CN110357832B - Preparation method of aromatic amine compound, EphB4 kinase inhibitor and derivatives thereof - Google Patents

Preparation method of aromatic amine compound, EphB4 kinase inhibitor and derivatives thereof Download PDF

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CN110357832B
CN110357832B CN201910610239.3A CN201910610239A CN110357832B CN 110357832 B CN110357832 B CN 110357832B CN 201910610239 A CN201910610239 A CN 201910610239A CN 110357832 B CN110357832 B CN 110357832B
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CN110357832A (en
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周强辉
陈树清
王鹏
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Wuhan University WHU
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Abstract

The invention provides a preparation method of an aromatic amine compound, an EphB4 kinase inhibitor and derivatives thereof. The aromatic amine compound is prepared by taking aryl boric acid or aryl boric acid ester and an O-benzoyl-hydroxylamine compound as initial raw materials, stirring and reacting in an organic solvent at 30-100 ℃ in an air atmosphere under the action of a palladium catalyst, a norbornene derivative and alkali, and separating and purifying after reaction. The raw materials used by the method are cheap and easy to obtain, the reaction is finished without halogen ion residue, and the reaction condition is mild. Meanwhile, the invention also provides a method for synthesizing the EphB4 kinase inhibitor and the derivative thereof, and the EphB4 kinase inhibitor and the derivative thereof can be synthesized by only one simple step on the basis of the 3,5 site double aminated halogenated benzene or halogenated benzene-like synthesized by the invention.

Description

Preparation method of aromatic amine compound, EphB4 kinase inhibitor and derivatives thereof
Technical Field
The invention relates to a synthetic method of an aromatic amine compound, an EphB4 kinase inhibitor and derivatives thereof, belonging to the field of organic synthesis and pharmaceutical chemistry.
Background
Aromatic amine compounds are widely found in natural products and medicinal agents having biological activity, for example, the commonly used antipsychotic drug aripiprazole, anti-type II diabetes repaglinide, antibacterial drug linezolid and kinase inhibitor EphB4 which are already on the market all contain aromatic amine skeleton structure. At present, the method for constructing and synthesizing the arylamine compound through C-N construction mainly comprises the following steps: (1) constructing a C-N bond catalyzed by copper; (2) constructing a C-N bond catalyzed by palladium; (3) constructing a C-N bond catalyzed by nickel; (4) constructing a C-N bond catalyzed by cobalt; (5) the method can only obtain arylamine products of in-situ amination with specific positions, and can not realize direct amination of C-H bonds of other inert sites of the aromatic ring.
3, 5-di (1-morpholine) aniline is used as a core fragment of an EphB4 kinase inhibitor, and the synthesis of the intermediate can be completed by 3 steps mainly by using expensive halogenated nitrobenzene as a starting material in the existing report method, so that the synthetic route is long and the cost is high.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a method for synthesizing aromatic amine derivatives from aryl boric acid or boric acid ester ortho-position C-H bond amine, which realizes ortho-position amination in-situ protonation of aryl boric acid or boric acid ester, has easily obtained raw materials, does not have the halogen residue problem, is simple and convenient to operate, does not need to add extra proton sources and phosphine ligands, has mild reaction conditions and is insensitive to water and oxygen. Based on the method for synthesizing the ortho-aminated arylamine compound, the invention discloses a method for efficiently synthesizing the EphB4 kinase inhibitor, which only needs three steps, and the 4-halogen substituted aryl boric acid or aryl boric acid ester as the initial raw material is cheap and easy to obtain, thereby greatly reducing the synthesis steps and the cost and improving the synthesis efficiency.
The technical scheme provided by the invention is as follows:
a method for synthesizing aromatic amine compounds, comprising the steps of: in the air atmosphere, using aryl boric acid or aryl boric acid ester A as an initial raw material, using O-formyl-hydroxylamine compound B as an amination reagent, using a palladium catalyst and a norbornene derivative as a synergistic catalyst, using alkali as an accelerator, placing the above materials in an organic solvent at 30-100 ℃, stirring for reaction, separating and purifying after the reaction is finished, and obtaining a mono-substituted aromatic amine compound C or a di-substituted aromatic amine compound D, wherein the reaction formula is as follows:
Figure BDA0002122118570000011
wherein:
R1is one of hydrogen, aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, silicon group, amino, cyano, nitro, amido, sulfonyl, alkoxy and halogen;
R2the substituent group is one or more of aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, silicon base, amino, cyano, nitro, amido, sulfonyl, alkoxy and halogen; n represents R2N is more than or equal to 0 and less than or equal to 3;
R3is hydrogen, C1-20Alkyl, aryl, heterocyclic aryl;
R4is hydrogen, aryl, heterocyclic aryl, C1-20An alkyl group;
R5、R6is heterocyclic alkane, heteroaromatic ring or substituent on nitrogen which forms a ring with nitrogen, and the substituent is hydrogen, aryl, heterocyclic aryl, C1-20One of alkyl, ester group, amido, sulfonyl, alkoxy, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, alkanoyl, sulfonyl, phthaloyl and azide;
x, Y, Z is N or CH.
Preferably, the norbornene derivative has the following structure:
Figure BDA0002122118570000021
wherein:
R7is a substituent on a five-membered ring, o represents the number of the substituent, and o is more than or equal to 0 and less than or equal to 8;
R8is a substituent on a double bond, p represents the number of the substituent, and p is more than or equal to 0 and less than or equal to 2;
R7、R8independently selected from the group consisting of carboxylate, ester, cyano, nitro, amido, sulfonyl, C of a metal ion M1-10Alkoxy, aryl, heterocyclic aryl, C1-10One of alkyl and halogen, wherein M is Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+One of (1); when o is greater than or equal to 2, each R7The same or different; when p is 2, each R8Are identical to each otherOr may be different.
Preferably, the process of the invention preferably uses a palladium catalyst to promote the reaction, which palladium catalyst that may be used includes zero or divalent palladium salts, such as: pd (PPh)3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(O2CCF3)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2And the like. Commercial reagents can be used without special treatment.
The method of the present invention preferably uses a base to promote the reaction, and sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tripotassium phosphate, potassium formate, sodium hydroxide, sodium tert-butoxide, etc. can be used. Commercial reagents can be used without special treatment.
Preferably, the organic solvent is methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylene glycol, methyl tert-butyl ether, 1, 4-epoxyhexaalkane, 1, 3-epoxyhexaalkane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, C4-12Saturated alkane of (C)3-12Fluoro or chloro alkane, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C3-12One or more of saturated alkyl nitrile and dimethyl sulfoxide.
Preferably, the synergistic catalyst is a palladium catalyst and norbornene, and the palladium catalyst is Pd (OAc)2The alkali is potassium carbonate, and the organic solvent is 1, 4-dioxane and dimethyl sulfoxide.
According to the method, the feeding molar ratio of two reactants is arylboronic acid or arylboronic acid ester, namely O-formyl-hydroxylamine compound (1-10): 1, and preferably 1.5: 1.
The method has the reaction time within 48 hours and the reaction temperature of 30-100 ℃. The heating process may use an oil bath (e.g., silicone oil, paraffin oil, etc.) or other heating means.
The invention preferably carries out post-treatment, including suction filtration, concentration and purification, on the reaction product after the reaction is finished.
The suction filtration process can be carried out using a sand core funnel under reduced pressure.
The concentration process can adopt methods such as atmospheric distillation, reduced pressure distillation and the like, for example, reduced pressure concentration by a rotary evaporator.
The purification process is to obtain a pure product by column chromatography.
The invention also provides an ortho-aminated aromatic amine compound prepared by the method.
The invention also provides a method for preparing the EphB4 kinase inhibitor and the derivative thereof, which comprises the following steps: reacting 4-halogen substituted phenylboronic acid or phenylboronic acid ester E with an O-formyl-hydroxylamine compound B in an organic solvent under the action of a palladium catalyst, alkali and a norbornene derivative in an air atmosphere to obtain an intermediate F, separating and purifying the obtained intermediate, and carrying out copper-catalyzed Ullmann amination reaction on the intermediate F and an amine reagent G to obtain a compound EphB4 kinase inhibitor or a derivative H thereof, wherein the reaction formula is as follows:
Figure BDA0002122118570000031
wherein:
w is one of fluorine, chlorine, bromine, iodine and trifluoromethanesulfonate;
R5、R6is heterocyclic alkane, heteroaromatic ring or substituent on nitrogen which forms a ring with nitrogen, and the substituent is hydrogen, aryl, heterocyclic aryl, C1-20One of alkyl, ester group, amido, sulfonyl, alkoxy, tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, alkanoyl, sulfonyl, phthaloyl and azide;
R9is hydrogen, C1-20Alkyl, aryl, heterocyclic aryl;
R10、R11is heterocyclic alkane, heteroaromatic ring or substituent on nitrogen which forms a ring with nitrogen, and the substituent is hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester group, amido, sulfonyl, alkoxy, tert-butyloxycarbonyl, carbobenzoxy, benzyl, p-methoxybenzyl, alkanoyl, sulfonyl, phthaloyl and azide.
The methods and conditions of the Ullmann amination reaction are conventional in the art for such reactions.
The invention also provides an EphB4 kinase inhibitor and a derivative thereof, which are prepared by the method.
The method of the invention can efficiently prepare the aromatic amine compound, and compared with the prior art, the method of the invention has the following advantages:
1. the main raw material related by the invention is arylboronic acid or arylboronic acid ester, the raw material can be a commercialized reagent, special treatment is not needed, and the price is low and the variety is various;
2. the reaction involved in the method is simple and convenient to operate, is not sensitive to water and oxygen, and is an important improvement compared with the prior reaction which needs to be carried out under the protection of inert gas;
3. the reaction involved in the method of the invention does not need to add extra ligand and proton source, and compared with the prior reaction which uses phosphine ligand and equivalent alcohol as proton source, the reaction cost is greatly reduced;
4. the reaction related to the method has good tolerance and universality to functional groups, and the substituent can be alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, ester group, nitro, halogen atoms (F, Cl, Br, I) and the like.
5. The method can prepare a large amount of aromatic amine compounds (gram level), and lays a good foundation for industrial production.
6. The halogenated benzene (or halogenated benzene-like) with double amination at the 3, 5-position prepared by the method can be efficiently and quickly (only one step is needed) converted into the EphB4 kinase inhibitor and the derivative thereof.
Detailed Description
The present invention is further illustrated by the following examples, it being noted that the invention is not limited to the examples described below.
Example 1: preparation of Compound I-1
Figure BDA0002122118570000041
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), morpholine 4-benzoate (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (yellow solid, yield 84%).1H NMR(400MHz,CDCl3):δ7.76–7.70(m,3H),7.42(t,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),7.28–7.25(m,1H),7.13(s,1H),3.94–3.91(m,4H),3.28–3.26(m,4H)；13C NMR(100MHz,CDCl3) δ 149.2,134.6,129.0,128.8,127.6,126.9,126.5,123.7,119.1,110.2,67.1, 49.9; HRMS (ESI-TOF) theoretical calculation: c14H16NO+[M+H+]214.1226, found: 214.1228.
example 2: preparation of Compound I-2
Figure BDA0002122118570000042
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 4-methyl-1-naphthaleneboronic acid pinacol ester (80.4mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, and the filtrate was successively saturated with waterWashing with sodium chloride aqueous solution once, drying with organic solvent Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (colorless oily liquid, yield 68%).1H NMR(400MHz,CDCl3):δ7.90(d,J＝8.3Hz,1H),7.74(d,J＝8.1Hz,1H),7.45(t,J＝7.5Hz,1H),7.38(t,J＝7.5Hz,1H),7.14(s,1H),7.02(s,1H),3.94–3.92(m,4H),3.28–3.26(m,4H),2.69(s,3H)；13C NMR(100MHz,CDCl3) Delta 148.8,135.4,134.9,128.2,127.5,126.2,124.0,123.5,119.8,108.7,67.1,49.9, 19.8; HRMS (ESI-TOF) theoretical calculation: c15H18NO+[M+H+]228.1383, found: 228.1382.
example 3: preparation of Compound I-3
Figure BDA0002122118570000051
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 4-methoxy-1-naphthaleneboronic acid pinacol ester (85.2mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (brown oily liquid, yield 62%).1H NMR(400MHz,CDCl3):δ8.13(d,J＝8.3Hz,1H),7.67(d,J＝8.2Hz,1H),7.44(t,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),6.75(s,1H),6.60(s,1H),4.00(s,3H),3.94–3.92(m,4H),3.27–3.25(m,4H)；13C NMR(100MHz,CDCl3) Delta 156.3,149.8,135.3,127.1,126.6,123.1,121.9,121.7,103.2,98.0,67.1,55.5, 50.4; HRMS (ESI-TOF) theoretical calculation: c15H18NO2 +[M+H+]244.1332, found: 244.1334.
example 4: preparation of Compound I-4
Figure BDA0002122118570000052
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 4-bromo-1-naphthaleneboronic acid pinacol ester (99.6mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (yellow oily liquid, yield 68%).1H NMR(400MHz,CDCl3):δ8.08(d,J＝8.2Hz,1H),7.67(d,J＝7.5Hz,1H),7.58(d,J＝2.4Hz,1H),7.47–7.38(m,2H),7.07(d,J＝2.3Hz,1H),3.91–3.89(m,4H),3.26–3.23(m,4H)；13C NMR(100MHz,CDCl3) δ 149.2,135.4,127.30,127.28,127.27,126.9,124.9,123.7,122.9,110.2,66.9, 49.6; HRMS (ESI-TOF) theoretical calculation: c14H15BrNO+[M+H+]292.0332, found: 292.0332.
example 5: preparation of Compound I-5
Figure BDA0002122118570000061
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-pyreneboronic acid pinacol ester (98.4mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, and the filtrateWashing with water and saturated aqueous sodium chloride solution, drying with Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (yellow solid, yield 70%).1H NMR(400MHz,CDCl3):δ8.12(d,J＝7.6Hz,2H),8.03–8.01(m,2H),7.96–7.88(m,3H),7.72(s,2H),4.01–3.99(m,4H),3.47–3.45(m,4H)；13C NMR(100MHz,CDCl3) Delta 149.7,132.4,130.3,128.0,127.1,125.2,124.9,124.8,119.9,112.7,67.2, 50.1; HRMS (ESI-TOF) theoretical calculation: c20H18NO+[M+H+]288.1383, found: 288.1385.
example 6: preparation of Compound I-6
Figure BDA0002122118570000062
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-methylphenylboronic acid pinacol ester (65.4mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (colorless oily liquid, yield 70%).1H NMR(400MHz,CDCl3):δ7.20–7.16(m,1H),6.75–6.71(m,3H),3.88–3.85(m,4H),3.17–3.14(m,4H),2.34(s,3H)；13C NMR(100MHz,CDCl3) Delta 151.5,139.0,129.2,121.1,116.7,113.0,67.1,49.6, 21.9; HRMS (ESI-TOF) theoretical calculation: c11H16NO+[M+H+]178.1226, found: 178.1229.
example 7: preparation of Compound I-7
Figure BDA0002122118570000063
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-ethylphenylboronic acid pinacol ester (69.6mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (colorless oily liquid, yield 61%).1H NMR(400MHz,CDCl3):δ7.21(t,J＝7.8Hz,1H),6.78–6.75(m,3H),3.89–3.86(m,4H),3.18–3.16(m,4H),2.63(q,J＝7.6Hz,2H),1.25(t,J＝7.8Hz,3H)；13C NMR(100MHz,CDCl3) Delta 151.5,145.4,129.2,119.9,115.6,113.2,67.1,49.6,29.3, 15.8; HRMS (ESI-TOF) theoretical calculation: c12H18NO+[M+H+]192.1383, found: 192.1385.
example 8: preparation of Compound I-8
Figure BDA0002122118570000071
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-isopropylphenylboronic acid pinacol ester (69.6mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (colorless)Oily liquid, 44% yield).1H NMR(400MHz,CDCl3):δ7.22(t,J＝7.8Hz,1H),6.81–6.74(m,3H),3.89–3.86(m,4H),3.18–3.16(m,4H),2.87(hept,J＝6.9Hz,1H),1.26(s,3H),1.25(s,3H)；13C NMR(100MHz,CDCl3) Delta 151.5,150.1,129.2,118.5,114.4,113.3,67.1,49.7,34.6, 24.2; HRMS (ESI-TOF) theoretical calculation: c13H20NO+[M+H+]206.1539, found: 206.1543.
example 9: preparation of Compound I-9
Figure BDA0002122118570000072
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-trifluoromethylphenylboronic acid pinacol ester (81.6mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-1 (colorless oily liquid, yield 39%).1H NMR(400MHz,CDCl3):δ7.37(t,J＝8.2Hz,1H),7.12–7.05(m,3H),3.88–3.86(m,4H),3.21–3.19(m,4H)；13C NMR(100MHz,CDCl3):δ151.52,131.63(q,J＝31.8Hz),129.76,124.40(q,J＝272.4Hz),118.58,118.57,116.37(q,J＝3.9Hz),112.00(q,J＝3.9Hz),66.86,48.97；19F NMR(376MHz,CDCl3) Delta-62.7; HRMS (ESI-TOF) theoretical calculation: c11H13F3NO+[M+H+]232.0944, found: 232.0946.
example 10: preparation of Compound I-10
Figure BDA0002122118570000081
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-methoxyphenylboronic acid pinacol ester (70.2mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-10 (colorless oily liquid, yield 39%).1H NMR(400MHz,CDCl3):δ7.22–7.17(m,1H),6.55–6.52(m,1H),6.46–6.44(m,2H),3.87–3.84(m,4H),3.80(s,3H),3.17–3.14(m,4H)；13C NMR(100MHz,CDCl3) Delta 160.7,152.8,123.0,108.6,104.8,102.3,67.0,55.3, 49.4; HRMS (ESI-TOF) theoretical calculation: c11H16NO2 +[M+H+]194.1176, found: 194.1177.
example 11: preparation of Compound I-11
Figure BDA0002122118570000082
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), pinacol ester of 2-trifluoromethoxyphenylboronic acid (86.4mg,0.3mmol), morpholine 4-benzoate (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-11 (colorless oily liquid, productRate 38%).1H NMR(400MHz,CDCl3):δ7.28–7.24(m,1H),6.83–6.80(m,1H),6.73–6.71(m,2H),3.87–3.85(m,4H),3.18–3.16(m,4H)；13C NMR(100MHz,CDCl3):δ152.7,150.4,130.2,120.6(q,J＝255.2Hz),113.6,111.8,108.2,66.8,48.9；19F NMR(376MHz,CDCl3) Delta-57.47; HRMS (ESI-TOF) theoretical calculation: c11H13F3NO2 +[M+H+]248.0893, found: 248.0895.
example 12: preparation of Compound I-12
Figure BDA0002122118570000091
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), methyl 2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (78.6mg,0.3mmol), morpholinyl 4-benzoate (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-12 (yellow oily liquid, yield 75%).1H NMR(400MHz,CDCl3):δ7.57(s,1H),7.53(d,J＝7.7Hz,1H),7.32(t,J＝7.9Hz,1H),7.10–7.07(m,1H),3.89(s,3H),3.87–3.85(m,4H),3.20–3.18(m,4H)；13C NMR(100MHz,CDCl3) δ 167.4,151.3,131.1,129.3,121.1,120.1,116.4,66.9,52.2, 49.2; HRMS (ESI-TOF) theoretical calculation: c12H16NO3 +[M+H+]222.1125, found: 222.1125.
example 13: preparation of Compound I-13
Figure BDA0002122118570000092
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-nitrophenylboronic acid pinacol ester (74.7mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-13 (yellow solid, yield 77%).1H NMR(400MHz,CDCl3):δ7.73–7.66(m,2H),7.40(t,J＝8.1Hz,1H),7.18(dd,J＝8.3,2.5Hz,1H),3.89–3.87(m,4H),3.26–3.24(m,4H)；13C NMR(100MHz,CDCl3) δ 152.0,149.4,129.9,121.0,114.3,109.6,66.7, 48.6; HRMS (ESI-TOF) theoretical calculation: c10H12N2NaO3 +[M+Na+]231.0740, found: 231.0737.
example 14: preparation of Compound I-14
Figure BDA0002122118570000101
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-methyl-3-fluorophenylboronic acid pinacol ester (70.8mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-14 (yellow solid, yield 77%)。1H NMR(400MHz,CDCl3):δ6.91(t,J＝9.0Hz,1H),6.74–6.67(m,2H),3.86–3.84(m,4H),3.08–3.05(m,4H),2.25(s,3H)；13C NMR(100MHz,CDCl3):δ156.1(d,J＝236.6Hz),147.7(d,J＝2.6Hz),125.2(d,J＝17.8Hz),119.3(d,J＝4.6Hz),115.3(d,J＝22.9Hz),114.9(d,J＝7.5Hz),67.1,50.5,15.1(d,J＝3.3Hz)；19F NMR(376MHz,CDCl3) Delta-128.3; HRMS (ESI-TOF) theoretical calculation: c11H15FNO+[M+H+]196.1132, found: 196.1133.
example 15: preparation of Compound I-15
Figure BDA0002122118570000102
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-methyl-3-fluorophenylboronic acid pinacol ester (70.8mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-15 (yellow oily liquid, yield 56%).1H NMR(400MHz,CDCl3):δ6.49(s,1H),6.41(s,1H),6.39(s,1H),3.85–3.83(m,4H),3.15–3.13(m,4H),2.30(s,3H)；13C NMR(100MHz,CDCl3):δ163.9(d,J＝242.6Hz),152.8(d,J＝10.5Hz),140.7(d,J＝9.7Hz),111.7(d,J＝2.2Hz),107.3(d,J＝21.3Hz),99.8(d,J＝25.3Hz),66.9,49.1,21.9(d,J＝2.3Hz)；19F NMR(376MHz,CDCl3) Delta-113.4; HRMS (ESI-TOF) theoretical calculation: c11H15FNO+[M+H+]196.1132, found: 196.1135.
example 16: preparation of Compound I-16
Figure BDA0002122118570000111
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-methyl-4-chlorobenzeneboronic acid pinacol ester (75.6mg,0.3mmol), 4-benzoylmorpholine ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-16 (yellow oily liquid, yield 62%).1H NMR(400MHz,CDCl3):δ6.69–6.68(m,2H),6.59(s,1H),3.85–3.83(m,4H),3.15–3.12(m,4H),2.29(s,3H)；13C NMR(100MHz,CDCl3) Delta 152.3,140.4,134.8,120.7,114.6,112.9,66.9,49.1, 21.7; HRMS (ESI-TOF) theoretical calculation: c11H15ClNO+[M+H+]212.0837, found: 212.0839.
example 17: preparation of Compound I-17
Figure BDA0002122118570000112
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2, 4-dimethylbenzeneboronic acid pinacol ester (69.6mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, and removing solvent under reduced pressurePurifying by column chromatography to obtain compound I-17 (yellow oily liquid, yield 60%).1H NMR(400MHz,CDCl3):δ6.57(s,3H),3.87–3.85(m,4H),3.16–3.14(m,4H),2.30(s,6H)；13C NMR(100MHz,CDCl3) Delta 151.5,138.8,122.1,113.8,67.1,49.7, 21.8; HRMS (ESI-TOF) theoretical calculation: c12H18NO+[M+H+]192.1383, found: 192.1387.
example 18: preparation of Compound I-18
Figure BDA0002122118570000121
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), methyl 3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (82.8mg,0.3mmol), morpholine 4-benzoate (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-18 (colorless oily liquid, yield 74%).1H NMR(400MHz,CDCl3):δ7.68–7.66(m,2H),7.23(d,J＝7.6Hz,1H),3.89(s,3H),3.86–3.84(m,4H),2.94–2.92(m,4H),2.36(s,3H)；13C NMR(100MHz,CDCl3) δ 167.3,151.4,138.5,131.3,128.8,124.7,120.2,67.4,52.3,52.1, 18.3; HRMS (ESI-TOF) theoretical calculation: c13H18NO3 +[M+H+]236.1281, found: 236.1283.
example 19: preparation of Compound I-19
Figure BDA0002122118570000122
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2, 4-difluorophenylboronic acid pinacol ester (72.0mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-19 (yellow oily liquid, yield 69%).1H NMR(400MHz,CDCl3):δ6.39–6.32(m,2H),6.28(tt,J＝8.8,2.2Hz,1H),3.84–3.82(m,4H),3.15–3.13(m,4H)；13C NMR(100MHz,CDCl3):δ164.1(dd,J＝244.3,15.8Hz),153.4(t,J＝12.2Hz),98.0–97.7(m),94.6(t,J＝26.1Hz),66.6,48.4；19F NMR(376MHz,CDCl3) Delta-119.0(s); HRMS (ESI-TOF) theoretical calculation: c10H12F2NO+[M+H+]200.0881, found: 200.0877.
example 20: preparation of Compound I-20
Figure BDA0002122118570000131
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2, 4-dimethoxyphenylboronic acid pinacol ester (79.2mg,0.3mmol), 4-phenylformic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-20 (colorless oily liquid, yield 52%).1H NMR(400MHz,CDCl3):δ6.084–6.079(m,2H),6.05–6.04(m,1H),3.86–3.83(m,4H),3.78(s,6H),3.15–3.12(m,4H)；13C NMR(100MHz,CDCl3) Delta 161.6,153.4,94.8,91.9,67.0,55.4, 49.5; HRMS (ESI-TOF) theoretical calculation: c12H18NO3 +[M+H+]224.1281, found: 224.1276.
example 21: preparation of Compound I-21
Figure BDA0002122118570000132
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), methyl 5-fluoro-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (84.0mg,0.3mmol), morpholine 4-benzoate (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-21 (colorless oily liquid, yield 52%).1H NMR(400MHz,CDCl3):δ7.36(s,1H),7.20–7.17(m,1H),6.74(dt,J＝11.6,2.3Hz,1H),3.90(s,3H),3.87–3.84(m,4H),3.21–3.19(m,4H)；13C NMR(100MHz,CDCl3):δ166.5(d,J＝3.7Hz),163.6(d,J＝244.1Hz),152.8(d,J＝9.9Hz),132.5(d,J＝9.8Hz),112.0(d,J＝2.3Hz),107.2(d,J＝23.8Hz),106.5(d,J＝25.5Hz),66.7,52.5,48.6；19F NMR(376MHz,CDCl3) Delta-111.4; HRMS (ESI-TOF) theoretical calculation: c12H15FNO3 +[M+H+]240.1030, found: 240.1024.
example 22: preparation of Compound I-22
Figure BDA0002122118570000141
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2- (2-bromophenoxy) -methylphenylboronic acid pinacol ester (116.4mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-22 (colorless oily liquid, yield 55%).1H NMR(400MHz,CDCl3):δ7.56(dd,J＝7.9,1.6Hz,1H),7.31–7.21(m,2H),7.09(s,1H),6.97–6.93(m,2H),6.88–6.83(m,2H),5.13(s,2H),3.88–3.86(m,4H),3.20–3.18(m,4H)；13C NMR(100MHz,CDCl3) Delta 155.1,151.7,137.7,133.5,129.5,128.6,122.3,118.5,115.2,114.1,114.0,112.6,71.0,67.0, 49.3; HRMS (ESI-TOF) theoretical calculation: c17H19BrNO2 +[M+H+]348.0594, found: 348.0589.
example 23: preparation of Compound I-23
Figure BDA0002122118570000142
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2- (2-iodophenoxy) -methylphenylboronic acid pinacol ester (130.8mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in this order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-23 (colorless oily liquid, yield 51%).1H NMR(400MHz,CDCl3):δ7.79(dd,J＝7.8,1.6Hz,1H),7.30–7.25(m,2H),7.14(t,J＝1.9Hz,1H),7.00–6.95(m,1H),6.88–6.84(m,2H),6.72(td,J＝7.6,1.3Hz,1H),5.12(s,2H),3.88–3.86(m,4H),3.21–3.18(m,4H)；13C NMR(100MHz,CDCl3) δ 157.3,151.7,139.6,137.7,129.6,129.4,123.0,118.4,115.2,114.2,112.9,87.0,71.0,67.0, 49.4; HRMS (ESI-TOF) theoretical calculation: c17H19INO2 +[M+H+]396.0455, found: 396.0454.
example 24: preparation of Compound I-24
Figure BDA0002122118570000151
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol), potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-fluoro-6-methyl-5-pyridineboronic acid pinacol ester (71.1mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL) as catalysts, followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-24 (colorless oily liquid, yield 43%).1H NMR(400MHz,CDCl3):δ7.56(s,1H),7.04(dd,J＝10.1,1.9Hz,1H),3.87–3.85(m,4H),3.10–3.07(m,4H),2.28(s,3H)；13C NMR(100MHz,CDCl3):δ154.5(d,J＝236.8Hz),138.2(d,J＝14.3Hz),134.5(d,J＝23.8Hz),131.6(d,J＝4.6Hz),128.2(d,J＝4.8Hz),66.9,50.4(d,J＝3.7Hz),17.8；19F NMR(376MHz,CDCl3) Delta-78.1; HRMS (ESI-TOF) theoretical calculation: c10H14FN2O+[M+Na+]197.1085, trueMeasuring: 197.1086.
example 25: preparation of Compound I-25
Figure BDA0002122118570000152
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol), potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 2-methoxy-6-methyl-3-pyridineboronic acid pinacol ester (74.7mg,0.3mmol), 4-benzoic acid morpholinyl ester (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL) as catalysts, followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-25 (colorless oily liquid, yield 44%).1H NMR(400MHz,CDCl3):δ6.25(d,J＝1.9Hz,1H),5.88(d,J＝2.0Hz,1H),3.88(s,3H),3.81–3.79(m,4H),3.23–3.21(m,4H),2.36(s,3H)；13C NMR(100MHz,CDCl3) δ 165.6,158.6,156.6,102.9,90.3,66.6,53.4,46.9, 24.7; HRMS (ESI-TOF) theoretical calculation: c11H17N2O2 +[M+H+]209.1285, found: 209.1289.
example 26: preparation of Compound I-26
Figure BDA0002122118570000161
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 5-quinolineboronic acid pinacol ester (76.5mg,0.3mmol), 4-morpholinylbenzoate (41.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was passed through celiteFiltering, washing with ethyl acetate, washing the filtrate with water and saturated aqueous sodium chloride solution, drying with Na as organic solvent2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-26 (yellow solid, yield 74%).1H NMR(400MHz,CDCl3):δ6.25(d,J＝1.9Hz,1H),5.88(d,J＝2.0Hz,1H),3.88(s,3H),3.81–3.79(m,4H),3.23–3.21(m,4H),2.36(s,3H)；13C NMR(100MHz,CDCl3) δ 165.6,158.6,156.6,102.9,90.3,66.6,53.4,46.9, 24.7; HRMS (ESI-TOF) theoretical calculation: c11H17N2O2 +[M+H+]209.1285, found: 209.1289.
example 27: preparation of Compound I-27
Figure BDA0002122118570000162
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (110.4mg,0.8mmol), norbornene (37.6mg,0.4mmol), 4-fluorophenylboronic acid pinacol ester (66.6mg,0.3mmol), 4-benzoic acid morpholinyl ester (82.8mg,0.4mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-27 (white solid, yield 42%).1H NMR(400MHz,CDCl3):δ6.18–6.16(m,2H),6.13(d,J＝2.1Hz,1H),3.85–3.82(m,8H),3.14–3.12(m,8H)；13C NMR(100MHz,CDCl3):δ164.8(d,J＝240.1Hz),153.5(d,J＝12.1Hz),98.4(d,J＝2.0Hz),94.9(d,J＝25.7Hz),66.9,49.3；19F NMR(376MHz,CDCl3) Delta-109.7; HRMS (ESI-TOF) theoretical calculation: c14H20FN2O2 +[M+H+]267.1503, found: 267.1502.
example 28: preparation of Compound I-28
Figure BDA0002122118570000171
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (110.4mg,0.8mmol), norbornene (37.6mg,0.4mmol), 4-chlorobenzeneboronic acid pinacol ester (71.4mg,0.3mmol), 4-benzoylmorpholine ester (82.8mg,0.4mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-28 (colorless oily liquid, yield 47%).1H NMR(400MHz,CDCl3):δ6.43(s,1H),6.42(s,1H),6.28(t,J＝2.1Hz,1H),3.84–3.82(m,8H),3.14–3.12(m,8H)；13C NMR(100MHz,CDCl3) δ 153.1,135.8,108.0,101.5,66.9, 49.3; HRMS (ESI-TOF) theoretical calculation: c14H20ClN2O2 +[M+H+]283.1208, found: 283.1207.
example 29: preparation of Compound I-29
Figure BDA0002122118570000172
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (110.4mg,0.8mmol), norbornene (37.6mg,0.4mmol), 4-bromobenzeneboronic acid pinacol ester (84.6mg,0.3mmol), 4-benzoylmorpholine ester (82.8mg,0.4mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in this order, and the organic solvent was addedDried Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-29 (colorless oily liquid, yield 44%).1H NMR(400MHz,CDCl3):δ6.57(s,1H),6.57(s,1H),6.32(t,J＝2.1Hz,1H),3.84–3.81(m,8H),3.14–3.11(m,8H)；13C NMR(100MHz,CDCl3) δ 153.3,124.1,111.0,102.1,66.9, 49.4; HRMS (ESI-TOF) theoretical calculation: c14H20BrN2O2 +[M+H+]327.0703, found: 327.0704.
example 30: preparation of Compound I-30
Methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(3,5-dimorpholinophenyl)propanoate(3ad)
Figure BDA0002122118570000181
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (110.4mg,0.8mmol), norbornene (37.6mg,0.4mmol), methyl 2- (di (t-butoxycarbonyl) amino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate (151.5mg,0.3mmol), morpholine 4-benzoate (82.8mg,0.4mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-30 (colorless oily liquid, yield 26%).1H NMR(400MHz,CDCl3):δ6.30–6.28(m,3H),5.13(dd,J＝10.5,4.8Hz,1H),3.84–3.81(m,8H),3.74(s,3H),3.32(dd,J＝14.0,4.8Hz,1H),3.17–3.12(m,1H)，3.12–3.09(m,8H),1.39(s,18H)；13C NMR(100MHz,CDCl3) δ 171.1,152.5,151.9,139.2,109.9,102.7,83.0,67.1,59.4,52.4,49.9,36.8, 28.0; HRMS (ESI-TOF) theoretical calculation: c28H43N3NaO8 +[M+Na+]572.2941, found: 572.2941.
example 31: preparation of Compound I-31
Figure BDA0002122118570000182
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-piperidinecarboxylate (41.0mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-31 (white solid, yield 57%).1H NMR(400MHz,CDCl3):δ7.72–7.64(m,3H),7.39–7.35(m,1H),7.30–7.23(m,2H),7.12(d,J＝2.5Hz,1H),3.28–3.21(m,4H),1.79–1.73(m,4H),1.65–1.58(m,2H)；13C NMR(100MHz,CDCl3) Delta 150.2,134.8,128.6,128.4,127.5,126.8,126.2,123.2,120.3,110.5,51.2,26.0, 24.5; HRMS (ESI-TOF) theoretical calculation: c15H18N+[M+H+]212.1434, found: 212.1432.
example 32: preparation of Compound I-32
Figure BDA0002122118570000191
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid-4-methylpiperidine ester (43.8mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. The reaction is cooled toAfter room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water, then with saturated aqueous sodium chloride, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-32 (yellow solid, yield 70%).1H NMR(400MHz,CDCl3):δ7.64–7.59(m,3H),7.33–7.29(m,1H),7.22–7.18(m,2H),7.06(s,1H),3.72–3.68(m,2H),2.73–2.66(m,2H),1.73–1.69(m,2H),1.55–1.42(m,2H),1.39–1.29(m,2H),0.93(d,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3) Delta 149.9,134.8,128.6,128.4,127.5,126.8,126.2,123.2,120.3,110.5,50.5,34.3,30.9, 22.1; HRMS (ESI-TOF) theoretical calculation: c16H20N+[M+H+]226.1590, found: 226.1592.
example 33: preparation of Compound I-33
Figure BDA0002122118570000192
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid-4-phenylpiperidine ester (43.8mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-33 (yellow solid, yield 72%).1H NMR(400MHz,CDCl3):δ7.74–7.69(m,3H),7.42–7.37(m,1H),7.35–7.18(m,8H),3.95–3.92(m,2H),2.93–2.86(m,2H),2.74–2.66(m,1H),2.02–1.91(m,4H)；13C NMR(100MHz,CDCl3) Delta 149.8,146.2,134.8,128.8,128.7,128.5,127.5,127.01,126.8,126.5,126.3,123.4,120.3,110.7,51.0,42.7, 33.5; HRMS (ESI-TOF) theoretical calculation: c21H22N+[M+H+]288.1747, found: 288.1747.
example 34: preparation of Compound I-34
Figure BDA0002122118570000193
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid-4-hydroxypiperidine ester (43.8mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-34 (white solid, 73% yield).1H NMR(400MHz,CDCl3):δ7.72–7.66(m,3H),7.41–7.37(m,1H),7.30–7.24(m,2H),7.13(d,J＝2.4Hz,1H),3.89–3.83(m,1H),3.68–3.63(m,2H),3.02–2.95(m,2H),2.07–2.01(m,2H),1.78–1.69(m,3H)；13C NMR(100MHz,CDCl3) Delta 149.2,134.7,128.8,128.5,127.5,126.8,126.3,123.4,120.1,110.7,68.0,47.8, 34.3; HRMS (ESI-TOF) theoretical calculation: c15H18NO+[M+H+]228.1383, found: 228.1378.
example 35: preparation of Compound I-35
Figure BDA0002122118570000201
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid-4- ((tert-butyldimethylsilyl) oxy) piperidine ester (67.0mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane(2.0mL), and then heated to 70 ℃ to react for 12 hours under an air protective atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-35 (white solid, yield 45%).1H NMR(400MHz,CDCl3):δ7.71–7.66(m,3H),7.40–7.36(m,1H),7.30–7.24(m,2H),7.14(d,J＝1.9Hz,1H),3.94–3.88(m,1H),3.57–3.51(m,2H),3.14–3.08(m,2H),1.96–1.90(m,2H),1.77–1.69(m,2H),0.91(s,9H),0.09(s,6H)；13C NMR(100MHz,CDCl3) Delta 149.5,134.8,128.7,128.4,127.5,126.8,126.3,123.3,120.0,110.5,67.6,47.1,34.5,26.0,18.5, -4.5; HRMS (ESI-TOF) theoretical calculation: c21H32NOSi+[M+H+]342.2248, found: 342.2243.
example 36: preparation of Compound I-36
Figure BDA0002122118570000202
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid-4-hydroxymethylpiperidine ester (47.0mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-36 (purple solid, yield 83%).1H NMR(400MHz,CDCl3):δ7.70–7.66(m,3H),7.40–7.36(m,1H),7.30–7.25(m,2H),7.14(s,1H),3.79–3.75(m,1H),3.66–3.53(m,3H),2.83–2.77(m,1H),2.66–2.60(m,1H),2.01–1.90(m,1H),1.87–1.67(m,4H),1.26–1.11(m,1H)；13C NMR(100MHz,CDCl3) δ 149.9,134.7,128.7,128.5,127.5,126.8,126.3,123.4,120.4,110.8,66.2,53.8,51.0,38.7,27.2, 24.8; HRMS (ESI-TOF) theoretical calculation: c16H20NO+[M+H+]242.1539, found: 242.1547.
example 37: preparation of Compound I-37
Figure BDA0002122118570000211
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid-4- (hydroxydiphenylmethyl) piperidine ester (77.4mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-37 (yellow solid, 53% yield).1H NMR(400MHz,CDCl3):δ7.70–7.65(m,3H),7.53–7.51(m,4H),7.40–7.19(m,9H),7.10(s,1H),3.86–3.81(m,2H),2.84–2.77(m,2H),2.66–2.58(m,1H),2.13(s,1H),1.69–1.60(m,4H)；13C NMR(100MHz,CDCl3) Delta 149.5,145.9,134.7,128.7,128.5,128.4,127.5,126.8,126.3,125.9,123.4,120.2,110.6,79.7,50.7,44.3, 26.6; HRMS (ESI-TOF) theoretical calculation: c28H28NO+[M+H+]394.2165, found: 394.2169.
example 38: preparation of Compound I-38
Figure BDA0002122118570000212
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst and potassium carbonate (69.0mg,0.5 mm)ol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 8-benzoic acid-1, 4-dioxo-8-azaspiro [4.5 ]]Decyl ester (52.6mg,0.2mmol), dimethyl sulfoxide (0.8mL), and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-38 (yellow solid, yield 57%).1H NMR(400MHz,CDCl3):δ7.74–7.68(m,3H),7.43–7.39(m,1H),7.32–7.27(m,2H),7.16(d,J＝2.4Hz,1H),4.02(s,4H),3.47–3.42(m,4H),1.95–1.89(m,4H)；13C NMR(100MHz,CDCl3) δ 148.9,134.7,128.8,128.5,127.5,126.8,126.3,123.4,120.1,110.8,107.3,64.5,48.2, 34.7; HRMS (ESI-TOF) theoretical calculation: c17H20NO2 +[M+H+]270.1489, found: 270.1489.
example 39: preparation of Compound I-39
Figure BDA0002122118570000221
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), ethyl 1-benzoyloxypiperidine-3-carboxylate (52.6mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-39 (yellow oily liquid, yield 71%).1H NMR(400MHz,CDCl3):δ7.74–7.69(m,3H),7.43–7.39(m,1H),7.32–7.29(m,2H),7.17(s,1H),4.21(q,J＝7.1Hz,2H),3.85–3.81(m,1H),3.63–3.59(m,1H),3.17–3.11(m,1H),2.95–2.88(m,1H),2.79–2.72(m,1H),2.09–2.06(m,1H),1.92–1.67(m,3H),1.31(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3) δ 174.0,149.4,134.7,128.8,128.6,127.5,126.8,126.3,123.5,120.4,110.9,60.7,52.6,50.3,41.6,27.1,24.4, 14.4; HRMS (ESI-TOF) theoretical calculation: c18H22NO2 +[M+H+]284.1645, found: 284.1639.
example 40: preparation of Compound I-40
Figure BDA0002122118570000222
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), ethyl 1-benzoyloxypiperidine-4-carboxylate (52.6mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-40 (yellow oily liquid, yield 59%).1H NMR(400MHz,CDCl3):δ7.72–7.66(m,3H),7.41-7.37(m,1H),7.30–7.25(m,2H),7.12(d,J＝2.3Hz,1H),4.17(q,J＝7.1Hz,2H),3.75(dt,J＝12.4,3.2Hz,2H),2.86(td,J＝12.3,2.8Hz,2H),2.51–2.43(m,1H),2.15–1.86(m,4H),1.28(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3) δ 175.0,149.5,134.7,128.8,128.6,127.5,126.8,126.3,123.5,120.2,110.8,60.6,49.7,41.2,28.2, 14.4; HRMS (ESI-TOF) theoretical calculation: c18H22NO2 +[M+H+]284.1645, found: 284.1639.
example 41: preparation of Compound I-41
Figure BDA0002122118570000231
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid-4-benzoylpiperazine ester (61.8mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-41 (yellow oily liquid, yield 43%).1H NMR(400MHz,CDCl3):δ7.76–7.68(m,3H),7.49–7.39(m,6H),7.35–7.29(m,1H),7.26–7.24(m,1H),7.12(s,1H),3.99(brs,2H),3.64(brs,2H),3.35(brs,2H),3.21(brs,2H)；13C NMR(100MHz,CDCl3) Delta 170.5,148.8,135.7,134.5,130.0,129.1,129.0,128.7,127.6,127.2,126.9,126.6,124.0,119.8,111.2,50.3,50.1,47.7, 42.2; HRMS (ESI-TOF) theoretical calculation: c21H21N2O+[M+H+]317.1648, found: 317.1649.
example 42: preparation of Compound I-42
Figure BDA0002122118570000232
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), pinacol-1-naphthaleneboronic acid ester (76.2mg,0.3mmol), benzyl 4-benzoyloxy-1-piperazinecarboxylate (67.8mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, and the filtrate was washed with water and saturated aqueous sodium chloride solution one by oneDrying the organic solvent with Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-42 (yellow solid, 50% yield).1H NMR(400MHz,CDCl3):δ7.76–7.66(m,3H),7.44–7.28(m,7H),7.27–7.22(m,1H),7.11(s,1H),5.18(s,2H),3.71(t,J＝5.1Hz,4H),3.24(s,4H)；13C NMR(100MHz,CDCl3) Delta 155.4,149.0,136.7,134.5,129.0,128.9,128.7,128.2,128.1,127.6,126.9,126.5,123.9,119.9,111.1,67.4,49.9, 43.9; HRMS (ESI-TOF) theoretical calculation: c22H23N2O2 +[M+H+]347.1754, found: 347.1751.
example 43: preparation of Compound I-43
Figure BDA0002122118570000241
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), tert-butyl 4-benzoyloxy-1-piperazinecarboxylate (61.2mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-43 (white solid, yield 60%).1H NMR(400MHz,CDCl3):δ7.76–7.67(m,3H),7.41(t,J＝7.1Hz,1H),7.34–7.24(m,2H),7.12(d,J＝2.3Hz,1H),3.63(t,J＝5.1Hz,4H),3.23(t,J＝5.2Hz,4H),1.50(s,9H)；13C NMR(100MHz,CDCl3) Delta 154.9,149.2,134.6,129.0,128.9,127.6,126.9,126.5,123.8,119.9,111.0,80.1,49.9, 28.6; HRMS (ESI-TOF) theoretical calculation: c19H24N2NaO2 +[M+Na+]335.1730, found: 335.1731.
example 44: preparation of Compound I-44
Figure BDA0002122118570000242
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), thiomorpholinyl 1-benzoate (44.6mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-44 (white solid, 56% yield).1H NMR(400MHz,CDCl3):δ7.75–7.68(m,3H),7.44–7.40(m,1H),7.33–7.29(m,1H),7.22(dd,J＝9.0,2.5Hz,1H),7.13(m,1H),3.65–3.63(m,4H),2.83–2.81(m,4H)；13C NMR(100MHz,CDCl3) δ 149.2,134.7,129.0,128.6,127.6,126.8,126.5,123.7,120.3,111.5,52.5, 27.1; HRMS (ESI-TOF) theoretical calculation: c14H16NS+[M+H+]230.0998, found: 230.0993.
example 45: preparation of Compound I-45
Figure BDA0002122118570000243
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-benzoic acid pyrrole ester (38.2mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, and the filtrate was successively washed with water and saturated sodium chloride waterWashing the solution once, drying the organic solvent by Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-45 (white solid, yield 42%).1H NMR(400MHz,CDCl3):δ7.70–7.62(m,3H),7.36–7.32(m,1H),7.17–7.14(m,1H),7.00(dd,J＝9.0,2.5Hz,1H),6.76(d,J＝2.4Hz,1H),3.43–3.40(m,4H),2.08–2.04(m,4H)；13C NMR(100MHz,CDCl3) Delta 146.0,135.4,128.9,127.7,126.4,126.3,125.9,121.3,115.8,104.8,48.0, 25.7; HRMS (ESI-TOF) theoretical calculation: c14H16N+[M+H+]198.1277, found: 198.1276.
example 46: preparation of Compound I-46
Figure BDA0002122118570000251
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), 1-cycloheximide benzoate (43.8mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-46 (yellow oily liquid, yield 33%).1H NMR(400MHz,CDCl3):δ7.69–7.65(m,2H),7.61(d,J＝8.3Hz,1H),7.36–7.32(m,1H),7.17–7.10(m,2H),6.88(d,J＝2.5Hz,1H),3.60–3.57(m,4H),1.88–1.84(m,4H),1.60–1.56(m,4H)；13C NMR(100MHz,CDCl3) Delta 146.9,135.5,129.0,127.5,126.2,126.0,121.4,115.3,104.6,49.6,28.0, 27.2; HRMS (ESI-TOF) theoretical calculation: c16H20N+[M+H+]226.1590, found: 226.1591.
example 47: preparation of Compound I-47
Figure BDA0002122118570000252
To a reaction tube equipped with a magnetic stirrer were added palladium acetate (4.5mg, 0.02mmol) as a catalyst, potassium carbonate (69.0mg,0.5mmol), norbornene (37.6mg,0.4mmol), 1-naphthaleneboronic acid pinacol ester (76.2mg,0.3mmol), O-benzoyl-N-benzyl-N-methylhydroxylamine (48.2mg,0.2mmol), dimethyl sulfoxide (0.8mL) and 1, 4-dioxane (2.0mL), followed by heating to 70 ℃ for 12 hours under an air-protecting atmosphere. After the reaction was cooled to room temperature, the mixture was filtered through celite, washed with ethyl acetate, the filtrate was washed once with water and saturated aqueous sodium chloride solution in that order, and the organic solvent was dried over Na2SO4Drying, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound I-47 (yellow oily liquid, yield 35%).1H NMR(400MHz,CDCl3):δ7.68–7.61(m,3H),7.37–7.29(m,3H),7.26–7.24(m,3H),7.21–7.14(m,2H),6.95(d,J＝2.6Hz,1H),4.64(s,2H),3.09(s,3H)；13C NMR(100MHz,CDCl3) δ 147.8,139.0,135.2,129.0,128.7,127.6,127.1,127.0,126.9,126.4,126.3,122.1,116.3,106.3,56.9, 38.8; HRMS (ESI-TOF) theoretical calculation: c18H18N+[M+H+]248.1434, found: 248.1427.
example 48: preparation of Compound II-1
Figure BDA0002122118570000261
The method comprises the following steps: under the protection of argon gas, a reaction tube which is dry and is provided with a magnetic stirring bar is added with a catalyst cuprous iodide (1.0mg, 0.005mmol) and a ligand N1,N2Bis (4-methyl-2-phenyl) oxalamide (7.98mg,0.019mmol), potassium phosphate (44.5mg,0.21mmol), aryl chloride I-28(28mg, 0.1mmol), aqueous ammonia (w/w 25%, 46. mu.L, 0.3mmol), and dimethyl sulfoxide (0.2mL), followed by heating at 120 ℃ for 48 hours under an argon atmosphere. After the reaction is cooled to room temperature, the mixture is directly purified by column chromatographyCompound II-1 (white solid, 61% yield) was recovered along with starting material I-28 (32% recovery).
The second method comprises the following steps: under the protection of argon gas, a reaction tube which is dry and is provided with a magnetic stirring bar is added with cuprous oxide (1.2mg, 0.008mmol) serving as a catalyst and N serving as a ligand1- (2-methylnaphthyl), N2- (2-Furanylmethyl) -ethanediamide (2.32mg,0.008mmol), potassium hydroxide (11.8mg,0.21mmol), aryl bromide I-29(53mg, 0.16mmol), aqueous ammonia (w/w 25%, 64. mu.L, 0.8mmol) and ethanol (0.2mL), followed by heating at 80 ℃ for 24 hours under an argon atmosphere. After the reaction was cooled to room temperature, the mixture was directly concentrated under reduced pressure and then purified by direct column chromatography to give compound II-1 (white solid, yield 64%).1H NMR(400MHz,CDCl3):δ5.92(t,J＝2.1Hz,1H),5.84(d,J＝1.9Hz,2H),3.83–3.81(m,8H),3.12–3.09(m,8H)；13C NMR(100MHz,CDCl3) Delta 153.5,148.1,95.8,95.3,67.1, 49.7; HRMS (ESI-TOF) theoretical calculation: c14H22N3O2 +[M+H+]264.1706, found: 264.1701.

Claims (5)

1. a method for synthesizing aromatic amine compounds, comprising the steps of: taking aryl boric acid or aryl boric acid ester A as an initial raw material, taking O-formyl-hydroxylamine compound B as an amination reagent, taking a palladium catalyst and a norbornene derivative as a synergistic catalyst, taking alkali as an accelerator, placing the materials in an organic solvent at 30-100 ℃, stirring for reaction, separating and purifying after the reaction is finished to obtain a monobasic substituted aromatic amine compound C, wherein the reaction formula is shown as the following formula (1); when the substituent R is1When the hydrogen atom is used, the obtained product is a binary substituted aromatic amine compound D, and the reaction formula is shown as the following formula (2):
(1)
Figure FDA0003481304860000011
(2)
Figure FDA0003481304860000012
wherein:
R1is one of hydrogen, aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, amino, cyano, nitro, amido, sulfonyl, alkoxy and halogen;
R2is an aromatic ring, a heteroaromatic ring or a substituent for replacing hydrogen on the Ar ring, wherein the aromatic ring, the heteroaromatic ring or the substituent is combined with the Ar ring, and the substituent is one or more of aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, amino, cyano, nitro, amido, sulfonyl, alkoxy and halogen; n represents R2N is more than or equal to 0 and less than or equal to 3;
R3is hydrogen, C1-20Alkyl, aryl, heterocyclic aryl;
R4is hydrogen, aryl, heterocyclic aryl, C1-20An alkyl group;
R5、R6is heterocyclic alkane, heteroaromatic ring or substituent on nitrogen which forms a ring with nitrogen, and the substituent is hydrogen, aryl, heterocyclic aryl, C1-20One of alkyl, benzyl and p-methoxybenzyl;
x, Y, Z is N or CH;
the norbornene derivative has the following structure:
Figure FDA0003481304860000013
wherein:
R7is a substituent on a five-membered ring, o represents the number of the substituent, and o is more than or equal to 0 and less than or equal to 8;
R8is a substituent on a double bond, p represents the number of the substituent, and p is more than or equal to 0 and less than or equal to 2;
R7、R8independently selected from the group consisting of carboxylate, ester, cyano, nitro, amido, sulfonyl, C of a metal ion M1-10Alkoxy, aryl, heterocyclic aryl, C1-10One of alkyl and halogen, wherein M is Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+One kind of (1).
2. The method of claim 1, wherein: the palladium catalyst is Pd (PPh)3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(O2CCF3)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2Or [ Pd (allyl) Cl]2The alkali is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tripotassium phosphate, potassium formate, potassium bicarbonate, potassium hydroxide, sodium hydroxide and sodium tert-butoxide.
3. The method of claim 1, wherein: the organic solvent is methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylene glycol, methyl tert-butyl ether, 1, 4-epoxyhexaalkane, 1, 3-epoxyhexaalkane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, C4-12Saturated alkane of (C)3-12Fluoro or chloro alkane, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C3-12One or more of saturated alkyl nitrile and dimethyl sulfoxide.
4. The method of claim 1, wherein: the synergistic catalyst is palladium catalyst and norbornene, and the palladium catalyst is Pd (OAc)2The alkali is potassium carbonate, and the organic solvent is 1, 4-dioxane and dimethyl sulfoxide.
5. A method for preparing a compound, comprising the steps of: reacting a compound E and an O-formyl-hydroxylamine compound B in an organic solvent under the action of a palladium catalyst, alkali and a norbornene derivative in an air atmosphere to obtain an intermediate F, separating and purifying the obtained intermediate, and carrying out copper-catalyzed Ullmann amination reaction on the intermediate F and an amine reagent G to obtain a compound H, wherein the reaction formula is as follows:
Figure FDA0003481304860000021
wherein:
x is one of fluorine, chlorine, bromine, iodine and trifluoromethanesulfonate;
R5、R6is heterocyclic alkane, heteroaromatic ring or substituent on nitrogen which forms a ring with nitrogen, and the substituent is hydrogen, aryl, heterocyclic aryl, C1-20One of alkyl, benzyl and p-methoxybenzyl;
R9is hydrogen, C1-20Alkyl, aryl, heterocyclic aryl;
R10、R11is heterocyclic alkane, heteroaromatic ring or substituent on nitrogen which forms a ring with nitrogen, and the substituent is hydrogen, aryl, heterocyclic aryl, C1-20One of alkyl, ester group, amido, sulfonyl, alkoxy, tert-butyloxycarbonyl, carbobenzoxy, benzyl, p-methoxybenzyl, alkanoyl and phthaloyl;
the norbornene derivative has the following structure:
Figure FDA0003481304860000031
wherein:
R7is a substituent on a five-membered ring, o represents the number of the substituent, and o is more than or equal to 0 and less than or equal to 8;
R8is a substituent on a double bond, p represents the number of the substituent, and p is more than or equal to 0 and less than or equal to 2;
R7、R8independently selected from the group consisting of carboxylate, ester, cyano, nitro, amido, sulfonyl, C of a metal ion M1-10Alkoxy, aryl, heterocyclic aryl, C1-10One of alkyl and halogen, wherein M is Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+One kind of (1).
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CN111039813B (en) * 2019-12-24 2022-07-01 江南大学 Synthetic method of aromatic amide compound
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008132505A1 (en) * 2007-04-27 2008-11-06 Astrazeneca Ab N' - (phenyl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diamine derivatives as ephb4 kinase inhibitors for the treatment of proliferative conditions
WO2009010794A1 (en) * 2007-07-19 2009-01-22 Astrazeneca Ab 2,4-diamino-pyrimidine derivatives
CN101668749A (en) * 2007-02-28 2010-03-10 阿斯利康(瑞典)有限公司 Novel pyrimidine derivatives 698
WO2011009695A1 (en) * 2009-07-21 2011-01-27 Universität Zürich New anti-angiogenic compounds
CN102558095A (en) * 2011-12-13 2012-07-11 大连理工大学 Method for preparing aromatic amine compound
CN104744190A (en) * 2015-03-26 2015-07-01 浙江大学 Method for preparing o-alkynyl phenylamine derivative

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101668749A (en) * 2007-02-28 2010-03-10 阿斯利康(瑞典)有限公司 Novel pyrimidine derivatives 698
WO2008132505A1 (en) * 2007-04-27 2008-11-06 Astrazeneca Ab N' - (phenyl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diamine derivatives as ephb4 kinase inhibitors for the treatment of proliferative conditions
WO2009010794A1 (en) * 2007-07-19 2009-01-22 Astrazeneca Ab 2,4-diamino-pyrimidine derivatives
WO2011009695A1 (en) * 2009-07-21 2011-01-27 Universität Zürich New anti-angiogenic compounds
CN102558095A (en) * 2011-12-13 2012-07-11 大连理工大学 Method for preparing aromatic amine compound
CN104744190A (en) * 2015-03-26 2015-07-01 浙江大学 Method for preparing o-alkynyl phenylamine derivative

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Inhibitors of the tyrosine kinase EphB4. Part 3: Identification of non-benzodioxole-based kinase inhibitors;Catherine Bardelle 等;《Bioorganic & Medicinal Chemistry Letters》;20100916;第20卷;第6242-6245页 *
Ortho vs Ipso: Site-Selective Pd and Norbornene-Catalyzed Arene C-H Amination Using Aryl Halides;Zhe Dong 等;《Journal of The American Chemical Society》;20131120;第135卷;第S3页表S1，第S6页第4-6段，第S14页第3-6段 *
Redox-neutral ortho-C–H amination of pinacol arylborates via palladium(II)/norbornene catalysis for aniline synthesis;Shuqing Chen 等;《Chemical Science》;20190723;第10卷;第8384-8389页 *
The discovery of a Palladium(Ⅱ)-initiated borono-Catellani reaction;Shuqing Chen 等;《Angew. Chem. Int. Ed.》;20180516;第57卷;第7162页表1 *
Zhe Dong 等.Ortho vs Ipso: Site-Selective Pd and Norbornene-Catalyzed Arene C-H Amination Using Aryl Halides.《Journal of The American Chemical Society》.2013,第135卷第18350-18353页. *

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