CN110476977A - A kind of 2- (1- adamantane formamido) application of the methylcarbamoyl ethyl esters compound as fungicide - Google Patents

A kind of 2- (1- adamantane formamido) application of the methylcarbamoyl ethyl esters compound as fungicide Download PDF

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CN110476977A
CN110476977A CN201910792574.XA CN201910792574A CN110476977A CN 110476977 A CN110476977 A CN 110476977A CN 201910792574 A CN201910792574 A CN 201910792574A CN 110476977 A CN110476977 A CN 110476977A
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adamantane
formamido
phenyl
ethyl esters
esters compound
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CN110476977B (en
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翁建全
孔瑶蕾
庞凯胜
谭成侠
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Zhejiang University of Technology ZJUT
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
    • A01N37/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof containing the group, wherein Cn means a carbon skeleton not containing a ring; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

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Abstract

The invention discloses a kind of 2- (1- adamantane formamido) application of the methylcarbamoyl ethyl esters compound as fungicide, shown in the structure such as formula (I) of 2- (1- adamantane formamido) the methylcarbamoyl ethyl esters compound:

Description

A kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound is as fungicide Application
Technical field
The present invention relates to a kind of 2- (1- adamantane formamido) application of the methylcarbamoyl ethyl esters compound as fungicide.
Background technique
Adamantane have unique chemical property and physical property, can apply pesticide (chemical reagent, 2016,38 (03): 224-230), medical (Chemical Reviews, 2013,113 (5): 3516-3604), photoelectric material In multiple fields such as (Tetrahedron, 2013,69 (48): 10357-10360).According to the literature, adamantane derivative has Sterilization (Journal of Organic Chemistry, 1999,64 (24): 8916-8921, organic chemistry, 2014,34 (12): 2543-2550), desinsection (Chinese Journal of Chemistry, 2011,31 (4): 486-489), the weeding (material containing energy Material, 2017,25 (01): 76-85, fine chemistry industry information, 1986 (10): 11-14) etc. pesticide activities, caused agricultural chemicals research and development person More and more concerns.In addition, adamantane is typically considered to that special lipophilicity can be provided, therefore the introducing of adamantane structure can Enhance the lipophilicity and stability of compound, so as to improve the dynamic metabolism of compound.
Amides compound has broad-spectrum biological activity, is widely applied in pesticide and medicine and other fields.In pesticide Field, amides compound have sterilization (organic chemistry, 2003,23 (10): 1131-1134), desinsection (Chinese Chemical Letters, 2013,24:673-676), weeding (organic chemistry, 2013,33 (12): 2538-2544) and anti- Bioactivity such as viral (applied chemistry .2012,29 (7): 762-768).Meanwhile ester type compound is also because have good kill Worm (Chemosphere, 2013,90 (11): 2705-2713), sterilization (pesticide, 2009,48 (2): 150-152, applied chemistry, 2001 (08): 640-642), weeding (Chem Industry Engin Prog, 2002,21 (3): 169-171,185, grain with Grease, 2010 (7): 41-43) etc. pesticide activities, so as to cause the extensive concern of people.Contain in many commercialization pesticide structures There are ester group structure, such as pyrethroid insecticides cycloprothrin, cyfloxylate；Fungicide nitrothalisopropyl, smart furalaxyl；It removes Careless agent acrinathrin, butafenacil etc..
Good pesticide activity is all had in view of adamantane derivative, amide and ester type compound, in order to find to dive Pesticide poullant, the present invention is using the method for active substructure splicing by adamantane, amide and three kinds of ester group knots Structure mutually splices, and design has synthesized serial 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound, and is intended to find that it is new Pesticide activity.
Serial 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound that the present invention designs and synthesizes, structure with And bioactivity research is showed no document report.
Summary of the invention
In order to solve above-mentioned technical problem of the existing technology, the purpose of the present invention is to provide a kind of 2- (1- Buddha's warrior attendants Alkane formamido) application of the methylcarbamoyl ethyl esters compound as fungicide.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is shown in the structure such as formula (I) of the 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound:
In formula (I), R is phenyl, substituted-phenyl or substituted pyridinyl；H or substitution pyrrole on the phenyl ring of the substituted-phenyl The substituted base of H on the pyridine ring of piperidinyl is monosubstituted or polysubstituted, and described monosubstituted or polysubstituted substituent group is each independently Alkoxy, nitro, C1~C5 halogenated alkyl or the halogen of alkyl, C1~C3 selected from C1~C5.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign be described monosubstituted or polysubstituted substituent group be each independently selected from methyl, tert-butyl, n-pentyl, methoxyl group, nitro, Trifluoromethyl, F or Cl.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign be in formula (I), R be phenyl, 2- chlorphenyl, 3- chlorphenyl, 4- chlorphenyl, 2- fluorophenyl, 3- fluorophenyl, 4- fluorophenyl, 2- nitrobenzophenone, 3- aminomethyl phenyl, 4- aminomethyl phenyl, 4- tert-butyl-phenyl, 4- n-pentyl phenyl, 4- methoxyphenyl, 2,3- Dichlorophenyl, 2,4 dichloro benzene base, 2- trifluoromethyl, 2,4,5- trifluorophenyl, -4 aminomethyl phenyl of 3- nitro, 2,6- difluoro Phenyl, 2,3,5,6- tetrafluoro phenyl, 2- chloropyridine base, 5,6- dichloropyridine base or the chloro- 5- fluorine pyridyl group of 2,6- bis-.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is the synthetic method of the 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound, comprising the following steps:
1) formyl chloride will be replaced to be dissolved in solvent A as shown in formula (III), preparation obtains replacing formyl solutions of chlorine；
2) the intermediate N 2- hydroxyethyl -1- adamantane formamide as shown in formula (II), solvent B and acid binding agent are mixed It closes, stirring and dissolving, the substitution formyl solutions of chlorine of step 1) preparation is then slowly added dropwise dropwise under condition of ice bath, is added dropwise Afterwards, it reacts at room temperature, TLC is monitored to after reaction, reaction solution is filtered, and after filtrate precipitation removes solvent, gained precipitation is remaining The 2- as shown in formula (I) (1- adamantane formamido) methylcarbamoyl ethyl esters compound is made through column chromatography for separation in object；
In formula (III), R is phenyl, substituted-phenyl or substituted pyridinyl；H or substitution pyrrole on the phenyl ring of the substituted-phenyl The substituted base of H on the pyridine ring of piperidinyl is monosubstituted or polysubstituted, and described monosubstituted or polysubstituted substituent group is each independently Alkoxy, nitro, C1~C5 halogenated alkyl or the halogen of alkyl, C1~C3 selected from C1~C5.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is to replace the molar ratio of formyl chloride shown in N-2- hydroxyethyl -1- adamantane formamide shown in formula (II) and formula (III) For 1:1~5.0, preferably 1:1~1.5.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is that solvent A is identical with solvent B, and the solvent B is tetrahydrofuran or acetonitrile, preferably tetrahydrofuran；In step 1), prepare Substitution formyl solutions of chlorine concentration be 0.25~0.5mol/L.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is that the acid binding agent is triethylamine or pyridine, preferably triethylamine.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is that the molar ratio of N-2- hydroxyethyl -1- adamantane formamide and acid binding agent shown in formula (II) is 1:1~5, preferably 1:1.2~2.
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is that the molar ratio of the N-2- hydroxyethyl -1- adamantane formamide as shown in formula (II) and solvent B are 1:30~150, excellent It is selected as 1:70~120；It is characterized in that the time reacted at room temperature is 1~5 hour, preferably 2~4 hours in step 2).
A kind of described 2- (the 1- adamantane formamido) application of methylcarbamoyl ethyl esters compound as fungicide, it is special Sign is in step 2) that the eluant, eluent that column chromatography for separation uses is the mixing of ethyl acetate and petroleum ether that volume ratio is 1:3~8 Liquid.
Compared with prior art, the beneficial effects of the present invention are embodied in:
The present invention provides a kind of novel 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compounds as sterilization The application of agent especially has the fungies such as tomato early blight bacterium, fusarium graminearum, Sclerotinia sclerotiorum and botrytis cinerea pers Preferable inhibitory effect shows 2- of the invention (1- adamantane formamide from the antibacterial activity test result of the embodiment of the present invention Base) methylcarbamoyl ethyl esters compound, certain inhibitory activity is shown to for examination target.Compound In, Io, Iv, Iw to kind Eggplant early epidemic germ inhibiting rate is up to 50% or more, and wherein compound Iw is to tomato early blight bacterium inhibiting rate up to 67.8%；Chemical combination Object Ib, Id, Ik, Il, Ip, Iu are to fusarium graminearum inhibiting rate up to 55% or more, and wherein compound Ik is to wheat scab Bacterium inhibiting rate is up to 71.8%；Ii, Ij are to botrytis cinerea pers inhibiting rate up to 50% or more, and wherein compound Ij is to cucumber grey mold Germ inhibiting rate is up to 51.2%；In addition, all compounds reach 55% or more to Sclerotinia sclerotiorum inhibiting rate, wherein changing Close the inhibitory activity that object Ik shows up to 88.0% to Sclerotinia sclerotiorum inhibiting rate.
Specific embodiment
The present invention is further explained in the light of specific embodiments, but the scope of protection of the present invention is not limited thereto.
The synthesis of 1 compound Ia of embodiment (R=phenyl):
1.5mmol chlorobenzoyl chloride is dissolved in 5mL tetrahydrofuran, preparation obtains the tetrahydro of chlorobenzoyl chloride (1.5mmol) Tetrahydrofuran solution (5mL).
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (10mL) with And chlorobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (1.8mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (5mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:5 and the mixed liquor of petroleum ether) obtain white solid, as benzoic acid -2- (1- adamantane formamido) Ethyl ester, calculating its yield is 67.4%.M.p.:101~104 DEG C；
1H NMR(500MHz,DMSO-d6) δ 7.97 (dd, J=8.0,0.5Hz, 2H), 7.68-7.63 (m, 1H), 7.56- 7.50 (m, 2H), 6.17 (s, 1H), 4.27 (t, J=5.5Hz, 2H), 3.43 (q, J=5.5Hz, 2H), 1.94 (s, 3H), 1.74 (d, J=2.5Hz, 6H), 1.69-1.58 (m, 6H)；
HRMS(ESI)calcd C20H25NO3[M+H]+327.1859,found 327.1723。
The synthesis of 2 compound Ib of embodiment (R=2- chlorphenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (12mL) with And 2- chlorobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.7mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (6mL) of (2.0mmol).After being added dropwise, 4h is reacted at room temperature, the hydrochloride filtrate of triethylamine is filtered to remove Revolving removes solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is the ethyl acetate that volume ratio is 1:4 With the mixed liquor of petroleum ether) white solid is obtained, as 2- chlorobenzoic acid -2- (1- adamantane formamido) ethyl ester calculates it Yield is 65.3%.M.p.:120~123 DEG C；
1H NMR(500MHz,CDCl3) δ 7.83 (dd, J=7.5,1.0Hz, 1H), 7.49-7.42 (m, 2H), 7.37- 7.32 (m, 1H), 6.11 (s, 1H), 4.44 (t, J=5.0Hz, 2H), 3.66 (q, J=5.5Hz, 2H), 2.03 (s, 3H), 1.85 (d, J=2.5Hz, 6H), 1.76-1.66 (m, 6H)；
HRMS(ESI)calcd C20H24ClNO3[M+H]+361.1418,found 361.1457。
The synthesis of 3 compound Ic of embodiment (R=3- chlorphenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (12mL) with And 3- chlorobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.7mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (6mL) of (2.0mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:3 and the mixed liquor of petroleum ether) obtain white solid, as 3- chlorobenzoic acid -2- (1- adamantane formamide Base) ethyl ester, calculating its yield is 52.5%.M.p.:127~130 DEG C；
1H NMR(500MHz,CDCl3) δ 7.94 (s, 1H), 7.86 (d, J=7.5Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.34 (t, J=8.0Hz, 1H), 6.23 (s, 1H), 4.38 (t, J=5.0Hz, 2H), 3.60 (dd, J=10.5,5.5Hz, 2H),1.97(s,3H),1.80(s,6H),1.70–1.61(m,6H)；
HRMS(ESI)calcd C20H24ClNO3[M+H]+361.1433,found 361.1486。
The synthesis of 4 compound Id of embodiment (R=4- chlorphenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (12mL) with And 4- chlorobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.7mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (6mL) of (2.0mmol).After being added dropwise, 4h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:4 and the mixed liquor of petroleum ether) obtain white solid, as 4- chlorobenzoic acid -2- (1- adamantane formamide Base) ethyl ester, calculating its yield is 50.4%.M.p.:136~138 DEG C；
1H NMR(500MHz,CDCl3) δ 7.97 (d, J=8.5Hz, 2H), 7.42 (d, J=8.5Hz, 2H), 6.07 (s, 1H), 4.42 (t, J=5.0Hz, 2H), 3.64 (dd, J=10.5,5.0Hz, 2H), 2.02 (s, 3H), 1.83 (d, J=2.5Hz, 6H),1.75–1.66(m,6H)；
HRMS(ESI)calcd C20H24ClNO3[M+H]+361.1419,found 361.1399。
The synthesis of 5 compound Ie of embodiment (R=2- fluorophenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (8.5mL) with And 2- fluorobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.25mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (4mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:4 and the mixed liquor of petroleum ether) obtain yellow solid, as 2- fluobenzoic acid -2- (1- adamantane formamide Base) ethyl ester, calculating its yield is 66.7%.M.p.:107~109 DEG C；
1H NMR(500MHz,CDCl3) δ 7.95 (td, J=7.5,2.0Hz, 1H), 7.58-7.52 (m, 1H), 7.24 (t, J =7.5Hz, 1H), 7.16 (dd, J=10.5,8.5Hz, 1H), 6.13 (s, 1H), 4.43 (t, J=5.0Hz, 2H), 3.66 (dd, J=10.5,5.5Hz, 2H), 2.04 (s, 3H), 1.86 (d, J=2.5Hz, 6H), 1.77-1.68 (m, 6H)；
HRMS(ESI)calcd C20H24FNO3[M+H]+345.1744,found 345.1771。
The synthesis of 6 compound If of embodiment (R=3- fluorophenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (8.5mL) with And 3- fluorobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.25mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (4mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:3 and the mixed liquor of petroleum ether) obtain white solid, as 3- fluobenzoic acid -2- (1- adamantane formamide Base) ethyl ester, calculating its yield is 66.8%.M.p.:121~124 DEG C；
1H NMR(500MHz,CDCl3) δ 7.75 (d, J=7.5Hz, 1H), 7.62 (d, J=9.0Hz, 1H), 7.38-7.31 (m, 1H), 7.22-7.15 (m, 1H), 6.33 (s, 1H), 4.35 (t, J=5.5Hz, 2H), 3.57 (q, J=5.5Hz, 2H), 1.93 (s, 3H), 1.77 (d, J=1.0Hz, 6H), 1.67-1.58 (m, 6H)；
HRMS(ESI)calcd C20H24FNO3[M+H]+345.1717,found 345.1773。
The synthesis of 7 Compound Ig per of embodiment (R=4- fluorophenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (8.5mL) with And 4- fluorobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.25mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (4mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:4 and the mixed liquor of petroleum ether) obtain yellow solid, as 4- fluobenzoic acid -2- (1- adamantane formamide Base) ethyl ester, calculating its yield is 57.2%.M.p.:115~117 DEG C；
1H NMR(500MHz,CDCl3)δ8.06–8.02(m,2H),7.13–7.08(m,2H),6.11(s,1H),4.41 (t, J=5.5Hz, 2H), 3.63 (q, J=5.5Hz, 2H), 2.01 (s, 3H), 1.82 (d, J=2.5Hz, 6H), 1.75-1.64 (m,6H)；
HRMS(ESI)calcd C20H24FNO3[M+H]+345.141,found 345.1743。
The synthesis of 8 compound Ih of embodiment (R=2- nitrobenzophenone):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 2- nitrobenzoyl chloride is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of (2.0mmol).After being added dropwise, 4h is reacted at room temperature, is then filtered to remove reaction generates three The hydrochloride of ethamine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume Than the mixed liquor of ethyl acetate and petroleum ether for 1:4) obtain faint yellow solid, as 2- nitrobenzoic acid -2- (1- adamantane Formamido) ethyl ester, calculating its yield is 49.6%.M.p.:116~119 DEG C；
1H NMR(500MHz,CDCl3) δ 8.87-8.82 (m, 1H), 8.46-8.41 (m, 1H), 8.37 (d, J=8.0Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 6.07 (s, 1H), 4.49 (t, J=5.0Hz, 2H), 3.68 (q, J=5.5Hz, 2H), 2.03 (s, 3H), 1.84 (d, J=2.5Hz, 6H), 1.75-1.67 (m, 6H)；
HRMS(ESI)calcd C20H24N2O5[M+H]+372.1742,found 372.1712。
The synthesis of 9 compound Ii of embodiment (R=3- aminomethyl phenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (12mL) with And 3- methyl benzoyl chloride is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (6mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:6 and the mixed liquor of petroleum ether) obtain faint yellow solid, as 3- methyl benzoic acid -2- (1- adamantane first Amide groups) ethyl ester, calculating its yield is 64.7%.M.p.:98~100 DEG C；
1H NMR(500MHz,CDCl3) δ 7.86-7.82 (m, 2H), 7.38 (d, J=7.5Hz, 1H), 7.33 (t, J= 15.5,8.0Hz, 1H), 6.18 (s, 1H), 4.42 (t, J=5.0Hz, 2H), 3.64 (q, J=5.5Hz, 2H), 2.40 (s, 3H), 2.02 (s, 3H), 1.84 (d, J=2.5Hz, 6H), 1.76-1.66 (m, 6H)；
HRMS(ESI)calcd C21H27NO3[M+H]+341.2045,found 341.2012。
The synthesis of 10 compound Ij of embodiment (R=4- aminomethyl phenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (12mL) with And 4- methyl benzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (6mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:6 and the mixed liquor of petroleum ether) obtain faint yellow solid, as 4- methyl benzoic acid -2- (1- adamantane first Amide groups) ethyl ester, calculating its yield is 54.4%.M.p.:93~95 DEG C；
1H NMR(500MHz,CDCl3) δ 7.93 (d, J=8.0Hz, 2H), 7.25 (d, J=8.0Hz, 2H), 6.13 (s, 1H), 4.41 (t, J=5.0Hz, 2H), 3.64 (q, J=4.5Hz, 2H), 2.42 (s, 3H), 2.02 (s, 3H), 1.84 (d, J= 2.5Hz,6H),1.74–1.65(m,6H)；
HRMS(ESI)calcd C21H27NO3[M+H]+341.2023,found 341.2062。
The synthesis of 11 compound Ik of embodiment (R=4- tert-butyl-phenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 4- tert-butyl benzoyl is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of chlorine (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove what reaction generated The hydrochloride of triethylamine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is body Product is than being the ethyl acetate of 1:6 and the mixed liquor of petroleum ether) obtain yellow solid, as 4- p t butylbenzoic acid -2- (1- Buddha's warrior attendant Alkane formamido) ethyl ester, calculating its yield is 49.9%.M.p.:122~124 DEG C；
1H NMR(500MHz,CDCl3) δ 7.97 (d, J=8.5Hz, 2H), 7.48 (d, J=8.5Hz, 2H), 6.13 (s, 1H), 4.43 (t, J=5.5Hz, 2H), 3.64 (q, J=5.5Hz, 2H), 2.03 (s, 3H), 1.85 (d, J=2.5Hz, 6H), 1.76–1.67(m,6H),1.35(s,9H)；
HRMS(ESI)calcd C24H33NO3[M+H]+383.2553,found 383.2524。
The synthesis of 12 compound Il of embodiment (R=4- n-pentyl phenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 4- n-amylbenzene formyl is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of chlorine (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove what reaction generated The hydrochloride of triethylamine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is body Product is than being the ethyl acetate of 1:6 and the mixed liquor of petroleum ether) obtain yellow solid, as 4- n-amylbenzene formic acid -2- (1- Buddha's warrior attendant Alkane formamido) ethyl ester, calculating its yield is 49.9%.M.p.:122~124 DEG C；
1H NMR(500MHz,CDCl3) δ 7.91 (d, J=8.5Hz, 2H), 7.20 (d, J=8.5Hz, 2H), 6.30 (s, 1H), 4.37 (t, J=5.5Hz, 2H), 3.60 (q, J=5.5Hz, 2H), 2.62-2.58 (m, 2H), 1.97 (s, 3H), 1.81 (d, J=2.5Hz, 6H), 1.69-1.60 (m, 6H), 1.60-1.56 (m, 2H), 1.30-1.24 (m, 4H), 0.85 (t, J= 7.0Hz,3H)；
HRMS(ESI)calcd C25H35NO3[M+H]+397.2556,found 397.2544。
The synthesis of 13 compound Im of embodiment (R=4- methoxyphenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (12mL) with And 4- methoxy benzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.2mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (6mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:8 and the mixed liquor of petroleum ether) obtain faint yellow solid, as 4- methoxy benzoic acid -2- (1- adamantane Formamido) ethyl ester, calculating its yield is 61.6%.M.p.:124~126 DEG C；
1H NMR(500MHz,CDCl3)δ8.02–7.99(m,2H),6.96–6.93(m,2H),6.10(s,1H),4.41 (t, J=5.0Hz, 2H), 3.88 (s, 3H), 3.64 (q, J=5.5Hz, 2H), 2.04 (s, 3H), 1.84 (d, J=2.5Hz, 6H),1.76–1.67(m,6H)；
HRMS(ESI)calcd C21H27NO4[M+H]+357.1945,found 357.1946。
The synthesis of 14 compound In of embodiment (R=2,3- dichlorophenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 2,3- dichloro-benzoyl is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of chlorine (2.0mmol).After being added dropwise, 4h is reacted at room temperature, is then filtered to remove what reaction generated The hydrochloride of triethylamine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is body Product is than being the ethyl acetate of 1:4 and the mixed liquor of petroleum ether) obtain white solid, as 2,3- dichlorobenzoic acid -2- (1- Buddha's warrior attendant Alkane formamido) ethyl ester, calculating its yield is 50.5%.M.p.:102~105 DEG C；
1H NMR(500MHz,CDCl3) δ 7.63-7.58 (m, 1H), 7.58-7.52 (m, 1H), 7.23 (t, J=7.5Hz, 1H), 6.19 (s, 1H), 4.38 (t, J=5.0Hz, 2H), 3.58 (q, J=5.5Hz, 2H), 1.96 (s, 3H), 1.78 (d, J= 2.0Hz,6H),1.69–1.58(m,6H)；；
HRMS(ESI)calcd C20H23Cl2NO3[M+H]+395.1113,found 395.1233。
The synthesis of 15 compound Io of embodiment (R=2,4- dichlorophenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 2,4- dichloro-benzoyl is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of chlorine (2.0mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove what reaction generated The hydrochloride of triethylamine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is body Product is than being the ethyl acetate of 1:5 and the mixed liquor of petroleum ether) obtain faint yellow solid, as 2,4- dichlorobenzoic acid -2- (1- gold Rigid alkane formamido) ethyl ester, calculating its yield is 56.1%.M.p.:108~110 DEG C；
1H NMR(500MHz,CDCl3) δ 7.82 (d, J=8.5Hz, 1H), 7.49 (d, J=2.0Hz, 1H), 7.36-7.32 (m, 1H), 6.09 (s, 1H), 4.44 (t, J=5.0Hz, 2H), 3.66 (q, J=5.5Hz, 2H), 2.04 (s, 3H), 1.85 (d, J =2.5Hz, 6H), 1.76-1.66 (m, 6H)；
HRMS(ESI)calcd C20H23Cl2NO3[M+H]+395.1131,found 396.0213。
The synthesis of 16 compound Ip of embodiment (R=2- trifluoromethyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (9mL) and 2- trifluoromethyl benzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.7mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (4.5mL) of (1.5mmol).After being added dropwise, 3h is reacted at room temperature, is then filtered to remove reaction generates three The hydrochloride of ethamine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume Than the mixed liquor of ethyl acetate and petroleum ether for 1:3) obtain white solid, as 2- trifluoromethylbenzoic acid -2- (1- Buddha's warrior attendant Alkane formamido) ethyl ester, calculating its yield is 65.6%.M.p.:127~129 DEG C；
1H NMR(500MHz,CDCl3)δ7.76–7.72(m,1H),7.69–7.66(m,1H),7.58–7.53(m,2H), 6.21 (s, 1H), 4.35 (t, J=5.5Hz, 2H), 3.56 (q, J=5.5Hz, 2H), 1.94 (s, 3H), 1.78 (d, J= 2.5Hz,6H),1.67–1.58(m,6H)；
HRMS(ESI)calcd C21H24F3NO3[M+H]+395.1742,found 396.0242。
The synthesis of 17 compound Iq of embodiment (R=2,4,5- trifluorophenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14mL) with And 2,4,5- trifluoro-benzene formyls are slowly added dropwise in acid binding agent triethylamine (2.8mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7mL) of chlorine (1.5mmol).After being added dropwise, 4h is reacted at room temperature, is then filtered to remove reaction generates three The hydrochloride of ethamine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume Than the mixed liquor of ethyl acetate and petroleum ether for 1:3) obtain faint yellow solid, as 2,4,5- trifluoro-benzoic acid -2- (1- gold Rigid alkane formamido) ethyl ester, calculating its yield is 73.3%.M.p.:143~145 DEG C；
1H NMR(500MHz,CDCl3)δ7.85–7.77(m,1H),7.08–6.99(m,1H),6.05(s,1H),4.43 (t, J=5.0Hz, 2H), 3.64 (q, J=5.5Hz, 2H), 2.04 (s, 3H), 1.85 (d, J=2.5Hz, 6H), 1.76-1.67 (m,6H)；
HRMS(ESI)calcd C20H22F3NO3[M+H]+381.1640,found 381.1599。
The synthesis of 18 compound Ir of embodiment (R=3- nitro-4-methyl phenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 3- nitro-4-methyl is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of chlorobenzoyl chloride (1.5mmol).After being added dropwise, 4h is reacted at room temperature, reaction is then filtered to remove The hydrochloride of the triethylamine of generation, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue through column chromatography for separation (elution Agent is the mixed liquor of the ethyl acetate that volume ratio is 1:4 and petroleum ether) obtain yellow solid, as -4 methylbenzene first of 3- nitro Acid -2- (1- adamantane formamido) ethyl ester, calculating its yield is 58.7%.M.p.:89~92 DEG C；
1H NMR(500MHz,CDCl3) δ 8.42 (d, J=1.5Hz, 1H), 8.05-8.00 (m, 1H), 7.35 (d, J= 8.0Hz, 1H), 6.36 (s, 1H), 4.35 (t, J=5.5Hz, 2H), 3.57 (q, J=5.5Hz, 2H), 2.53 (s, 3H), 1.91 (s, 3H), 1.75 (d, J=2.5Hz, 6H), 1.66-1.57 (m, 6H)；
HRMS(ESI)calcd C21H26N2O5[M+H]+386.1845,found 386.0845。
The synthesis of 19 compound Is of embodiment (R=2,6- difluorophenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (12mL) with And 2,6- difluoro benzoyl chloride is slowly added dropwise in acid binding agent triethylamine (2.7mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (6mL) of (1.5mmol).After being added dropwise, 4h is reacted at room temperature, is then filtered to remove three second that reaction generates The hydrochloride of amine, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is volume ratio For the ethyl acetate of 1:3 and the mixed liquor of petroleum ether) obtain white solid, as 2,6- difluoromethyl benzoic acid -2- (1- Buddha's warrior attendant Alkane formamido) ethyl ester, calculating its yield is 65.6%.M.p.:127~129 DEG C；
1H NMR(500MHz,CDCl3) δ 7.49-7.42 (m, 1H), 6.99 (t, J=8.0Hz, 2H), 6.07 (s, 1H), 4.45 (t, J=5.5Hz, 2H), 3.64 (q, J=5.5Hz, 2H), 2.05 (s, 3H), 1.86 (d, J=2.5Hz, 6H), 1.77- 1.68(m,6H)；
HRMS(ESI)calcd C20H23F2NO3[M+H]+363.1640,found 363.1545。
The synthesis of 20 compound It of embodiment (R=2,3,5,6- tetrafluoro phenyl):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14mL) with And 2,3,5,6- phenyl tetrafluoride first are slowly added dropwise in acid binding agent triethylamine (2.7mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7mL) of acyl chlorides (2.25mmol).After being added dropwise, 4h is reacted at room temperature, reaction is then filtered to remove and generates Triethylamine hydrochloride, filtrate revolving removes solvents tetrahydrofurane, and gained rotates residue, and through column chromatography for separation, (eluant, eluent is Volume ratio is the ethyl acetate of 1:3 and the mixed liquor of petroleum ether) obtain white solid, as 2,3,5,6- tetrafluorobenzoic aid -2- (1- adamantane formamido) ethyl ester, calculating its yield is 65.6%.M.p.:127~129 DEG C；
1H NMR(500MHz,CDCl3) δ 7.29-7.20 (m, 1H), 6.03 (s, 1H), 4.48 (t, J=10.5,5.0Hz, 2H), 3.64 (q, J=5.5Hz, 2H), 2.04 (s, 3H), 1.85 (d, J=2.5Hz, 6H), 1.76-1.68 (m, 6H)；
HRMS(ESI)calcd C20H21F4NO3[M+H]+399.1539,found 399.1565。
The synthesis of 21 compound Iu of embodiment (R=2- chloropyridine base):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 2- chloropyridine -3- first is slowly added dropwise in acid binding agent triethylamine (2.4mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of acyl chlorides (2.25mmol).After being added dropwise, 4h is reacted at room temperature, is then filtered to remove reaction life At triethylamine hydrochloride, filtrate revolving remove solvents tetrahydrofurane, gained rotate residue through column chromatography for separation (eluant, eluent For the mixed liquor of ethyl acetate and petroleum ether that volume ratio is 1:5) obtain white solid, as 2- chlorine apellagrin -2- (1- adamantane Formamido) ethyl ester, calculating its yield is 70.1%.M.p.:99~102 DEG C；
1H NMR(500MHz,CDCl3)δ8.44–8.40(m,1H),8.12–8.07(m,1H),7.30–7.26(m,1H), 6.21 (s, 1H), 4.35 (t, J=5.5Hz, 2H), 3.55 (q, J=5.5Hz, 2H), 1.91 (s, 3H), 1.73 (q, J= 12.5Hz,6H),1.64–1.55(m,6H)；
HRMS(ESI)calcd C19H23ClN2O3[M+H]+362.1485,found 362.1439。
The synthesis of 22 compound Iv of embodiment (R=5,6- dichloropyridine base):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And 5,6- dichloropyridine-is slowly added dropwise in acid binding agent triethylamine (3.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of 3- formyl chloride (2.25mmol).After being added dropwise, 4h is reacted at room temperature, is then filtered to remove anti- The hydrochloride for the triethylamine that should be generated, filtrate revolving remove solvents tetrahydrofurane, and gained revolving residue (is washed through column chromatography for separation De- agent is the mixed liquor of the ethyl acetate that volume ratio is 1:5 and petroleum ether) obtain white solid, as 5,6- dichloro-nicotinic acid -2- (1- adamantane formamido) ethyl ester, calculating its yield is 62.8%.M.p.:126~129 DEG C；
1H NMR(500MHz,CDCl3) δ 8.86 (d, J=2.0Hz, 1H), 8.35 (d, J=2.0Hz, 1H), 6.01 (s, 1H), 4.46 (t, J=5.5Hz, 2H), 3.65 (q, J=5.5Hz, 2H), 2.03 (s, 3H), 1.83 (d, J=2.0Hz, 6H), 1.75–1.66(m,6H)；
HRMS(ESI)calcd C19H22Cl2N2O3[M+H]+396.1030,found 396.0038。
The synthesis of 23 compound Iw of embodiment (the chloro- 5- fluorine pyridyl group of R=2,6- bis-):
By intermediate N 2- hydroxyethyl -1- adamantane formamide (0.335g, 1.5mmol), tetrahydrofuran (14.6mL) And the chloro- 5- fluorine of 2,6- bis- is slowly added dropwise in acid binding agent triethylamine (2.0mmol) mixing, stirring and dissolving dropwise under condition of ice bath The tetrahydrofuran solution (7.5mL) of pyridine -3- formyl chloride (2.25mmol).After being added dropwise, 3h is reacted at room temperature, subsequent mistake filters out The hydrochloride for the triethylamine that dereaction generates, filtrate revolving remove solvents tetrahydrofurane, and gained rotates residue through column chromatography point White solid, the chloro- 5- of as 2,6- bis- are obtained from (mixed liquor that eluant, eluent is the ethyl acetate that volume ratio is 1:3 and petroleum ether) Fluorine nicotinic acid -2- (1- adamantane formamido) ethyl ester, calculating its yield is 58.9%.M.p.:134~136 DEG C；
1H NMR(500MHz,CDCl3) δ 8.01 (d, J=7.5Hz, 1H), 6.20 (s, 1H), 4.39 (t, J=5.0Hz, 2H), 3.59 (q, J=5.5Hz, 2H), 1.95 (s, 3H), 1.76 (d, J=2.0Hz, 6H), 1.69-1.58 (m, 6H)；
HRMS(ESI)calcd C19H21Cl2FN2O3[M+H]+414.0929,found 414.0836。
The test of 24 antifungal activity of embodiment:
Test target: tomato early blight bacterium (Alternariasolani, AI), fusarium graminearum (Gibberella Zeae, GZ), Sclerotinia sclerotiorum (Sclerotinia sclerotiorum, SS), botrytis cinerea pers (Botrytis cinerea,BC)。
2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound label prepared by Examples 1 to 23 is to be measuredization Close object.
Test process: each untested compound with DMSO be dissolved into concentration be 30 μ g/ μ L EC mother liquor it is spare.Using inhibition zone Method tests untested compound under 50mg/L dosage to the indoor bactericidal activity of target fungus, separately sets solvent clear water control (CK) And the fluxapyroxad that effective content is 50mg/L compares (FP).
Test method: the EC mother liquor of 50 μ L is drawn with liquid-transfering gun, is dissolved in the tween water of 2.95mL, is made into 500mg/L's Medical fluid.It is put into sterilized culture dish with the medical fluid 1mL that liquid-transfering gun draws 500mg/L, places into the PDA culture medium of 9mL, shake It is even, it is cooling, the culture dish of the pastille culture medium of the final concentration of 50mg/L of untested compound is made.It is beaten with punch and takes round bacterium It is chosen with transfer needle to the culture dish center of pastille culture medium after cake, the culture dish of pastille culture medium is then placed in 27 DEG C of incubator Middle culture measures colony diameter after 48~72h.The pure increment of bacterium colony is bacterium colony average diameter in the difference of bacteria cake diameter, antibacterial Rate (%) calculation method is referring to following formula.
Above-mentioned pastille culture medium method obtains blank control group after the same method as a result, above-mentioned drug containing culture using clear water Base method obtains drug control group result using fluxapyroxad after the same method.
Inhibiting rate (%)=[(the pure increment of the blank control bacterium colony-pure increment of processing bacterium colony)/pure life of blank control bacterium colony Long amount] × 100%
Test result is shown in Table 1.
1 Ia of table~Iw compound bactericidal activity (bacteriostasis rate %) at 50mg/L
Note: FP is control drug, and CK is blank control.
1 bactericidal activity test result of table shows 2- of the invention (1- adamantane formamido) methylcarbamoyl ethyl esters chemical combination Object shows certain inhibitory activity to for examination target.Compound In, Io, Iv, Iw reach tomato early blight bacterium inhibiting rate 50% or more, wherein compound Iw is to tomato early blight bacterium inhibiting rate up to 67.8%；Compound Ib, Id, Ik, Il, Ip, Iu couple Fusarium graminearum inhibiting rate is up to 55% or more, and wherein compound Ik is to fusarium graminearum inhibiting rate up to 71.8%；Ii, Ij is to botrytis cinerea pers inhibiting rate up to 50% or more, and wherein compound Ij is to botrytis cinerea pers inhibiting rate up to 51.2%； In addition, all compounds reach 55% or more to Sclerotinia sclerotiorum inhibiting rate, wherein compound Ik is to Sclerotinia sclerotiorum Inhibiting rate shows up to 88.0% inhibitory activity.
Content described in this specification is only to enumerate to inventive concept way of realization, and protection scope of the present invention is not answered When the concrete form for being seen as limited by embodiment and being stated.

Claims (10)

1. a kind of 2- (1- adamantane formamido) application of the methylcarbamoyl ethyl esters compound as fungicide, it is characterised in that institute Shown in the structure such as formula (I) for stating 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound:
In formula (I), R is phenyl, substituted-phenyl or substituted pyridinyl；H or substituted pyridinyl on the phenyl ring of the substituted-phenyl Pyridine ring on H be substituted base it is monosubstituted or polysubstituted, described monosubstituted or polysubstituted substituent group is each independently selected from The alkyl of C1 ~ C5, the alkoxy of C1 ~ C3, nitro, C1 ~ C5 halogenated alkyl or halogen.
2. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as described in claim 1 is as fungicide Using, it is characterised in that described monosubstituted or polysubstituted substituent group is each independently selected from methyl, tert-butyl, n-pentyl, first Oxygroup, nitro, trifluoromethyl, F or Cl.
3. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as described in claim 1 is as fungicide Using, it is characterised in that in formula (I), R be phenyl, 2- chlorphenyl, 3- chlorphenyl, 4- chlorphenyl, 2- fluorophenyl, 3- fluorophenyl, 4- fluorophenyl, 2- nitrobenzophenone, 3- aminomethyl phenyl, 4- aminomethyl phenyl, 4- tert-butyl-phenyl, 4- n-pentyl phenyl, 4- methoxyl group Phenyl, 2,3- dichlorophenyl, 2,4 dichloro benzene base, 2- trifluoromethyl, 2,4,5- trifluorophenyl, -4 methylbenzene of 3- nitro Base, 2,6- difluorophenyl, 2,3,5,6- tetrafluoro phenyl, 2- chloropyridine base, 5,6- dichloropyridine base or the chloro- 5- fluorine pyridine of 2,6- bis- Base.
4. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as described in claim 1 is as fungicide Using, it is characterised in that the synthetic method of 2- (1- adamantane formamido) the methylcarbamoyl ethyl esters compound, including it is following Step:
1) formyl chloride will be replaced to be dissolved in solvent A as shown in formula (III), preparation obtains replacing formyl solutions of chlorine；
It 2) will the intermediate as shown in formula (II)N- 2- hydroxyethyl -1- adamantane formamide, solvent B and acid binding agent mixing, The substitution formyl solutions of chlorine of step 1) preparation, after being added dropwise, room is then slowly added dropwise in stirring and dissolving dropwise under condition of ice bath Temperature reaction, TLC are monitored to after reaction, reaction solution are filtered, and after filtrate precipitation removes solvent, gained precipitation residue is through column The 2- as shown in formula (I) (1- adamantane formamido) methylcarbamoyl ethyl esters compound is made in chromatography；
In formula (III), R is phenyl, substituted-phenyl or substituted pyridinyl；H or substituted pyridinyl on the phenyl ring of the substituted-phenyl Pyridine ring on H be substituted base it is monosubstituted or polysubstituted, described monosubstituted or polysubstituted substituent group is each independently selected from The alkyl of C1 ~ C5, the alkoxy of C1 ~ C3, nitro, C1 ~ C5 halogenated alkyl or halogen.
5. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as claimed in claim 4 is as fungicide Application, it is characterised in that shown in formula (II)NReplace first shown in -2- hydroxyethyl -1- adamantane formamide and formula (III) The molar ratio of acyl chlorides is 1: 1~5.0, preferably 1: 1 ~ 1.5.
6. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as claimed in claim 4 is as fungicide Application, it is characterised in that solvent A is identical with solvent B, and the solvent B is tetrahydrofuran or acetonitrile, preferably tetrahydrofuran；Step It is rapid 1) in, preparation substitution formyl solutions of chlorine concentration be 0.25 ~ 0.5 mol/L.
7. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as claimed in claim 4 is as fungicide Using, it is characterised in that the acid binding agent is triethylamine or pyridine, preferably triethylamine.
8. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as claimed in claim 4 is as fungicide Application, it is characterised in that shown in formula (II)NThe molar ratio of -2- hydroxyethyl -1- adamantane formamide and acid binding agent is 1: 1~5, preferably 1: 1.2~2.
9. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as claimed in claim 4 is as fungicide Application, it is characterised in that as shown in formula (II)NThe molar ratio of -2- hydroxyethyl -1- adamantane formamide and solvent B are 1: 30~150, preferably 1: 70~120；It is characterized in that the time reacted at room temperature is 1 ~ 5 hour, preferably in step 2 2 ~ 4 hours.
10. a kind of 2- (1- adamantane formamido) methylcarbamoyl ethyl esters compound as claimed in claim 4 is as fungicide Application, it is characterised in that in step 2, eluant, eluent that column chromatography for separation uses for ethyl acetate that volume ratio is 1:3 ~ 8 with The mixed liquor of petroleum ether.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW332143B (en) * 1996-03-22 1998-05-21 Basf Ag Carboxamide
CN102167673A (en) * 2011-03-14 2011-08-31 广东工业大学 Surfactant containing adamantane and preparation method thereof
CN102361553A (en) * 2009-03-26 2012-02-22 陶氏环球技术有限责任公司 Biocidal composition of 2,6-dimethyl-m-dioxane-4-ol acetate and methods of use
CN106811962A (en) * 2016-12-30 2017-06-09 安徽比伦生活用纸有限公司 A kind of preparation method of efficient sterilizing ability napkin paper
CN109053287A (en) * 2018-09-12 2018-12-21 赵旭萌 A kind of killing pests and preventing diseases poison foliar fertilizer and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW332143B (en) * 1996-03-22 1998-05-21 Basf Ag Carboxamide
CN102361553A (en) * 2009-03-26 2012-02-22 陶氏环球技术有限责任公司 Biocidal composition of 2,6-dimethyl-m-dioxane-4-ol acetate and methods of use
CN102167673A (en) * 2011-03-14 2011-08-31 广东工业大学 Surfactant containing adamantane and preparation method thereof
CN106811962A (en) * 2016-12-30 2017-06-09 安徽比伦生活用纸有限公司 A kind of preparation method of efficient sterilizing ability napkin paper
CN109053287A (en) * 2018-09-12 2018-12-21 赵旭萌 A kind of killing pests and preventing diseases poison foliar fertilizer and preparation method thereof

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