
4CH
3),2.26–2.02(m,1H,CHCH(CH
3)
2),1.34–1.11(m,6H,OCH(CH
3)
2),1.04–0.85(m,6H,CHCH(CH
3)
2).
Embodiment 63:N-(1-(4-hydroxy 3-methoxybenzene base-2-is to methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15f's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.02–6.77(m,7H,Ar-H),6.73(d,J＝6.3Hz,1H,CHCONH),5.73(s,1H,OH),5.29(s,1H,OCONH),5.23(s,1H,Ar-CH),4.90(dt,J＝12.4,6.2Hz,1H,OCH(CH
3)
2),4.17(d,J＝5.8Hz,2H,OCH
2),4.09–3.96(m,1H,OCONHCH),3.88(d,J＝4.4Hz,3H,C
6H
3OCH
3),3.79(s,3H,C
6H
4OCH
3),2.18(s,1H,CHCH(CH
3)
2),1.21(dd,J＝14.7,6.0Hz,6H,OCH(CH
3)
2),0.95(tt,J＝44.1,22.0Hz,6H,CHCH(CH
3)
2).
Embodiment 64:N-(1-(4-hydroxy 3-methoxybenzene base-2-O-methoxy phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15g's is synthetic
1H?NMR(400MHz,CDCl
3)δ7.12(d,J＝6.6Hz,1H,Ar-H),7.06(d,J＝7.2Hz,2H,?Ar-H),6.99(dd,J＝6.4,4.0Hz,4H,Ar-H),6.96–6.87(m,1H,CHCONH),5.73(s,1H,OH),5.32(t,J＝8.5Hz,1H,OCONH),5.25(s,1H,Ar-CH),4.88(tt,J＝12.4,6.2Hz,1H,OCH(CH
3)
2),4.23(dd,J＝10.2,5.2Hz,2H,OCH
2),4.14–3.98(m,1H,OCONHCH),3.91–3.87(m,6H,C
6H
3OCH
3+C
6H
4OCH
3),2.26–2.10(m,1H,CHCH(CH
3)
2),1.34–1.11(m,6H,OCH(CH
3)
2),1.03–0.81(m,6H,CHCH(CH
3)
2).
The physical and chemical parameter table of compound 15
Embodiment 65:N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16a's is synthetic
By N-(1-(4-hydroxy 3-methoxybenzene base-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide (1.0g, 2.25mmol) be dissolved in 60mL acetone, add Anhydrous potassium carbonate (0.47g, 3.37mmol), stirring at room 1h, drips propargyl bromide (0.40g, 10mL acetone soln 3.37mmol), drip off half an hour, drips off and change backflow into, backflow 30h.After raw material point no longer changes, precipitation, 100mL methylene dichloride dissolves resistates, and 100mL1mol/L sodium hydroxide solution is washed organic layer twice, and 100mL washing organic layer once, anhydrous magnesium sulfate drying organic layer, precipitation, with ethyl alcohol recrystallization, obtains 0.86g pale solid, yield: 79.6%, fusing point: 139-141 ℃.
1H?NMR(400MHz,CDCl
3)δ7.28(s,2H,Ar-H),7.15–6.76(m,7H,Ar-H+CHCONH),5.38(d,J＝25.9Hz,2H,OCONH+Ar-CH),4.84(s,1H,OCH(CH
3)
2),4.74(d,J＝7.8Hz,2H,CHCCH
2),4.20(s,2H,OCH
2Ar),4.07(s,1H,OCONHCH),3.84(d,J＝6.0Hz,3H,C
6H
3OCH
3),2.52(s,1H,CH
2CCH),2.15(s,1H,CHCH(CH
3)
2),1.18(d,J＝19.6Hz,6H,OCH(CH
3)
2),0.95(t,J＝17.5Hz,6H,CHCH(CH
3)
2).
According to the method for embodiment 65, select suitable raw material and reagent, make respectively the compound of 16b to 16g.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 66:N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16b's is synthetic
White solid, fusing point: 155-157 ℃.
1H?NMR(400MHz,CDCl
3)δ6.99–6.81(m,5H,Ar-H),6.79–6.66(m,2H,Ar-H),6.56(d,J＝6.6Hz,1H,CHCONH),5.23(s,1H,OCONH),5.04(s,1H,Ar-CH),4.80(dt,J＝12.5,6.3Hz,1H,OCH(CH
3)
2),4.68(d,J＝2.3Hz,2H,CHCCH
2),4.12(qd,J＝9.7,5.0Hz,2H,OCH
2Ar),3.92(dd,J＝17.4,9.3Hz,1H,OCONHCH),3.79(s,3H,C
6H
3OCH
3),2.43(t,J＝2.3Hz,1H,CH
2CCH),2.10(d,J＝5.8Hz,1H,CHCH(CH
3)
2),1.21–1.02(m,6H,OCH(CH
3)
2),0.96–0.76(m,6H,CHCH(CH
3)
2).
Embodiment 67:N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16c's is synthetic
White solid, fusing point: 167-169 ℃.
1H?NMR(400MHz,CDCl
3)δ7.13–6.91(m,7H,Ar-H),6.84(s,1H,CHCONH),5.34(s,1H,OCONH),5.21(s,1H,Ar-CH),4.87(d,J＝6.2Hz,1H,OCH(CH
3)
2),4.76(s,2H,CHCCH
2),4.33(d,J＝9.2Hz,1H,OCH
2Ar),4.24(s,1H,OCH
2Ar),4.05(d,J＝7.2Hz,1H,OCONHCH),3.89(s,3H,C
6H
3OCH
3),2.52(s,1H,CH
2CCH),2.17(s,1H,CHCH(CH
3)
2),1.23(t,J＝5.9Hz,6H,OCH(CH
3)
2),1.08–0.81(m,H,CHCH(CH
3)
2).
Embodiment 68:N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16d's is synthetic
White solid, fusing point: 133-135 ℃.
1H?NMR(400MHz,CDCl
3)δ7.35–7.10(m,2H,Ar-H),7.11–6.72(m,6H,Ar-H+CHCONH),5.33(s,2H,OCONH+Ar-CH),4.81(s,1H,OCH(CH
3)
2),4.74(s,2H,CHCCH
2),4.16(s,2H,OCH
2Ar),4.05(s,1H,OCONHCH),3.84(s,3H,C
6H
3OCH
3),2.51(s,1H,CH
2CCH),2.13(s,1H,CHCH(CH
3)
2),1.27–1.10(m,6H,OCH(CH
3)
2),1.05–0.84(m,6H,CHCH(CH
3)
2).
Embodiment 69:N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16e's is synthetic
White solid, fusing point: 159-161 ℃.
1H?NMR(400MHz,CDCl
3)δ7.08(d,J＝6.0Hz,2H,?Ar-H),6.97(d,J＝16.0Hz,4H,Ar-H+CHCONH),6.78(s,2H,Ar-H),5.33(s,2H,OCONH+Ar-CH),4.86(s,1H,OCH(CH
3)
2),4.75(s,2H,CHCCH
2),4.19(s,2H,OCH
2Ar),4.06(s,1H,OCONHCH),3.86(s,3H,C
6H
3OCH
3),2.52(s,1H,CH
2CCH),2.30(s,3H,Ar-CH
3),2.16(s,1H,CHCH(CH
3)
2),1.31–1.07(m,6H,OCH(CH
3)
2),1.07–0.86(m,6H,CHCH(CH
3)
2).
Embodiment 70:N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16f's is synthetic
White solid, fusing point: 147-149 ℃.
1H?NMR(400MHz,CDCl
3)δ6.87(dd,J＝26.2,8.8Hz,4H,Ar-H+CHCONH),6.72(s,4H,Ar-H),5.21(d,J＝8.3Hz,2H,OCONH+Ar-CH),4.77(s,1H,OCH(CH
3)
2),4.64(d,J＝6.7Hz,2H,CHCCH
2),4.07(d,J＝3.9Hz,2H,OCH
2Ar),3.96(s,1H,OCONHCH),3.76(s,3H,C
6H
3OCH
3),3.67(s,3H,C
6H
4OCH
3),2.42(s,1H,CH
2CCH),2.06(s,1H,CHCH(CH
3)
2),1.11(d,J＝6.2Hz,6H,OCH(CH
3)
2),0.86(dd,J＝35.7,6.8Hz,6H,CHCH(CH
3)
2).
Embodiment 71:N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16g's is synthetic
White solid, fusing point: 177-179 ℃.
1H?NMR(400MHz,CDCl
3)δ7.10–6.71(m,8H,Ar-H+CHCONH),5.17(s,2H,OCONH+Ar-CH),4.79(s,1H,OCH(CH
3)
2),4.66(s,2H,CHCCH
2),4.15(s,2H,OCH
2Ar),3.98(d,J＝23.0Hz,1H,OCONHCH),3.79(s,6H,C
6H
3OCH
3+o-C
6H
4OCH
3),2.42(s,1H,CH
2CCH),2.CHCH(CH
3)
208(s,1H,CHCH(CH
3)
2),1.13(s,6H,OCH(CH
3)
2),0.83(d,J＝24.1Hz,6H,CHCH(CH
3)
2).
Synthesizing of embodiment 72:2-hydroxyl-1-(3,4-Dimethoxyphenyl) ethyl ketone 17
The bromo-1-of 2-(3,4-Dimethoxyphenyl) ethyl ketone (30.0g, 115.8mmol) is dissolved in 250mL ethanol, adds 50mL water, adds two hydration sodium formiate (48.2g, 463.2mmol) powder, backflow 6h.After completion of the reaction, precipitation is removed ethanol, and resistates adds 100mL water, and 100mL ethyl acetate extraction three times, merges organic layer, and anhydrous magnesium sulfate drying organic layer filters, precipitation, thick product reduced pressure chromatography (sherwood oil: ethyl acetate=5:1; Sherwood oil: ethyl acetate=3:1), obtain white crystal 22.1g.Fusing point: 83-84 ℃.Yield: 97.3%.
1H?NMR(400MHz,CDCl
3)δ7.60–7.43(m,2H,Ar-H),6.92(d,J＝8.2Hz,1H,Ar-H),4.85(s,2H,CH
2),3.97(s,3H,Ar-m-OCH
3),3.96(s,3H,Ar-p-OCH
3),3.60(s,1H,OH).
Synthesizing of embodiment 73:2-hydroxyl-1-(3,4-Dimethoxyphenyl) ethyl ketone oxime 18
2-hydroxyl-1-(3,4-Dimethoxyphenyl) ethyl ketone 17 (20.0g, 101.9mmol), be dissolved in 300mL ethanol, add oxammonium hydrochloride (10.6g, 152.9mmol), stirring at room adds sodium hydroxide (6.4g, 159.9mmol) solid in batches, add half an hour, adds rear backflow 4h.Precipitation is removed ethanol, adds 100mL water, and 100mL ethyl acetate extraction three times, merges organic layer, and anhydrous magnesium sulfate drying filters, precipitation, and ethyl alcohol recrystallization obtains clear crystal 17.8g, fusing point: 136-140 ℃; Yield: 82.7%.
1H?NMR(400MHz,CDCl
3)δ7.34–7.15(m,2H,Ar-H),6.92(dd,J＝13.9,8.3Hz,1H,Ar-H),4.76(s,2H,CH
2),3.95–3.91(m,6H,Ar-m-OCH
3+Ar-p-OCH
3).
The physical and chemical parameter table of compound 16
Synthesizing of embodiment 74:2-(3,4-Dimethoxyphenyl)-2-monoethanolamine 19
2-hydroxyl-1-(3,4-Dimethoxyphenyl) ethyl ketone oxime 18 (5.0g, 23.7mmol) is dissolved in 300mL ethanol, adds 0.5gPd/C, and 2.0mL concentrated hydrochloric acid is driven air away to inflated with nitrogen in autoclave, fills hydrogen exchange nitrogen three times.Fill hydrogen 20atm, stirring at room 24h.After having reacted, cross filtering Pd/C, precipitation, product recrystallization precipitation being obtained with ethanol.The salt that recrystallization obtains, in ethanol, adds 1.2eq sodium hydrate solid, and stirring at room 1h neutralizes.Precipitation is removed ethanol, and product is dissolved in 100mL methylene dichloride, and 50mL washes organic layer, MgSO
4dry organic layer, precipitation obtains 3.2g faint yellow solid.Fusing point: 110-120 ℃; Yield: 68.5%.The nuclear magnetic data of this ammonium salt is:
1h NMR (400MHz, DMSO) δ 8.44 (s, 3H, NH
3 +), 7.22 (s, 1H, Ar-H), 7.07 – 6.88 (m, 2H, Ar-H), 5.54 (s, 1H, CH), 4.17 (s, 1H, OH), 3.77 (s, 3H, Ar-m-OCH
3), 3.75 (s, 3H, Ar-p-OCH
3), 3.68 (s, 2H, CH
2).
Synthesizing of embodiment 75:N-(1-(3,4-Dimethoxyphenyl) ethyl-2-hydroxyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 20
At-10 ℃, by isopropyl chlorocarbonate (2.92g, 60mL THF solution 25.9mmol) drops in the 100mLTHF solution of 3-methyl-2-isopropoxy carbonyl aminobutyric acid 9 (5.26g, 25.9mmol) and N-methylmorpholine (2.62g, 25.9mmol).1h drips off, and continues to stir two hours.Drip the 80mLTHF solution of 2-(3,4-Dimethoxyphenyl)-2-monoethanolamine 19 (5.0g, 25.4mmol).Add half an hour, adds rear room temperature reaction 10h.Filter precipitation.Ethyl alcohol recrystallization, obtains white solid 8.1g.Fusing point: 179-183 ℃; Yield: 81.8%.
1H?NMR(300MHz,CDCl
3)δ7.09–6.59(m,4H,Ar-H,Ar-H+CHCONH),5.32(dd,J＝45.8,8.1Hz,1H,OCONH),4.96(d,J＝4.8Hz,1H,Ar-CH),4.77(d,J＝5.8Hz,1H,OCH(CH
3)
2),3.78(s,8H,CHCH
2O+Ar-m-OCH
3+Ar-p-OCH
3),2.14–1.90(m,1H,CHCH(CH
3)
2),1.15(d,J＝5.6Hz,6H,OCH(CH
3)
2),0.99–0.75(m,6H,CHCH(CH
3)
2).
Embodiment 76:N-(1-(3,4-Dimethoxyphenyl)-2-benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21a's is synthetic
Low-temp reaction device is adjusted to-10 ℃, by N-, (1-(3,4-Dimethoxyphenyl) ethyl-2-hydroxyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 20 (0.50g, (0.078g content is 60% 1.31mmol) to add 15mL sodium hydride, 15mLDMF suspension liquid 1.96mmol), stir 20min, dissolve.The 10mLDMF solution that drips benzyl bromine (0.34g, 1.96mmol), drip off half an hour, drips off and continue to stir 6h.After completion of the reaction, by product impouring 300mL water, standing 1h, separates out white solid, filters, and solid is dried and obtained 0.34g white solid, yield 54.9%; Fusing point: 147-149 ℃.
1H?NMR(400MHz,CDCl
3)δ7.32(dt,J＝13.5,5.6Hz,5H,Ar-H),6.86(d,J＝13.9Hz,3H,Ar-H),6.67(d,J＝7.4Hz,1H,CHCONH),5.21(d,J＝8.2Hz,1H,OCONH),5.15(d,J＝2.7Hz,1H,Ar-CH),4.91(s,1H,OCH(CH
3)
2),4.62–4.46(m,2H,C
6H
4CH
2O),4.01(dd,J＝13.4,7.1Hz,1H,OCONHCH),3.91–3.82(m,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.74(d,J＝4.2Hz,2H,CHCH
2O),2.14(s,1H,CHCH(CH
3)
2),1.37–1.11(m,6H,OCH(CH
3)
2),1.04–0.81(m,6H,CHCH(CH
3)
2).
According to the method for embodiment 76, select suitable raw material and reagent, make respectively the compound of 21b to 21g.It should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
Embodiment 77:N-(1-(3,4-Dimethoxyphenyl)-2-is to fluorine benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21b
1H?NMR(300MHz,CDCl
3)δ7.33–7.12(m,2H,Ar-H),7.11–6.89(m,2H,Ar-H),6.75(dt,J＝14.6,4.3Hz,3H,Ar-H),6.58(dd,J＝14.6,7.7Hz,1H,CHCONH),5.18–4.97(m,2H,OCONH+Ar-CH),4.82(dd,J＝12.4,6.2Hz,1H,OCH(CH
3)
2),4.51(d,J＝2.6Hz,2H,C
6H
4CH
2O),3.98–3.84(m,1H,OCONHCH),3.77(d,J＝5.1Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.68(d,J＝4.4Hz,2H,CHCH
2O),2.03(d,J＝5.4Hz,1H,CHCH(CH
3)
2),1.24–1.05(m,?6H,OCH(CH
3)
2),0.91–0.73(m,6H,CHCH(CH
3)
2).
Embodiment 78:N-(fluorine benzyloxy ethyl between 1-(3,4-Dimethoxyphenyl)-2-)-3-methyl-2-isopropoxy carbonyl amido butyramide 21c
1H?NMR(400MHz,CDCl
3)δ7.29–7.15(m,1H,Ar-H),6.98–6.84(m,3H,Ar-H),6.81–6.70(m,3H,Ar-H),6.66(d,J＝7.5Hz,1H,CHCONH),5.23–5.09(m,1H,OCONH),5.06(s,1H,Ar-CH),4.80(s,1H,OCH(CH
3)
2),4.43(dd,J＝19.1,10.4Hz,2H,C
6H
4CH
2O),3.93(dd,J＝14.9,7.5Hz,1H,OCONHCH),3.81–3.73(m,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.68–3.56(m,2H,CHCH
2O),2.05(d,J＝4.3Hz,1H,CHCH(CH
3)
2),1.22–1.00(m,6H,OCH(CH
3)
2),0.93–0.71(m,6H,CHCH(CH
3)
2).
Embodiment 79:N-(the adjacent fluorine benzyloxy of 1-(3,4-Dimethoxyphenyl)-2-ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21d
1H?NMR(400MHz,CDCl
3)δ7.33–7.15(m,2H,Ar-H),7.11–6.90(m,2H,Ar-H),6.84–6.66(m,3H,Ar-H),6.64(t,J＝7.4Hz,1H,CHCONH),5.14(s,1H,OCONH),5.09–4.98(m,1H,Ar-CH),4.86–4.68(m,1H,OCH(CH
3)
2),4.62–4.40(m,2H,C
6H
4CH
2O),3.92(dd,J＝14.1,7.2Hz,1H,OCONHCH),3.76(dd,J＝6.5,3.2Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.67(d,J＝4.6Hz,2H,CHCH
2O),2.16–1.95(m,1H,CHCH(CH
3)
2),1.26–0.99(m,6H,OCH(CH
3)
2),0.92–0.72(m,6H,CHCH(CH
3)
2).
Embodiment 80:N-(1-(3,4-Dimethoxyphenyl)-2-is to chlorine benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21e
H?NMR(400MHz,CDCl
3)δ7.21(t,J＝6.9Hz,2H,Ar-H),7.11(d,J＝8.2Hz,2H,Ar-H),6.74(dd,J＝9.6,5.4Hz,3H,Ar-H),6.57(d,J＝7.3Hz,1H,CHCONH),5.07(dd,J＝15.0,9.9Hz,2H,OCONH+Ar-CH),4.79(td,J＝12.6,6.3Hz,1H,OCH(CH
3)
2),4.39(dt,J＝12.2,9.0Hz,2H,C
6H
4CH
2O),3.96–3.82(m,1H,OCONHCH),3.82–3.72(m,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.63(d,J＝2.9Hz,2H,CHCH
2O),2.04(d,J＝6.5Hz,1H,CHCH(CH
3)
2),1.22–1.02(m,6H,OCH(CH
3)
2),0.93–0.70(m,6H,CHCH(CH
3)
2).
Embodiment 81:N-(1-(3,4-Dimethoxyphenyl)-2-is to methyl benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21f
1H?NMR(300MHz,CDCl
3)δ7.08(s,4H,Ar-H),6.76(q,J＝8.2Hz,3H,Ar-H),6.51(s,1H,CHCONH),5.04(s,2H,,Ar-CH),4.83(dd,J＝12.3,6.2Hz,1H,OCH(CH
3)
2),4.47–4.29(m,2H,C
6H
4CH
2O),3.92(s,1H,OCONHCH),3.77(d,J＝7.9Hz,6H,Ar-m-OCH
3+Ar-p-OCH
3),3.62(d,J＝3.9Hz,2H,CHCH
2O),2.27(s,3H,C
6H
4CH
3),2.03(s,1H,CHCH(CH
3)
2),1.26–?1.03(m,6H,OCH(CH
3)
2),0.82(tt,J＝21.8,10.9Hz,6H,CHCH(CH
3)
2).
The physico-chemical property table of compound 21
Embodiment 82: active testing EXPERIMENTAL EXAMPLE
The mensuration of in vitro Plating fungicidal activity
By breaking into the access of bacterium sheet containing in the culture dish of 50 μ g/mL liquids for examination germ, put into 25 ℃ of biochemical cultivation case dark culturing, 3 days " Invest, Then Investigate " fungistatic effects.Every processing repeats for 3 times.Take only add sterilized water not adding medicine person be contrast.The results are shown in Table 1.(％)
Table 1: the in vitro fungicidal activity of compound (ppm, inhibiting rate %)
*: "-": activity is not tested
Phytophthora capsici live body fungicidal activity is measured
All test samples all adopt 50 μ g/mL.By spray method, medicament is evenly sprayed on cucumber seedling, (every mL suspension is containing 1 * 10 after natural air drying, to inoculate Pseudoperonospora cubensis
5individual sporocyst), in the greenhouse of average daytime 22 ℃ of temperature, night 17 ℃ of temperature, cultivate.Every processing repeats 4 times, waits to contrast abundant morbidity " Invest, Then Investigate " disease index [(1) formula], by (2) formula, calculates prevention effect.The results are shown in Table 2.
(1) disease index (DI)=(∑ (sick value of series * this disease level diseased plant number) * 100)/(sick level maximum * investigation strain number)
(2) preventive effect=[(contrast average disease index-process average disease index)/contrast average disease index] * 100
The percentage ratio that accounts for whole leaf area by lesion area is formulated classification, and standard is as follows: standard: 0 grade---without scab; 1 grade---below 5%; 3 grades---; 6%～10%; 5 grades---11%～25%; 7 grades---26%～50%; 9 grades---more than 50%.
Table 2: compound to the live body fungicidal activity of Phytophthora capsici (50ppm, inhibiting rate %)
The mensuration of cucumber downy mildew live body fungicidal activity
All test samples all adopt 100 μ g/mL.Pseudoperonospora cubensis adopts spore suspension spray inoculation, in fine day, the morning reagent agent and contrast medicament is evenly sprayed in cucumber cotyledons, after 2 hours, inoculates pathogenic bacteria, and moisturizing is cultivated.Wait to contrast abundant morbidity " Invest, Then Investigate " preventive effect, formula is as follows: preventive effect %=(the contrast state of an illness-processing state of an illness)/contrast state of an illness * 100%.The results are shown in Table 3.
Table 3: compound is to the live body fungicidal activity of cucumber downy mildew (inhibiting rate %)
*: "-": activity is not tested.
Claims (11)
1. there is the compound shown in following general formula (I) or its pharmacy acceptable salt:
Wherein,
R
1hydrogen, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6alkynyl, benzyl, described benzyl benzene ring hydrogen is optionally selected from halogen, hydroxyl, cyano group, C by 1-5
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6the substituting group of alkynyl replaces;
R
2be an optional 1-5 substituting group, be selected from hydrogen, hydroxyl, cyano group, halogen, C
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6alkynyl, benzyloxy, phenyl, described benzyloxy and phenyl benzene ring hydrogen are optionally selected from halogen, hydroxyl, C by 1-5
1-6alkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, halo C
1-6alkyl, halo C
1-6alkoxyl group, halo C
2-6thiazolinyl, halo C
2-6the substituting group of alkynyl replaces;
N is 0 to 5 integer.
2. the compound shown in general formula according to claim 1 (I) or its pharmacy acceptable salt, is characterized in that:
R
1for hydrogen, methyl, ethyl, propargyl;
R
2for hydrogen, methyl, ethyl, halogen, methoxyl group;
N is 0,1.
3. the compound shown in general formula according to claim 1 (I) or its pharmacy acceptable salt, described compound is selected from:
N-(1-(3,4-Dimethoxyphenyl)-2-is to fluorophenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(the adjacent fluorophenoxy ethyl of 1-(3,4-Dimethoxyphenyl)-2-)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-is to chlorophenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-phenoxy group ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-is to methylphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(methylphenoxy ethyl between 1-(3,4-Dimethoxyphenyl)-2-)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-is to methoxyphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-O-methoxy phenoxy group ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(the adjacent fluorophenoxy of 4-hydroxy 3-methoxybenzene base-2-) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-hydroxy 3-methoxybenzene base-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-hydroxy 3-methoxybenzene base-2-is to chlorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-hydroxy 3-methoxybenzene base-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-hydroxy 3-methoxybenzene base-2-is to methylphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-hydroxy 3-methoxybenzene base-2-is to methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-hydroxy 3-methoxybenzene base-2-O-methoxy phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(the adjacent fluorophenoxy of 4-alkynes propoxy--3-p-methoxy-phenyl-2-) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to chlorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to methylphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-is to methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(4-alkynes propoxy--3-p-methoxy-phenyl-2-O-methoxy phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-is to methyl benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(the adjacent fluorine benzyloxy of 1-(3,4-Dimethoxyphenyl)-2-ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(fluorine benzyloxy ethyl between 1-(3,4-Dimethoxyphenyl)-2-)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-is to fluorine benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;
N-(1-(3,4-Dimethoxyphenyl)-2-is to chlorine benzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide.
4. the preparation method of the compound shown in general formula claimed in claim 1 (I), the method comprises the following steps:
Acetovanillone is reacted with alkylating reagent and obtains compound (2) in methylene dichloride under the effect of alkali; Compound (2) obtains compound (3) through cupric bromide bromination reaction in ethyl acetate; Compound (3) obtains compound (4) with the phenol reactant shown in formula (II) in acetone under the effect of Anhydrous potassium carbonate; Compound (4) successively adds oxammonium hydrochloride and sodium hydroxide in ethanol, and reaction obtains compound (5); Compound (5) is dissolved in ethanol, adds 10%Pd/C, concentrated hydrochloric acid, passes into hydrogen reducing and obtains compound (6); By NaOH water dissolution, add Valine, stir, under low temperature, under condition, isopropyl chlorocarbonate is added drop-wise in reaction solution, drip Bi Shengzhi room temperature, continue to be stirred to and react completely, once, diluted acid adjusts pH to acid to organic solvent washing, organic solvent extraction, dry, precipitation obtains compound (9); Compound (9) is dissolved with THF, under cold condition, add alkali and Vinyl chloroformate, under this condition, be stirred to and react completely, compound (6) is dissolved with THF, be added drop-wise in reaction solution, drip Bi Shengzhi room temperature, continue to stir, precipitation, ethyl alcohol recrystallization obtains compound (10), and reaction scheme is as follows:
Wherein, R
1, R
2as claim 1 defines.
5. the preparation method of the compound shown in general formula claimed in claim 1 (I), the method comprises the following steps:
Acetovanillone is obtained to compound (11) through cupric bromide bromination reaction in ethyl acetate; Compound (11) obtains compound (12) with the phenol reactant shown in formula (II) in acetone under the effect of Anhydrous potassium carbonate; Compound (12) successively adds oxammonium hydrochloride and sodium hydroxide in ethanol, and reaction obtains compound (13); Compound (13) is dissolved in ethanol, adds 10%Pd/C, concentrated hydrochloric acid, passes into hydrogen reducing and obtains compound (14); Compound (9) is dissolved with THF, under cold condition, add alkali and Vinyl chloroformate, under this condition, be stirred to and react completely, compound (14) is dissolved with THF, be added drop-wise in reaction solution, drip Bi Shengzhi room temperature, continue to stir, precipitation, ethyl alcohol recrystallization obtains compound (15); Compound (15) is reacted with propargyl bromide and obtains compound (16) in acetone under Anhydrous potassium carbonate effect, and reaction scheme is as follows:
Wherein, R
2as claim 1 defines.
6. the preparation method of the compound shown in general formula claimed in claim 1 (I), the method comprises the following steps:
Compound (3) under the effect of sodium formiate, adds sodium hydroxide reaction to obtain compound (17) in ethanol; Compound (17) successively adds oxammonium hydrochloride and sodium hydroxide in ethanol, and reaction obtains compound (18); Compound (18) is dissolved in ethanol, adds 10%Pd/C, concentrated hydrochloric acid, passes into hydrogen reducing and obtains compound (19); Compound (9) is dissolved with THF, under cold condition, add alkali and Vinyl chloroformate, under this condition, be stirred to and react completely, compound (19) is dissolved with THF, be added drop-wise in reaction solution, drip Bi Shengzhi room temperature, continue to stir, precipitation, ethyl alcohol recrystallization obtains compound (20); Compound (20) is reacted and obtains compound (21) with the cylite shown in formula (III) in DMF under sodium hydride effect, and reaction scheme is as follows:
Wherein, R
2as claim 1 defines.
7. general formula intermediate (13):
R wherein
2as claim 1-2 any one defines.
8. general formula intermediate (14):
R wherein
2as claim 1-2 any one defines.
9. general formula intermediate (20):
。
10. a pesticide composition, the compound that comprises any one in claim 1-2 and pharmacy acceptable salt thereof and carrier.
In 11. claim 1-2, any one compound and pharmacy acceptable salt thereof are as the application in bactericidal agent for preventing and treating Plant diseases.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410280228.0A CN104016886B (en) | 2014-06-20 | 2014-06-20 | A kind of N-1,2-bis-replaces ethyl valine amide carbamate derivatives and application |
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| CN201410280228.0A CN104016886B (en) | 2014-06-20 | 2014-06-20 | A kind of N-1,2-bis-replaces ethyl valine amide carbamate derivatives and application |
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| CN104945293A (en) * | 2015-06-18 | 2015-09-30 | 南开大学 | Sulfur-containing amino acid amide carbamate derivatives and application |
| CN105037211A (en) * | 2015-07-27 | 2015-11-11 | 南开大学 | Threonyl amine carbamate derivative and application |
| CN105037207A (en) * | 2015-06-18 | 2015-11-11 | 南开大学 | (Iso-)leucinamide carbamate derivative and application |
| CN106243000A (en) * | 2016-07-26 | 2016-12-21 | 南开大学 | A kind of Valinamide carbamate derivatives containing propargyl epoxide and application |
| CN107954882A (en) * | 2017-11-22 | 2018-04-24 | 上海泰禾国际贸易有限公司 | A kind of preparation method of 2- amino -2- (the 4- tert-butyl group -2- ethoxyl phenenyls) ethanol |
| CN108440444A (en) * | 2018-05-17 | 2018-08-24 | 湖南博隽生物医药有限公司 | A kind of 2- methyl -4- trifluoromethyls -5- thiazole carboxamides compounds |
| CN109020792A (en) * | 2018-09-10 | 2018-12-18 | 中国科学院青岛生物能源与过程研究所 | A method of synthesis β-O-4 lignin dimer model compound |
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| CN104945293A (en) * | 2015-06-18 | 2015-09-30 | 南开大学 | Sulfur-containing amino acid amide carbamate derivatives and application |
| CN105037207A (en) * | 2015-06-18 | 2015-11-11 | 南开大学 | (Iso-)leucinamide carbamate derivative and application |
| CN104945293B (en) * | 2015-06-18 | 2017-04-12 | 南开大学 | Sulfur-containing amino acid amide carbamate derivatives and application |
| CN105037211A (en) * | 2015-07-27 | 2015-11-11 | 南开大学 | Threonyl amine carbamate derivative and application |
| CN106243000A (en) * | 2016-07-26 | 2016-12-21 | 南开大学 | A kind of Valinamide carbamate derivatives containing propargyl epoxide and application |
| CN106243000B (en) * | 2016-07-26 | 2017-12-05 | 南开大学 | A kind of Valinamide carbamate derivatives of base containing propynyloxy and application |
| CN107954882A (en) * | 2017-11-22 | 2018-04-24 | 上海泰禾国际贸易有限公司 | A kind of preparation method of 2- amino -2- (the 4- tert-butyl group -2- ethoxyl phenenyls) ethanol |
| CN108440444A (en) * | 2018-05-17 | 2018-08-24 | 湖南博隽生物医药有限公司 | A kind of 2- methyl -4- trifluoromethyls -5- thiazole carboxamides compounds |
| CN111226949A (en) * | 2018-05-17 | 2020-06-05 | 湖南博隽生物医药有限公司 | Environment-friendly plant bactericide |
| CN109020792A (en) * | 2018-09-10 | 2018-12-18 | 中国科学院青岛生物能源与过程研究所 | A method of synthesis β-O-4 lignin dimer model compound |
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