A Z-formyl enamide derivative and preparation method thereof

Abstract

The present invention provides a Z-enamide derivative and a preparation method thereof, and belongs to the technical field of organic chemical synthesis. The Z-enamide derivative of the present invention has a structure shown in Formula I. After biological activity evaluation, it is found that the compound has an inhibitory effect on H1975 lung cancer cells, and the minimum IC50 value is 48.69uM. The preparation method of the compound is to heat N-allylamide, a catalyst and an additive in an organic solvent in an oil bath for reaction. The present invention utilizes an inexpensive low-valent tungsten catalytic system to achieve highly selective isomerization of N-allylamide compounds, thereby providing a rapid preparation method of a Z-enamide derivative. The method has low cost, a wide range of substrate applications, simple operation, high atom economy, environmental friendliness, and good industrial application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and in particular to a Z-enamide derivative and a preparation method thereof. Background Art

[0002] Enamides, as compounds containing an electron-rich alkenyl skeleton, are an important class of organic synthons widely used in organic synthesis. They are also widely present in natural products and drug molecules and are an important class of pharmacophores (Cancer Treat. Rev. 2009, 35, 707; Chem. Sci. 2022, 13, 9056). Therefore, the precise synthesis and transformation of enamides have always attracted the attention of organic chemists and have been developed to a certain extent. Traditional enamide synthesis is through the condensation reaction of amides with aldehydes or ketones, but this method has harsh reaction conditions, low yields and poor cis-trans selectivity. Copper-catalyzed cross-coupling reactions of amides and alkenyl halides are also powerful tools for the synthesis of E-enamides (Nat. Prod. Rep. 2014, 31, 514). In addition, the rapidly developing carbon-hydrogen functionalization of enamides also provides an efficient route for the synthesis of enamide derivatives (Org. Lett. 2021, 23, 8262; Chem. Sci. 2019, 10, 8792; Org. Biomol. Chem. 2020, 18, 1504). Although scientists have tried to achieve the construction of Z-enamides through transition metal-catalyzed N-allylamide isomerization reactions, only the Trost group achieved highly selective Z-enamide synthesis using the precious metal ruthenium catalyst CpRu(MeCN)3PF6 in 2017, but it is only applicable to the synthesis of secondary enamides (J. Am. Chem. Soc. 2017, 139, 5133). It can be seen that the effective methods reported so far tend to synthesize thermodynamically stable E-enamides rather than Z-enamides, and they are subject to at least one limitation, such as harsh reaction conditions, poor selectivity, the use of precious metals, and product structural diversity.

[0003] As a rare metal, tungsten has a wide range of commercial applications in modern society. Low-valent tungsten has great differences in reactivity due to its potential for redox cycles such as redox addition and reduction elimination. Low-valent tungsten catalysts have good stability and tolerance to various functional groups. my country is rich in tungsten ore resources, and its tungsten production and total exports rank first in the world. Compared with the ruthenium catalyst CpRu(MeCN)3PF6 (≈3000 yuan / 1g) used in the above report to achieve highly selective Z-enamide synthesis, hexacarbonyl tungsten catalysts are very cheap (≈50 yuan / 1g). Therefore, it is of scientific and practical significance to develop universal, efficient, highly selective and low-cost new synthesis methods based on tungsten chemistry. Summary of the invention

[0004] Based on the above content, the present invention aims to provide a Z-enamide derivative and a preparation method thereof. The present invention uses an inexpensive low-valent tungsten catalytic system to achieve highly selective isomerization of N-allylamide compounds, thereby providing a rapid preparation method of Z-enamide derivatives. The prepared compounds have an inhibitory effect on H1975 lung cancer cells, with a minimum IC50 value of 48.69uM.

[0005] In order to achieve the above object, the present invention provides the following technical solution: a Z-enamide derivative having a structure shown in Formula I:

[0006]

[0007] Among them, R 1 is aryl, heteroaryl, alkyl, alkenyl, alkoxy or chiral amino; R 2 is hydrogen, alkyl or alkenyl; R 3 is hydrogen or alkyl; R 4 is hydrogen, alkyl, phenyl, ester or bis-naphthalene alcohol borate; R 5 is hydrogen or bis-naphthoic acid borate; wherein R 1 With R 2 Can be connected into a ring.

[0008] Preferably, the Z-enamide derivative is selected from one of the following structural formulas:

[0009]

[0010] The present invention also provides a method for preparing a Z-enamide derivative, wherein N-allylamide, a catalyst and an additive are subjected to oil bath heating reaction in an organic solvent to obtain the Z-enamide derivative.

[0011] Preferably, the structural formula of the N-allyl amide is as shown in Formula II:

[0012]

[0013] Among them, R 1 is aryl, heteroaryl, alkyl, alkenyl, alkoxy or chiral amino; R 2 is hydrogen, alkyl or alkenyl; R 3 is hydrogen or alkyl; R 4 is hydrogen, alkyl, phenyl, ester or bis-naphthalene alcohol borate; R 5 is hydrogen or bis-naphthoic acid borate; wherein R 1 With R 2 Can be connected into a ring.

[0014] Preferably, the catalyst is tungsten hexacarbonyl, tungsten tricarbonyl triacetonitrile, molybdenum hexacarbonyl, manganese bromide pentacarbonyl, rhenium bromide pentacarbonyl or dirhenium decacarbonyl; and the molar ratio of the N-allyl amide compound to the catalyst is 1:(0.05-0.2).

[0015] Preferably, the additive is acetic acid, benzoic acid, pivalic acid, triethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium pivalate, sodium carbonate, sodium bicarbonate, lithium hydroxide, lithium carbonate, potassium tert-butoxide, potassium hydroxide, dipotassium hydrogen phosphate, cesium fluoride, cesium carbonate or pinacol; the molar ratio of the N-allyl amide compound to the additive is 1:(0.1-2).

[0016] Preferably, the organic solvent includes acetonitrile, 1,4-dioxane, acetone, tetrahydrofuran, N,N-dimethylformamide, dichloroethane, toluene, trifluorotoluene or dimethyl sulfoxide; the dosage ratio of the N-allylamide compound to the organic solvent is 0.2mmol:1-3mL.

[0017] Preferably, the reaction is carried out under the protection of an inert gas, the reaction temperature is 70 to 120° C., and the reaction time is 12 to 48 hours.

[0018] Preferably, after the reaction is completed, a separation step and a purification step are also included.

[0019] Preferably, the separation step adopts liquid extraction; and the purification step adopts column chromatography.

[0020] Beneficial technical effects:

[0021] The invention provides a rapid synthesis method of Z-enamide. The synthesis method provided by the invention has low cost, wide substrate application range, simple operation, high atom economy, environmental friendliness and good industrial application prospect. DETAILED DESCRIPTION

[0022] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0023] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0024] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0025] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.

[0026] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0027] The present invention provides a Z-enamide derivative having a structure shown in Formula I:

[0028]

[0029] Among them, R 1 is aryl, heteroaryl, alkyl, alkenyl, alkoxy or chiral amino; R 2 is hydrogen, alkyl or alkenyl; R 3 is hydrogen or alkyl; R 4 is hydrogen, alkyl, phenyl, ester or bis-naphthalene alcohol borate; R 5 is hydrogen or bis-naphthoic acid borate; wherein R 1 With R 2 Can be connected into a ring.

[0030] In some embodiments, the Z-enamide derivative is selected from one of the following structural formulas:

[0031]

[0032] The present invention also provides a method for preparing a Z-enamide derivative, wherein N-allylamide, a catalyst and an additive are subjected to oil bath heating reaction in an organic solvent to obtain the Z-enamide derivative.

[0033] In some embodiments, the structural formula of the N-allyl amide is as shown in Formula II:

[0034]

[0035] Among them, R 1 is aryl, heteroaryl, alkyl, alkenyl, alkoxy or chiral amino; R 2 is hydrogen, alkyl or alkenyl; R 3 is hydrogen or alkyl; R 4 is hydrogen, alkyl, phenyl, ester or bis-naphthalene alcohol borate; R 5 is hydrogen or bis-naphthoic acid borate; wherein R 1 With R 2 Can be connected into a ring.

[0036] The reaction equation of the Z-formula enamide derivative is as follows:

[0037]

[0038] In some embodiments, the N-allyl amide is selected from the following structural formula:

[0039]

[0040] In some embodiments, the catalyst is tungsten hexacarbonyl, tungsten tricarbonyl triacetonitrile, molybdenum hexacarbonyl, manganese bromide pentacarbonyl, rhenium bromide pentacarbonyl or dirhenium decacarbonyl; and the molar ratio of the N-allyl amide compound to the catalyst is 1:(0.05-0.2).

[0041] In some embodiments, the additive is acetic acid, benzoic acid, pivalic acid, triethylamine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium pivalate, sodium carbonate, sodium bicarbonate, lithium hydroxide, lithium carbonate, potassium tert-butoxide, potassium hydroxide, dipotassium hydrogen phosphate, cesium fluoride, cesium carbonate or pinacol; the molar ratio of the N-allyl amide compound to the additive is 1:(0.1-2).

[0042] In some embodiments, the organic solvent includes acetonitrile, 1,4-dioxane, acetone, tetrahydrofuran, N,N-dimethylformamide, dichloroethane, toluene, trifluorotoluene or dimethyl sulfoxide; the dosage ratio of the N-allylamide compound to the organic solvent is 0.2 mmol:1 to 3 mL.

[0043] In some embodiments, the reaction is carried out under the protection of an inert gas, the reaction temperature is 70 to 120° C., and the reaction time is 12 to 48 hours.

[0044] In some embodiments, the inert gas is nitrogen and / or argon.

[0045] In some embodiments, the reaction further comprises a separation step and a purification step after completion.

[0046] In some embodiments, the separation step uses liquid extraction; and the purification step uses column chromatography.

[0047] In some embodiments, the extractant used in the liquid phase extraction is ethyl acetate.

[0048] In some embodiments, after the liquid extraction, the upper layer is collected, dried with anhydrous sodium sulfate, and ethyl acetate is evaporated to obtain crude crystals. After recrystallization, the crude crystals are chromatographed on a 200-400 mesh silica gel column, and the eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:1 to 15.

[0049] The principle of the present invention is that N-allyl amide is first coordinated with the catalyst, and zero-valent tungsten undergoes oxidative addition to obtain the corresponding π-allyl tungsten intermediate, which is then eliminated by β-hydrogen to obtain the final product.

[0050] In order to better understand the present invention, the content of the present invention is further explained below in conjunction with the embodiments, but the content of the present invention is not limited to the following embodiments.

[0051] Example 1

[0052] To a 25 mL Shrek tube, weighed N-allylbenzamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=5 / 1-4 / 1) to obtain a white solid with a yield of 83%, Z / E>95 / 5.

[0053] The reaction equation is as follows:

[0054]

[0055] The structural characterization data of the obtained target product are shown below:

[0056] 1 HNMR(400MHz,Chloroform-d)δ7.85-7.76(m,2H),7.68-7.56(m,1H),7.55-7.51(m,1H),7.50-7.44( m,2H),6.95(ddq,J=10.7,8.9,1.8Hz,1H),4.95(dq,J=9.0,7.1Hz,1H),1.71(dd,J=7.0,1.8Hz,3H).

[0057] The structure of the target compound is inferred from the above characterization data as follows:

[0058]

[0059] This is consistent with the data reported in the literature J.Am.Chem.Soc.2017,139,5133.

[0060] Example 2

[0061] To a 25 mL Shrek tube, weighed N-allyl-1-methyl-1H-indole-2-carboxamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=6 / 1-5 / 1) to obtain a white solid with a yield of 79%, Z / E=93 / 7.

[0062] The reaction equation is as follows:

[0063]

[0064] The structural characterization data of the obtained target product are shown below:

[0065] 1 HNMR (400MHz, DMSO-d6) δ9.62(d,J=9.9Hz,1H),7.67(d,J=7.9Hz,1H),7.55(d,J=8.4Hz,1H),7.31(s,1H),7.31-7.27(m,1H ),7.12(t,J=7.5Hz,1H),6.73(tt,J=9.8,1.8Hz,1H),4.87(dq,J=9.1,7.1Hz,1H),3.97(s,3H),1.74(dd,J=7.1,1.8Hz,3H).

[0066] 13 CNMR(100MHz,DMSO-d6)δ159.8,138.7,131.3,125.5,123.9,122.2,121.7,120.2,110.5,107.2,106.0,31.4,11.7.

[0067] HRMS (ESI) m / zcalcdforC 13 H 15 N2O+ [M+H] + 215.1179, found 215.1175.

[0068] The structure of the target compound is inferred from the above characterization data as follows:

[0069]

[0070] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, with the lowest IC 50 The value is 64.16uM.

[0071] Example 3

[0072] To a 25 mL Shrek tube, weighed N-allylcinnamamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=5 / 1-4 / 1) to obtain a white solid with a yield of 82%, Z / E>95 / 5.

[0073] The reaction equation is as follows:

[0074]

[0075] The structural characterization data of the obtained target product are shown below:

[0076] 1 HNMR(400MHz,Chloroform-d)δ7.72(d,J=15.6Hz,1H),7.54(d,J=4.3Hz,1H),7.52(d,J=2.0Hz,1H),7.41-7.35(m,3H),7.11(d,J= 10.8Hz,1H),6.89(ddq,J=10.8,9.0,1.8Hz,1H),6.47(d,J=15.5Hz,1H),4.89(dq,J=9.0,7.1Hz,1H),1.69(dd,J=7.0,1.8Hz,3H).

[0077] The structure of the target compound is inferred from the above characterization data as follows:

[0078]

[0079] This is consistent with the data reported in the literature Adv.Synth.Catal.2015,357,3321.

[0080] Example 4

[0081] To a 25 mL Shrek tube, weighed N-allyl-2-phenylacetamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=5 / 1-4 / 1) to obtain a white solid with a yield of 77%, Z / E=93 / 7.

[0082] The reaction equation is as follows:

[0083]

[0084] The structural characterization data of the obtained target product are shown below:

[0085] 1 HNMR(400MHz,Chloroform-d)δ7.42-7.37(m,2H),7.36-7.32(m,1H),7.32-7.28(m,2H),6.82(s,1H),6. 68(ddq,J=10.7,8.8,1.8Hz,1H),4.76(dq,J=8.6,7.1Hz,1H),3.66(s,2H),1.35(dd,J=7.0,1.7Hz,3H).

[0086] The structure of the target compound is inferred from the above characterization data as follows:

[0087]

[0088] This is consistent with the data reported in the literature Adv.Synth.Catal.2015,357,3321.

[0089] Example 5

[0090] To a 25 mL Shrek tube, weighed N-allyl-2,3,4,5,6-pentafluorobenzamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for full reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 5 / 1-4 / 1) to obtain a white solid with a yield of 75%, formula Z.

[0091] The reaction equation is as follows:

[0092]

[0093] The structural characterization data of the obtained target product are shown below:

[0094] 1 HNMR (400MHz, DMSO-d6) δ10.32(d,J=7.9Hz,1H),6.67(t,J=8.4Hz,1H),4.98(dq,J=9.1,7.1Hz,1H),1.66(dd,J=7.1,1.8Hz,3H).

[0095] 13 CNMR(100MHz,DMSO-d6)δ154.6,144.6,142.4,140.1,138.2,135.7,121.3,112.0,109.3,11.5.

[0096] 19 FNMR (376MHz, DMSO-d6) δ-141.60--141.76(m),-152.67(t,J=22.1Hz),-161.36--161.58(m).

[0097] HRMS (ESI) m / zcalcdforC 10 H7F5NO + [M+H] + 252.0442, found 252.0436.

[0098] The structure of the target compound is inferred from the above characterization data as follows:

[0099]

[0100] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, with the lowest IC 50The value is 65.71uM.

[0101] Example 6

[0102] To a 25 mL Shrek tube, weighed N-allyl-2-phenoxyacetamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 4 / 1-3 / 1) to obtain a white solid with a yield of 72%, Z / E>95 / 5.

[0103] The reaction equation is as follows:

[0104]

[0105] The structural characterization data of the obtained target product are shown below:

[0106] 1 HNMR(400MHz,Chloroform-d)δ8.08(s,1H),7.34(tt,J=7.5,2.5Hz,2H),7.05(t,J=7.4Hz,1H),6.97-6.93(m, 2H), 6.77 (ddq, J=10.7, 8.8, 1.8Hz, 1H), 4.94 (dq, J=9.1, 7.1Hz, 1H), 4.57 (s, 2H), 1.64 (dd, J=7.1, 1.8Hz, 3H).

[0107] The structure of the target compound is inferred from the above characterization data as follows:

[0108]

[0109] This is consistent with the data reported in the literature Adv.Synth.Catal.2015,357,3321.

[0110] Example 7

[0111] To a 25 mL Shrek tube, weighed 2-allyl-2-azaspiro[4.5]decan-1-one (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for full reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=6 / 1-5 / 1) to obtain a white solid with a yield of 84%, Z / E>95 / 5.

[0112] The reaction equation is as follows:

[0113]

[0114] The structural characterization data of the obtained target product are shown below:

[0115] 1 HNMR(400MHz,Chloroform-d)δ6.88(dq,J=14.3,1.7Hz,1H),4.92(dq,J=13.5,6.7Hz,1H),3. 22(s,2H),2.33(s,2H),1.72(dd,J=6.7,1.6Hz,3H),1.62(d,J=7.2Hz,2H),1.51-1.47(m,8H).

[0116] 13 CNMR(100MHz,Chloroform-d)δ171.9,124.6,106.8,57.0,44.5,37.3,36.1,25.6,23.0,15.3.

[0117] HRMS (ESI) m / zcalcdforC 12 H 20 NO + [M+H] + 194.1539, found 194.1536.

[0118] The structure of the target compound is inferred from the above characterization data as follows:

[0119]

[0120] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, IC 50 >80uM.

[0121] Example 8

[0122] To a 25 mL Shrek tube, weighed 3-allyl-7,8-dimethoxy-1,3-dihydro-2H-benzazepin-2-one (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for full reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=5 / 1-4 / 1) to obtain a white solid with a yield of 35%, formula Z.

[0123] The reaction equation is as follows:

[0124]

[0125] The structural characterization data of the obtained target product are shown below:

[0126] 1 HNMR(400MHz,Chloroform-d)δ7.01(dd,J=14.2,1.8Hz,1H),6.80(s,1H),6.75(s,1H),6.48(d,J=9.1Hz,1H),6.34 (d,J=9.1Hz,1H),5.27(dq,J=13.6,6.7Hz,1H),3.89(s,3H),3.88(s,3H),3.49(s,2H),1.74(dd,J=6.8,1.7Hz,3H).

[0127] 13 CNMR(100MHz,Chloroform-d)δ167.2,150.2,148.3,127.8,126.5,125.5,125.1,119.0,113.6,111.4,109.8,56.2,43.1,15.5.

[0128] HRMS (ESI) m / zcalcdforC 15 H 18 NO3 + [M+H] + 260.1281, found 260.1276.

[0129] The structure of the target compound is inferred from the above characterization data as follows:

[0130]

[0131] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, IC 50 >80uM.

[0132] Example 9

[0133] To a 25 mL Shrek tube, weighed N-(2-methylallyl)benzamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 5 / 1-4 / 1) to obtain a white solid with a yield of 86%.

[0134] The reaction equation is as follows:

[0135]

[0136] The structural characterization data of the obtained target product are shown below:

[0137] 1 HNMR(400MHz,Chloroform-d)δ7.79(dd,J=6.9,1.5Hz,2H),7.55-7.50(m,1H),7.4 6(t,J=7.3Hz,2H),7.40(s,1H),6.75(d,J=10.3Hz,1H),1.78(s,3H),1.72(s,3H).

[0138] The structure of the target compound is inferred from the above characterization data as follows:

[0139]

[0140] This is consistent with the data reported in the literature Adv.Synth.Catal.2023,365,605.

[0141] Example 10

[0142] To a 25 mL Shrek tube, weighed tert-butyl (2-methylallyl)carbamate (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=15 / 1-10 / 1) to obtain a white solid with a yield of 68%.

[0143] The reaction equation is as follows:

[0144]

[0145] The structural characterization data of the obtained target product are shown below:

[0146] 1 HNMR(400MHz,Chloroform-d)δ6.22(d,J=10.6Hz,1H),5.92(d,J=8.0Hz,1H),1.66(s,3H),1.56(s,3H),1.46(s,9H).

[0147] The structure of the target compound is inferred from the above characterization data as follows:

[0148]

[0149] This is consistent with the data reported in the literature (J.Am.Chem.Soc., 2007, 129, 292).

[0150] Embodiment 11

[0151] To a 25 mL Shrek tube, weighed N-(2-phenylallyl)benzamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for full reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 8 / 1-6 / 1) to obtain a white solid with a yield of 40%, Formula E.

[0152] The reaction equation is as follows:

[0153]

[0154] The structural characterization data of the obtained target product are shown below:

[0155] 1 HNMR(400MHz,Chloroform-d)δ7.89-7.84(m,2H),7.72(d,J=11.3Hz,1H),7.59-7.55(m,1H),7.52-7.4 8(m,2H),7.46-7.42(m,3H),7.35(dd,J=8.5,6.9Hz,2H),7.24(d,J=7.3Hz,1H),2.14(d,J=1.3Hz,3H).

[0156] The structure of the target compound is inferred from the above characterization data as follows:

[0157]

[0158] This is consistent with the data reported in the literature J.Am.Chem.Soc.2017,139,5133.

[0159] Example 12

[0160] To a 25 mL Shrek tube, weighed ethyl 2-(acetylaminomethyl)acrylate (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), pinacol (0.6 mmol) and tetrahydrofuran (4 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for full reaction for 12 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. It was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 3 / 1-2 / 1) to obtain a white solid with a yield of 75%, Formula E.

[0161] The reaction equation is as follows:

[0162]

[0163] The structural characterization data of the obtained target product are shown below:

[0164] 1 HNMR(400MHz,DMSO-d6)δ9.88(d,J=11.6Hz,1H),7.83(dd,J=11.7,1.0Hz,1H),4 .10(q,J=7.1Hz,2H),2.07(s,3H),1.79(d,J=1.1Hz,3H),1.21(t,J=7.1Hz,3H).

[0165] 13CNMR(100MHz,DMSO-d6)δ169.0,168.0,132.4,106.4,59.9,22.8,14.4,11.0.

[0166] HRMS (ESI) m / z calculation for C8H 14 NO3 + [M+H] + 172.0968, found 172.0963.

[0167] The structure of the target compound is inferred from the above characterization data as follows:

[0168]

[0169] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, with the lowest IC 50 The value is 62.94uM.

[0170] Example 13

[0171] To a 25 mL Shrek tube, weighed N-allyl-2-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)acetamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, and the nitrogen was replaced, filled with nitrogen, and placed in a 100°C oil bath for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. It was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 6 / 1-5 / 1) to obtain a light yellow liquid with a yield of 71%, and Z / E>95 / 5.

[0172] The reaction equation is as follows:

[0173]

[0174] The structural characterization data of the obtained target product are shown below:

[0175] 1HNMR(400MHz,Chloroform-d)δ8.16(d,J=10.3Hz,1H),6.72(ddq,J=10.6,8.7,1.8Hz,1H),4.87(dq,J=9.0,7.1Hz,1H),4.14 (d,J=15.4Hz,1H),3.90(d,J=15.3Hz,1H),3.19(td,J=10.6,4.2Hz,1H),2.18(hd,J=7.0,2.9Hz,1H),2.07(dtd,J=12.1,3.8, 1.9Hz,1H),1.65(dt,J=9.3,3.4Hz,2H),1.62(dd,J=7.0,1.8Hz,3H),1.41-1.34(m,1H),1.33-1.27(m,1H),1.02(td,J=13.3 ,12.7,3.7Hz,1H),0.94(d,J=2.1Hz,3H),0.92(d,J=1.5Hz,3H),0.91-0.88(m,1H),0.88-0.83(m,1H),0.81(d,J=7.0Hz,3H).

[0176] 13 CNMR(100MHz,Chloroform-d)δ167.7,121.0,106.4,80.9,67.8,48.3,40.4,34.5,31.5,26.5,23.4,22.3,21.0,16.5,10.7.

[0177] HRMS (ESI) m / zcalcdforC 15 H 28 NO2 + [M+H] + 254.2115, found 254.2108.

[0178] The structure of the target compound is inferred from the above characterization data as follows:

[0179]

[0180] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, with the lowest IC 50 The value is 48.69uM.

[0181] Embodiment 14

[0182] To a 25 mL Shrek tube, weighed tert-butyl (3-(allylamino)-3-oxopropyl)carbamate (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), pinacol (0.6 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for sufficient reaction for 12 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=4 / 1-3 / 1) to obtain a white solid with a yield of 58% and Z / E=94 / 6.

[0183] The reaction equation is as follows:

[0184]

[0185] The structural characterization data of the obtained target product are shown below:

[0186] 1 HNMR(400MHz,Chloroform-d)δ7.28(s,1H),6.70(ddq,J=10.7,8.9,1.8Hz,1H),5.12(s,1H),4.82(dq,J =9.1,7.1Hz,1H),3.44(q,J=6.2Hz,2H),2.51(t,J=6.0Hz,2H),1.62(dd,J=7.1,1.8Hz,3H),1.43(s,9H).

[0187] The structure of the target compound is inferred from the above characterization data as follows:

[0188]

[0189] This is consistent with the data reported in the literature J.Am.Chem.Soc.2017,139,5133.

[0190] Embodiment 15

[0191] To a 25 mL Shrek tube, weighed tert-butyl ((2S)-1-((1-hydroxybut-3-en-2-yl)amino)-1-oxopropane-2-yl)carbamate (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, and nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for sufficient reaction for 12 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=2 / 1-1 / 1) to obtain a white solid with a yield of 68%, formula Z.

[0192] The reaction equation is as follows:

[0193]

[0194] The structural characterization data of the obtained target product are shown below:

[0195] 1 HNMR(400MHz,Chloroform-d)δ8.15(s,1H),5.07(q,J=7.0Hz,1H),4.88(s,1H),4.38(s,1H) ,4.30-4.22(m,1H),4.16(s,2H),1.63(d,J=7.0Hz,3H),1.46(s,9H),1.40(d,J=7.1Hz,3H).

[0196] The structure of the target compound is inferred from the above characterization data as follows:

[0197]

[0198] This is consistent with the data reported in the literature J.Am.Chem.Soc.2017,139,5133.

[0199] Example 16

[0200] To a 25 mL Shrek tube, weighed tert-butyl (S)-(2-((1-(allylamino)-4-methyl-1-oxopentan-2-yl)amino)-2-oxoethyl)carbamate (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, and nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for sufficient reaction for 48 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=3 / 1-2 / 1) to obtain a white solid with a yield of 66%, formula Z.

[0201] The reaction equation is as follows:

[0202]

[0203] The structural characterization data of the obtained target product are shown below:

[0204] 1 HNMR(400MHz,Chloroform-d)δ8.12(d,J=10.6Hz,1H),6.75(d,J=8.1Hz,1H),6.63(ddq ,J=10.6,8.8,1.7Hz,1H),5.22(t,J=5.9Hz,1H),4.84(dq,J=9.0,7.1Hz,1H),4.49(td,J =8.4,5.6Hz,1H),3.88-3.74(m,2H),1.75-1.69(m,1H),1.69-1.64(m,1H),1.62(dd,J=7 .1,1.8Hz,3H),1.58(dd,J=13.3,4.3Hz,1H),1.44(s,9H),0.93(dd,J=11.7,6.2Hz,6H).

[0205] 13 CNMR(100MHz,Chloroform-d)δ170.5,169.4,156.2,121.7,107.3,80.7,51.9,44.5,40.2,28.4,24.8,23.1,22.1,11.2

[0206] HRMS (ESI) m / zcalcdforC 16 H 30 N3O4 + [M+H] + 328.2231, found 328.2222.

[0207] The structure of the target compound is inferred from the above characterization data as follows:

[0208]

[0209] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, IC 50 >80uM.

[0210] Embodiment 17

[0211] To a 25 mL Shrek tube, weighed tert-butyl (S)-2-(((S)-1-((2-(allylamino)-2-oxoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, and nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100° C. for sufficient reaction for 12 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate=1 / 1-ethyl acetate) to obtain a white solid with a yield of 71% and Z / E=94 / 6.

[0212] The reaction equation is as follows:

[0213]

[0214] The structural characterization data of the obtained target product are shown below:

[0215] 1 HNMR(400MHz,DMSO-d6)δ9.23(d,J=10.3Hz,1H),8.24(dt,J=10.3,5.0Hz,1H),7.78(d,J=8.4Hz ,1H),6.51(ddq,J=10.7,8.9,1.7Hz,1H),4.70(dq,J=9.1,7.1Hz,1H),4.28-4.16(m,1H),4.12( t,J=7.7Hz,1H),3.84(t,J=5.0Hz,2H),3.40-3.33(m,1H),3.30-3.21(m,1H),2.15-1.92(m,2H) ,1.89-1.69(m,3H),1.63(dd,J=7.0,1.2Hz,3H),1.35(d,J=28.7Hz,9H),0.88(t,J=7.3Hz,6H).

[0216] 13CNMR(100MHz,DMSO-d6)δ172.5,171.4,166.9,153.4,121.9,105.2,78.4,59.3,58.0,46.5,41.8,31.1,30.4,28.0,23.0,19.3,18.4,11.2.

[0217] HRMS (ESI) m / zcalcdforC 20 H 35 N4O5 + [M+H] + 411.2602, found 411.2593.

[0218] The structure of the target compound is inferred from the above characterization data as follows:

[0219]

[0220] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, IC 50 >80uM.

[0221] Embodiment 18

[0222] To a 25 mL Shrek tube, weighed N-allyl-4-(N,N-dipropylaminosulfonyl)benzamide (0.4 mmol), hexacarbonyl tungsten (0.04 mmol), lithium hydroxide (0.1 mmol) and tetrahydrofuran (4 mL) were added in sequence, the nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction was completed, water was used to quench the reaction, and ethyl acetate (15 mL×3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 4 / 1-3 / 1) to obtain a white solid with a yield of 71% and Z / E>95 / 5.

[0223] The reaction equation is as follows:

[0224]

[0225] The structural characterization data of the obtained target product are shown below:

[0226] 1HNMR (400MHz, DMSO-d6) δ9.84(d,J=9.2Hz,1H),8.05(d,J=1.8Hz,1H),8.04(d,J=2.0Hz,1H),7.90(d,J=2.0Hz,1H),7.89(d,J=1.9Hz,1H),6.73( td,J=9.4,1.5Hz,1H),4.92(dq,J=9.0,7.1Hz,1H),3.12-2.99(m,4H),1.73(dd,J=7.1,1.8Hz,3H),1.48(h,J=7.4Hz,4H),0.82(t,J=7.4Hz,6H).

[0227] 13 CNMR(100MHz,DMSO-d6)δ164.1,142.0,137.7,129.0,126.8,122.6,108.6,49.8,21.7,11.8,11.1.

[0228] HRMS (ESI) m / zcalcdforC 16 H 25 N2O3S + [M+H] + 325.1580, found 325.1574.

[0229] The structure of the target compound is inferred from the above characterization data as follows:

[0230]

[0231] It was found that this class of compounds had an inhibitory effect on H1975 lung cancer cells, IC 50 >80uM.

[0232] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a Z-enamide derivative, characterized in that: N-allylamide, a catalyst and an additive are heated in an organic solvent in an oil bath for reaction to obtain a Z-enamide derivative; The Z-enamide derivative has a structure shown in Formula I: Formula I; Wherein, R1 is aryl, heteroaryl, alkyl, alkenyl, alkoxy or chiral amino; R2 is hydrogen, alkyl or alkenyl; R3 is hydrogen or alkyl; R4 is hydrogen, alkyl, phenyl, ester or bis-xanaphthene borate; R5 is hydrogen or bis-xanaphthene borate; wherein R1 and R2 can be connected to form a ring; The catalyst is tungsten hexacarbonyl; The additive is lithium hydroxide or pinacol.

2. The method for preparing a Z-enamide derivative according to claim 1, characterized in that: The Z-enamide derivative is selected from one of the following structural formulas: 。 3. The preparation method according to claim 1, characterized in that: The structural formula of the N-allylamide is shown in Formula II: Formula II; Among them, R1 is aryl, heteroaryl, alkyl, alkenyl, alkoxy or chiral amino; R2 is hydrogen, alkyl or alkenyl; R3 is hydrogen or alkyl; R4 is hydrogen, alkyl, phenyl, ester or bis-xanaphoyl borate; R5 is hydrogen or bis-xanaphoyl borate; wherein R1 and R2 can be connected to form a ring.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the N-allylamide compound to the catalyst is 1:0.05-0.

2.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the N-allylamide compound to the additive is 1:0.1-2.

6. The preparation method according to claim 1, characterized in that: The organic solvent includes acetonitrile, 1,4-dioxane, acetone, tetrahydrofuran, N,N-dimethylformamide, dichloroethane, toluene, trifluorotoluene or dimethyl sulfoxide; the dosage ratio of the N-allylamide compound to the organic solvent is 0.2 mmol:1~3 mL.

7. The preparation method according to claim 1, characterized in that: The reaction is carried out under the protection of an inert gas, at a temperature of 70 to 120° C., for a time of 12 to 48 hours.

8. The preparation method according to claim 1, characterized in that: After the reaction is completed, the steps of separation and purification are also included.

9. The preparation method according to claim 8, characterized in that: The separation step adopts liquid extraction; the purification step adopts column chromatography.

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