CN113233993B - Ferulic acid amide derivative and synthetic method thereof - Google Patents

Ferulic acid amide derivative and synthetic method thereof Download PDF

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CN113233993B
CN113233993B CN202110537257.0A CN202110537257A CN113233993B CN 113233993 B CN113233993 B CN 113233993B CN 202110537257 A CN202110537257 A CN 202110537257A CN 113233993 B CN113233993 B CN 113233993B
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CN113233993A (en
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吴剑
张仁凤
郭声鑫
陈顺红
魏盼盼
郑志国
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • A01N37/36—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 at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
    • A01N37/38—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 at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

The invention discloses a preparation method and application of a ferulic acid amide derivative, wherein the structure of the derivative is shown as the following general formula I:
Figure DDA0003070255010000011
R1is alkyl halohydrocarbon or substituted phenyl of C1-C10, and the substituent of the substituted phenyl is H, halogen, CF3、OCH3、OCF3、CH(CH3)2Or NO2(ii) a R is H, methyl, ethylOr a propyl group; n is selected from 1,2, 3 and 4. The compound has excellent antibacterial activity, can be used for preventing and treating bacteria such as rice bacterial blight, citrus canker, bacterial leaf streak of rice and the like, and can be used for agricultural sterilization.

Description

Ferulic acid amide derivative and synthetic method thereof
Technical Field
The invention belongs to the field of chemicals, and particularly relates to a preparation method of a ferulic acid amide derivative prepared from a halogenated hydrocarbon ferulic acid derivative through a condensing agent, and an application of the ferulic acid enamine derivative in inhibiting plant pathogens.
Background
In the creation of new green pesticides, ferulic acid amide is a compound with wide biological activity, is an important segment in a plurality of drug molecular structures, is also an important drug intermediate, and is increasingly widely applied in the fields of pharmaceutical chemistry, natural product chemistry, pesticide chemistry and the like (Gan, X.h.et, al.J.Agric.food Chem.2017,65, 4367-one 4377; T J Coffel. . et, al.CN, 200880019016. x). Therefore, ferulic acid plays an important role in pesticides. Meanwhile, amide is an important structure in ferulic acid amide derivatives and is a common group in current commercial pesticides, and 20 varieties of pesticides containing amide structures, such as chlorantraniliprole, flubendiamide, bactericide boscalid, diyne amide and fluopicolide, in registered pesticides all contain amide structures. In recent years, the attention of researchers containing ferulic acid amide structure has been paid, and researchers successively disclose that compounds containing the amide structure have excellent antibacterial activity in their articles (BMC chemistry.2013,30, doi.org/10.1186/1752-.
Ferulic acid amide derivatives have been an important research object. They are not only synthetic organic intermediates for pharmaceuticals, but also excellent pesticides, antiviral agents, antibacterial agents, regulating plant growth agents, herbicides, and the like, and more about the application of ferulic acid amide, they are found in the reports [ bioorg.med.chem.lett.2017,27, 4096-; J.Agric.food.chem,2017,65, 4367-4377; chem.2020,44, 2374-.
Disclosure of Invention
The invention aims to splice a halogenated hydrocarbon ferulic acid structure and an amide structure, provides a ferulic acid-containing amide derivative with a novel structure, and provides application of the compound in the aspect of antibiosis.
The structural general formula of the compound provided by the invention is shown as I:
Figure BDA0003070255000000021
in the compounds of the formula I, R1Is alkyl halohydrocarbon or substituted phenyl of C1-C10, and the substituent of the substituted phenyl is H, halogen, CF3、OCH3、OCF3、CH(CH3)2Or NO2(ii) a R is H, methyl, ethyl or propyl; n is selected from 1,2, 3 and 4.
Further, R1Is alkyl halohydrocarbon or substituted phenyl of C2-C6, and the substituent of the substituted phenyl is H, F, Br, Cl or I; n is 2, 3 or 4.
Further, R1Alkyl halohydrocarbons having carbon numbers of 2 to 5; n is 3 or 4.
The ferulic acid amide derivative is applied to an antibacterial or anti-plant virus agent.
The compound is applied to the antibacterial agent for preventing and treating bacterial blight of rice, citrus canker and bacterial leaf streak of rice.
The compound is applied to preventing and treating plant germs.
Still further, in the context of the present invention, some preferred compounds have the following structure:
1210: methyl (E) -1- (3- (3-methoxy-4- ((2-methylbenzyl) oxy) phenyl) acrylamide) cyclohexane-1-carboxylate
1211: methyl (E) -1- (3- (3-methoxy-4- ((3-methylbenzyl) oxy) phenyl) acrylamido) cyclohexane-1-carboxylate
1212: methyl (E) -1- (3- (4- ((4-fluoro-3- (trifluoromethyl) benzyl) oxy) -3-methoxyphenyl) acrylamide) cyclohexane-1-carboxylate
1213: methyl (E) -1- (3- (4- ((4-chlorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1214: methyl (E) -1- (3- (4- ((3-chloro-2-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamide) cyclohexane-1-carboxylate
1215: methyl (E) -1- (3- (4- ((2, 6-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1216: methyl (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethoxy) benzyl) oxy) phenyl) acrylamide) cyclohexane-1-carboxylate
1217: methyl (E) -1- (3- (4- ((3-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1218: methyl (E) -1- (3- (4- ((2-chlorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1219: methyl (E) -1- (3- (4- ((3, 4-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1220: methyl (E) -1- (3- (4- ((3, 5-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1221: methyl (E) -1- (3- (4- ((2-chloro-5-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1222: methyl (E) -1- (3- (4- (benzyloxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate methyl ester
1223: methyl (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethyl) benzyl) oxy) phenyl) acrylamide) cyclohexane-1-carboxylate
1224: methyl (E) -1- (3- (4- ((2, 5-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylate
1225: methyl (E) -1- (3- (4- ((3-bromophenyl) oxy) -3-methoxyphenyl) acrylamide) cyclohexane-1-carboxylate
1226: methyl (E) -1- (3- (4- ((4-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamide) cyclohexane-1-carboxylate
1227: (E) -1- (3- (4- (3-chloropropoxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid methyl ester
1228: (E) -1- (3- (3-methoxy-4- ((2-methylbenzyl) oxy) phenyl) acrylamido) cyclohexane-1-carboxylic acid
1229: (E) -1- (3- (3-methoxy-4- ((3-methylbenzyl) oxy) phenyl) acrylamido) cyclohexane-1-carboxylic acid
1230: (E) -1- (3- (4- ((4-fluoro-3- (trifluoromethyl) benzyl) oxy) -3-methoxyphenyl) acrylamide) cyclohexane-1-carboxylic acid
1231: (E) -1- (3- (4- ((4-chlorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1232: (E) -1- (3- (4- (3-chloropropoxy) -3-methoxyphenyl) acrylamide) cyclohexane-1-carboxylic acid
1233: (E) -1- (3- (4- ((2, 6-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1234: (E) -1- (3- (4- ((2-chloro-4-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1235: (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethoxy) benzyl) oxy) phenyl) acrylamide) cyclohexane-1-carboxylic acid
1236: (E) -1- (3- (4- ((3-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1237: (E) -1- (3- (4- ((2-chlorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1238: (E) -1- (3- (4- ((3, 4-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1239: (E) -1- (3- (4- ((3, 5-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1240: (E) -1- ((3- (4- ((2-chloro-5-fluorobenzyl) oxy) -3-methoxyphenyl) allyl) amino) cyclohexane-1-carboxylic acid
1241: (E) -1- (3- (4- (benzyloxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1242: (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethyl) benzyl) oxy) phenyl) acrylamide) cyclohexane-1-carboxylic acid
1243: (E) -1- (3- (4- ((2, 5-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1244: (E) -1- (3- (4- ((3-bromophenyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1245: (E) -1- (3- (4- ((4-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclohexane-1-carboxylic acid
1246: (E) -1- (3- (4- (3-chloropropoxy) -3-methoxyphenyl) acrylamide) cyclohexane-1-carboxylic acid
1247: (E) -1- (3- (3-methoxy-4- ((2-methylbenzyl) oxy) phenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester.
1248 (E) -1- (3- (3-methoxy-4- ((3-methylbenzyl) oxy) phenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1249 methyl 1- (3- (4- ((4-fluoro-3- (trifluoromethyl) benzyl) oxy) -3-methoxyphenyl) propylamino) cyclopentane-1-carboxylate
1250 methyl (E) -1- (3- (4- ((3-chloro-2-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylate
1251 (E) -1- (3- (4- ((2, 6-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1252: (E) -1- (3- (4- ((2-chloro-4-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester.
1253: (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethoxy) benzyl) oxy) phenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1254: (E) -1- (3- (4- ((3-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1255: (E) -1- (3- (4- ((3, 5-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1256: (E) -1- (3- (4- ((2-chloro-5-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1257: (E) -1- (3- (4- (benzyloxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1258: (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethyl) benzyl) oxy) phenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1259: (E) -1- (3- (4- ((4-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid ethyl ester
1260: (E) -1- (3- (3-methoxy-4- ((2-methylbenzyl) oxy) phenyl) acrylamido) cyclopentane-1-carboxylic acid
1261: 1- (3- (3-methoxy-4- ((3-methylbenzyl) oxy) phenyl) propylamino) cyclopentane-1-carboxylic acid
1262: (E) -1- (3- (4- ((4-fluoro-3- (trifluoromethyl) benzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1263 (E) -1- (3- (4- ((3-chloro-2-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1264 (E) -1- (3- (4- ((2-chloro-4-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1265 (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethoxy) benzyl) oxy) phenyl) acrylamido) cyclopentane-1-carboxylic acid
1266 (E) -1- (3- (4- ((3-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1267 (E) -1- (3- (4- ((2-chlorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1268 (E) -1- (3- (4- ((3, 4-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1269 (E) -1- (3- (4- ((2-chloro-5-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1270 (E) -1- (3- (4- (benzyloxy) -3-methoxyphenyl) acrylamide) cyclopentane-1-carboxylic acid
1271 (E) -1- (3- (3-methoxy-4- ((4- (trifluoromethyl) benzyl) oxy) phenyl) acrylamido) cyclopentane-1-carboxylic acid
1272 (E) -1- (3- (4- ((2, 5-difluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1273 (E) -1- (3- (4- ((3-bromophenyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
1274 (E) -1- (3- (4- ((4-fluorobenzyl) oxy) -3-methoxyphenyl) acrylamido) cyclopentane-1-carboxylic acid
The above compounds were prepared according to the following scheme. Specific operations can be carried out by referring to the method disclosed in the application number CN 101679346.
1210-, 1226-, 1228-, 1246-, 1247-and 1274.
Figure BDA0003070255000000071
R2H, halogen, CF3、OCH3、OCF3、CH(CH3)2Or NO2；
1227. 1246 synthetic route
Figure BDA0003070255000000072
R3Halogen.
The invention has the beneficial effects that: the invention provides a novel amide compound containing ferulic acid, which is obtained by active splicing of natural products of ferulic acid and an amide structure. The biological activity test result shows that the compound provided by the invention has good prevention and treatment effects on bacteria. because-OH in carboxyl has unique properties such as a hydrogen-like simulation effect, fat solubility, a penetration effect and the like, the water solubility of the compound is better, and the bacteriostatic activity of the compound is improved.
Detailed Description
Example 1 preparation of 1210
The first step is as follows:
mixing ferulic acid methyl ester (1.0mmol) and potassium carbonate K2CO3(1.2mmol) and potassium iodide KI (0.5mmol) were added to a 50mL single neck flask, 8mL of DMF was added to the flask, and the mixture was stirred at room temperatureActivating for 3-4 h at the temperature, then adding o-methylbenzyl chloride (1.2mmol) into the mixture, after the reaction is finished, pouring the reaction liquid into water, stirring until a large amount of solids are separated out, and performing suction filtration to obtain an intermediate 1.
The second step is that:
adding the intermediate 1(1.0mol) and 7mL of methanol, heating and stirring, adding a sodium hydroxide solution (5.0mol) into the reaction solution, removing the solution after the reaction is finished, pouring the solution into water, adjusting acid by using 4M hydrochloric acid until solid is separated out, and filtering to obtain an intermediate 2.
The third step:
adding the intermediate 2(1.0mol) and 2- (7-azobenzotriazole) - (2.0mol) N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) into a 25mL single-neck bottle, adding 9mL acetonitrile, starting stirring at normal temperature, adding (1.2mol) N, N-Diisopropylethylamine (DIPEA) into the reaction bottle, adding 1-aminocyclohexane-1-carboxylic acid methyl ester (1.0mol), after the reaction is finished, pouring the reaction into water, stirring until a large amount of solids are separated out, and carrying out suction filtration to obtain the target product.
1210 physicochemical Properties: yellow solid, 88.3%, 129-130 ℃;
1 H NMR(400MHz,DMSO)δ8.15(s,1H),7.85–7.72(m,3H),7.60(t,J＝7.3Hz,1H),7.32(d,J＝15.7Hz,1H),7.21(d,J＝1.7Hz,1H),7.15–6.98(m,2H),6.69(d,J＝15.8Hz,1H),5.26(s,2H),3.83(s,3H),3.56(s,3H),3.06(s,3H),1.98(d,J＝13.3Hz,2H),1.71(s,2H),1.53(s,5H),1.38–1.16(m,1H).
13 CNMR(101MHz,DMSO)δ174.95,165.25,149.71,149.20,139.43,135.26,133.36,130.89,129.25,128.94,127.95,127.84,125.02,121.89,120.44,113.85,110.60,67.11,58.41,55.95,52.21,42.31,41.92,32.43,25.32,21.50.
HRMS(ESI):Calculated for C26H35N2O5[M+NH4]+:455.25405,found:455.25439
example 2: 1211 preparation
1211 is prepared analogously to example 1, except that o-methylbenzyl chloride in the first step is replaced by 1- (chloromethyl) -3-toluene.
1211 physicochemical properties: yellow solid, 83.3%, 185-;
1 HNMR(400MHz,DMSO)δ8.14(s,1H),7.41(d,J＝7.3Hz,1H),7.32(d,J＝
15.7Hz,1H),7.25(dd,J＝5.4,3.9Hz,2H),7.22(d,J＝6.9Hz,1H),7.19(s,1H),7.12(d,J＝1.4Hz,2H),6.68(d,J＝15.7Hz,1H),5.10(s,2H),3.81(s,3H),3.56(s,3H),2.33(s,3H),1.98(d,J＝13.3Hz,2H),1.81–1.61(m,2H),1.53(s,5H),1.31–1.18(m,1H).
13 CNMR(101MHz,DMSO)δ174.96,165.31,149.69,139.56,137.25,135.24,130.60,129.18,128.65,128.40,126.25,121.99,120.12,113.69,110.32,68.98,58.40,55.89,52.21,32.44,25.33,21.50,18.89.
HRMS(ESI):Calculated for C26H32NO5[M+H]+:438.22750,found:438.22702
preparation of example 3:1212
1212 was prepared similarly to example 1, except that o-methylbenzyl chloride in the first step was changed to 4- (bromomethyl) -1-fluoro-2- (trifluoromethyl) benzene.
1212, physicochemical properties: yellow solid, 39.3%, 100-;
1H NMR(400MHz,DMSO)δ8.15(s,1H),7.90(d,J＝7.0Hz,1H),7.60–7.56(m,1H),7.53(dd,J＝8.4,4.4Hz,1H),7.32(d,J＝15.7Hz,1H),7.20(s,1H),7.11(s,2H),6.68(d,J＝15.7Hz,1H),5.20(s,2H),3.83(s,3H),2.69(s,3H),1.98(d,J＝13.3Hz,2H),1.70(d,J＝9.2Hz,2H),1.53(s,5H),1.25(d,J＝6.0Hz,1H).
13 C NMR(101MHz,DMSO)δ174.95,165.26,150.40(d,J＝248.4Hz),149.67,140.06,139.44,135.10,134.65(q,J＝4.0Hz),123.07(q,J＝272.2Hz),121.91,121.23,120.40,117.98,117.77,114.04,110.45,68.89,58.40,55.92,52.22,32.41,25.31,21.49.
19 FNMR(376MHz,DMSO)δ-60.04,-117.14.
HRMS(ESI):Calculated for C26H28NO5F4[M+H]+:510.18981,found:510.18939
example 4 preparation of 1213
1213 was prepared similarly to example 1, except that o-methylchlorobenzyl in the first step was changed to 1-chloro-4- (chloromethyl) benzene.
1213 physicochemical Properties: yellow solid, 67.7%, 145-146 deg.C;
1 H NMR(400MHz,DMSO)δ8.15(s,1H),7.47(s,4H),7.32(d,J＝15.7Hz,1H),7.19(d,J＝1.5Hz,1H),7.09(t,J＝4.2Hz,1H),7.06(d,J＝8.4Hz,1H),6.68(d,J＝15.7Hz,1H),5.13(s,2H),3.83(s,3H),2.69(s,3H),1.98(d,J＝13.3Hz,2H),1.71(dd,J＝11.9,7.7Hz,2H),1.52(s,5H),1.28–1.23(m,1H).
13 C NMR(101MHz,DMSO)δ174.96,165.29,149.63,149.35,139.50,136.38,132.97,130.11,128.93,121.93,121.23,120.23,113.82,110.38,69.42,58.39,55.90,52.21,38.71,32.42,25.32,21.49.
HRMS(ESI):Calculated for C25H29NO5Cl[M+H]+:458.17288,found:458.17236
preparation of example 5:1214
1214 was prepared similarly to example 1, except that o-methylbenzyl chloride in the first step was changed to 1- (bromomethyl) -3-chloro-2-fluorobenzene.
1214 physicochemical properties: yellow solid, 76.8%, 153-;
1 H NMR(400MHz,DMSO)δ8.15(s,1H),7.62(t,J＝6.9Hz,1H),7.54(t,J＝6.4Hz,1H),7.32(d,J＝15.6Hz,1H),7.28(d,J＝7.8Hz,1H),7.20(s,1H),7.12(s,2H),6.68(d,J＝15.8Hz,1H),5.20(s,2H),3.82(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.77–1.63(m,2H),1.53(s,5H),1.25(d,J＝5.6Hz,1H).
13 C NMR(101MHz,DMSO)δ174.95,165.25,156.02(d,J＝248.8Hz),149.64,149.13,139.43,131.13,129.99,129.95,128.93,126.23(d,J＝14.3Hz),126.02,125.98,121.88,120.44,113.95,110.50,64.57,64.54,58.40,55.90,52.21,32.43,25.33,21.50.
19 F NMR(376MHz,DMSO)δ-120.62.
HRMS(ESI):Calculated for C25H28NO5FCl[M+H]+:476.16346,found:476.16275
example 6 preparation of 1215
1215 is prepared similarly to example 1, except that the o-methylbenzyl chloride in the first step is changed to 2- (bromomethyl) -1, 3-difluorobenzene.
Physical and chemical properties of 1215: yellow solid, 99.8%, 136-;
1 H NMR(400MHz,DMSO)δ8.18(s,1H),7.56(d,J＝5.7Hz,1H),7.53(d,J＝3.9Hz,1H),7.35(d,J＝3.1Hz,1H),7.22(s,1H),7.20(s,1H),7.19(d,J＝1.4Hz,1H),7.16–7.14(m,1H),6.70(d,J＝15.8Hz,1H),5.13(s,2H),3.78(d,J＝1.9Hz,3H),3.57(s,3H),1.99(d,J＝13.2Hz,2H),1.83–1.64(m,2H),1.51(d,J＝18.0Hz,5H),1.25(dd,J＝12.3,6.1Hz,1H).
13 C NMR(101MHz,DMSO)δ174.97,168.35,165.26,161.78(d,J＝249.2Hz),161.70(d,J＝249.2Hz),151.64,149.66,149.21,144.48,139.45,135.10,129.35,121.24,117.64,113.83(d,J＝22.4Hz),112.29(d,J＝24.6Hz),111.08,110.37,58.39,56.02,55.78,52.23,32.41,25.31,21.48.
19 F NMR(376MHz,DMSO)δ-115.03,-115.05.
HRMS(ESI):Calculated for C25H28NO5F2[M+H]+:460.19301,found:460.19244
preparation of example 7:1216
1216 is prepared analogously to example 1, except that o-methylbenzyl chloride in the first step is replaced by 1- (chloromethyl) -4- (trifluoromethoxy) benzene.
Physicochemical properties of 1216: white solid, 84.0%, 116-.
1 H NMR(400MHz,DMSO)δ8.14(s,1H),7.59(dd,J＝8.9,2.4Hz,2H),7.41(d,J＝7.9Hz,2H),7.32(d,J＝15.7Hz,1H),7.20(d,J＝1.4Hz,1H),7.14–7.04(m,2H),6.68(d,J＝15.7Hz,1H),5.17(d,J＝4.0Hz,2H),3.83(s,3H),3.56(s,3H),2.05–1.88(m,2H),1.78–1.65(m,2H),1.52(t,J＝13.3Hz,5H),1.28(d,J＝17.0Hz,1H).
13 C NMR(101MHz,DMSO)δ174.95,165.28,149.63,149.37,139.49,136.87,130.19,128.61,121.94,121.57,120.27,117.44,113.78,110.39,69.35,58.40,55.90,52.20,32.43,25.32,21.50.
19 F NMR(376MHz,DMSO)δ-56.80.
HRMS(ESI):Calculated for C26H29NO6F3[M+H]+:508.19415,found:508.19360
Example 8 preparation of 1217
1217 preparation was carried out analogously to example 1, except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -3-fluorobenzene.
1217 physicochemical Properties: yellow solid, 68.1%, 153-.
1 H NMR(400MHz,DMSO)δ8.14(s,1H),7.45(dd,J＝8.0,2.0Hz,1H),7.30(t,J＝3.2Hz,3H),7.22–7.16(m,2H),7.10–7.06(m,2H),6.68(d,J＝15.7Hz,1H),5.16(s,2H),3.84(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.75–1.63(m,2H),1.52(s,5H),1.32–1.20(m,1H).
13 CNMR(101MHz,DMSO)δ174.95,165.28,162.64(d,J＝243.6Hz),149.66,149.32,139.48,131.01,130.93,128.64,124.13,124.11,121.94,120.29,115.14(d,J＝20.9Hz),114.79(d,J＝21.8Hz),113.85,110.41,69.44,58.40,55.93,52.21,32.43,25.33,21.50.
19 FNMR(376MHz,DMSO)δ-113.14.
HRMS(ESI):Calculated for C25H29NO5F[M+H]+:442.20243,found:442.20169
Example 9 preparation of 1218
1218 was prepared similarly to example 1, except that o-methylbenzyl chloride in the first step was changed to 1- (bromomethyl) -2-chlorobenzene.
Physicochemical properties of 1218: yellow solid, 98.9%, 128-;
1 HNMR(400MHz,DMSO)δ8.15(s,1H),7.60(dd,J＝5.4,4.0Hz,1H),7.53(qd,J＝9.6,5.6Hz,2H),7.43–7.39(m,2H),7.33(d,J＝15.7Hz,1H),7.21(d,J＝1.3Hz,1H),7.11(d,J＝2.8Hz,1H),6.69(d,J＝15.8Hz,1H),5.18(d,J＝3.1Hz,2H),3.83(s,3H),3.56(s,3H),1.98(d,J＝13.2Hz,2H),1.71(dd,J＝11.9,7.4Hz,2H),1.50(d,J＝17.4Hz,5H),1.25(dd,J＝9.3,7.0Hz,1H).
13 CNMR(101MHz,DMSO)δ174.95,165.27,149.64,149.35,139.47,134.63,133.14,130.73,130.46,129.86,128.76,127.88,121.93,120.34,113.75,110.54,67.89,58.40,56.17,55.94,52.22,32.43,25.33,21.50.
HRMS(ESI):Calculated for C25H29NO5Cl[M+H]+:458.17288,found:458.17224
example 10 preparation of 1219
1219 preparation was carried out analogously to example 1, except that o-methylbenzyl chloride in the first step was changed to 4- (chloromethyl) -1, 2-difluorobenzene.
1219 physicochemical Properties: yellow solid, 86.5%, 107-;
1 HNMR(400MHz,DMSO)δ8.16(s,1H),7.52(dd,J＝7.9,3.2Hz,1H),7.50–7.44(m,1H),7.32(d,J＝15.6Hz,2H),7.20(d,J＝1.5Hz,1H),7.13–7.01(m,2H),6.68(d,J＝15.8Hz,1H),5.12(s,2H),3.83(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.87–1.60(m,2H),1.52(t,J＝13.7Hz,5H),1.25(dd,J＝12.5,6.3Hz,1H).
13 C NMR(101MHz,DMSO)δ174.96,168.36,165.26,150.42(d,J＝244.5Hz),149.63,139.47,135.13,129.36,128.69,127.94,125.27,121.93,120.31,118.05(d,J＝17.3Hz),117.39(d,J＝17.6Hz),113.85,110.35,69.00,58.38,55.89,52.22,32.41,25.32,21.49.
19 FNMR(376MHz,DMSO)δ-138.57,-139.74.
HRMS(ESI):Calculated for C25H28NO5F2[M+H]+:460.19301,found:460.19235
example 11 preparation of 1220
1220 is prepared analogously to example 1, except that o-methylbenzyl chloride in the first step is replaced by 1- (chloromethyl) -3, 5-difluorobenzene.
1220 physicochemical properties: yellow solid, 98.4%, 107-;
1 H NMR(400MHz,DMSO)δ8.15(s,1H),7.32(d,J＝15.7Hz,1H),7.24–7.20(m,2H),7.19–7.16(m,2H),7.10(dd,J＝8.4,1.7Hz,1H),7.05(d,J＝8.4Hz,1H),6.68(d,J＝15.8Hz,1H),5.17(s,2H),3.85(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.76–1.62(m,2H),1.54(d,J＝9.0Hz,5H),1.28–1.20(m,1H).
13 C NMR(101MHz,DMSO)δ174.95,165.26,162.93(d,J＝246.4Hz),162.80(d,J＝246.3Hz),149.69,149.05,142.11,139.42,128.89,121.89,120.43,113.99,111.07,110.94(d,J＝11.8Hz),110.81,110.50,103.72,68.96,58.40,55.97,52.21,32.43,25.32,21.50.
19 F NMR(376MHz,DMSO)δ-109.60,-109.62.
HRMS(ESI):Calculated for C25H28NO5F2[M+H]+:460.19301,found:460.19272
example 12 preparation of 1221
1221 was prepared similarly to example 1, except that o-methylchlorobenzyl in the first step was changed to 2-chloro-1- (chloromethyl) -4-fluorobenzene.
1221 physicochemical Properties: yellow solid, 89.2%, 174-;
1 HNMR(400MHz,DMSO)δ8.16(s,1H),7.70–7.62(m,1H),7.54(dd,J＝8.9,2.6Hz,1H),7.38–7.32(m,1H),7.30(d,J＝2.9Hz,1H),7.20(s,1H),7.12(s,2H),6.69(d,J＝15.8Hz,1H),5.15(s,2H),3.82(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.77–1.66(m,2H),1.50(d,J＝17.7Hz,5H),1.33–1.21(m,1H).
13 CNMR(101MHz,DMSO)δ174.96,168.35,165.25,162.25(d,J＝248.1Hz),149.61,149.26,139.46,134.32,132.54,132.44,131.15,128.81,121.92,120.35,117.29(d,J＝25.3Hz),115.04(d,J＝21.2Hz),113.77,110.46,67.37,58.38,55.90,52.22,32.41,25.32,21.50.
19 F NMR(376MHz,DMSO)δ-111.48.
HRMS(ESI):Calculated for C25H28NO5ClF[M+H]+:476.16346,found:476.16327
preparation of example 13:1222
1222 was prepared similarly to example 1, except that o-methylbenzyl chloride in the first step was changed to (chloromethyl) benzene.
1222 physicochemical properties: yellow solid, 94.6%, 175-;
1 HNMR(400MHz,DMSO)δ8.15(s,1H),7.48–7.43(m,3H),7.42–7.38(m,2H),7.34(d,J＝3.8Hz,1H),7.19(s,1H),7.09(s,2H),6.67(d,J＝15.7Hz,1H),5.13(d,J＝4.0Hz,2H),3.82(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.82–1.62(m,2H),1.50(d,J＝17.8Hz,5H),1.32–1.15(m,1H).
13 CNMR(101MHz,DMSO)δ174.97,168.38,165.29,151.64,149.60,149.58,144.59,139.53,137.30,128.92,128.38,122.98,122.00,121.23,120.13,117.29,113.64,110.25,70.25,58.37,55.85,52.22,32.42,25.33,21.50.
HRMS(ESI):Calculated for C25H30NO5[M+H]+:424.21185,found:424.21158
example 14 preparation of 1223
1223 was prepared similarly to example 1, except that o-methylbenzyl chloride in the first step was changed to 1- (chloromethyl) -4- (trifluoromethyl) benzene.
1223 physicochemical Properties: yellow solid, 95.2%, 140-;
1 HNMR(400MHz,DMSO)δ8.16(s,1H),7.79(d,J＝8.2Hz,3H),7.68(d,J＝8.1Hz,3H),7.32(d,J＝15.7Hz,1H),7.21(d,J＝1.4Hz,1H),7.09(dt,J＝13.1,4.9Hz,2H),6.68(d,J＝15.8Hz,1H),5.26(s,3H),3.85(s,4H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.81–1.64(m,2H),1.50(d,J＝18.0Hz,5H),1.36–1.08(m,1H).
13 C NMR(101MHz,DMSO)δ174.96,168.36,165.26,151.44,149.63,149.21,144.49,142.26,139.46,128.83(q,J＝31.7Hz),128.71,128.57,125.84(q,J＝3.6Hz),124.71(q,J＝272.1Hz),121.92,120.32,117.50,113.82,110.39,69.34,58.38,55.92,52.21,32.41,25.32,21.49.
19 F NMR(376MHz,DMSO)δ-60.93.
HRMS(ESI):Calculated for C26H29NO5F3[M+H]+:492.19923,found:492.19928
preparation of example 15:1224
1224 was prepared similarly to example 1, except that o-methylbenzyl chloride in the first step was changed to 2- (bromomethyl) -1, 4-difluorobenzene.
1224 physicochemical properties: yellow solid, 90.3%, 125-;
1 H NMR(400MHz,DMSO)δ8.16(s,1H),7.63–7.48(m,1H),7.38–7.32(m,2H),7.31(d,J＝2.1Hz,1H),7.21(s,1H),7.12(d,J＝9.2Hz,2H),6.69(d,J＝15.8Hz,1H),5.15(s,2H),3.83(d,J＝1.7Hz,3H),3.56(s,3H),1.98(d,J＝13.2Hz,2H),1.79–1.63(m,2H),1.58–1.41(m,5H),1.30–1.20(m,1H).
13 CNMR(101MHz,DMSO)δ174.96,168.35,165.24,158.51(d,J＝242.5Hz),156.88(d,J＝245.0Hz),151.63,149.63,149.11,139.43,128.92,121.91,120.43,117.57(d,J＝24.6Hz),117.50(d,J＝22.4Hz),117.27(d,J＝17.1Hz),117.07(d,J＝12.9Hz),113.88,110.42,64.17,58.38,55.89,52.22,32.41,25.32,21.49.
19 FNMR(376MHz,DMSO)δ-118.49,-123.59.
HRMS(ESI):Calculated for C25H28NO5F2[M+H]+:460.19301,found:460.19266
preparation of example 16:1225
1225 was prepared similarly to example 1 except that o-methylbenzyl chloride in the first step was changed to 1-bromo-3- (chloromethyl) benzene.
1225 physicochemical Properties: yellow solid, 99.8%, 97-98 deg.C;
1 HNMR(400MHz,DMSO)δ8.15(s,1H),7.47–7.43(m,2H),7.40(d,J＝1.6Hz,1H),7.39–7.36(m,1H),7.34(d,J＝3.8Hz,1H),7.19(s,1H),7.08(d,J＝6.2Hz,2H),6.67(d,J＝15.7Hz,1H),5.13(d,J＝4.0Hz,2H),3.82(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.78–1.63(m,2H),1.50(d,J＝17.8Hz,5H),1.34–1.19(m,1H).
13 C NMR(101MHz,DMSO)δ174.97,168.38,165.29,151.64,149.60,149.58,144.59,139.53,137.30,128.92,128.42,128.38,122.00,121.23,120.13,117.29,113.64,110.25,70.25,58.37,55.85,52.22,32.42,25.33,21.50.
HRMS(ESI):Calculated for C25H27BrNO5[M-H]-:500.10671,found:500.10541
example 17 preparation of 1226
1226 was prepared similarly to example 1, except that o-methylbenzyl chloride in the first step was changed to 1- (chloromethyl) -4-fluorobenzene.
1226 physicochemical Properties: yellow solid, 98.0%, 143- & ltSUB & gt 144 & deg.C;
1 HNMR(400MHz,DMSO)δ8.15(s,1H),7.52(dd,J＝6.4,2.1Hz,2H),7.32(d,J＝15.7Hz,1H),7.28–7.21(m,3H),7.19(d,J＝0.9Hz,1H),7.09(s,1H),6.68(d,J＝15.7Hz,1H),5.11(d,J＝3.8Hz,2H),3.82(s,3H),3.56(s,3H),1.98(d,J＝13.3Hz,2H),1.80–1.62(m,2H),1.50(d,J＝17.9Hz,5H),1.32–1.14(m,1H).
13 CNMR(101MHz,DMSO)δ174.97,168.37,165.28,162.30(d,J＝243.7Hz),151.64,149.61,149.45,139.51,133.52,130.67,130.59,128.47,121.97,121.23,120.18,115.74(d,J＝21.4Hz),113.71,110.26,69.53,58.38,55.85,52.22,32.42,25.32,21.49.
19 FNMR(376MHz,DMSO)δ-114.28.
HRMS(ESI):Calculated for C25H29FNO5[M+H]+:444.20243,found:444.20218
example 18 preparation of 1227
1227 was prepared similarly to example 1, except that the o-methylbenzyl chloride in the first step was changed to 1-bromo-3-chloropropane.
1227 physicochemical Properties: white solid, 59.7%, 117-;
1 HNMR(500MHz,DMSO)δ8.10(s,1H),7.26(d,J＝15.7Hz,1H),7.13(d,J＝1.6Hz,1H),7.05(dd,J＝8.3,1.7Hz,1H),6.98(d,J＝8.3Hz,1H),6.62(d,J＝15.7Hz,1H),4.07(t,J＝6.0Hz,2H),3.77(s,3H),3.75(t,J＝6.4Hz,2H),3.51(s,3H),2.13(dd,J＝12.5,6.2Hz,2H),1.93(d,J＝13.3Hz,2H),1.72–1.59(m,2H),1.47(t,J＝15.6Hz,5H),1.23(d,J＝20.5Hz,1H).
13 C NMR(126MHz,DMSO)δ175.02,165.34,149.65,149.58,139.58,128.47,122.09,120.20,113.47,110.39,65.51,58.43,55.93,52.28,42.51,32.47,32.22,25.38,21.55.
HRMS(ESI):Calculated for C21H29NO5Cl[M+H]+:410.17288,found:410.17233
preparation of example 19:1228
The first step is as follows:
mixing ferulic acid methyl ester (1.0mmol) and potassium carbonate K2CO3(1.2mmol) and potassium iodide KI (0.5mmol) are added into a 50mL single-neck bottle, 8mL of DMF is added into the bottle, activation is carried out for 3-4 h at normal temperature, then o-methylbenzyl chloride (1.2mmol) is added into the mixture, after the reaction is finished, the reaction liquid is poured into water and stirred until a large amount of solid is separated out, and the intermediate 1 is obtained by suction filtration.
The second step is that:
adding the intermediate 1(1.0mol) and 7mL of methanol, heating and stirring, adding a sodium hydroxide solution (5.0mol) into the reaction solution, removing the solution after the reaction is finished, pouring the solution into water, adjusting acid by using 4M hydrochloric acid until solid is separated out, and filtering to obtain an intermediate 2.
The third step:
adding the intermediate 2(1.0mol) and 2- (7-azobenzotriazole) - (2.0mol) N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) into a 25mL single-neck bottle, adding 9mL acetonitrile, starting stirring at normal temperature, adding (1.2mol) N, N-Diisopropylethylamine (DIPEA) into the reaction bottle, adding 1-aminocyclohexane-1-carboxylic acid methyl ester (1.0mol), after the reaction is finished, pouring the reaction into water, stirring until a large amount of solids are separated out, and carrying out suction filtration to obtain an intermediate 3.
The fourth step:
adding the intermediate 3(1.0mol) and 7mL of methanol, starting heating and stirring, adding a sodium hydroxide solution (5.0mol) into the reaction solution, removing the solution after the reaction is finished, pouring the solution into water, adjusting acid by using 4M hydrochloric acid until solid is separated out, and carrying out suction filtration to obtain the final target product.
1228 physicochemical Properties: white solid, 80.0%, 86-88 deg.C;
1 H NMR(400MHz,DMSO)δ12.15(s,1H),8.01(s,1H),7.40(s,1H),7.26(dd,J＝36.6,20.1Hz,5H),7.12(s,1H),6.71(d,J＝15.0Hz,1H),5.10(s,2H),3.81(s,3H),2.33(s,3H),2.01(s,2H),1.68(s,2H),1.52(s,5H),1.23(s,1H).
13 C NMR(101MHz,DMSO)δ176.09,165.27,149.67,149.60,139.15,137.25,135.24,130.60,129.19,128.67,128.49,126.26,121.87,120.62,113.71,110.31,68.99,58.28,55.93,32.28,25.46,21.55,18.91.
HRMS(ESI):Calculated for C25H30NO5[M+H]+:424.21185,found:424.21082
preparation of example 20:1229
1229 was prepared similarly to example 19, except that o-methylbenzyl chloride in the first step was changed to 1- (chloromethyl) -3-toluene.
1229 physicochemical Properties: white solid, 95.7%, 87-88 ℃;
1 HNMR(400MHz,DMSO)δ12.14(s,1H),7.98(s,1H),7.41(d,J＝7.2Hz,1H),7.31(d,J＝15.7Hz,1H),7.27–7.20(m,3H),7.18(d,J＝1.3Hz,1H),7.13–7.11(m,2H),6.70(d,J＝15.7Hz,1H),5.10(s,2H),3.81(s,3H),2.33(s,3H),2.03(d,J＝13.1Hz,2H),1.69(dd,J＝17.8,6.6Hz,2H),1.51(t,J＝16.8Hz,5H),1.24(d,J＝7.1Hz,1H).
13 CNMR(101MHz,DMSO)δ176.18,165.26,149.69,149.61,139.12,137.25,135.26,130.59,129.18,128.65,128.52,126.26,121.86,120.66,113.71,110.30,68.98,58.33,55.89,32.30,25.48,21.58,18.90.
HRMS(ESI):Calculated for C25H29NO5Na[M+Na]+:446.19379,found:446.19293
preparation of example 21:1230
1230 was prepared similarly to example 19, except that o-methylbenzyl chloride in the first step was changed to 4- (bromomethyl) -1-fluoro-2- (trifluoromethyl) benzene.
Physicochemical properties of 1230: white solid, 99.8%, 78-80 deg.C;
1 HNMR(400MHz,DMSO)δ12.15(s,1H),7.98(s,1H),7.90(d,J＝7.0Hz,1H),7.86–7.82(m,1H),7.57(dd,J＝10.6,8.8Hz,1H),7.31(d,J＝15.7Hz,1H),7.20(s,1H),7.10(s,2H),6.71(d,J＝15.7Hz,1H),5.20(s,2H),3.83(s,3H),2.03(d,J＝13.1Hz,2H),1.69(dd,J＝17.9,6.6Hz,2H),1.51(dd,J＝24.7,11.1Hz,5H),1.24(d,J＝7.1Hz,1H).
13 CNMR(101MHz,DMSO)δ176.18,165.20,158.93(d,J＝253.6Hz),149.68,149.09,138.99,135.22,135.13,134.67(q,J＝3.7Hz),128.98,123.09(q,J＝275.3Hz),121.72,120.96,117.97,117.77,116.82(d,J＝12.5Hz),114.07,110.43,68.90,58.35,55.91,37.40,32.29,25.47,21.57.
19 F NMR(376MHz,DMSO)δ-60.04,-117.16.
HRMS(ESI):Calculated for C25H25NO5F[M-H]-:494.15851,found:494.16146
example 22 preparation of 1231
1231 was prepared similarly to example 19 except that o-methylchlorobenzyl in the first step was changed to 1-chloro-4- (chloromethyl) benzene.
The physicochemical properties of 1231 are white solid, 70.2%, 84-86 ℃;
1 H NMR(400MHz,DMSO)δ12.14(s,1H),7.99(s,1H),7.47(s,4H),7.30(d,J＝15.7Hz,1H),7.18(d,J＝1.3Hz,1H),7.08(d,J＝1.4Hz,1H),7.07(s,1H),6.69(d,J＝15.7Hz,1H),5.12(s,2H),3.82(s,3H),2.02(d,J＝13.1Hz,2H),1.68(t,J＝10.5Hz,2H),1.50(dd,J＝25.0,11.1Hz,5H),1.24(d,J＝4.6Hz,1H).
13 CNMR(101MHz,DMSO)δ176.11,165.25,149.64,149.27,139.11,136.40,132.97,130.11,128.93,128.68,121.82,120.73,113.85,110.38,69.42,58.31,55.91,32.28,25.45,21.55.
HRMS(ESI):Calculated for C24H26NO5ClNa[M+Na]+:446.13917,found:446.13831
example 23 preparation of 1232
1232 was prepared similarly to example 19 except that o-methylchlorobenzyl in the first step was changed to 1- (bromomethyl) -3-chloro-2-fluorobenzene.
The physicochemical properties of 1232 are white solid, 99.4 percent and 88 to 90 ℃;
1 H NMR(400MHz,DMSO)δ11.86(s,1H),7.92(s,1H),7.61(t,J＝6.9Hz,1H),7.53(t,J＝6.6Hz,1H),7.31(d,J＝6.2Hz,1H),7.28(s,1H),7.19(s,1H),7.10(s,2H),6.73(d,J＝15.7Hz,1H),5.19(s,2H),3.81(s,3H),2.08(d,J＝10.8Hz,2H),1.68(d,J＝10.6Hz,2H),1.54–1.40(m,5H),1.23(d,J＝6.9Hz,1H).
13 C NMR(101MHz,DMSO)δ165.17,155.99(d,J＝251.1Hz),149.63,148.96,138.63,131.10,129.96,129.93,129.19,126.32,126.18,126.01,125.96,121.70,120.26,120.09,113.94,110.46,64.55,55.88,32.35,25.65,21.79.
19 F NMR(376MHz,DMSO)δ-120.63.
HRMS(ESI):Calculated for C24H25NO5FClNa[M+Na]+:484.12975,found:484.12820
example 24 preparation of 1233
1233 was prepared similarly to example 19 except that o-methylbenzyl chloride in the first step was changed to 2- (bromomethyl) -1, 3-difluorobenzene.
Physicochemical properties of 1233: white solid, 79.4%, 96-98 ℃;
1 HNMR(400MHz,DMSO)δ7.99(s,1H),7.58–7.47(m,2H),7.32(d,J＝15.6Hz,1H),7.22(s,1H),7.20–7.17(m,3H),6.60(dd,J＝92.5,15.8Hz,1H),5.12(s,2H),3.78(d,J＝2.0Hz,3H),2.03(d,J＝13.1Hz,2H),1.69(t,J＝10.5Hz,2H),1.51(t,J＝17.1Hz,5H),1.24(d,J＝7.4Hz,1H).
13 CNMR(101MHz,DMSO)δ176.15,165.19,161.78(d,J＝248.6Hz),161.71(d,J＝249.3Hz),149.76,149.14,144.24,138.98,129.20,128.52,122.83,121.76,121.04,113.80,161.71(d,J＝249.3Hz),112.61(d,J＝19.5Hz),112.41,111.13,58.70,58.34,55.80,32.29,25.48,21.57.
19 F NMR(376MHz,DMSO)δ-114.97,-115.02.
HRMS(ESI):Calculated for C24H25NO5F2Na[M+Na]+:468.15930,found:468.15787
example 25 preparation of 1234
1234 was prepared similarly to example 19, except that o-methylchlorobenzyl in the first step was changed to 1- (bromomethyl) -2-chloro-4-fluorobenzene.
Physicochemical properties of 1234: white solid, 56.3%, 77-78 ℃;
1 HNMR(400MHz,DMSO)δ7.92(s,1H),7.61(dd,J＝8.4,6.3Hz,1H),7.49(dd,J＝8.7,2.2Hz,1H),7.28–7.23(m,2H),7.15(s,1H),7.06(s,2H),6.67(d,J＝15.7Hz,1H),5.09(s,2H),3.77(s,3H),2.00(d,J＝12.7Hz,2H),1.64(t,J＝10.9Hz,2H),1.47(t,J＝15.0Hz,5H),1.18(d,J＝2.7Hz,2H).
13 CNMR(126MHz,DMSO)δ165.26,162.29(d,J＝248.1Hz),149.71,149.22,138.96,134.33,134.25,132.55,132.47,131.23,131.20,129.06,121.82,121.14,117.33(d,J＝25.2Hz),115.08(d,J＝20.9Hz),113.93,110.58,67.46,55.98,32.38,25.58,21.70.
19 F NMR(471MHz,DMSO)δ-111.43.
HRMS(ESI):Calculated for C24H26NO5FCl[M+H]+:462.14781,found:4462.1470
example 26 preparation of 1235
1235 was prepared similarly to example 19 except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -4- (trifluoromethoxy) benzene.
Physicochemical properties of 1235: white solid, 90.7%, 78-80 ℃;
1 H NMR(400MHz,DMSO)δ7.98(s,1H),7.60(d,J＝2.1Hz,1H),7.58(d,J＝2.5Hz,1H),7.41(d,J＝8.0Hz,2H),7.31(d,J＝15.7Hz,1H),7.19(s,1H),7.09(s,2H),6.70(d,J＝15.7Hz,1H),5.16(s,2H),3.83(s,3H),2.03(d,J＝13.1Hz,2H),1.73–1.63(m,2H),1.52(t,J＝11.6Hz,5H),1.23(d,J＝3.4Hz,1H).
13 C NMR(101MHz,DMSO)δ176.14,165.23,149.64,149.29,148.39,139.07,136.89,130.19,128.73,121.82,121.57,120.80,113.80,110.38,69.35,58.33,55.90,32.29,25.47,21.56.
19 FNMR(376MHz,DMSO)δ-56.80.
HRMS(ESI):Calculated for C25H27NO5F3[M+H]+:494.17850,found:494.17786
example 27 preparation of 1236
1236 was prepared similarly to example 19 except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -3-fluorobenzene.
Physicochemical properties of 1235: white solid, 93.8%, 75-77 ℃;
1 H NMR(500MHz,DMSO)δ7.93(s,1H),7.40(dd,J＝8.1,1.9Hz,1H),7.25(d,J＝14.8Hz,3H),7.16–7.12(m,2H),7.04(d,J＝1.6Hz,1H),7.01(d,J＝8.4Hz,1H),6.65(d,J＝15.7Hz,1H),5.11(s,2H),3.79(s,3H),1.99(d,J＝13.0Hz,2H),1.64(t,J＝10.7Hz,2H),1.47(dd,J＝16.4,13.1Hz,5H),1.22–1.12(m,1H).
13 C NMR(126MHz,DMSO)δ176.33,165.27,162.69(d,J＝243.4Hz),149.72,149.28,140.40,139.04,131.06,128.85,124.18,124.16,121.86,120.97,115.19(d,J＝20.8Hz),1114.85(d,J＝21.9Hz),113.93,110.46,69.50,58.48,55.99,55.88,32.36,25.55,21.66.
13 C NMR(471MHz,DMSO)δ-113.06.
HRMS(ESI):Calculated for C24H27NO5F[M+H]+:428.18678,found:428.18637
example 28 preparation of 1237
1237 was prepared similarly to example 19 except that o-methylbenzyl chloride in the first step was changed to 1- (bromomethyl) -2-chlorobenzene.
Physicochemical properties of 1237: white solid, 84.6%, 77-79 ℃;
1 H NMR(400MHz,DMSO)δ7.98(s,1H),7.62–7.58(m,1H),7.52(dd,J＝5.6,3.5Hz,1H),7.42–7.38(m,2H),7.31(d,J＝16.3Hz,1H),7.20(s,1H),7.12–7.03(m,2H),6.71(d,J＝15.7Hz,1H),5.17(s,2H),3.82(d,J＝2.2Hz,3H),2.04(d,J＝12.8Hz,2H),1.69(t,J＝10.7Hz,2H),1.50(dd,J＝24.7,11.4Hz,5H),1.24(d,J＝7.0Hz,1H).
13 C NMR(101MHz,DMSO)δ165.22,149.65,149.25,138.95,134.65,134.59,133.13,130.71,130.44,129.86,128.92,127.88,121.79,121.02,113.78,113.59,111.11,110.52,67.89,58.49,55.93,32.32,25.52,21.64.
HRMS(ESI):Calculated for C24H27NO5Cl[M+H]+:444.15723,found:444.15668
example 29 preparation of 1238
1238 is prepared similarly to example 19 except that o-methylbenzyl chloride in the first step is changed to 4- (chloromethyl) -1, 2-difluorobenzene.
Physicochemical properties of 1238: white solid, 99.2%, 94-96 deg.C;
1 H NMR(400MHz,DMSO)δ12.15(s,1H),7.98(s,1H),7.56–7.39(m,2H),7.31(d,J＝15.7Hz,2H),7.19(d,J＝1.4Hz,1H),7.14–7.03(m,2H),6.70(d,J＝15.7Hz,1H),5.11(s,2H),3.83(s,3H),2.02(d,J＝13.0Hz,2H),1.73–1.61(m,2H),1.50(dd,J＝24.2,11.0Hz,5H),1.24(d,J＝7.3Hz,1H).
13 C NMR(101MHz,DMSO)δ176.08,165.23,149.78(dd,J＝245.5,12.5Hz),149.67,149.51(dd,J＝245.4,12.4Hz),149.15,,139.07,128.84,125.20,121.79,120.82,118.03(d,J＝17.1Hz),117.36(d,J＝17.4Hz),113.94,110.42,69.03,58.30,55.92,32.22,25.46,21.55.
19 F NMR(376MHz,DMSO)δ-138.58,-139.77.
HRMS(ESI):Calculated for C24H26NO5F2[M+H]+:446.17736,found:446.17679
example 30 preparation of 1239
1239 was prepared similarly to example 19 except that o-methylbenzyl chloride in the first step was changed to 1- (chloromethyl) -3, 5-difluorobenzene.
Physicochemical properties of 1239: white solid, 94.7%, 79-80 deg.C;
1 H NMR(400MHz,DMSO)δ7.97(s,1H),7.30(d,J＝15.7Hz,1H),7.21(d,J＝1.4Hz,2H),7.18(d,J＝6.9Hz,2H),7.09(dd,J＝8.4,1.5Hz,1H),7.05(d,J＝8.4Hz,1H),6.71(d,J＝15.7Hz,1H),5.17(s,2H),3.85(s,3H),2.04(d,J＝13.0Hz,2H),1.68(t,J＝10.7Hz,2H),1.52(t,J＝12.8Hz,5H),1.24(d,J＝7.4Hz,1H).
13 C NMR(101MHz,DMSO)δ165.20,162.93(d,J＝246.2Hz),162.79(d,J＝246.3Hz),149.69,148.94,142.22,142.13,142.04,138.89,129.05,121.75,121.11,114.02,111.06,110.93(d,J＝12.1Hz),110.80,110.49,103.84(d,J＝25.8Hz),68.97,58.50,55.97,32.31,25.51,21.63.
19 F NMR(376MHz,DMSO)δ-109.59,-109.62.
HRMS (ESI):Calculated for C24H26NO5F2[M+H]+:446.17736,found:446.17642
example 31 preparation of 1240
1240 is prepared similarly to example 19, except that o-methylchlorobenzyl in the first step is changed to 2-chloro-1- (chloromethyl) -4-fluorobenzene.
Physicochemical properties of 1240: white solid, 93.1%, 129-130 ℃;
1 H NMR(400MHz,DMSO)δ8.12(d,J＝69.3Hz,1H),7.71(dd,J＝8.6,6.3Hz,1H),7.59(dd,J＝8.8,2.6Hz,1H),7.43–7.34(m,2H),7.26(s,1H),7.17(s,2H),6.75(dd,J＝15.7,8.1Hz,1H),5.20(s,2H),3.88(s,3H),2.06(dd,J＝19.4,14.3Hz,2H),1.75(dd,J＝16.9,7.1Hz,2H),1.59(d,J＝9.3Hz,5H),1.29(d,J＝6.7Hz,1H).
13 C NMR(101MHz,DMSO)δ174.95,165.27,162.24(d,J＝248.1Hz),149.65,149.27,139.46,134.25(d,J＝11.8Hz),132.47(d,J＝10.9Hz),128.84,121.91,120.38,117.40,117.15,115.14,114.93,113.85,110.53,67.40,58.40,55.93,52.22,32.43,25.33,21.50.
19 F NMR(376MHz,DMSO)δ-111.50.
HRMS(ESI):Calculated for C24H26NO5FCl[M+H]+:462.14781,found:462.14725
example 32 preparation of 1241
1241 is prepared analogously to example 19, with the exception that the o-methylbenzyl chloride in the first step is replaced by (chloromethyl) benzene.
Physicochemical properties of 1241: white solid, 89.6%, 99-101 deg.C;
1 H NMR(400MHz,DMSO)δ8.06(d,J＝66.2Hz,1H),7.46(d,J＝7.0Hz,2H),7.41(dd,J＝6.9,1.7Hz,2H),7.39–7.35(m,1H),7.35–7.32(m,1H),7.18(s,1H),7.10–6.98(m,2H),6.68(dd,J＝15.7,7.8Hz,1H),5.13(d,J＝3.4Hz,2H),3.82(s,3H),2.09–1.89(m,2H),1.69(dd,J＝17.1,6.9Hz,2H),1.52(s,5H),1.25(s,1H).
13 C NMR(101MHz,DMSO)δ176.17,174.96,165.30,165.25,149.64,139.54,139.11,137.32,128.92,128.36,121.99,121.86,120.69,120.15,113.73,110.32,70.28,58.39,55.89,52.21,32.43,25.47,21.57.
HRMS(ESI):Calculated for C24H28NO5[M+H]+:410.19620,found:410.19574
EXAMPLE 33 preparation of 1242
1242 is prepared analogously to example 19, with the exception that the o-methylbenzyl chloride in the first step is replaced by 1- (chloromethyl) -4- (trifluoromethyl) benzene.
1242 physicochemical properties: white solid, 95.7%, 92-93 ℃;
1 H NMR(400MHz,DMSO)δ7.99(s,1H),7.78(d,J＝8.2Hz,2H),7.67(d,J＝8.1Hz,2H),7.31(d,J＝15.7Hz,1H),7.20(d,J＝1.4Hz,1H),7.13–6.96(m,2H),6.70(d,J＝15.7Hz,1H),5.25(s,2H),3.84(s,3H),2.02(d,J＝13.1Hz,2H),1.78–1.61(m,2H),1.50(dd,J＝23.7,11.1Hz,5H),1.24(d,J＝7.3Hz,1H).
13 C NMR(101MHz,DMSO)δ176.08,165.23,149.67,149.15,144.47,142.29,139.05,128.85,128.56,125.83(q,J＝3.7Hz),124.71(q,J＝272.0Hz),121.79,120.84,113.90,113.69,111.16,110.46,69.38,58.30,55.95,32.28,25.46,21.55.
19 FNMR(376MHz,DMSO)δ-60.93.
HRMS(ESI):Calculated for C25H27NO5F3[M+H]+:478.18358,found:478.18289
example 34 preparation of 1243
1243 is prepared analogously to example 19, with the exception that the o-methylbenzyl chloride in the first step is replaced by 2- (bromomethyl) -1, 4-difluorobenzene.
1243 physicochemical properties: white solid, 86.8%, 94-95 ℃;
1 H NMR(400MHz,DMSO)δ7.99(s,1H),7.41(d,J＝3.3Hz,1H),7.34(dd,J＝7.3,2.0Hz,2H),7.29(d,J＝2.6Hz,1H),7.20(s,1H),7.12(s,2H),6.71(dd,J＝15.7,2.5Hz,1H),5.15(s,2H),3.82(d,J＝1.9Hz,3H),2.03(d,J＝12.7Hz,2H),1.69(t,J＝11.1Hz,2H),1.51(t,J＝17.9Hz,5H),1.24(d,J＝7.6Hz,1H).
13 C NMR(101MHz,DMSO)δ176.21,165.22,158.51(d,J＝242.1Hz),156.88(d,J＝242.4Hz).,149.67,149.04,138.98,129.08,121.77,121.01,117.35,117.11,113.98,113.75,111.15,110.49,64.20,58.39,55.91,32.30,25.48,21.58.
19 F NMR(376MHz,DMSO)δ-118.47,-123.59.
HRMS (ESI):Calculated for C24H26NO5F2[M+H]+:446.17736,found:446.17667
EXAMPLE 35 preparation of 1244
1244 is prepared analogously to example 19, except that o-methylbenzyl chloride in the first step is replaced by 1-bromo-3- (chloromethyl) benzene.
1244 physicochemical properties: white solid, 100%, 73-75 ℃;
1 H NMR(500MHz,DMSO)δ7.94(s,1H),7.62(s,1H),7.49(dd,J＝15.2,8.4Hz,2H),7.35–7.30(m,2H),7.26(d,J＝15.7Hz,1H),7.15(d,J＝1.7Hz,1H),7.05(dd,J＝8.4,1.7Hz,1H),7.02(d,J＝8.6Hz,1H),6.65(d,J＝15.7Hz,1H),5.10(d,J＝5.3Hz,2H),3.79(d,J＝1.7Hz,3H),1.98(d,J＝13.1Hz,2H),1.70–1.57(m,2H),1.52–1.39(m,5H),1.26–1.09(m,1H).
13 C NMR(126MHz,DMSO)δ176.17,165.28,149.70,149.26,140.26,140.19,139.10,131.22,130.88,128.85,127.25,122.93,122.20,121.86,120.89,117.68,113.93,110.45,69.40,58.37,55.97,32.35,25.53,21.63.
HRMS(ESI):Calculated for C24H27NO5Br[M+H]+:488.10671,found:488.10623
EXAMPLE 36 preparation of 1245
1245 is prepared analogously to example 19, except that o-methylbenzyl chloride in the first step is replaced by 1- (chloromethyl) -4-fluorobenzene.
Physicochemical properties of 1245: white solid, 92.9%, 96-97 deg.C;
1 H NMR(500MHz,DMSO)δ7.95(s,1H),7.48–7.43(m,3H),7.26(d,J＝15.8Hz,1H),7.19(d,J＝2.2Hz,1H),7.14(s,1H),7.04(d,J＝2.1Hz,2H),6.66(d,J＝15.7Hz,1H),5.06(d,J＝5.4Hz,2H),3.77(d,J＝1.4Hz,3H),1.98(d,J＝13.1Hz,2H),1.70–1.56(m,2H),1.46(dt,J＝15.4,10.9Hz,5H),1.24–1.13(m,1H).
13 C NMR(126MHz,DMSO)δ176.15,168.42,165.30,162.35(d,J＝243.7Hz),149.69,149.44,144.58,139.13,133.61,130.69,130.63,128.68,121.88,120.80,115.88,115.71,113.85,110.39,69.62,58.36,55.93,32.35,25.53,21.62.
19 F NMR(471MHz,DMSO)δ-114.21.
HRMS(ESI):Calculated for C24H27NO5F[M+H]+:428.18678,found:428.18625
example 37 preparation of 1246
1246 is prepared analogously to example 19, with the exception that the o-methylbenzyl chloride in the first step is replaced by 1-bromo-3-chloropropane.
1246 physicochemical properties: off-white solid, 79.8%, 77-79 ℃;
1 H NMR(500MHz,DMSO)δ7.94(s,1H),7.25(d,J＝15.7Hz,1H),7.11(d,J＝6.0Hz,1H),7.05(dd,J＝11.1,4.3Hz,1H),6.96(dd,J＝11.9,5.9Hz,1H),6.67–6.60(m,1H),4.07(t,J＝6.0Hz,2H),3.98(t,J＝6.4Hz,3H),3.77(d,J＝3.1Hz,2H),3.74(d,J＝6.4Hz,2H),2.16–2.09(m,2H),1.97(d,J＝13.0Hz,2H),1.63(t,J＝10.8Hz,2H),1.49–1.38(m,5H),1.18(d,J＝4.6Hz,1H).
13 C NMR(126MHz,DMSO.)δ176.17,165.30,149.58,139.18,128.58,121.96,120.69,113.51,110.39,68.99,65.52,58.49,58.33,55.93,42.51,32.33,32.22,29.47,25.52,21.61.
HRMS(ESI):Calculated for C20H26NO5ClNa[M+Na]+418.13917, found 418.13834 preparation of example 38:1247
The first step is as follows:
mixing ferulic acid methyl ester (1.0mmol) and potassium carbonate K2CO3(1.2mmol) and potassium iodide KI (0.5mmol) are added into a 50mL single-mouth bottle, 8mL of DMF is added into the bottle, activation is carried out for 3-4 h at normal temperature, then ortho-methyl benzyl chloride (1.2mmol) is added into the mixture, after the reaction is finished, the reaction solution is poured into water and stirred until a large amount of solid is separated out, and the intermediate 1 is obtained by suction filtration.
The second step is that:
adding the intermediate 1(1.0mol) and 7mL of methanol, heating and stirring, adding a sodium hydroxide solution (5.0mol) into the reaction solution, removing the solution after the reaction is finished, pouring the solution into water, adjusting acid by using 4M hydrochloric acid until solid is separated out, and filtering to obtain an intermediate 2.
The third step:
adding the intermediate 2(1.0mol) and HATU (2.0mol) into a 25mL single-neck bottle, adding 9mL acetonitrile, stirring at normal temperature, adding DIPEA (1.2mol) into the reaction bottle, adding 1-aminocyclopentane-1-carboxylic acid ethyl ester (1.0mol), after the reaction is finished, pouring the reaction into water, stirring until a large amount of solids are separated out, and carrying out suction filtration to obtain the target product.
1247 physicochemical properties: yellow solid, 77.3%, 94-95 deg.C;
1 H NMR(500MHz,DMSO)δ8.38(s,1H),7.76(d,J＝7.8Hz,1H),7.70(dd,J＝13.4,6.1Hz,2H),7.55(t,J＝7.4Hz,1H),7.29(d,J＝15.8Hz,1H),7.17(d,J＝1.7Hz,1H),7.07(dd,J＝8.3,1.7Hz,1H),7.01(d,J＝8.4Hz,1H),6.51(d,J＝15.7Hz,1H),5.21(s,2H),3.99(q,J＝7.1Hz,2H),3.78(s,3H),2.18–1.96(m,2H),1.86(dt,J＝11.3,5.1Hz,2H),1.64(t,J＝7.3Hz,4H),1.08(t,J＝7.1Hz,3H).
13 C NMR(126MHz,DMSO)δ174.07,165.39,149.76,149.22,139.29,135.33,133.41,130.90,129.29,128.95,127.42,127.18,126.61,126.56,121.84,120.42,113.89,110.72,67.13,65.60,60.72,56.00,36.87,24.44,14.61.
HRMS(ESI):Calculated for C26H32NO5[M+H]+:438.22750,found:438.22723
example 39 preparation of 1248
1248 is prepared analogously to example 38, except that o-methylbenzyl chloride in the first step is replaced by 1- (chloromethyl) -3-toluene.
1248 physicochemical Properties: white solid, 18.3%, 125-;
1 H NMR(500MHz,DMSO)δ8.38(s,1H),7.36(d,J＝7.5Hz,1H),7.29(d,J＝15.8Hz,1H),7.22–7.13(m,4H),7.08(s,2H),6.50(d,J＝15.8Hz,1H),5.05(s,2H),3.99(q,J＝7.1Hz,2H),3.76(s,3H),2.28(s,3H),2.09–1.98(m,2H),1.86(dt,J＝11.4,5.2Hz,2H),1.68–1.59(m,4H),1.08(t,J＝7.1Hz,3H).
13 C NMR(126MHz,DMSO)δ174.09,165.45,149.73,139.44,137.30,135.28,130.65,129.22,128.71,128.40,126.31,121.94,120.08,113.73,110.44,69.02,65.60,60.73,55.94,36.87,24.43,18.95,14.61.
HRMS(ESI):Calculated for C26H32NO5[M+H]+:438.22750,found:438.22751
EXAMPLE 40 preparation of 1249
1249 is prepared analogously to example 38, except that o-methylbenzyl chloride in the first step is replaced by 4- (bromomethyl) -1-fluoro-2- (trifluoromethyl) benzene. Changing the 1-aminocyclopentane-1-carboxylic acid ethyl ester in the third step into 1-aminocyclopentane-1-carboxylic acid methyl ester.
1249 physicochemical properties: yellow solid, 83.8%, 86-88 ℃;
1 H NMR(400MHz,DMSO)δ8.42(s,1H),7.89(d,J＝7.0Hz,1H),7.59–7.56(m,1H),7.53(dd,J＝8.4,4.4Hz,1H),7.33(d,J＝15.7Hz,1H),7.20(d,J＝1.4Hz,1H),7.11(d,J＝1.5Hz,1H),7.10(s,1H),6.55(d,J＝15.8Hz,1H),5.20(s,2H),3.82(s,3H),2.69(s,3H),2.09(dd,J＝8.2,5.2Hz,2H),1.90(d,J＝6.6Hz,2H),1.68(s,4H).
13 C NMR(101MHz,DMSO)δ174.02,165.35,150.39(d,J＝250.9Hz),149.68,139.26,135.21,135.12,135.10,134.67,134.63,129.35,128.80,123.06(d,J＝272.0Hz),121.70,120.17(d,J＝30.1Hz),117.88(d,J＝20.6Hz),114.07,110.55,68.89,65.54,60.67,55.92,36.81,24.37.
19 F NMR(376MHz,DMSO)δ-60.03,-117.15.
HRMS(ESI):Calculated for C25H26NO5F4[M+H]+:496.17416,found:496.17283
example 41 preparation of 1250
1250 is prepared similarly to example 38, except that o-methylbenzyl chloride in the first step is changed to 1- (bromomethyl) -3-chloro-2-fluorobenzene and ethyl 1-aminocyclopentane-1-carboxylate in the third step is changed to methyl 1-aminocyclopentane-1-carboxylate.
1250, white solid, 95.7 percent, 134-135 ℃;
1 H NMR(400MHz,DMSO)δ8.45(s,1H),7.57–7.47(m,2H),7.31(d,J＝3.7Hz,1H),7.28(d,J＝8.0Hz,1H),7.20(s,1H),7.12(s,2H),6.55(d,J＝15.8Hz,1H),5.20(s,2H),3.81(s,3H),3.57(s,3H),2.12–2.05(m,2H),1.95–1.88(m,2H),1.68(s,4H).
13 C NMR(126MHz,DMSO)δ174.69,165.43,156.07(d,J＝249.0Hz),149.70,149.19,139.46,131.18,130.03,130.01,128.94,126.28(d,J＝14.3Hz),126.07,126.04,121.85,120.36,114.01,110.64,65.54,64.62,64.60,55.96,52.44,36.92,24.40.
19 F NMR(471MHz,DMSO)δ-120.52.
HRMS (ESI):Calculated for C24H26NO5ClF[M+H]+:462.14781,found:462.14722
EXAMPLE 42 preparation of 1251
1251 was prepared similarly to example 38 except that o-methylbenzyl chloride in the first step was changed to 2- (bromomethyl) -1, 3-difluorobenzene.
1251 physicochemical Properties: yellow solid, 99.7%, 120-;
1 H NMR(500MHz,DMSO)δ8.37(s,1H),7.55–7.49(m,1H),7.30(d,J＝15.7Hz,1H),7.16(d,J＝7.9Hz,2H),7.14–7.12(m,2H),7.08(dd,J＝8.4,1.7Hz,1H),6.52(d,J＝15.8Hz,1H),5.07(s,2H),4.00(q,J＝7.1Hz,2H),3.73(s,3H),2.09–1.99(m,2H),1.90–1.81(m,2H),1.63(dd,J＝7.6,4.2Hz,4H),1.08(t,J＝7.0Hz,3H).
13 C NMR(126MHz,)δ174.06,165.39,161.83(d,J＝249.1Hz),161.77(d,J＝249.5Hz),149.77,149.26,139.27,132.38,129.10,121.84,120.50,114.11,112.44,112.24,110.58,65.61,60.72,58.77,55.86,36.87,24.44,14.61.
19 F NMR(471MHz,)δ-114.93,-114.94.
HRMS(ESI):Calculated for C25H28NO5F2[M+H]+:460.19301,found:460.19266
EXAMPLE 43 preparation of 1252
1252 was prepared similarly to example 38, except that o-methylchlorobenzyl in the first step was changed to 1- (bromomethyl) -2-chloro-4-fluorobenzene.
1252 physicochemical properties: yellow solid, 95.2%, 107-;
1 H NMR(500MHz,DMSO)δ8.38(s,1H),7.63–7.57(m,1H),7.50(d,J＝2.8Hz,1H),7.48(dd,J＝3.9,2.2Hz,1H),7.29(d,J＝15.8Hz,1H),7.15(d,J＝1.3Hz,1H),7.11–6.94(m,2H),6.51(d,J＝15.7Hz,1H),5.10(d,J＝4.6Hz,2H),3.99(q,J＝7.1Hz,2H),3.77(s,3H),2.15–1.95(m,2H),1.86(dt,J＝11.2,5.2Hz,2H),1.63(dd,J＝11.0,7.7Hz,4H),1.08(t,J＝7.1Hz,3H).
13 C NMR(126MHz,)δ194.56,174.07,168.40,165.40,162.29(d,J＝247.8Hz),151.65,149.69,149.30,139.31,134.25,132.47,128.85,121.86,120.36,117.34(d,J＝25.3Hz),115.09(d,J＝21.2Hz),113.89,110.65,67.44,65.60,60.72,55.97,36.87,24.43,14.61.
19 F NMR(471MHz,DMSO)δ-111.42.
HRMS(ESI):Calculated for C25H28FClNO5[M+H]+:438.22750,found:438.22702
EXAMPLE 44 preparation of 1253
1253 was prepared similarly to example 38, except that o-methylbenzyl chloride in the first step was changed to 1- (chloromethyl) -4- (trifluoromethoxy) benzene.
1253 physicochemical Properties: yellow solid, 62.3%, 77-79 deg.C;
1 H NMR(500MHz,DMSO)δ8.37(s,1H),7.55(d,J＝1.6Hz,1H),7.53(d,J＝1.5Hz,1H),7.38–7.34(m,3H),7.28(d,J＝15.7Hz,1H),7.15(d,J＝1.7Hz,1H),7.04(d,J＝6.5Hz,1H),6.50(d,J＝15.8Hz,1H),5.12(d,J＝5.6Hz,2H),3.99(q,J＝7.1Hz,2H),3.78(d,J＝1.3Hz,3H),2.05(ddd,J＝13.4,10.0,5.4Hz,2H),1.86(dt,J＝11.3,5.3Hz,2H),1.65–1.60(m,4H),1.08(t,J＝7.1Hz,3H).
13 C NMR(101MHz,DMSO)δ174.02,168.37,165.35,151.61,149.61,149.33,148.37,144.53,139.30,136.88,130.19,128.55,121.83,121.59,121.55(d,J＝278.1Hz),121.22,117.42,113.73,110.42,69.30,65.53,60.66,55.87,36.80,24.37,14.55. 19F NMR(471MHz,DMSO)δ-56.72.
HRMS(ESI):Calculated for C26H29NO5F3[M+H]+:492.19923,found:492.19879
EXAMPLE 45 preparation of 1254
1254 was prepared similarly to example 38, except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -3-fluorobenzene.
1254 physicochemical properties: yellow solid, 72.2%, 91-92 ℃;
1 H NMR(500MHz,DMSO)δ8.37(s,1H),7.43–7.34(m,1H),7.25(ddd,J＝12.7,10.2,8.6Hz,3H),7.17–7.09(m,2H),7.04(dt,J＝18.5,5.3Hz,2H),6.50(d,J＝15.8Hz,1H),5.11(s,2H),3.99(q,J＝7.2Hz,2H),3.79(s,3H),2.05(ddd,J＝14.0,10.3,5.7Hz,2H),1.92–1.76(m,2H),1.72–1.55(m,4H),1.08(t,J＝7.2Hz,3H).
13 C NMR(126MHz,DMSO)δ174.07,165.41,162.69(d,J＝243.6Hz),149.71,149.34,139.34,131.06,131.00,128.65,124.18,124.16,121.88,120.27,115.20(d,J＝21.0Hz).,114.93,114.75,113.89,110.54,69.48,65.59,60.71,55.98,36.87,24.43,14.61.
19 F NMR(471MHz,DMSO)δ-113.05.
HRMS(ESI):Calculated for C25H29NO5F[M+H]+:442.20243,found:442.20236
EXAMPLE 46 preparation of 1255
1255 is prepared similarly to example 38, except that o-methylbenzyl chloride in the first step is changed to 1- (chloromethyl) -3, 5-difluorobenzene.
1255 physicochemical properties: yellow solid, 88.7%, 145-146 deg.C;
1 H NMR(500MHz,DMSO)δ8.38(s,1H),7.28(d,J＝15.7Hz,1H),7.16–7.14(m,2H),7.13(d,J＝2.1Hz,1H),7.12(s,1H),7.05(dd,J＝8.4,1.9Hz,1H),6.99(dd,J＝8.4,5.3Hz,1H),6.46(dd,J＝40.4,15.8Hz,1H),5.13(d,J＝4.9Hz,2H),3.99(q,J＝7.1Hz,2H),3.79(s,3H),2.08–1.98(m,2H),1.86(dt,J＝11.4,5.2Hz,2H),1.66–1.60(m,4H),1.07(t,J＝7.1Hz,3H).
13 C NMR(126MHz,DMSO)δ221.10,174.08,165.41,162.97(d,J＝246.3Hz),162.86(d,J＝246.3Hz),151.69,149.74,149.07,139.30,129.41,128.89,125.08,121.84,121.29,110.98(dd,J＝19.7,6.0Hz),110.64,103.89(d,J＝23.7Hz),103.66(d,J＝19.5Hz),65.60,60.73,56.03,54.11,36.86,24.42,14.60.
19 F NMR(471MHz,DMSO)δ-109.49,-109.51.
HRMS (ESI):Calculated for C25H28NO5F2[M+H]+:460.19301,found:460.19247
example 47 preparation of 1256
1256 was prepared similarly to example 38, except that o-methylchlorobenzyl in the first step was changed to 2-chloro-1- (chloromethyl) -4-fluorobenzene.
1256 physicochemical properties: yellow solid, 99.6%, 110-;
1 H NMR(500MHz,DMSO)δ8.38(s,1H),7.61(dd,J＝6.3,2.4Hz,1H),7.53–7.45(m,2H),7.29(d,J＝15.7Hz,1H),7.26–7.21(m,1H),7.15(d,J＝1.3Hz,1H),7.09–7.04(m,1H),6.51(d,J＝15.7Hz,1H),5.10(d,J＝4.6Hz,2H),3.99(q,J＝7.2Hz,2H),3.77(s,3H),2.11–1.97(m,2H),1.86(dt,J＝11.4,5.3Hz,2H),1.73–1.52(m,4H),1.08(t,J＝7.1Hz,3H).
13 C NMR(126MHz,DMSO)δ174.07,168.41,165.41,162.29(d,J＝248.2Hz),151.69,149.69,139.33,132.49,129.41,121.86,121.29,120.34,117.44,117.24,115.17,115.00,113.89,110.65,67.44,65.60,60.73,55.98,36.87,24.43,14.61.
19 F NMR(471MHz,DMSO)δ-111.40.
HRMS (ESI):Calculated for C25H28NO5ClF[M+H]+:476.16346,found:476.16339
EXAMPLE 48 preparation of 1257
1257 was prepared similarly to example 38, except that o-methylchlorobenzyl in the first step was changed to (chloromethyl) benzene.
1257 physicochemical Properties: yellow solid, 99.6%, 120-;
1 H NMR(500MHz,DMSO)δ8.37(s,1H),7.48(dd,J＝8.4,4.4Hz,1H),7.43–7.38(m,3H),7.36(dd,J＝7.1,1.4Hz,2H),7.30(s,1H),7.14(d,J＝1.7Hz,1H),7.02(d,J＝4.9Hz,1H),6.49(d,J＝15.8Hz,1H),5.07(s,2H),3.99(q,J＝7.1Hz,2H),3.77(s,3H),2.14–1.98(m,2H),1.86(dt,J＝11.3,5.3Hz,2H),1.62(dd,J＝7.6,4.2Hz,4H),1.07(t,J＝7.1Hz,3H).
13 C NMR(126MHz,DMSO)δ174.09,168.44,165.45,151.70,150.21,149.74,149.68,149.62,144.65,139.41,137.35,128.98,128.40,123.02,121.29,117.35,113.75,110.45,70.27,65.59,60.73,55.93,36.87,24.43,14.61.
HRMS(ESI):Calculated for C25H30NO5[M+H]+:424.21185,found:424.21140
EXAMPLE 49 preparation of 1258
1258 was prepared similarly to example 38, except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -4- (trifluoromethyl) benzene.
1258 physicochemical properties: yellow solid, 99.7%, 136-;
1 H NMR(500MHz,DMSO)δ8.38(s,1H),7.49–7.47(m,1H),7.46(d,J＝1.4Hz,1H),7.30(dd,J＝17.1,8.8Hz,2H),7.16(d,J＝1.7Hz,1H),7.00(dd,J＝8.4,6.1Hz,2H),6.42(d,J＝16.0Hz,1H),5.21(s,2H),3.99(q,J＝7.1Hz,2H),3.79(s,3H),2.10–1.98(m,2H),1.86(dt,J＝11.3,5.2Hz,2H),1.62(dd,J＝7.4,4.1Hz,4H),1.07(t,J＝7.1Hz,3H).
13 C NMR(126MHz,DMSO)δ174.08,168.41,165.42,151.68,149.83,149.77,149.25,144.55,129.40,128.89(d,J＝31.5Hz),128.60,128.17,125.89(d,J＝4.1Hz),124.75(d,J＝273.6Hz),122.94,121.28,117.56,113.71,111.19,69.36,65.60,60.73,56.22,36.86,24.42,14.59.
19 F NMR(471MHz,DMSO)δ-60.85.
HRMS(ESI):Calculated for C26H29NO5F3[M+H]+:492.19923,found:492.19910
EXAMPLE 50 preparation of 1259
1259 was prepared similarly to example 38, except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -4-fluorobenzene.
1259 physicochemical properties: yellow solid, 99.9%, 115-;
1 H NMR(500MHz,DMSO)δ8.37(s,1H),7.46(dt,J＝7.8,3.5Hz,3H),7.28(d,J＝15.7Hz,1H),7.18(d,J＝1.4Hz,1H),7.14(d,J＝1.4Hz,1H),7.05–6.98(m,2H),6.50(d,J＝15.9Hz,1H),5.06(d,J＝5.5Hz,2H),3.99(q,J＝7.0Hz,2H),3.76(d,J＝0.8Hz,3H),2.04(dt,J＝13.1,8.6Hz,2H),1.86(dt,J＝11.3,5.2Hz,2H),1.70–1.59(m,4H),1.07(t,J＝7.1Hz,3H).
13 C NMR(126MHz,DMSO)δ174.08,168.43,165.44,162.34(d,J＝243.7Hz),151.69,149.49,144.62,139.39,130.62,129.41,128.50,122.99,121.29,120.16,117.40,115.80(d,J＝21.3Hz),113.82,110.47,69.57,65.60,60.73,55.93,36.87,24.43,14.60.
19 F NMR(471MHz,DMSO)δ-114.20.
HRMS(ESI):Calculated for C25H29NO5F[M+H]+:442.20243,found:442.20221
preparation of example 51:1260
The first step is as follows:
mixing ferulic acid methyl ester (1.0mmol) and potassium carbonate K2CO3(1.2mmol) and potassium iodide KI (0.5mmol) are added into a 50mL single-neck bottle, 8mL of DMF is added into the bottle, activation is carried out for 3-4 h at normal temperature, then o-methylbenzyl chloride (1.2mmol) is added into the mixture, after the reaction is finished, the reaction liquid is poured into water and stirred until a large amount of solid is separated out, and the intermediate 1 is obtained by suction filtration.
The second step is that:
adding the intermediate 1(1.0mol) and 7mL of methanol, heating and stirring, adding a sodium hydroxide solution (5.0mol) into the reaction solution, removing the solution after the reaction is finished, pouring the solution into water, adjusting acid by using 4M hydrochloric acid until solid is separated out, and filtering to obtain an intermediate 2.
The third step:
adding the intermediate 2(1.0mol) and HATU (2.0mol) into a 25mL single-neck bottle, adding 9mL acetonitrile, stirring at normal temperature, adding DIPEA (1.2mol) into the reaction bottle, adding 1-aminocyclopentane-1-carboxylic acid ethyl ester (1.0mol), after the reaction is finished, pouring the reaction into water, stirring until a large amount of solids are separated out, and carrying out suction filtration to obtain an intermediate 3.
The fourth step:
adding the intermediate 3(1.0mol) and 7mL of methanol, starting heating and stirring, adding a sodium hydroxide solution (5.0mol) into the reaction solution, removing the solution after the reaction is finished, pouring the solution into water, adjusting acid by using 4M hydrochloric acid until solid is separated out, and carrying out suction filtration to obtain the final target product.
1260 physical and chemical properties: white solid, 77.5%, 164-;
1 H NMR(500MHz,DMSO)δ8.20(s,1H),7.76(d,J＝7.9Hz,1H),7.73–7.69(m,2H),7.56(d,J＝7.7Hz,1H),7.26(d,J＝15.7Hz,1H),7.17(d,J＝1.8Hz,1H),7.05(dd,J＝8.4,1.8Hz,1H),7.00(d,J＝8.4Hz,1H),6.55(d,J＝15.7Hz,1H),5.20(s,2H),3.77(s,3H),2.05–1.99(m,2H),1.92–1.86(m,2H),1.64(d,J＝4.8Hz,4H).
13 C NMR(126MHz,DMSO)δ165.17,149.78,149.13,138.85,135.36,133.41,130.88,129.28,129.15,127.41,127.17,126.60,126.55,121.77,121.23,113.93,110.73,67.14,65.71,56.03,36.92,24.96.
HRMS(ESI):Calculated for C24H31N2O5[M+NH4]+:427.22275,found:427.22134
example 52 preparation of 1261
1261 is prepared analogously to example 51, except that o-methylbenzyl chloride in the first step is replaced by 1- (chloromethyl) -3-toluene.
1261 physicochemical Properties: white solid, 99.0%, 188-;
1 H NMR(400MHz,DMSO)δ12.17(s,1H),8.28(s,1H),7.41(d,J＝7.2Hz,1H),7.32(d,J＝15.7Hz,1H),7.26–7.22(m,3H),7.18(s,1H),7.12(d,J＝1.7Hz,2H),6.58–6.53(m,1H),5.10(s,2H),3.81(s,3H),2.33(s,3H),2.11–2.04(m,2H),1.95–1.90(m,2H),1.67(s,4H).
13 C NMR(101MHz,DMSO)δ175.84,165.34,149.69,149.62,139.14,137.24,135.25,130.59,129.16,128.64,128.47,126.25,121.78,120.48,113.71,110.38,68.98,65.46,55.89,36.85,24.54,18.90.
HRMS(ESI):Calculated for C24H27NO5Na[M+Na]+:432.17814,found:432.17664
EXAMPLE 53 preparation of 1262
1262 is prepared analogously to example 51, except that o-methylbenzyl chloride in the first step is replaced by 4- (bromomethyl) -1-fluoro-2- (trifluoromethyl) benzene and ethyl 1-aminocyclopentane-1-carboxylate in the third step is replaced by methyl 1-aminocyclopentane-1-carboxylate.
1262 physicochemical Properties: white solid, 78.1%, 83-84 deg.C;
1 H NMR(400MHz,DMSO)δ12.18(s,1H),8.28(s,1H),7.89(d,J＝7.0Hz,1H),7.86–7.80(m,1H),7.57(dd,J＝10.5,8.9Hz,1H),7.32(d,J＝15.7Hz,1H),7.20(s,1H),7.10(s,2H),6.57(d,J＝15.8Hz,1H),5.20(s,2H),3.82(s,3H),2.12–2.03(m,2H),1.95–1.89(m,2H),1.68(s,4H).
13 C NMR(101MHz,DMSO)δ175.93,165.26,158.91(d,J＝251.4Hz),149.69,149.10,138.98,134.67(q,J＝3.7Hz),128.94,127.06(q,J＝4.1Hz),123.06(q,J＝272.1Hz),120.83,117.98,117.77,116.92(q,J＝32.3Hz).,114.08,110.52,68.90,65.49,55.92,36.84,24.59.
19 F NMR(376MHz,DMSO)δ-60.04(s),-117.18(s).
HRMS(ESI):Calculated for C24H24NO5F4[M+H]+:482.15851,found:482.15707
EXAMPLE 54 preparation of 1263
1263 is prepared analogously to example 51, except that o-methylbenzyl chloride in the first step is replaced by 1- (bromomethyl) -3-chloro-2-fluorobenzene and ethyl 1-aminocyclopentane-1-carboxylate in the third step is replaced by methyl 1-aminocyclopentane-1-carboxylate.
1263 physical and chemical properties of white solid, 93.0%, 81-82 deg.C;
1 H NMR(400MHz,DMSO)δ12.22(s,1H),8.29(s,1H),7.64–7.59(m,1H),7.56–7.50(m,1H),7.34–7.27(m,2H),7.19(s,1H),7.12(s,2H),6.57(d,J＝15.8Hz,1H),5.20(s,2H),3.81(s,3H),2.09(dt,J＝12.7,7.8Hz,2H),1.98–1.89(m,2H),1.68(s,4H).
13 C NMR(101MHz,DMSO)δ175.94,165.26,156.00(d,J＝248.9Hz),149.64,149.05,138.97,131.11,129.96,129.93,129.01,126.32,126.18,126.02,120.85,120.18(d,J＝17.2Hz),113.96,110.56,65.49,64.56,64.53,55.90,36.84,24.60.
19 F NMR(376MHz,DMSO)δ-120.62.
HRMS(ESI):Calculated for C23H24NO5ClF[M+H]+:448.13216,found:448.13251
example 55 preparation of 1264
1264 is prepared similarly to example 51, except that o-methylbenzyl chloride in the first step is changed to 1- (bromomethyl) -2-chloro-4-fluorobenzene.
1264 physicochemical Properties: white solid, 93.4%, 93-94 ℃;
1 H NMR(500MHz,DMSO)δ12.15(s,1H),8.25(s,1H),7.64–7.58(m,1H),7.51–7.47(m,1H),7.28(dd,J＝23.7,8.0Hz,2H),7.15(d,J＝8.2Hz,1H),7.06(d,J＝4.9Hz,2H),6.47(dd,J＝47.6,15.8Hz,1H),5.10(d,J＝5.1Hz,2H),3.77(d,J＝1.2Hz,3H),2.04(dd,J＝12.6,7.9Hz,2H),1.92–1.81(m,2H),1.63(t,J＝6.8Hz,4H).
13 C NMR(126MHz,DMSO)δ175.82,168.39,165.38,162.29(d,J＝248.1Hz),149.71,149.26,144.54,139.12,132.54,128.96,121.77,120.75,117.33(d,J＝25.1Hz),117.33(d,J＝25.1Hz),113.93,113.70,111.24,110.67,67.46,65.52,55.99,36.90,24.56.
19 F NMR(471MHz,DMSO)δ-111.40.
HRMS(ESI):Calculated for C23H24NO5ClF[M+H]+:448.13216,found:448.13193
EXAMPLE 56 preparation of 1265
1265 was prepared similarly to example 51, except that o-methylbenzyl chloride in the first step was changed to 1- (chloromethyl) -4- (trifluoromethoxy) benzene.
1265 physicochemical Properties: yellow solid, 93.3%, 96-98 ℃;
1 H NMR(400MHz,DMSO)δ8.29(s,1H),7.59(d,J＝8.7Hz,2H),7.41(d,J＝8.4Hz,3H),7.32(d,J＝15.7Hz,1H),7.19(s,1H),7.12–7.05(m,1H),6.56(d,J＝15.8Hz,1H),5.17(d,J＝5.0Hz,2H),3.82(s,3H),2.09(dd,J＝8.2,5.0Hz,2H),1.92(d,J＝12.9Hz,2H),1.68(d,J＝6.5Hz,4H).
13 C NMR(101MHz,DMSO)δ175.81,165.33,149.64,149.30,148.37,148.36,139.08,136.89,130.18,128.68,121.73,121.57,120.61,113.81,113.59,111.08,110.47,69.35,65.47,55.90,36.84,24.52.
19 F NMR(376MHz,DMSO)δ-56.81.
HRMS(ESI):Calculated for C24H25NO6F3[M+H]+:480.16285,found:480.16226
example 57 preparation of 1266
1266 preparation was carried out analogously to example 51, except that o-methylbenzyl chloride in the first step was changed to 1- (chloromethyl) -3-fluorobenzene.
1266 physicochemical Properties: white solid, 87.8%, 177- > 178 ℃;
1 H NMR(500MHz,DMSO)δ8.24(s,1H),7.40(d,J＝6.2Hz,1H),7.23(dd,J＝
10.8,4.2Hz,3H),7.14(d,J＝1.6Hz,1H),7.12(dd,J＝8.2,2.2Hz,1H),7.05–7.00(m,2H),6.51(d,J＝15.7Hz,1H),5.11(s,2H),3.78(s,3H),2.11–2.00(m,2H),1.88(dd,J＝8.3,4.6Hz,2H),1.62(d,J＝7.2Hz,4H).
13 C NMR(126MHz,DMSO)δ175.93,165.37,162.69(d,J＝243.4Hz),149.72,149.30,140.40,140.34,139.11,131.06,131.00,128.77,124.15,121.79,120.72,115.19(d,J＝20.8Hz),114.92,114.84(d,J＝21.7Hz).,110.56,69.50,65.54,56.00,36.90,24.61.
19 F NMR(471MHz,DMSO)δ-113.06.
HRMS(ESI):Calculated for C23H25NO5F[M+H]+:414.17113,found:141.17053
EXAMPLE 58 preparation of 1267
1267 was prepared similarly to example 51 except that o-methylbenzyl chloride in the first step was changed to 1- (bromomethyl) -2-chlorobenzene.
1267 physicochemical Properties: white solid, 96.3%, 91-93 ℃;
1 H NMR(500MHz,DMSO)δ8.25(s,1H),7.57–7.52(m,1H),7.50–7.46(m,1H),7.36(dd,J＝5.6,3.3Hz,2H),7.28(d,J＝15.7Hz,1H),7.15(d,J＝1.2Hz,1H),7.07–7.03(m,2H),6.52(d,J＝15.8Hz,1H),5.13(d,J＝5.3Hz,2H),3.78(s,3H),2.05(dd,J＝8.3,4.9Hz,2H),1.91–1.81(m,2H),1.63(dd,J＝8.3,5.0Hz,4H).
13 C NMR(126MHz,DMSO)δ175.86,165.38,149.70,149.34,139.12,134.70,133.18,130.76,130.50,129.92,128.89,127.94,123.00,121.79,120.74,113.84,110.67,67.95,65.53,56.22,56.00,36.91,24.59.
HRMS(ESI):Calculated for C23H25NO5Cl[M+H]+:430.14158,found:430.14117
example 59 preparation of 1268
1268 is prepared analogously to example 51, except that o-methylbenzyl chloride in the first step is replaced by 4- (chloromethyl) -1, 2-difluorobenzene.
1268 physicochemical Properties: white solid, 89.5%, 86-187 ℃;
1 H NMR(400MHz,DMSO)δ8.30(s,1H),7.53(dd,J＝6.5,4.5Hz,1H),7.47(dd,J＝8.5,2.3Hz,1H),7.32(d,J＝15.7Hz,2H),7.19(d,J＝1.4Hz,1H),7.13–6.98(m,2H),6.56(d,J＝15.8Hz,1H),5.12(d,J＝4.6Hz,2H),3.83(s,3H),2.09(d,J＝13.4Hz,2H),1.96–1.81(m,2H),1.67(t,J＝6.9Hz,4H).
13 C NMR(101MHz,DMSO)δ175.77,168.34,165.34,149.51(dd,J＝245.5,12.3Hz),149.78(dd,J＝245.5,12.6Hz),149.66,149.15,144.49,139.07,128.79,125.16,121.70,120.66,118.03(d,J＝17.1Hz),117.35(d,J＝17.4Hz),113.95,110.51,69.03,65.46,55.92,36.84,24.50.
19 F NMR(376MHz,DMSO)δ-138.57,-139.77.
HRMS (ESI):Calculated for C23H24NO5F2[M+H]+:432.16171,found:432.16129
example 60 preparation of 1269
1269 is prepared analogously to example 51, except that o-methylchlorobenzyl in the first step is replaced by 2-chloro-1- (chloromethyl) -4-fluorobenzene.
1269 physicochemical Properties: yellow solid, 85.0%, 191-192 ℃;
1 H NMR(500MHz,DMSO)δ8.24(s,1H),7.27(d,J＝15.8Hz,1H),7.16(dd,J＝4.8,1.9Hz,2H),7.13(s,1H),7.12(s,1H),7.05(dd,J＝8.4,1.6Hz,1H),7.01–6.98(m,1H),6.52(d,J＝15.8Hz,1H),5.12(d,J＝5.9Hz,2H),3.79(s,3H),2.04(dt,J＝12.9,7.9Hz,2H),1.88(dd,J＝12.7,6.0Hz,2H),1.62(t,J＝6.8Hz,4H).
13 C NMR(126MHz,DMSO)δ175.86,165.36,162.97(d,J＝246.4Hz),149.75,149.04,139.08,129.01,121.75,120.82,114.09,111.08,110.98(d,J＝14.0Hz),110.88,110.65,103.77,69.03,65.53,56.04,36.90,24.58.
19 FNMR(471MHz,DMSO)δ-109.49.
HRMS(ESI):Calculated for C23H24NO5FCl[M+H]+:448.13216,found:448.13156
preparation of example 61:1270
1270 was prepared similarly to example 51, except that o-methylchlorobenzyl in the first step was changed to (chloromethyl) benzene.
1270 physical and chemical properties: white solid, 77.6%, 170-;
1 H NMR(500MHz,DMSO)δ8.25(s,1H),7.60(d,J＝6.2Hz,1H),7.49(dd,J＝12.1,3.2Hz,2H),7.32–7.29(m,1H),7.27–7.22(m,2H),7.14(s,1H),7.06(s,2H),6.52(d,J＝15.8Hz,1H),5.10(d,J＝5.1Hz,2H),3.77(s,3H),2.04(dd,J＝8.2,4.9Hz,2H),1.91–1.84(m,2H),1.63(t,J＝6.8Hz,4H).
13 C NMR(126MHz,DMSO)δ175.85,165.37,163.28,161.31,149.71,149.26,139.11,132.55,128.96,122.98,121.77,120.77,117.43,117.23,115.17,115.00,113.94,110.67,67.46,65.52,55.99,36.90,24.58.
HRMS(ESI):Calculated for C23H26NO5[M+H]+:396.18055,found:396.18018
example 62 preparation of 1271
1271 was prepared similarly to example 51, except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -4- (trifluoromethyl) benzene.
1271 physical and chemical properties: yellow solid, 89.4%, 163-164 ℃;
1 H NMR(500MHz,DMSO)δ8.25(s,1H),7.61(s,2H),7.48(d,J＝15.9Hz,1H),7.32(d,J＝1.9Hz,1H),7.27(d,J＝15.8Hz,1H),7.14(dd,J＝5.9,1.8Hz,2H),7.01(d,J＝6.0Hz,1H),6.42(d,J＝16.0Hz,1H),5.20(s,2H),3.79(s,3H),2.04(dt,J＝12.8,7.9Hz,2H),1.91–1.82(m,2H),1.62(t,J＝7.0Hz,4H).
13 C NMR(126MHz,DMSO)δ175.82,168.39,165.39,149.84,149.79,149.72,149.21,144.54,142.26,139.12,128.93(d,J＝20.6Hz),128.60,128.18,125.89(q,J＝3.5Hz),121.83(q,J＝279.3Hz),121.76,117.57,113.74,111.23,69.38,65.51,56.24,36.90,24.56.
19 F NMR(471MHz,DMSO)δ-60.84.
HRMS(ESI):Calculated for C24H25NO5F3[M+H]+:464.16793,found:464.16739
example 63 preparation of 1272
1272 was prepared similarly to example 51 except that the o-methylbenzyl chloride in the first step was changed to 2- (bromomethyl) -1, 4-difluorobenzene.
1272 physicochemical properties: white solid, 79.7%, 166-;
1 H NMR(500MHz,DMSO)δ8.24(s,1H),7.48(d,J＝15.9Hz,1H),7.31(d,J＝1.5Hz,2H),7.15(d,J＝3.2Hz,2H),7.07(s,2H),6.43(d,J＝15.9Hz,1H),5.10(s,2H),3.77(s,3H),2.04(d,J＝12.3Hz,2H),1.88(d,J＝12.4Hz,2H),1.63(s,4H).
13 C NMR(126MHz,DMSO)δ176.01,168.56,165.33,158.57(d,J＝240.5Hz),156.93(d,J＝242.5Hz),149.79,149.10,144.29,139.04,129.09,122.89,121.75,120.92,117.57(d,J＝15.8Hz),117.43,117.19,113.81,111.22,65.56,64.26,56.20,36.91,24.65.
19 F NMR(471MHz,DMSO)δ-118.37,-123.48.
HRMS(ESI):Calculated for C2H24NO5F2[M+H]+:432.16171,found:432.16122
example 64 preparation of 1273
1273 was prepared similarly to example 51, except that o-methylchlorobenzyl in the first step was changed to 1-bromo-3- (chloromethyl) benzene.
1273, the physicochemical properties are: white solid, 94.5%, 105-;
1 H NMR(400MHz,DMSO)δ12.22(s,1H),8.31(s,1H),7.66(s,1H),7.56–7.52(m,2H),7.45(dd,J＝10.8,4.1Hz,2H),7.32(d,J＝15.7Hz,1H),7.19(d,J＝1.6Hz,1H),7.06(d,J＝4.1Hz,1H),6.56(d,J＝15.8Hz,1H),5.14(d,J＝5.1Hz,2H),3.83(d,J＝1.4Hz,3H),2.09(dt,J＝13.0,8.0Hz,2H),1.93(dd,J＝12.6,6.1Hz,2H),1.67(t,J＝6.9Hz,4H).
13 C NMR(101MHz,DMSO)δ175.78,168.36,165.32,149.68,149.20,144.52,140.19,139.06,131.17,130.82,128.70,127.20,122.92,122.15,120.62,117.46,113.83,110.44,69.31,65.44,55.90,36.83,24.50.
HRMS(ESI):Calculated for C23H25NO5Br[M+H]+:474.09106,found:474.09048
example 65 preparation of 1274
1274 was prepared similarly to example 51, except that o-methylchlorobenzyl in the first step was changed to 1- (chloromethyl) -4-fluorobenzene.
1274 physicochemical properties: white solid, 85.2%, 169- & ltSUB & gt 170- & gt;
1 H NMR(400MHz,DMSO)δ12.22(s,1H),8.31(s,1H),7.51–7.46(m,2H),7.32(d,J＝15.7Hz,1H),7.26(s,1H),7.24(s,1H),7.18(d,J＝5.0Hz,1H),7.08(s,1H),6.56(d,J＝15.8Hz,1H),5.11(d,J＝4.9Hz,2H),3.81(d,J＝1.3Hz,3H),2.09(dt,J＝12.9,7.9Hz,2H),1.93(dd,J＝12.5,6.1Hz,2H),1.67(t,J＝6.8Hz,4H).
13 C NMR(101MHz,DMSO)δ175.77,168.36,165.32,162.27(d,J＝243.7Hz),150.01,149.59,149.37,139.09,133.56,130.64,130.56,128.52,127.87,122.94,121.73,115.73(d,J＝21.4Hz),113.63(d,J＝22.1Hz),110.36,69.52,65.43,55.85,36.83,24.50.
19 F NMR(376MHz,DMSO)δ-114.30.
HRMS(ESI):Calculated for C23H25NO5F[M+H]+:414.17113,found:414.17059
example 66: test for antibacterial Activity of target Compound (anti-plant bacterium Activity test)
The resistance of the compounds to plant bacterial diseases was determined by nephelometry. The concentration of the primary screen was 100. mu.g/mL and 50. mu.g/mL, respectively.
(test method)
The target compounds were tested for the resistance to Xanthomonas citri (Xac) and Xanthomonas oryzae (Xoo) by the turbidity method
And the inhibition activity of rice streak germ (Xoc), the specific operation steps are as follows:
A. 1500mL of secondary water/ultrasonic water are added into a 5000mL beaker, and 15g of glucose, 7.5g of peptone, 1.5g of yeast powder and 4.5g of beef extract are added under stirring. After all the materials are dissolved, 5mol/L sodium hydroxide solution is used for adjusting the pH value to be 7.0-7.2.
B. Cleaning and sterilizing the test tubes, placing the test tubes on a test tube rack, using a pipette to pipette 4.0mL of the solution obtained in the first step (1) into each test tube, adding a rubber plug, packaging every 6 test tubes once, and sterilizing the test tubes at 121 ℃ for 20min by using a sterilizing pot for later use:
C. 0.00375-0.0042g of a compound sample to be detected is weighed and put in a centrifuge tube, after 150 mu L of LDMSO is dissolved, 80 mu L and 40 mu L of the compound sample are respectively transferred into the centrifuge tube which is numbered after sterilization, 40 mu L of LDMSO is additionally added into the centrifuge tube which is filled with 40 mu L of sample solution, 4mL of 1% Tween-20 is added into the centrifuge tube, meanwhile, thiediazole copper or bismerthiazol is used as a contrast agent, and DMSO is used as a blank contrast.
D. 1mL of the solution was removed from each tube to 3 tubes in (2) (run before alcohol lamp to prevent other bacterial contamination).
E. Taking a blank 96-well plate, measuring a blank OD value, excluding holes with OD values larger than 0.05, adding 200 mu L (4) of solution in each available hole to measure the OD value and record, finally, inoculating 40 mu L of activated citrus canker pathogen or tobacco ralstonia solanacearum or rice bacterial leaf blight strain into each test tube, wrapping the test tube with newspaper, carrying out shake culture in a constant temperature shaking table at 28 ℃ and 180rpm for 24-48 h, measuring the OD value of the solution in the test tube during the period to track the growth state of bacteria, and taking 200 mu L of solution in the test tube to measure the OD value and record after the culture is finished.
F. The calculation formula of the inhibition rate of the compound on bacteria is as follows,
corrected OD value-bacteria-containing medium OD value-sterile medium OD value
Inhibition (%) - (OD value of control medium bacterial liquid after correction-OD value of toxic medium after correction)/OD value of control medium bacterial liquid after correction × 100
Test results of biological activity against plant pathogens
TABLE 1 inhibition of 1210-1246 bacteria at the concentrations set for each of the three bacteriaa
Figure BDA0003070255000000411
Figure BDA0003070255000000421
TABLE 2 Compounds1247-1274 shows inhibition rate of three bacteria at set concentrationa
Figure BDA0003070255000000422
aThe average test was carried out three times,bthe inhibitory activity of commercial thiabendazole copper and bismerthiazol is used as a positive control.
The inhibition activity of the target compound against Sclerotinia citrea, Blakeslea oryzae and Microphyllum oryzae was tested at a test concentration of 100 μ Ag/mL by the turbidity method using commercial agents such as Thiobium and bismerthiazol as positive controls (see tables 1 and 2). The test results show that: the partial compounds have certain inhibition rates on the tested plant pathogenic bacteria, wherein when the concentration is 100 mu g/mL, the inhibition rates of the compounds 1210, 1212, 1214-1216, 1219-1220, 1222, 1226-1227, 1229, 1231-1236, 1238-1246, 1248, 1251, 1254-1257, 1259, 1262, 1264-1265, 1268-1271 and 1273 on the rice leaf blight bacteria (Xoo) exceed that of thielavia (65.8 percent) and leaf cumidine (67.8 percent); the inhibition rates of compounds 1210, 1212, 1214, 1219, 1226-1227, 1230, 1233, 1235, 1239, 1242-1245, 1259-1260, 1262 on citrus canker (Xac) are all higher than that of thielavia (51.2%) and that of bismerthiazol (56.4%); the inhibition rates of the compounds 1213, 1218-. When the concentration is 50 mu g/mL, the inhibition rates of the compounds 1210, 1212, 1214-1216, 1219-1220, 1222, 1223, 1226-1227, 1229, 1231-1236, 1238-1246, 1248, 1251, 1254-1257, 1259, 1261-1262, 1264-1265, 1267-1271 and 1273 on the blight bacteria (Xoo) of rice are all higher than that of the thionine (34.6%) and the bismerthiazol (47.3%); the inhibition rates of the compounds 1211, 1214-, 1215, 1219, 1228, 1230, 1233, 1235, 1239-, 1240, 1242, 1244, 1262 and 1271 on citrus canker bacteria (Xac) are all higher than that of thiencone (22.0%) and bismerthiazol (44.8%); the inhibition rates of compounds 1212-, 1214, 1216, 1218-, 1220, 1225-, 1226, 1230-, 1232, 1234-, 1236, 1238-, 1239, 1242-, 1248-, 1260-, 1262, 1264-, 1267, 1269 and 1271-, 1274-on Scutellaria laterosporus (Xoc) are all higher than that of Thiobacillus copper (32.0%) and metconazole (39.8%)
The experimental activity data show that the ferulic acid amide derivative has a certain inhibition effect on plant pathogenic bacteria (citrus canker pathogenic bacteria, rice bacterial leaf blight pathogenic bacteria and rice bacterial leaf streak pathogenic bacteria), wherein part of target compounds have excellent inhibition activity on the plant pathogenic bacteria, can be used as a potential plant pathogenic bacteria inhibiting drug, and has a good application prospect.
In summary, the present invention is only a preferred embodiment, and is not limited in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention are within the scope of the technical solution of the present invention without departing from the technical solution of the present invention.

Claims (2)

1. A ferulic acid amide derivative, which is characterized in that: the structural general formula is shown as I:
Figure FDA0003654347140000011
in the compounds of the formula I, R1Is alkyl halohydrocarbon or substituted phenyl of C2-C5, and the substituent of the substituted phenyl is H, halogen, CF3、OCH3Or OCF3(ii) a R is H, methyl or ethyl; n is 3 or 4.
2. The use of the amide ferulate derivatives as claimed in claim 1 in the preparation of antibacterial agents for controlling bacterial blight, citrus canker and bacterial leaf streak of rice.
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