CN104016886B

CN104016886B - A kind of N-1,2-bis-replaces ethyl valine amide carbamate derivatives and application

Info

Publication number: CN104016886B
Application number: CN201410280228.0A
Authority: CN
Inventors: 赵卫光; 寇俊杰; 王志鹏; 于淑晶; 王红学; 边强; 鞠国栋
Original assignee: Nankai University
Current assignee: Nankai University
Priority date: 2014-06-20
Filing date: 2014-06-20
Publication date: 2016-06-15
Anticipated expiration: 2034-06-20
Also published as: CN104016886A

Abstract

The invention belongs to bactericide field, relate to a kind of N-1,2-bis-as shown in formula (I) and replace ethyl valine amide carbamate derivatives and pharmaceutically acceptable salt thereof, wherein substituent R¹、R², n there is the definition provided in description, the invention still further relates to the preparation method of the compound of formula (I), prepare the intermediate developed exclusively for it and it is in the application of controlling plant diseases.

Description

A kind of N-1,2-bis-replaces ethyl valine amide carbamate derivatives and application

Technical field

The invention belongs to pesticide field, replace ethyl valine amide carbamate derivatives particularly to N-1,2-bis-and apply as antibacterial.

Background technology

In agricultural production, it is often subject to the harm of the harmful organisms such as worm, grass, bacterium and causes grain drop in production even to have no harvest. Oomycete pathogen is the pathogen that agriculturally a class is important, and host range is wide, including veterinary antibiotics, flowers, forest, cotton, fiber crops, the various crop of wet goods. Oomycetes phytopathogen to host plant destructive strong, hazardness big, short incubation period, infect frequently again, thus within a season of growth of plant, pathogenic bacteria can blaze about infects, and is difficult to control to, thus causing the serious loss in agriculture and forestry.

Valine amide carbamate fungicide is the antibacterial 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 comes into operation, and with widely used antibacterial no interactions Drug resistance in the market. Raw material is simple, and cost is low, it is easy to industrialized production, and its catabolite is environmentally friendly. The all multiresistance pathogen that improvement is caused by the unreasonable use of benzamides antibacterial that use of this antibacterial serve important function. Therefore, valine amide carbamate derivatives causes showing great attention to of each big agro-chemical companies in the world in recent years, and the numerous and confused huge fund that puts into is used for the research and development of this series bactericidal agent.The valine amide carbamate fungicide that recent development is developed mainly includes iprovalicarb (Dutzmann, PflanzenschutzNachrichtenBayer, 1999,52 (1): 15-32), benzene metsulfovax (Reuveni, EurJPlantPathol, 2003,109:243-251), different benzene metsulfovax (Miyakeetal, JP08325235,2005) and Valiphenal (Gisietal, ModernCropProtectionCompounds, 2007:651-671).

The amino part of valine amide carbamate compound is optimized by the present invention, and design has synthesized a series of valine amide compound, and through the bactericidal activity of various plants pathogenic bacterium is tested, result shows that the compounds of this invention has good bactericidal activity.

Summary of the invention

It is an object of the invention to provide a kind of N-1,2-bis-and replace ethyl valine amide carbamate derivatives. This compounds has the bactericidal activity of excellence, prepares medicine and has a extensive future.

It is compound or its pharmaceutically acceptable salt with below formula (I) that N-1,2-bis-provided by the invention replaces ethyl valine amide carbamate derivatives:

Wherein, R¹It is hydrogen, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxyl, 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, C_2-6Thiazolinyl, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxyl, halo C_2-6Thiazolinyl, halo C_2-6The substituent group of alkynyl replaces, R¹It is preferably hydrogen, methyl, ethyl, propargyl;

R²It is optional 1-5 substituent group, selected from hydrogen, hydroxyl, cyano group, halogen, C_1-6Alkyl, C_1-6Alkoxyl, C_2-6Thiazolinyl, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxyl, 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, C_2-6Thiazolinyl, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxyl, halo C_2-6Thiazolinyl, halo C_2-6The substituent group of alkynyl replaces, R²It is preferably hydrogen, methyl, ethyl, halogen, methoxyl group;

N is the integer of 0 to 5, preferentially selects 0,1.

Moreover, it relates to compound as defined in formula (I) is as the purposes of bactericide.

In the present invention, term " alkyl " refers to the saturated hydrocarbons of straight or branched. The example of this type of substituent group includes but not limited to methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, hexyl.

Equally, term " alkoxyl " refers to the saturated alkoxyl of straight or branched. The example of this type of substituent group includes but not limited to methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen, hexyloxy.

Term " thiazolinyl " refers to the thiazolinyl of straight or branched, and the example of this type of substituent group includes but not limited to vinyl, 1-acrylic, 2-acrylic, 1-butylene base, crotyl, 1-pentenyl, 1-hexenyl.

Term " alkynyl " refers to the alkynyl of straight or branched, and the example of this type of substituent group includes but not limited to acetenyl, 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, 1-hexin base.

Term " haloalkyl " is straight or branched alkyl, can partly or entirely be substituted with halogen atoms at these alkyl hydrogen atom; Term " halogenated alkoxy ", " haloalkenyl group ", " halo alkynyl " definition similar with term " haloalkyl ".

Term " halogen " refers to fluorine, chlorine, bromine, iodine.

The present invention further provides composition pesticide, its formula (I) compound comprising effective dose and carrier. The present invention also provides for composition pesticide, one of its particular compound disclosed in embodiment part comprising effective dose and carrier.

The compounds of this invention (I) syntheti c route is as follows, all of raw material be all by the method described in these schematic diagrams, prepared by the method that organic chemistry filed is well-known to the ordinarily skilled artisan or commercially available. Whole finalization compounds of the present invention are all by the method described in these schematic diagrams or are prepared by similar method, and these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.

According to formula (I) compound of the present invention, R¹、R², n such as summary of the invention defined.

Work as R¹For 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 replaced, compound 4 and oxammonium hydrochloride. obtain compound 5, and compound 5 reduction obtains compound 6, and compound 6 and compound 9 obtain the compound shown in formula 10.

The preparation method that the present invention also provides for described formula 10 compound, the method comprises the steps:

1) Acetovanillone is dissolved in dichloromethane, adds sodium hydroxide, water, add tetrabutyl ammonium bromide and cook phase transfer catalyst, mechanical agitation. Dropping dimethyl sulfate, drips off, and room temperature continues stirring 2h. After raw material point disappears, stop stirring, stand separatory, organic solvent extraction water layer, after strong aqua ammonia is diluted, backwash organic layer twice, dry over magnesium sulfate, precipitation, obtain yellow oil, standing becomes white solid, obtains compound 2, and described organic solvent refers to ether, diisopropyl ether, ethyl acetate, dichloroethanes, chloroform or toluene.

2) 3,4-dimethoxy-acetophenones 2 are dissolved in ethyl acetate, backflow, it is dividedly in some parts copper bromide. Backflow 2h is continued after adding. Filter, ethyl acetate rinse filtering residue. Saturated NaHCO₃Solution washes organic layer, and saturated common salt is washed once. Anhydrous MgSO₄Dry organic layer, precipitation. Ethyl alcohol recrystallization, obtains compound 3.

3) fortified phenol is dissolved in acetone, adds Anhydrous potassium carbonate, 1h is stirred at room temperature. Add compound 3, continue stirring 6h. After raw material point disappears, precipitation, organic solvent dissolves again, and sodium hydroxide solution washes organic layer twice, dry over magnesium sulfate, precipitation. Ethyl alcohol recrystallization, obtains compound 4.

4) compound 4 is dissolved in ethanol, adds oxammonium hydrochloride., be dividedly in some parts sodium hydroxide, 8h is stirred at room temperature. After raw material point disappears, precipitation, again dissolves residual liquid with organic solvent, washes organic layer, organic solvent backwash water layer twice with water, merge organic layer, dry over magnesium sulfate, precipitation. Product recrystallization obtains compound 5.

5) compound 5 is dissolved in ethanol, adds 10%Pd/C, concentrated hydrochloric acid. In autoclave, inflated with nitrogen drives air away, fills hydrogen exchange nitrogen. It is flushed with hydrogen gas, 24h is stirred at room temperature. After having reacted, cross and filter Pd/C, add appropriate concentrated hydrochloric acid, product is fully converted to ammonium salt, precipitation, the product recrystallization obtained by precipitation with ethanol. The salt that recrystallization obtains, in ethanol, adds sodium hydrate solid, 1h is stirred at room temperature. Precipitation removes ethanol, and product is dissolved in organic solvent, washes organic layer, anhydrous MgSO₄Dry organic layer, precipitation obtains compound 6.

6) by sodium hydroxide water dissolution, add Valine, stir, under condition, isopropyl chlorocarbonate is added drop-wise in reactant liquor under low temperature, drip Bi Shengzhi room temperature, continue stirring to reacting completely, once, diluted acid adjusts pH to acid to organic solvent washing, organic solvent extraction, dry, precipitation obtains compound 9.

7) compound 6 is dissolved with THF, alkali and ethyl chloroformate is added under cryogenic conditions, stir under this condition to reacting completely, compound 9 THF is dissolved, is added drop-wise in reactant liquor, drip Bi Shengzhi room temperature, continue stirring 3h, precipitation, ethyl alcohol recrystallization obtains compound 10, and described alkali refers to sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, N-methylmorpholine or pyridine.

Work as R¹During for H, n=0, with Acetovanillone for raw material, direct bromo obtains product 11, then carries out nucleophilic substitution with phenol sodium, obtains product 12, then made oxime 13, be reduced with hydrogen to amine 14, obtains target compound 15 by mixed anhydride method. Synthetic route is as follows:

Work as R¹During for propargyl, synthetic route is as follows:

This route specific experiment step is as follows:

1) Acetovanillone 1 is dissolved in ethyl acetate, backflow, it is dividedly in some parts copper bromide. 1h adds, and continues backflow 2h. Filter, ethyl acetate rinse filtering residue. Saturated NaHCO₃Solution washes organic layer, and saturated common salt is washed once. MgSO₄Dry organic layer, precipitation. Reduce pressure chromatography, obtains compound 11.

2) fortified phenol sodium is dissolved in DMF, and lower temperature control 85-90 DEG C of stirring, the DMF solution of dropping bromo-4-hydroxy 3-methoxybenzene ethyl ketone 11, half an hour adds. Dripping off continuation reaction five minutes, stop heating, poured into by reactant liquor with in the frozen water that salt acid for adjusting pH is 3, organic solvent extraction repeatedly, merges organic layer, water backwash organic layer. Anhydrous magnesium sulfate dries organic layer, filters, precipitation, product column chromatography, obtains compound 12.

3) compound 12 is added to the water, and adds sodium acetate and oxammonium hydrochloride., stirring, and reflux 3h. After completion of the reaction, being cooled to room temperature, organic solvent extraction three times, merge organic layer, anhydrous magnesium sulfate dries organic layer, filters, precipitation. Product column chromatography, obtains compound 13.

4) compound 13 heating is dissolved in ethanol, is cooled to room temperature, add Pd/C, concentrated hydrochloric acid. In autoclave, inflated with nitrogen drives air away, and hydrogen exchange nitrogen is repeatedly. It is flushed with hydrogen gas, 24h is stirred at room temperature. After completion of the reaction, filtering, precipitation, product recrystallization obtains the hydrochlorate of compound 14.

5), at-10 DEG C, the THF solution of isopropyl chlorocarbonate is dropped in the THF solution of 3-methyl-2-isopropyl oxygen formamido group butanoic acid 9 and N-methylmorpholine. 1h drips off, and continues stirring two hours. The THF solution of dropping 1-(4-hydroxy 3-methoxybenzene base)-2-substituent phenoxy ethamine. Half an hour adds, and adds rear room temperature reaction 10h. Filtering, precipitation, organic solvent dissolves again, sodium carbonate washing organic layer, dilute hydrochloric acid salt acid elution organic layer, dry over magnesium sulfate, precipitation. Ethyl alcohol recrystallization, obtains compound 15.

6) compound 15 being dissolved in acetone, add Anhydrous potassium carbonate, 1h, the acetone soln of dropping propargyl bromide are stirred at room temperature, half an hour drips off, and drips off and changes backflow into, and reflux 30h. After raw material point no longer changes, precipitation, organic solvent dissolution residue, sodium hydroxide solution washes organic layer, washes organic layer, and anhydrous magnesium sulfate dries organic layer, precipitation, with ethyl alcohol recrystallization, obtains compound 16.

Formula intermediate 12:

Formula 12 intermediate develops, wherein R exclusively for preparing formula 15 compound²Determine according to the definition in above-mentioned formula 15.

Formula intermediate 13:

Formula 13 intermediate develops, wherein R exclusively for preparing formula 15 compound²Determine according to the definition in above-mentioned formula 15.

Formula intermediate 14:

Formula 14 intermediate develops, wherein R exclusively for preparing formula 15 compound²Determine according to the definition in above-mentioned formula 15.

Work as R¹For 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, is reduced to amine 19 through high pressure. Make amide 20 then through mixed anhydride method, eventually pass sodium hydride and pull out hydroxyl hydrogen, obtain target compound 21 with replacing benzyl bromine reaction. Synthetic route is as follows:

This route specifically comprises the following steps that

1) compound 3 is dissolved in ethanol, adds water, adds alkali, and reflux 6h. After completion of the reaction, precipitation removes ethanol, and residue adds water, is extracted with ethyl acetate, and merges organic layer, and anhydrous magnesium sulfate dries organic layer, filters, precipitation, thick product reduced pressure chromatography, obtains compound 17.

2) compound 17 is dissolved in ethanol, adds oxammonium hydrochloride., is stirred at room temperature, is dividedly in some parts sodium hydrate solid, and half an hour adds, and reflux after adding 4h. Precipitation removes ethanol, adds water, extraction into ethyl acetate three times, merges organic layer, and anhydrous magnesium sulfate dries, and filters, precipitation, recrystallization, obtains compound 18.

3) compound 18 is dissolved in ethanol, adds Pd/C, and concentrated hydrochloric acid, in autoclave, inflated with nitrogen drives air away, fills hydrogen exchange nitrogen three times. It is flushed with hydrogen gas, 24h is stirred at room temperature. After having reacted, cross and filter Pd/C, precipitation, the product recrystallization obtained by precipitation with ethanol. The salt that recrystallization obtains, in ethanol, adds sodium hydrate solid, is stirred at room temperature. Precipitation removes ethanol, and product is dissolved in organic solvent, washes organic layer, and dry organic layer, precipitation obtains compound 19.

4), at-10 DEG C, the THF solution of isopropyl chlorocarbonate is dropped in the THF solution of 3-methyl-2-isopropoxycarbonylamino butanoic acid 9 and N-methylmorpholine. Stirring two hours is continued after dripping off. The THF solution of dropping 2-(3,4-Dimethoxyphenyl)-2-ethylaminoethanol 19. Half an hour adds, and adds rear room temperature reaction 10h. Filter, precipitation. Recrystallization, obtains compound 20.

5) low-temp reaction device is adjusted to-10 DEG C, and compound 20 adds the DMF suspension of sodium hydride, stirring, dissolves. The DMF solution of dropping benzyl bromine, half an hour drips off, and drips off continuation stirring 6h. After completion of the reaction, being poured in frozen water by product, stand, precipitate out white solid, filter, solid is dried and is obtained compound 21.

Formula intermediate 20:

Formula 20 intermediate develops exclusively for preparing formula 21 compound.

Structural formula provided by the invention (I) compound is the compound of the bactericidal activity with excellence, can be used for preventing and treating disease such as downy mildew, late blight, frost epidemic disease etc. that Oomycete pathogen produces, concrete such as cucumber downy mildew, downy mildew of garpe, Chinese cabbage downy mildew, tomato late blight, the late blight of potato, Fructus Capsici late blight, peronophythora litchi, soybean phytophthora root rot etc. The compounds of this invention also can be suitably used for sclerotiniose, ring spot, gray mold, banded sclerotial blight etc. The compounds of this invention can directly use, it is also possible to uses plus the carrier agriculturally accepted, it is also possible to other bactericide compounded use.

Detailed description of the invention

Examples provided hereinafter and preparation example are further elucidated with and illustrate the compounds of this invention and preparation method thereof. Should be appreciated that the scope of following embodiment and preparation example the scope not limited the present invention in any way.

Embodiment 1: the preparation of dimethoxy-acetophenone 2

Acetovanillone 1 (50.0g, 300.9mmol) is dissolved in 200mLCH₂Cl₂, add sodium hydroxide (31.3g, 782.3mmol), 200mLH₂O, adds 4.0g tetrabutyl ammonium bromide and cooks phase transfer catalyst, mechanical agitation. Dropping dimethyl sulfate (49.4g, 391.2mmol), 1h drips off, and room temperature continues stirring 2h. After raw material point disappears, stop stirring, stand separatory, 100mL dichloromethane extraction water layer twice, after 200mL strong aqua ammonia is diluted to 400mL, backwash organic layer twice, 300mL washes organic layer twice, dry over magnesium sulfate, precipitation, obtain yellow oil 53.7g, stand and become white solid, fusing point: 45-46 DEG C. Yield: 99%.¹HNMR(300MHz,CDCl₃) δ 7.53 (m, 2H, Ar-H), 6.89 (d, J=8.3Hz, 1H, Ar-H), 4.09 3.85 (m, 6H, Ar-m-OCH₃+Ar-p-OCH₃),2.57(s,3H,COCH₃).

The synthesis of the bromo-1-of embodiment 2:2-(3,4-Dimethoxyphenyl) ethyl ketone 3

3,4-dimethoxy-acetophenones 2 (50.0g, 277.5mmol) are dissolved in 700mL ethyl acetate, backflow, it is dividedly in some parts copper bromide (123.9g, 554.9mmol). 1h adds, and continues backflow 2h. Filter, a small amount of ethyl acetate rinse filtering residue. The saturated NaHCO of 200mL₃Solution washes organic layer 3 times, and 200mL saturated common salt is washed once. Anhydrous MgSO₄Dry organic layer, precipitation. Ethyl alcohol recrystallization, obtains light tan solid 36.0g. Fusing point: 75-76 DEG C, productivity: 50.2%.¹HNMR(300MHz,CDCl₃) δ 7.75 7.43 (m, 2H, Ar-H), 6.92 (d, J=8.4Hz, 1H, Ar-H), 4.42 (s, 2H, CH₂), 3.96-3.98 (d, J=6.6Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃).

Embodiment 3:1-(3,4-the Dimethoxyphenyl)-2-synthesis to fluorophenoxy ethyl ketone 4a

Phenol (20.0g, 212.8mmol) is dissolved in 200mL acetone, adds K₂CO₃(30.8g, 223.4mmol) powder, is stirred at room temperature 1h. Add the bromo-1-of 2-(3,4-Dimethoxyphenyl) ethyl ketone 3 (57.8g, 223.4mmol), continue stirring 6h. After raw material point disappears, precipitation, 200mL dichloromethane dissolves again, and 100mL1mol/L sodium hydroxide solution washes organic layer twice, dry over magnesium sulfate, precipitation. Ethyl alcohol recrystallization, obtains white solid 49.4g, fusing point: 83-85 DEG C, yield 85.3%.¹HNMR(400MHz,CDCl₃)) δ 7.77 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-OCH₃+Ar-p-OCH₃).

According to the method for embodiment 3, select suitable raw material and reagent, prepare the compound of 4b to 4h respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

Embodiment 4:1-(3,4-the Dimethoxyphenyl)-2-synthesis to fluorophenoxy ethyl ketone 4b

White solid, fusing point: 125-126 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.59 (d, J=1.7Hz, 2H, Ar-H), 7.06 6.72 (m, 5H, Ar-H), 5.24 (s, 2H, CH₂), 3.98 (d, J=9.2Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃).

The synthesis of embodiment: 1-(3,4-Dimethoxyphenyl)-2-neighbour fluorophenoxy ethyl ketone 4c

White solid, fusing point: 110-111 DEG C.¹HNMR(300MHz,CDCl₃)δ7.79–7.47(m,2H,Ar-H),7.15–6.71(m,5H,Ar-H),5.32(s,2H,CH₂), 3.97 (d, J=6.3Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃).

The synthesis of embodiment 6:1-(3,4-Dimethoxyphenyl)-2-p-chlorophenyl ethyl ketone 4d

White solid, fusing point: 106-107 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.72 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, CH₂), 3.98 (d, J=10.1Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃).

Embodiment 7:1-(3,4-the Dimethoxyphenyl)-2-synthesis to methylphenoxy ethyl ketone 4e

White solid, fusing point: 89-91 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.69 (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, CH₂), 3.98 (d, J=8.7Hz, 6H, Ar-m-OCH3+Ar-p-OCH₃),2.31(s,3H,CH₃).

The synthesis of methylphenoxy ethyl ketone 4f between embodiment 8:1-(3,4-Dimethoxyphenyl)-2-

White solid, fusing point: 73-74 DEG C.¹HNMR(400MHz,CDCl₃) δ δ 7.69 (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, CH₂), 3.97 (d, J=8.4Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃),2.34(s,3H,CH₃).

Embodiment 9:1-(3,4-the Dimethoxyphenyl)-2-synthesis to methoxyphenoxy ethyl ketone 4g

White solid, fusing point: 96-98 DEG C.¹HNMR(400MHz,CDCl₃)) δ 7.65 (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, CH₂), 3.95 (d, J=8.0Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃),3.76(s,3H,C₆H₄OCH₃).

The synthesis of embodiment 10:1-(3,4-Dimethoxyphenyl)-2-o-methoxyphenoxy ethyl ketone 4h

White solid, fusing point: 89-90 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.70 (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, CH₂), 3.97 (d, J=7.2Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃),3.91(s,1H,C₆H₄OCH₃).

The synthesis of embodiment 11:1-(3,4-Dimethoxyphenyl)-2-phenoxy group acetophenone oxime 5a

1-(3,4-Dimethoxyphenyl)-2-phenoxy group ethyl ketone 4a (20.0g, 69.7mmol) is dissolved in 500mL ethanol, add oxammonium hydrochloride. (7.3g, 104.5mmol), be dividedly in some parts sodium hydroxide (4.2g, 104.5mmol), 0.5h adds. 8h is stirred at room temperature. After raw material point disappears, precipitation, with 400mL dichloromethane, residual liquid is dissolved again, 200mL washes organic layer, 100mL dichloromethane backwash water layer twice, merges organic layer, dry over magnesium sulfate, precipitation. Product ethyl alcohol recrystallization obtains white solid 16.8g. Fusing point: 85-87 DEG C, yield 84.1%.¹HNMR(400MHz,CDCl₃) δ 7.57 (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, CH₂), 3.87 (d, J=8.9Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃).

According to the method for embodiment 11, select suitable raw material and reagent, prepare the compound of 5b to 5h respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

Embodiment 12:1-(3,4-the Dimethoxyphenyl)-2-synthesis to fluorophenoxy acetophenone oxime 5b

White solid, fusing point: 81-85 DEG C,¹HNMR(300MHz,CDCl₃) 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, CH₂), 3.95 (d, J=6.9Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃).

The synthesis of embodiment 13:1-(3,4-Dimethoxyphenyl)-2-neighbour fluorophenoxy acetophenone oxime 5c

White solid, fusing point: 96-99 DEG C.¹HNMR(400MHz,CDCl₃)δ7.74–7.20(m,2H,Ar-H),7.10–6.70(m,5H,Ar-H),5.34–4.84(m,2H,CH₂),3.94–3.76(m,6H,Ar-m-OCH₃+Ar-p-OCH₃).

The synthesis of embodiment 14:1-(3,4-Dimethoxyphenyl)-2-p-chlorophenyl acetophenone oxime 5d

White solid, fusing point: 132-134 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.40 7.05 (m, 4H, Ar-H), 6.86 (t, J=8.4Hz, 3H, Ar-H), 5.24 (s, 2H, CH₂), 3.88 (d, J=8.7Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃).

Embodiment 15:1-(3,4-the Dimethoxyphenyl)-2-synthesis to methylphenoxy acetophenone oxime 5e

White solid, fusing point: 80-83 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.28 (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, CH₂),4.11–3.64(d,6H,Ar-m-OCH₃+Ar-p-OCH₃),2.30(s,3H,CH₃).

The synthesis of methylphenoxy acetophenone oxime 5f between embodiment 16:1-(3,4-Dimethoxyphenyl)-2-

White solid, fusing point: 91-92 DEG C.¹HNMR(300MHz,CDCl₃)δ7.34–6.95(m,3H,Ar-H),6.89–6.37(m,4H,Ar-H),5.21–4.66(s,2H,CH₂),3.83–3.65(d,6H,Ar-m-OCH₃+Ar-p-OCH₃), 2.21 (s, J=6.7Hz, 3H, CH₃).

Embodiment 17:1-(3,4-the Dimethoxyphenyl)-2-synthesis to methoxyphenoxy acetophenone oxime 5g

White solid, fusing point: 97-98 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.57 (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, CH₂), 3.87 (d, J=8.2Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃),3.68(s,3H,OCH₃).

The synthesis of embodiment 18:1-(3,4-Dimethoxyphenyl)-2-o-methoxyphenoxy acetophenone oxime 5h

White solid, fusing point: 116-117 DEG C.¹HNMR(400MHz,CDCl₃)δ7.40–7.15(m,3H, Ar-H),6.97–6.55(m,4H,Ar-H),5.27(s,2H,CH₂),3.82–3.77(d,6H,Ar-m-OCH₃+Ar-p-OCH₃),3.72(s,3H,OCH₃).

The synthesis of embodiment 19:1-(3,4-Dimethoxyphenyl)-2-phenoxyethylamine 6a

1-(3,4-Dimethoxyphenyl)-2-phenoxy group acetophenone oxime 5a (10.0g, 34.8mmol) heating is dissolved in 500mL ethanol, is cooled to room temperature, add 1.0gPd/C, 3mL concentrated hydrochloric acid. In autoclave, inflated with nitrogen drives air away, fills hydrogen exchange nitrogen three times. It is flushed with hydrogen gas 20atm, 24h is stirred at room temperature. After having reacted, cross and filter Pd/C, add appropriate concentrated hydrochloric acid, product is fully converted to ammonium salt, precipitation, the product recrystallization obtained by precipitation with ethanol. The salt that recrystallization obtains, in ethanol, adds 1.2eq sodium hydrate solid, 1h is stirred at room temperature and neutralizes. Precipitation removes ethanol, and product is dissolved in 100mL dichloromethane, and 50mL washes organic layer, MgSO₄Dry organic layer, precipitation obtains 7.5g faint yellow solid. Fusing point: 77-78 DEG C; Yield: 78.7%.¹HNMR(300MHz,CDCl₃) δ 7.29 (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, CHCH₂), 4.07 (dd, J=9.0,3.6Hz, 1H, CHCH₂), 3.91 (d, J=7.3Hz, 7H, Ar-m-OCH₃+Ar-p-OCH₃+NH₂CH),2.26–1.71(m,2H,NH₂).

According to the method for embodiment 19, select suitable raw material and reagent, prepare the compound of 6b to 6h respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

Embodiment 20:1-(3,4-the Dimethoxyphenyl)-2-synthesis to fluorophenoxy ethamine 6b

Faint yellow solid, fusing point: 96-99 DEG C;¹HNMR(400MHz,CDCl₃)δ7.09–6.91(m,4H,Ar-H),6.91–6.76(m,3H,Ar-H),4.50(s,1H,CHCH₂), 4.10 (d, J=7.7Hz, 1H, CHCH₂), 3.92 (d, J=7.7Hz, 7H, Ar-m-OCH₃+Ar-p-OCH₃+NH₂CH).

The synthesis of embodiment 21:1-(3,4-Dimethoxyphenyl)-2-neighbour fluorophenoxy ethamine 6c

Faint yellow solid, fusing point: 65-68 DEG C.¹HNMR(300MHz,CDCl₃) δ 7.11 6.63 (m, 7H, Ar-H), 4.36 (dd, J=8.8,3.5Hz, 1H, CHCH₂), 4.04 (dd, J=9.0,3.5Hz, 1H, CHCH₂), 3.88 (t, J=7.0Hz, 1H+NH₂CH), 3.82 (d, J=8.1Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃),1.82(s,2H,NH₂).

The synthesis of embodiment 22:1-(3,4-Dimethoxyphenyl)-2-p-chlorophenyl ethamine 6d

Faint yellow solid, fusing point: 94-97 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.26 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, CHCH₂), 4.03 (dd, J=8.9,3.7Hz, 1H, CHCH₂), 3.90 (dd, J=15.6,9.0Hz, 7H, Ar-m-OCH₃+Ar-p-OCH₃+NH₂CH),1.85(s,2H,NH₂).

Embodiment 23:1-(3,4-the Dimethoxyphenyl)-2-synthesis to methylphenoxy ethamine 6e

Faint yellow solid, fusing point: 68-72 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.19 6.95 (m, 4H, Ar-H), 6.86 (dd, J=18.9,8.1Hz, 3H, Ar-H), 4.40 (d, J=6.1Hz, 1H, CHCH₂), 4.04 (t, J=13.0Hz, 1H, CHCH₂), 3.88 (t, J=22.4Hz, 7H, Ar-m-OCH₃+Ar-p-OCH₃+NH₂CH),2.31(s,5H,Ar-CH₃+NH₂).

The synthesis of methylphenoxy ethamine 6f between embodiment 24:1-(3,4-Dimethoxyphenyl)-2-

Faint yellow solid, fusing point: 64-66 DEG C.¹HNMR(300MHz,CDCl₃) δ 7.12 6.36 (m, 7H, Ar-H), 4.30 (dd, J=8.5,3.8Hz, 1H, CHCH₂),4.02–3.87(m,1H,CHCH₂), 3.81 (t, J=8.8Hz, 7H, NH₂CH+Ar-m-OCH₃+Ar-p-OCH₃),2.25(s,3H,CH₃),2.14(s,2H,NH₂).

Embodiment 25:1-(3,4-the Dimethoxyphenyl)-2-synthesis to methoxyphenoxy ethamine 6g

Faint yellow solid, fusing point: 57-60 DEG C.¹HNMR(300MHz,CDCl₃) δ 7.09 6.95 (m, 2H, Ar-H), 6.92 6.76 (m, 5H, Ar-H), 4.38 (dd, J=8.9,3.4Hz, 1H, CHCH₂),4.01(m,1H,CHCH₂), 3.91 (d, J=6.3Hz, 7H, NH₂CH+Ar-m-OCH₃+Ar-p-OCH₃),3.78(s,3H,C₆H₄OCH₃),2.14(s,2H,NH₂).

The synthesis of embodiment 26:1-(3,4-Dimethoxyphenyl)-2-o-methoxyphenoxy ethamine 6h

Faint yellow solid, fusing point: 90-94 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.09 6.75 (m, 7H, Ar-H), 4.44 (dd, J=9.3,3.4Hz, 1H, CHCH₂), 4.12 (dd, J=9.3,3.4Hz, 1H, CHCH₂),3.91(s,4H,NH₂CH+C₆H₄OCH₃), 3.87 (d, J=5.4Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃),1.83(s,2H,NH₂).

The synthesis of embodiment 27:3-methyl-2-isopropoxycarbonylamino butanoic acid 9

By sodium hydroxide (12.0g, 0.3mol) 150ml water dissolution, add valine (17.5g, 0.15mol), stir. Under cryosel bath, it is cooled to about-10 DEG C, dropping isopropyl chlorocarbonate (20.3g, 0.18mol), drip and finish, remove cryosel bath, 1h, stopped reaction are stirred at room temperature. Once, aqueous phase 1M dilute hydrochloric acid adjusts pH to 2～3 to 50ml washed with diethylether, and ether extracts (50mL × 4), anhydrous MgSO₄Dry, precipitation obtains colorless oil 22.3g, and refrigerator freezing obtains white solid. Productivity 73.1%.¹HNMR(400MHz,CDCl₃)δ10.90(s,1H,COOH),5.22(s,1H,CHNHCO),5.04–4.84(m,1H,(CH₃)₂CHO), 4.34 (dd, J=8.9,4.3Hz, 1H, COCHNH), 2.24 (dd, J=12.0,6.1Hz, 1H, (CH₃)₂CHCH),1.25(s,6H,(CH₃)₂CHO),1.07–0.83(m,6H,(CH₃)₂CHCH).

The synthesis of embodiment 28:N-(1-(3,4-Dimethoxyphenyl)-2-Phenoxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10a

At-10 DEG C, by isopropyl chlorocarbonate (2.11g, 18.7mmol) 60mLTHF solution drop in the 80mLTHF solution of 3-methyl-2-isopropoxycarbonylamino butanoic acid 9 (3.80g, 18.7mmol) and N-methylmorpholine (1.88g, 18.7mmol). 1h drips off, and continues stirring two hours. The 60mLTHF solution of dropping 1-(3,4-Dimethoxyphenyl)-2-phenoxyethylamine 6a (5.0g, 18.3mmol). Half an hour adds, and adds rear room temperature reaction 10h. Filtering, precipitation, 200mL dichloromethane dissolves again, and 100mL1mol/L sodium carbonate washes twice, and 100mL1mol/L hydrochloric acid washes twice, dry over magnesium sulfate, precipitation. Ethyl alcohol recrystallization, obtains white solid 6.7g. Fusing point: 138-140 DEG C, yield 80.4%.¹HNMR(400MHz,CDCl₃) δ 7.37 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 (CH₃)₂),4.34–4.10(m,2H,OCH₂), 4.00 (dd, J=17.6,11.0Hz, 1H, OCONHCH), 3.86 (s, 6H, Ar-m-OCH₃+Ar-p-OCH₃), 2.17 (d, J=5.9Hz, 1H, CHCH (CH₃)₂),1.25–1.10(m,6H,OCH(CH₃)₂),1.05–0.83(m,6H,CHCH(CH₃)₂).

According to the method for embodiment 28, select suitable raw material and reagent, prepare the compound of 10b to 10h respectively.It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

The synthesis of embodiment 29:N-(1-(3,4-Dimethoxyphenyl)-2-is to fluorophenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10b

¹HNMR(400MHz,CDCl₃) δ 7.02 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 (CH₃)₂),4.27–4.10(m,2H,OCH₂), 3.98 (dd, J=15.3,8.6Hz, 1H, OCONHCH), 3.86 (s, 6H, Ar-m-OCH₃+Ar-p-OCH₃),2.15(s,1H,CHCH(CH₃)₂),1.29–1.09(m,6H,OCH(CH₃)₂),1.05–0.84(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 30:N-(1-(3,4-Dimethoxyphenyl)-2-neighbour's fluorophenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10c

¹HNMR(400MHz,CDCl₃) δ 7.16 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 (CH₃)₂), 4.31 (ddd, J=35.6,9.6,4.4Hz, 2H, OCH₂), 4.04 (d, J=6.5Hz, OCONHCH), 3.89 (d, J=7.2Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃), 2.20 (dd, J=13.1,6.5Hz, 1H, CHCH (CH₃)₂),1.30–1.10(m,6H,OCH(CH₃)₂),1.02–0.79(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 31:N-(1-(3,4-Dimethoxyphenyl)-2-p-chlorophenyl ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10d

¹HNMR(400MHz,CDCl₃) δ 7.24 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 (CH₃)₂),4.23–4.03(m,2H,OCH₂),3.99–3.85(m,1H,OCONHCH),3.79(s,6H,Ar-m-OCH₃+Ar-p-OCH₃),2.08(s,1H,CHCH(CH₃)₂),1.21–1.04(m,6H,OCH(CH₃)₂),0.97–0.76(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 32:N-(1-(3,4-Dimethoxyphenyl)-2-is to methylphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10e

¹HNMR(400MHz,CDCl₃) δ 7.07 (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 (CH₃)₂),4.27–4.06(m,2H,OCH₂), 3.98 (dd, J=14.8,8.1Hz, 1H, OCONHCH), 3.86 (s, 6H, Ar-m-OCH₃+Ar-p-OCH₃), 2.28 (s, 3H, Ar-CH3), 2.17 (d, J=6.3Hz, 1H, CHCH (CH₃)₂),1.34–1.14(m,6H,OCH(CH₃)₂),1.02–0.78(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 33:N-(between 1-(3,4-Dimethoxyphenyl)-2-methylphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10f

¹HNMR(400MHz,CDCl₃) δ 7.18 (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 (CH₃)₂), 4.19 (dd, J=17.5,7.7Hz, 2H, OCH₂), 4.06 (d, J=6.5Hz, 1H, OCONHCH), 3.88 (s, 6H, Ar-m-OCH₃+Ar-p-OCH₃),2.34(s,3H,Ar-CH₃),2.21–2.11(m,1H,CHCH(CH₃)₂),1.34–1.12(m,6H,OCH(CH₃)₂),1.08–0.82(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 34:N-(1-(3,4-Dimethoxyphenyl)-2-is to methoxyphenoxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10g

¹HNMR(400MHz,CDCl₃) δ 6.84 (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 (CH₃)₂),4.16–4.01(m,2H,OCH₂), 3.96 (d, J=7.3Hz, 1H, OCONHCH), 3.80 (d, J=6.3Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃),3.69(s,3H,C₆H₄-o-OCH₃),2.09(s,1H,CHCH(CH₃)₂),1.19–1.08(m,6H,OCH(CH₃)₂),0.93–0.76(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 35:N-(1-(3,4-Dimethoxyphenyl)-2-o-methoxyphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 10h

¹HNMR(400MHz,CDCl₃) δ 6.98 (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 (CH₃)₂),4.31–4.13(m,2H,OCH₂), 4.02 (dd, J=17.1,8.4Hz, 1H, OCONHCH), 3.90 3.80 (m, 9H, Ar-m-OCH₃+Ar-p-OCH₃+C₆H₄-o-OCH₃),2.26–2.02(m,1H,CHCH(CH₃)₂),1.29–1.12(m,6H,OCH(CH₃)₂),1.00–0.74(m,6H,CHCH(CH₃)₂).

The physical and chemical parameter table of compound 10

The synthesis of embodiment 36:2-bromo-1-(4-hydroxy 3-methoxybenzene base) ethyl ketone 11

Acetovanillone 1 (40.0g, 240.7mmol) is dissolved in 600mL ethyl acetate, backflow, it is dividedly in some parts copper bromide (105.4g, 471.8mmol).1h adds, and continues backflow 2h. Filter, with ethyl acetate rinse filtering residue. The saturated NaHCO of 200mL₃Solution washes organic layer 3 times, and 200mL saturated common salt is washed once. MgSO₄Dry organic layer, precipitation. Reduced pressure chromatography (petroleum ether: ethyl acetate=10:1; Petroleum ether: ethyl acetate=4:1), obtain light yellow solid 27.5g, fusing point: 59-60 DEG C, yield 46.8%.¹HNMR(400MHz,CDCl₃) δ 7.56 7.31 (m, 2H, Ar-H), 6.89 (t, J=8.9Hz, 1H, Ar-H), 6.11 (s, 1H, OH), 4.34 (s, 2H, CH₂),3.98–3.74(s,3H,CH₃).

The synthesis of embodiment 37:1-(4-hydroxy 3-methoxybenzene base)-2-phenoxy group ethyl ketone 12a

Sodium phenate (5.7g, 60.6mmol) is dissolved in 60mLDMF, and lower temperature control 85-90 DEG C of stirring, the DMF solution of dropping bromo-4-hydroxy 3-methoxybenzene ethyl ketone 11 (5.0g, 20.4mmol), half an hour adds. Drip off continuation reaction five minutes, stop heating, reactant liquor is poured in the frozen water that 500mL salt acid for adjusting pH is 3,50mL dichloromethane extraction 6 times, merge organic layer, 500mL water backwash organic layer 3 times. Anhydrous magnesium sulfate dries organic layer, filters, precipitation, product reduced pressure chromatography (petroleum ether: ethyl acetate=10:1; Petroleum ether: ethyl acetate=5:1) obtain white solid 4.4g, fusing point: 80-81 DEG C, yield: 84.1%.¹HNMR(300MHz,CDCl₃) δ 7.54 (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, CH₂),3.89(s,3H,CH₃).

According to the method for embodiment 37, select suitable raw material and reagent, prepare the compound of 12b to 12g respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

Embodiment 38:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to fluorophenoxy ethyl ketone 12b

White solid, fusing point: 96-97 DEG C,¹HNMR(400MHz,CDCl₃) 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, CH₂),3.99(s,3H,OCH₃).

The synthesis of embodiment 39:1-(4-hydroxy 3-methoxybenzene base)-2-neighbour fluorophenoxy ethyl ketone 12c

White solid, fusing point: 77-79 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.53 (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, CH₂),3.90(s,3H,CH₃).

The synthesis of embodiment 40:1-(4-hydroxy 3-methoxybenzene base)-2-p-chlorophenyl ethyl ketone 12d

White solid, fusing point: 86-87 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.64 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, CH₂),3.98(s,3H,CH₃).

Embodiment 41:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to methylphenoxy ethyl ketone 12e

White solid, fusing point: 85-87 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.70 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, CH₂), 3.97 (d, J=2.1Hz, 3H, OCH₃),2.31(s,3H,CH₃).

Embodiment 42:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to methoxyphenoxy ethyl ketone 12f

White solid, fusing point: 93-94 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.61 (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, CH₂),4.01–3.90(m,3H,C₆H₃OCH₃),3.77(s,3H,C6H₄OCH₃).

The synthesis of embodiment 43:1-(4-hydroxy 3-methoxybenzene base)-2-o-methoxyphenoxy ethyl ketone 12g

White solid, fusing point: 84-85 DEG C.¹HNMR(400MHz,CDCl₃)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,CH₂),3.96(s,3H,C₆H₃OCH₃),3.91(s,3H,C₆H₄OCH₃).

Embodiment 44:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to fluorophenoxy acetophenone oxime 13a

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), stirring, reflux 3h. After completion of the reaction, being cooled to room temperature, 50mL extraction into ethyl acetate three times, merge organic layer, anhydrous magnesium sulfate dries organic layer, filters, precipitation. Product reduced pressure chromatography (petroleum ether: ethyl acetate=10:1; Petroleum ether: ethyl acetate=4:1), obtain white crystal 4.3g, fusing point: 67-68 DEG C.¹HNMR(400MHz,CDCl₃)δ7.26(m,4H,Ar-H),7.03–6.77(m,4H,Ar-H),5.41–4.81(m,2H,CH₂), 3.90 (d, J=4.8Hz, 3H, CH₃).

According to the method for embodiment 44, select suitable raw material and reagent, prepare the compound of 13b to 13g respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

Embodiment 45:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to fluorophenoxy acetophenone oxime 13b

Clear crystal, fusing point: 118-119 DEG C,¹HNMR(400MHz,CDCl₃)δ7.27–7.18(m,2H,Ar-H),7.01–6.85(m,5H,Ar-H),5.25(s,2H,CH₂), 3.91 (d, J=4.6Hz, 3H, CH₃).

The synthesis of embodiment 46:1-(4-hydroxy 3-methoxybenzene base)-2-neighbour chlorophenoxy acetophenone oxime 13c

Clear crystal, fusing point: 77-79 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.34 (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, CH₂),3.93(s,3H,CH₃).

The synthesis of embodiment 47:1-(4-hydroxy 3-methoxybenzene base)-2-p-chlorophenyl acetophenone oxime 13d

Off-white color solid, fusing point: 93-95 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.31 7.17 (m, 4H, Ar-H), 6.91 (dd, J=13.9,8.5Hz, 3H, Ar-H), 5.30 4.75 (m, 2H, CH₂), 3.89 (d, J=4.8Hz, 3H, CH₃).

Embodiment 48:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to methylphenoxy acetophenone oxime 13e

White solid, fusing point: 112-115 DEG C.¹HNMR(300MHz,CDCl₃) δ 7.30 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, CH₂),3.88(s,3H,C₆H₃OCH₃), 2.30 (d, J=3.1Hz, 3H, CH₃).

Embodiment 49:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to methoxyphenoxy acetophenone oxime 13f

White solid, fusing point: 105-107 DEG C.¹HNMR(400MHz,CDCl₃)δ7.27–7.16(m,2H,Ar-H),6.97–6.74(m,5H,Ar-H),5.33–4.86(m,2H,CH₂),3.91(s,3H,C₆H₃OCH₃),3.78(s,3H,C₆H₄OCH₃).

The synthesis of embodiment 50:1-(4-hydroxy 3-methoxybenzene base)-2-o-methoxyphenoxy acetophenone oxime 13g

White solid, fusing point: 114-115 DEG C.¹HNMR(300MHz,CDCl₃) δ 7.21 (d, J=12.0Hz, 2H, Ar-H), 6.94 6.73 (m, 5H, Ar-H), 5.33 4.84 (m, 2H, CH₂),3.78(s,3H,C₆H₃OCH₃),3.68(s,3H,C₆H₄OCH₃).

The synthesis of embodiment 51:1-(4-hydroxy 3-methoxybenzene base)-2-phenoxyethylamine 14a hydrochlorate

1-(4-hydroxy 3-methoxybenzene base)-2-phenoxy group acetophenone oxime 13a (2.0g, 7.3mmol) heating is dissolved in 100mL ethanol, is cooled to room temperature, add 0.2gPd/C, 0.6mL concentrated hydrochloric acid. In autoclave, inflated with nitrogen drives air, hydrogen exchange nitrogen three times away. It is flushed with hydrogen gas 20atm, 24h is stirred at room temperature. After completion of the reaction, filtering, precipitation, product recrystallization obtains white solid 1.2g. Yield 63.8%.¹HNMR(300MHz,DMSO)δ9.29(s,1H,OH),8.76(s,3H,NH₃ ⁺), 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, CHCH₂),3.80(s,3H,OCH₃).

According to the method for embodiment 51, select suitable raw material and reagent, prepare the compound of 14b to 14g respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

Embodiment 52:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to fluorophenoxy ethamine 14b hydrochlorate

¹HNMR(300MHz,DMSO)δ9.20(s,1H,OH),7.85(s,3H,NH₃ ⁺), 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, CHCH₂),3.79(s,3H,OCH₃).

The synthesis of embodiment 53:1-(4-hydroxy 3-methoxybenzene base)-2-neighbour's fluorophenoxy ethamine 14c hydrochlorate

¹HNMR(400MHz,DMSO)δ9.30(s,1H,OH),8.84(s,3H,NH₃ ⁺), 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, CHCH₂),3.80(s,3H,OCH₃).

The synthesis of embodiment 54:1-(4-hydroxy 3-methoxybenzene base)-2-p-chlorophenyl ethamine 14d hydrochlorate

¹HNMR(400MHz,DMSO)δ9.29(s,1H,OH),8.70(s,3H,NH₃ ⁺), 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, CHCH₂),3.80(s,3H,OCH₃).

Embodiment 55:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to methylphenoxy ethamine 14e

¹HNMR(400MHz,CDCl₃)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,CHCH₂),3.82(s,4H,CHCH₂+OCH₃),2.21(s,3H,CH₃),1.67(s,2H,NH₂).

Embodiment 56:1-(4-hydroxy 3-methoxybenzene the base)-2-synthesis to methoxyphenoxy ethamine 14f hydrochlorate

¹HNMR(400MHz,DMSO)δ9.30(s,1H,OH),8.73(s,3H,NH₃ ⁺), 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, CHCH₂),3.81(s,3H,C₆H₃OCH₃),3.71(s,3H,C₆H₄OCH₃).

The synthesis of embodiment 57:1-(4-hydroxy 3-methoxybenzene base)-2-o-methoxyphenoxy ethamine 14g hydrochlorate

¹HNMR(400MHz,DMSO)δ9.28(s,1H,OH),8.71(s,3H,NH₃ ⁺), 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, CHCH₂),3.81(s,3H,C₆H₃OCH₃),3.78(s,3H,C₆H₄OCH₃).

The synthesis of embodiment 58:N-(1-(4-hydroxy 3-methoxybenzene base-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15a

At-10 DEG C, by isopropyl chlorocarbonate (0.44g, 12mLTHF solution 3.94mmol) drops in the 20mLTHF solution of 3-methyl-2-isopropyl oxygen formamido group butanoic acid 9 (0.80g, 3.94mmol) and N-methylmorpholine (0.40g, 3.94mmol). 1h drips off, and continues stirring two hours. The 60mLTHF solution of dropping 1-(4-hydroxy 3-methoxybenzene base)-2-phenoxyethylamine (1.0g, 3.86mmol). Half an hour adds, and adds rear room temperature reaction 10h. Filtering, precipitation, 40mL dichloromethane dissolves again, and 20mL1mol/L sodium carbonate washes twice, and 20mL1mol/L hydrochloric acid washes twice, dry over magnesium sulfate, precipitation. Ethyl alcohol recrystallization, obtains khaki solid 1.32g, yield 75.6%, fusing point: 137-140 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.29 (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 (CH₃)₂), 4.22 (ddd, J=14.9,9.5,5.2Hz, 2H, OCH₂), 4.10 3.96 (m, 1H, OCONHCH), 3.87 (d, J=6.1Hz, 3H, C₆H₃OCH₃), 2.14 (dd, J=24.9,18.5Hz, 1H, CHCH (CH₃)₂),1.34–1.10(m,6H,OCH(CH₃)₂),1.08–0.75(m,6H,CHCH(CH₃)₂).

According to the method for embodiment 58, select suitable raw material and reagent, prepare the compound of 15b to 15g respectively.It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

The synthesis of embodiment 59:N-(1-(4-hydroxy 3-methoxybenzene base-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15b

¹HNMR(400MHz,CDCl₃) δ 6.89 (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 (CH₃)₂),4.22–4.01(m,2H,OCH₂), 3.91 (dd, J=17.1,8.7Hz, 1H, OCONHCH), 3.80 (d, J=1.9Hz, 3H, C₆H₃OCH₃),2.09(s,1H,CHCH(CH₃)₂),1.18–1.05(m,6H,OCH(CH₃)₂),0.95–0.74(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 60:N-(1-(4-hydroxy 3-methoxybenzene base-2-neighbour's fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15c

¹HNMR(400MHz,CDCl₃) δ 7.16 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 (CH₃)₂),4.41–4.18(m,2H,OCH₂), 4.04 (s, 1H, OCONHCH), 3.90 (d, J=5.7Hz, 3H, C₆H₃OCH₃), 2.18 (d, J=6.9Hz, 1H, CHCH (CH₃)₂), 1.21 (dd, J=13.7,5.8Hz, 6H, OCH (CH₃)₂),1.04–0.80(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 61:N-(1-(4-hydroxy 3-methoxybenzene base-2-p-chlorophenyl) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15d

¹HNMR(400MHz,CDCl₃) δ 7.27 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 (CH₃)₂),4.33–4.07(m,2H,OCH₂), 4.10 3.95 (m, 1H, OCONHCH), 3.88 (d, J=7.5Hz, 3H, C₆H₃OCH₃), 2.16 (d, J=6.0Hz, 1H, CHCH (CH₃)₂),1.32–1.12(m,6H,OCH(CH₃)₂),1.03–0.88(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 62:N-(1-(4-hydroxy 3-methoxybenzene base-2-is to methylphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15e

¹HNMR(400MHz,CDCl₃) δ 7.09 (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 (CH₃)₂),4.28–4.07(m,2H,OCH₂), 4.07 3.94 (m, 1H, OCONHCH), 3.87 (d, J=6.6Hz, 3H, C₆H₃OCH₃),2.30(s,3H,C₆H₄CH₃),2.26–2.02(m,1H,CHCH(CH₃)₂),1.34–1.11(m,6H,OCH(CH₃)₂),1.04–0.85(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 63:N-(1-(4-hydroxy 3-methoxybenzene base-2-is to methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15f

¹HNMR(400MHz,CDCl₃) δ 7.02 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 (CH₃)₂), 4.17 (d, J=5.8Hz, 2H, OCH₂), 4.09 3.96 (m, 1H, OCONHCH), 3.88 (d, J=4.4Hz, 3H, C₆H₃OCH₃),3.79(s,3H,C₆H₄OCH₃),2.18(s,1H,CHCH(CH₃)₂), 1.21 (dd, J=14.7,6.0Hz, 6H, OCH (CH₃)₂), 0.95 (tt, J=44.1,22.0Hz, 6H, CHCH (CH₃)₂).

The synthesis of embodiment 64:N-(1-(4-hydroxy 3-methoxybenzene base-2-o-methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 15g

¹HNMR(400MHz,CDCl₃) δ 7.12 (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 (CH₃)₂), 4.23 (dd, J=10.2,5.2Hz, 2H, OCH₂),4.14–3.98(m,1H,OCONHCH),3.91–3.87(m,6H,C₆H₃OCH₃+C₆H₄OCH₃),2.26–2.10(m,1H,CHCH(CH₃)₂),1.34–1.11(m,6H,OCH(CH₃)₂),1.03–0.81(m,6H,CHCH(CH₃)₂).

The physical and chemical parameter table of compound 15

The synthesis of embodiment 65:N-(1-(4-propynyloxy base-3-methoxyphenyl-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16a

By N-(1-(4-hydroxy 3-methoxybenzene base-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide (1.0g, 2.25mmol) it is dissolved in 60mL acetone, add Anhydrous potassium carbonate (0.47g, 3.37mmol), 1h is stirred at room temperature, drips propargyl bromide (0.40g, 10mL acetone soln 3.37mmol), half an hour drips off, and drips off and changes backflow into, and reflux 30h.After raw material point no longer changes, precipitation, 100mL dichloromethane dissolves residue, and 100mL1mol/L sodium hydroxide solution washes organic layer twice, and 100mL washes organic layer once, anhydrous magnesium sulfate dries organic layer, precipitation, with ethyl alcohol recrystallization, obtains 0.86g pale white solid, yield: 79.6%, fusing point: 139-141 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.28 (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 (CH₃)₂), 4.74 (d, J=7.8Hz, 2H, CHCCH₂),4.20(s,2H,OCH₂Ar), 4.07 (s, 1H, OCONHCH), 3.84 (d, J=6.0Hz, 3H, C₆H₃OCH₃),2.52(s,1H,CH₂CCH),2.15(s,1H,CHCH(CH₃)₂), 1.18 (d, J=19.6Hz, 6H, OCH (CH₃)₂), 0.95 (t, J=17.5Hz, 6H, CHCH (CH₃)₂).

According to the method for embodiment 65, select suitable raw material and reagent, prepare the compound of 16b to 16g respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

The synthesis of embodiment 66:N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16b

White solid, fusing point: 155-157 DEG C.¹HNMR(400MHz,CDCl₃) δ 6.99 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 (CH₃)₂), 4.68 (d, J=2.3Hz, 2H, CHCCH₂), 4.12 (qd, J=9.7,5.0Hz, 2H, OCH₂Ar), 3.92 (dd, J=17.4,9.3Hz, 1H, OCONHCH), 3.79 (s, 3H, C₆H₃OCH₃), 2.43 (t, J=2.3Hz, 1H, CH₂CCH), 2.10 (d, J=5.8Hz, 1H, CHCH (CH₃)₂),1.21–1.02(m,6H,OCH(CH₃)₂),0.96–0.76(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 67:N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16c

White solid, fusing point: 167-169 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.13 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 (CH₃)₂),4.76(s,2H,CHCCH₂), 4.33 (d, J=9.2Hz, 1H, OCH₂Ar),4.24(s,1H,OCH₂Ar), 4.05 (d, J=7.2Hz, 1H, OCONHCH), 3.89 (s, 3H, C₆H₃OCH₃),2.52(s,1H,CH₂CCH),2.17(s,1H,CHCH(CH₃)₂), 1.23 (t, J=5.9Hz, 6H, OCH (CH₃)₂),1.08–0.81(m,H,CHCH(CH₃)₂).

The synthesis of embodiment 68:N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16d

White solid, fusing point: 133-135 DEG C.¹HNMR(400MHz,CDCl₃)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(CH₃)₂),4.74(s,2H,CHCCH₂),4.16(s,2H,OCH₂Ar),4.05(s,1H,OCONHCH),3.84(s,3H,C₆H₃OCH₃),2.51(s,1H,CH₂CCH),2.13(s,1H,CHCH(CH₃)₂),1.27–1.10(m,6H,OCH(CH₃)₂),1.05–0.84(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 69:N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16e

White solid, fusing point: 159-161 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.08 (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 (CH₃)₂),4.75(s,2H,CHCCH₂),4.19(s,2H,OCH₂Ar),4.06(s,1H,OCONHCH),3.86(s,3H,C₆H₃OCH₃),2.52(s,1H,CH₂CCH),2.30(s,3H,Ar-CH₃),2.16(s,1H,CHCH(CH₃)₂),1.31–1.07(m,6H,OCH(CH₃)₂),1.07–0.86(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 70:N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16f

White solid, fusing point: 147-149 DEG C.¹HNMR(400MHz,CDCl₃) δ 6.87 (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 (CH₃)₂), 4.64 (d, J=6.7Hz, 2H, CHCCH₂), 4.07 (d, J=3.9Hz, 2H, OCH₂Ar),3.96(s,1H,OCONHCH),3.76(s,3H,C₆H₃OCH₃),3.67(s,3H,C₆H₄OCH₃),2.42(s,1H,CH₂CCH),2.06(s,1H,CHCH(CH₃)₂), 1.11 (d, J=6.2Hz, 6H, OCH (CH₃)₂), 0.86 (dd, J=35.7,6.8Hz, 6H, CHCH (CH₃)₂).

The synthesis of embodiment 71:N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 16g

White solid, fusing point: 177-179 DEG C.¹HNMR(400MHz,CDCl₃)δ7.10–6.71(m,8H,Ar-H+CHCONH),5.17(s,2H,OCONH+Ar-CH),4.79(s,1H,OCH(CH₃)₂),4.66(s,2H,CHCCH₂),4.15(s,2H,OCH₂Ar), 3.98 (d, J=23.0Hz, 1H, OCONHCH), 3.79 (s, 6H, C₆H₃OCH₃+o-C₆H₄OCH₃),2.42(s,1H,CH₂CCH),2.CHCH(CH₃)₂08(s,1H,CHCH(CH₃)₂),1.13(s,6H,OCH(CH₃)₂), 0.83 (d, J=24.1Hz, 6H, CHCH (CH₃)₂).

The synthesis 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 formate (48.2g, 463.2mmol) powder, and reflux 6h. After completion of the reaction, precipitation removes ethanol, and residue adds 100mL water, 100mL extraction into ethyl acetate three times, merges organic layer, and anhydrous magnesium sulfate dries organic layer, filters, precipitation, thick product reduced pressure chromatography (petroleum ether: ethyl acetate=5:1; Petroleum ether: ethyl acetate=3:1), obtain white crystal 22.1g. Fusing point: 83-84 DEG C. Yield: 97.3%.¹HNMR(400MHz,CDCl₃) δ 7.60 7.43 (m, 2H, Ar-H), 6.92 (d, J=8.2Hz, 1H, Ar-H), 4.85 (s, 2H, CH₂),3.97(s,3H,Ar-m-OCH₃),3.96(s,3H,Ar-p-OCH₃),3.60(s,1H,OH).

The synthesis of embodiment 73:2-hydroxyl-1-(3,4-Dimethoxyphenyl) acetophenone oxime 18

2-hydroxyl-1-(3,4-Dimethoxyphenyl) ethyl ketone 17 (20.0g, 101.9mmol), it is dissolved in 300mL ethanol, adds oxammonium hydrochloride. (10.6g, 152.9mmol), it is stirred at room temperature, is dividedly in some parts sodium hydroxide (6.4g, 159.9mmol) solid, half an hour adds, and reflux after adding 4h. Precipitation removes ethanol, adds 100mL water, 100mL extraction into ethyl acetate three times, merges organic layer, and anhydrous magnesium sulfate dries, and filters, precipitation, and ethyl alcohol recrystallization obtains clear crystal 17.8g, fusing point: 136-140 DEG C; Yield: 82.7%.¹HNMR(400MHz,CDCl₃) δ 7.34 7.15 (m, 2H, Ar-H), 6.92 (dd, J=13.9,8.3Hz, 1H, Ar-H), 4.76 (s, 2H, CH₂),3.95–3.91(m,6H,Ar-m-OCH₃+Ar-p-OCH₃).

The physical and chemical parameter table of compound 16

The synthesis of embodiment 74:2-(3,4-Dimethoxyphenyl)-2-ethylaminoethanol 19

2-hydroxyl-1-(3,4-Dimethoxyphenyl) acetophenone oxime 18 (5.0g, 23.7mmol) is dissolved in 300mL ethanol, adds 0.5gPd/C, 2.0mL concentrated hydrochloric acid, and in autoclave, inflated with nitrogen drives air away, fills hydrogen exchange nitrogen three times. It is flushed with hydrogen gas 20atm, 24h is stirred at room temperature. After having reacted, cross and filter Pd/C, precipitation, the product recrystallization obtained by precipitation with ethanol. The salt that recrystallization obtains, in ethanol, adds 1.2eq sodium hydrate solid, 1h is stirred at room temperature and neutralizes. Precipitation removes ethanol, and product is dissolved in 100mL dichloromethane, and 50mL washes organic layer, MgSO₄Dry organic layer, precipitation obtains 3.2g faint yellow solid. Fusing point: 110-120 DEG C; Yield: 68.5%. The nuclear magnetic data of this ammonium salt is:¹HNMR(400MHz,DMSO)δ8.44(s,3H,NH₃ ⁺),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-OCH₃),3.75(s,3H,Ar-p-OCH₃),3.68(s,2H,CH₂).

The synthesis of embodiment 75:N-(1-(3,4-Dimethoxyphenyl) ethyl-2-hydroxyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 20

At-10 DEG C, by isopropyl chlorocarbonate (2.92g, 25.9mmol) 60mLTHF solution drop in the 100mLTHF solution of 3-methyl-2-isopropoxycarbonylamino butanoic acid 9 (5.26g, 25.9mmol) and N-methylmorpholine (2.62g, 25.9mmol). 1h drips off, and continues stirring two hours. The 80mLTHF solution of dropping 2-(3,4-Dimethoxyphenyl)-2-ethylaminoethanol 19 (5.0g, 25.4mmol). Half an hour adds, and adds rear room temperature reaction 10h. Filter, precipitation. Ethyl alcohol recrystallization, obtains white solid 8.1g. Fusing point: 179-183 DEG C; Yield: 81.8%.¹HNMR(300MHz,CDCl₃) δ 7.09 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 (CH₃)₂),3.78(s,8H,CHCH₂O+Ar-m-OCH₃+Ar-p-OCH₃),2.14–1.90(m,1H,CHCH(CH₃)₂), 1.15 (d, J=5.6Hz, 6H, OCH (CH₃)₂),0.99–0.75(m,6H,CHCH(CH₃)₂).

The synthesis of embodiment 76:N-(1-(3,4-Dimethoxyphenyl)-2-Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21a

Low-temp reaction device is adjusted to-10 DEG C, 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 1.96mmol), stirring 20min, dissolves.The 10mLDMF solution of dropping benzyl bromine (0.34g, 1.96mmol), half an hour drips off, and drips off continuation stirring 6h. After completion of the reaction, being poured into by product in 300mL water, stand 1h, precipitate out white solid, filter, solid is dried and is obtained 0.34g white solid, yield 54.9%; Fusing point: 147-149 DEG C.¹HNMR(400MHz,CDCl₃) δ 7.32 (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 (CH₃)₂),4.62–4.46(m,2H,C₆H₄CH₂O), 4.01 (dd, J=13.4,7.1Hz, 1H, OCONHCH), 3.91 3.82 (m, 6H, Ar-m-OCH₃+Ar-p-OCH₃), 3.74 (d, J=4.2Hz, 2H, CHCH₂O),2.14(s,1H,CHCH(CH₃)₂),1.37–1.11(m,6H,OCH(CH₃)₂),1.04–0.81(m,6H,CHCH(CH₃)₂).

According to the method for embodiment 76, select suitable raw material and reagent, prepare the compound of 21b to 21g respectively. It should be understood that the technical staff being proficient in this field can select suitable raw material and reagent according to the needs of embodiment.

Embodiment 77:N-(1-(3,4-Dimethoxyphenyl)-2-is to fluorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21b

¹HNMR(300MHz,CDCl₃) δ 7.33 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 (CH₃)₂), 4.51 (d, J=2.6Hz, 2H, C₆H₄CH₂O), 3.98 3.84 (m, 1H, OCONHCH), 3.77 (d, J=5.1Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃), 3.68 (d, J=4.4Hz, 2H, CHCH₂O), 2.03 (d, J=5.4Hz, 1H, CHCH (CH₃)₂),1.24–1.05(m, 6H,OCH(CH₃)₂),0.91–0.73(m,6H,CHCH(CH₃)₂).

Embodiment 78:N-(between 1-(3,4-Dimethoxyphenyl)-2-fluorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21c

¹HNMR(400MHz,CDCl₃) δ 7.29 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 (CH₃)₂), 4.43 (dd, J=19.1,10.4Hz, 2H, C₆H₄CH₂O), 3.93 (dd, J=14.9,7.5Hz, 1H, OCONHCH), 3.81 3.73 (m, 6H, Ar-m-OCH₃+Ar-p-OCH₃),3.68–3.56(m,2H,CHCH₂O), 2.05 (d, J=4.3Hz, 1H, CHCH (CH₃)₂),1.22–1.00(m,6H,OCH(CH₃)₂),0.93–0.71(m,6H,CHCH(CH₃)₂).

Embodiment 79:N-(1-(3,4-Dimethoxyphenyl)-2-neighbour's fluorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21d

¹HNMR(400MHz,CDCl₃) δ 7.33 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 (CH₃)₂),4.62–4.40(m,2H,C₆H₄CH₂O), 3.92 (dd, J=14.1,7.2Hz, 1H, OCONHCH), 3.76 (dd, J=6.5,3.2Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃), 3.67 (d, J=4.6Hz, 2H, CHCH₂O),2.16–1.95(m,1H,CHCH(CH₃)₂),1.26–0.99(m,6H,OCH(CH₃)₂),0.92–0.72(m,6H,CHCH(CH₃)₂).

Embodiment 80:N-(1-(3,4-Dimethoxyphenyl)-2-is to chlorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21e

HNMR(400MHz,CDCl₃) δ 7.21 (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 (CH₃)₂), 4.39 (dt, J=12.2,9.0Hz, 2H, C₆H₄CH₂O),3.96–3.82(m,1H,OCONHCH),3.82–3.72(m,6H,Ar-m-OCH₃+Ar-p-OCH₃), 3.63 (d, J=2.9Hz, 2H, CHCH₂O), 2.04 (d, J=6.5Hz, 1H, CHCH (CH₃)₂),1.22–1.02(m,6H,OCH(CH₃)₂),0.93–0.70(m,6H,CHCH(CH₃)₂).

Embodiment 81:N-(1-(3,4-Dimethoxyphenyl)-2-is to methylbenzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide 21f

¹HNMR(300MHz,CDCl₃) δ 7.08 (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 (CH₃)₂),4.47–4.29(m,2H,C₆H₄CH₂O), 3.92 (s, 1H, OCONHCH), 3.77 (d, J=7.9Hz, 6H, Ar-m-OCH₃+Ar-p-OCH₃), 3.62 (d, J=3.9Hz, 2H, CHCH₂O),2.27(s,3H,C₆H₄CH₃),2.03(s,1H,CHCH(CH₃)₂),1.26– 1.03(m,6H,OCH(CH₃)₂), 0.82 (tt, J=21.8,10.9Hz, 6H, CHCH (CH₃)₂).

The physicochemical property table of compound 21

Embodiment 82: active testing EXPERIMENTAL EXAMPLE

The mensuration of in vitro Plating bactericidal activity

By breaking in the culture dish that bacterium sheet accesses containing 50 μ g/mL medicinal liquids for examination pathogenic bacteria, put into dark culturing in 25 DEG C of biochemical cultivation cases, 3 days " Invest, Then Investigate " fungistatic effects.Often process 3 times and repeat. Only to add sterilized water not adding medicine person for comparison. Result is in Table 1. (%)

Table 1: the in vitro bactericidal activity (ppm, it is suppressed that rate %) of compound

*: "-": activity is not tested

Phytophthora capsici live body bactericidal activity measures

All test samples all adopt 50 μ g/mL. Uniformly being sprayed on cucumber seedling by medicament by nebulization, (every mL suspension is containing 1 × 10 to inoculate Pseudoperonospora cubensis after natural air drying⁵Individual Sporangium), in average daytime temperature 22 DEG C, night temperature 17 DEG C greenhouse in cultivate. Often process and repeat 4 times, wait to compare fully morbidity " Invest, Then Investigate " disease index [(1) formula], calculate prevention effect by (2) formula. Result is in Table 2.

(1) disease index (DI)=(∑ (sick value of series × this disease level diseased plant number) × 100)/(sick level peak × investigation strain number)

(2) preventive effect=[(compare average disease index-process average disease index)/compare average disease index] × 100

The percent accounting for whole leaf area by lesion area formulates classification, and standard is as follows: standard: 0 grade---without scab; 1 grade---less than 5%; 3 grades---; 6%～10%; 5 grades---11%～25%; 7 grades---26%～50%; 9 grades---more than 50%.

Table 2: the live body bactericidal activity to Phytophthora capsici (50ppm, it is suppressed that rate %) of compound

The mensuration of Fructus Cucumidis sativi downy mildew live body bactericidal activity

All test samples all adopt 100 μ g/mL. Pseudoperonospora cubensis adopts spore suspension spray inoculation, reagent agent and comparison medicament is uniformly sprayed in cucumber cotyledons the morning in fine day, inoculates pathogen after 2 hours, and moisturizing is cultivated. Waiting to compare fully morbidity " Invest, Then Investigate " preventive effect, formula is as follows: preventive effect %=(the comparison state of an illness-process state of an illness)/comparison state of an illness × 100%. Result is in Table 3.

Table 3: the compound live body bactericidal activity (suppression ratio %) to Fructus Cucumidis sativi downy mildew

*: "-": activity is not tested

Claims

1. there is the compound shown in below formula (I) or its pharmaceutically acceptable salt:

Wherein,

R¹It is hydrogen, C_1-6Alkyl, C_2-6The substituent group of alkynyl replaces;

R²It is optional 1-5 substituent group, selected from hydrogen, hydroxyl, halogen, C_1-6Alkyl, C_1-6The substituent group of alkoxyl replaces;

N is 0,1.

2. the compound shown in formula according to claim 1 (I) or its pharmaceutically acceptable salt, it is characterised in that:

R¹For hydrogen, methyl, ethyl, propargyl;

R²For hydrogen, methyl, ethyl, halogen, methoxyl group;

N is 0,1.

3. the compound shown in formula according to claim 1 (I) or its pharmaceutically 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-(1-(3,4-Dimethoxyphenyl)-2-neighbour's fluorophenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-p-chlorophenyl ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-Phenoxyethyl)-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-(between 1-(3,4-Dimethoxyphenyl)-2-methylphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-is to methoxyphenoxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-o-methoxyphenoxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-hydroxy 3-methoxybenzene base-2-neighbour's fluorophenoxy) 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-p-chlorophenyl) 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-methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-propynyloxy base-3-methoxyphenyl-2-phenoxy group) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-propynyloxy base-3-methoxyphenyl-2-neighbour's fluorophenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-propynyloxy base-3-methoxyphenyl-2-p-chlorophenyl) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to methylphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-propynyloxy base-3-methoxyphenyl-2-is to methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(4-propynyloxy base-3-methoxyphenyl-2-o-methoxyphenoxy) ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-is to methylbenzyloxy ethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-neighbour's fluorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(between 1-(3,4-Dimethoxyphenyl)-2-fluorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-is to fluorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide;

N-(1-(3,4-Dimethoxyphenyl)-2-is to chlorine Benzyloxyethyl)-3-methyl-2-isopropoxy carbonyl amido butyramide.

4. the preparation method of the compound shown in formula (I) described in claim 1, the method comprises the following steps:

Compound (3), in ethanol under the effect of sodium formate, adds sodium hydroxide and is obtained by reacting compound (17); Compound (17) successively adds oxammonium hydrochloride. and sodium hydroxide in ethanol, is obtained by reacting compound (18); Compound (18) dissolves in ethanol, adds 10%Pd/C, concentrated hydrochloric acid, passes into hydrogen reducing and obtain compound (19); Compound (9) is dissolved with THF, alkali and ethyl chloroformate is added under cryogenic conditions, stir under this condition to reacting completely, compound (19) is dissolved with THF, it is added drop-wise in reactant liquor, drips Bi Shengzhi room temperature, continue stirring, precipitation, ethyl alcohol recrystallization obtains compound (20);With the cylite shown in formula (III), compound (20) is obtained by reacting compound (21) in DMF under sodium hydride effect, and reaction scheme is as follows:

Wherein, R²As claim 1 is defined.

5. formula intermediate (20):

6. a composition pesticide, comprises the compound of any one in claim 1-2 and pharmaceutically acceptable salt thereof and carrier.

7. in claim 1-2 any one compound and pharmaceutically acceptable salt thereof as the application in bactericidal agent for preventing and treating plant disease.