Preparation method and application of oligo-amide and cyclic peptide based on inert amido bond insertion

Abstract

The invention provides a preparation method and application of oligo-amide and cyclic peptide based on inert amido bond insertion, and the preparation method comprises the following steps: mixing and reacting an amide compound with 2, 1-benzisoxazole salt and Lewis base to obtain the oligo-amide or cyclic peptide. The preparation method provided by the invention is simple to operate, avoids the use of transition metals and expensive ligands, is good in reaction economy, free of generation of byproducts in the reaction process, good in atom economy, mild in reaction condition, safe and efficient, has good substrate applicability, avoids de novo synthesis, is widely applied to later modification of drug molecules, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of oligopeptides and cyclic peptides based on the insertion of inert amide bonds. Background Art

[0002] Organic nitrogen-containing compounds widely exist in nature as an important vital substance and chemical intermediate, and the study of the properties of C-N bonds in nitrogen-containing compounds has become a hot topic in organic chemistry and biochemistry.

[0003] Amides are a class of important organic amines containing inert C-N bonds and are one of the most widely used elements in pharmaceuticals, pesticides, and functional materials. The strong resonance between the nitrogen lone pair and the carbonyl antibonding orbital makes the C-N bond in amides highly stable and rigid, and these properties are important factors determining the conformations of polypeptides, proteins, and related compounds. However, the remarkable stability of amides also means that the selective cleavage of amide bonds in organic reactions is very difficult. The cleavage of the amide C-N bond is mainly achieved through cross-coupling reactions, esterification reactions, and transamidation reactions. Zou et al. reported an efficient metal Pd-catalyzed acylation cross-coupling reaction of carboxamides with arylboronic acids by synergistically activating the C-N bond through independent modification of the activating group (Li, X.; Zou, G., Acylative Suzuki coupling of amides: acyl-nitrogen activation via synergy of independently modifiable activating groups. Chemical Communications 2015, 51(24), 5089-5092). The Garg team reported the activation of the amide C-N bond catalyzed by metal Ni, and the conversion of amides to esters through nucleophilic reactions with alcohols (Dander, J. E.; Garg, N. K., Breaking amides using nickel catalysis. ACS Catalysis 2017, 7(2), 1413-1423). Szostak et al. reported that under highly chemoselective conditions, N-Boc-activated secondary amides form products after amide exchange under the action of a Pd catalyst (Meng G, Lei P, Szostak M., A general method for two-step transamidation of secondary amides using commercially available, air- and moisture-stable palladium / NHC (N-heterocyclic carbene) complexes. Organic Letters 2017, 19(8), 2158-2161).

[0004] However, the above methods for transition metal-catalyzed amide C-N bond cleavage waste the amino part of the amide, showing inherent low atom economy. Therefore, a method for aminoacylation that incorporates both parts after amide C-N bond cleavage into the product to achieve multiple chemical bonds is of great value. Pintori et al. (Pintori, D.G.; Greaney, M.F., Insertion of benzene rings into the amide bond: One-step synthesis of acridines and acridones from aryl amides. Organic Letters 2010, 12(1), 168-171) and Zhang et al. (Zhang, Z., Yang, Y., Yu, Z., Xia, J., Lewis base-catalyzed amino-acylation of aryl allenes via C–N bond cleavage: Reaction development and mechanistic studies. ACS Catalysis 2020, 10(10), 5419-5429) reported aminoacylation reactions in which benzene rings and aryl alkenes were inserted into the amide bond after amide activation. Liu et al. reported an amide structure amplification reaction in which amino acids were inserted into the amide bond after in-situ activation of the amide (Liu, Z., Zhou, L., Liu, W.H., Amide skeletal elongation via amino acid insertion. Chemistry - A European Journal 2023, 29(46), e202301729). Although widely applied, these strategies require pre-activated or in-situ activated amide C-N bonds, limiting their late-stage applications.

[0005] In recent years, mild conditions and metal-free catalysis have become a new direction for the development of aminoacylation reactions of multiple chemical bonds. Currently, there are few studies on the aminoacylation and skeletal amplification of amide C-N bonds, and the methods are limited, requiring researchers to conduct deeper, broader research, exploration, development, and application of new methods and strategies. Oligoamides and cyclic peptides are structures widely present in drug molecules and natural products. Developing effective methods for synthesizing oligoamides and cyclic peptides is of great help for the preparation of drug molecules. However, there is currently no economical and mild-condition method for preparing oligoamides and cyclic peptides. Therefore, how to provide an economical and efficient method for preparing oligoamides and cyclic peptides has become an urgent problem to be solved. Summary of the Invention

[0006] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a preparation method and application of oligamide and cyclic peptide based on inert amide bond insertion. The preparation method provided by the present invention is simple in operation, avoids the use of transition metals and expensive ligands, has good reaction economy, no by-products are generated during the reaction process, has good atom economy, mild reaction conditions, is safe and efficient, has good substrate applicability, avoids de novo synthesis, is widely used in the late modification of drug molecules, and is suitable for large-scale production.

[0007] To achieve the purpose of this invention, the following technical solutions are adopted in the present invention:

[0008] On the one hand, the present invention provides a preparation method of oligamide and cyclic peptide based on inert amide bond insertion, and the preparation method includes the following steps:

[0009] Mix an amide compound with 2,1-benzisoxazolium salt and a Lewis base for reaction to obtain the oligamide or cyclic peptide;

[0010] The structure of the oligamide is shown as compound II’, and the structure of the cyclic peptide is shown as compound III’.

[0011] The reaction formula is shown as formula I or II:

[0012]

[0013] In the formula, R 1 , R 2 , R 3 , R 4 are independently selected from any one of hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C1-C12 alkoxy, substituted or unsubstituted C5-C12 aryl, and substituted or unsubstituted C4-C12 heteroaryl. The substituted groups are selected from any one of C1-C12 alkyl, C1-C12 alkoxy, C5-C12 aryl, C4-C12 heteroaryl, hydroxyl, amino, acyl, amido, nitro, carboxyl, halogen, sulfone, sulfoxide, and ester; the substituted groups exist independently or any two adjacent groups are connected to form a cyclic structure.

[0014] X - is selected from CF3SO2O - , BF4 - or ClO4 - .

[0015] Y is selected from O or S.

[0016] n represents the number of atoms in the ring structure of the lactam compound III and is selected from an integer of 4-40.

[0017] Among them, C1-C12 alkyl groups can be, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.; C3-C12 cycloalkyl groups can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; C1-C12 alkoxy groups can be, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.; C5-C12 aryl groups can be, for example, benzene, biphenyl, naphthalene, etc.; C4-C12 heteroaryl groups can be, for example, thiazolyl, thienyl, pyridyl, pyrimidinyl, quinolinyl, thiazinyl, pyrazinyl, etc.

[0018] The above preparation method is simple to operate. The synthesis can be achieved only through one-step reaction, avoiding the use of transition metals and expensive ligands. It has good reaction economy, no by-products are generated during the reaction process, good atom economy, mild reaction conditions, is safe and efficient, has good substrate applicability, avoids de novo synthesis, is widely used in the late modification of drug molecules, and is suitable for large-scale production.

[0019] Preferably, the Lewis base includes an organic base and / or an inorganic base.

[0020] Preferably, the organic base includes any one or a combination of at least two of triethylamine, potassium tert-butoxide, p-dimethylaminopyridine, N,N-diisopropylethylamine, or tetramethylethylenediamine.

[0021] Preferably, the inorganic base includes any one or a combination of at least two of sodium carbonate, cesium carbonate, potassium phosphate, or potassium acetate.

[0022] Preferably, the Lewis base is an organic base.

[0023] Preferably, the product is an oligomeric amide and the organic base is triethylamine.

[0024] Preferably, the product is a cyclic peptide and the organic base is tetramethylethylenediamine.

[0025] Preferably, the product is an oligomeric amide, and the molar ratio of the amide compound to the 2,1-benzisoxazolium salt is (1.2-1.5):1, such as 1.2:1, 1.3:1, 1.4:1, or 1.5:1, etc., but not limited to the values listed above. Other unlisted values within the above numerical range are equally applicable.

[0026] Preferably, the product is a cyclic peptide, and the molar ratio of the amide compound to the 2,1-benzisoxazolium salt is 1:(1.2-1.5), such as 1:1.2, 1:1.3, 1:1.4, or 1:1.5, etc., but not limited to the values listed above. Other unlisted values within the above numerical range are equally applicable.

[0027] Preferably, the product is an oligoamide, and the solvent for the reaction includes any one or a combination of at least two of acetonitrile, dichloromethane, or chloroform, preferably dichloromethane.

[0028] Preferably, the product is a cyclic peptide, and the solvent for the reaction includes any one or a combination of at least two of dichloromethane, toluene, or anisole, preferably anisole.

[0029] Preferably, the reaction is carried out in an inert gas environment.

[0030] Preferably, the temperature of the reaction is 10 - 70 °C, such as 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, or 70 °C, etc., but not limited to the values listed above, and other unlisted values within the above numerical range are equally applicable.

[0031] The above specific reagents and parameters can effectively improve the yield of the reaction and can more effectively prepare the product.

[0032] On the other hand, the present invention also provides the application of the preparation method as described above in the preparation of drug molecules.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The present invention provides a preparation method of oligoamide and cyclic peptide based on inert amide bond insertion. This preparation method is simple to operate, and the synthesis can be achieved only through one-step reaction, avoiding the use of transition metals and expensive ligands. The reaction has good economy, no by-products are generated during the reaction process, good atom economy, mild reaction conditions, is safe and efficient, has good substrate applicability, avoids de novo synthesis, is widely used in the late modification of drug molecules, and is suitable for large-scale production. Detailed Embodiments

[0035] To further elaborate on the technical means and effects adopted by the present invention, the following further illustrates the technical solution of the present invention in combination with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0036] Using linear secondary amide (I) and N-alkyl-2,1-benzoxazole tetrafluoroborate (II) as reaction raw materials, Et3N as a Lewis base, and CH2Cl2 as a solvent, under the protection of argon at 60 °C, novel aminoacylated amplified products after the ring-opening of 2,1-benzisoxazole with different substitutions were obtained.

[0037] Example 1

[0038]

[0039] Add 1-methyl-2,1-benzisoxazolium tetrafluoroborate (44.2 mg, 0.2 mmol), N-phenylbenzamide (59.2 mg, 0.3 mmol), Et3N (0.4 mmol) and CH2Cl2 (1 mL) to a 5 mL clean reaction flask. Then, under an argon atmosphere, place the reaction flask at 60 °C and stir the reaction. After the reaction system has continued for 12 h, stop the reaction, distill off the solvent under reduced pressure, and separate the residue by column chromatography to obtain the target product N-methyl-N-(2-(phenylcarbamoyl)phenyl)benzamide, a white solid, with a yield of 80%.

[0040] cis / trans = 8.7:1

[0041] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.42 (s, 1H trans ), 10.23 (s, 1H cis ), 7.70 (d, J = 7.8 Hz, 2H cis+trans ), 7.55 (d, J = 7.0 Hz, 1H cis+trans ), 7.45 (s, 1H cis+trans ), 7.37–7.33 (m, 6H cis +trans ), 7.25–7.11 (m, 4H cis+trans ), 3.29 (s, 3H cis+trans ).

[0042] Example 2

[0043]

[0044] Replace the N-phenylbenzamide used in Example 1 with an equimolar amount of N-phenylfuran-2-carboxamide, and the remaining steps are the same as in Example 1 to obtain the target product N-methyl-N-(2-(phenylcarbamoyl)phenyl)furan-2-carboxamide with the structure as above, a white solid, with a yield of 78%.

[0045] cis / trans > 20:1

[0046] 1 H NMR (600 MHz, DMSO-d6): δ cis= 10.23 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.61–7.58 (m, 4H), 7.54 (t, J = 7.5 Hz, 1H), 7.43 (dd, J = 8.0, 1.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H), 6.34 (s, 1H), 5.84 (s, 1H), 3.27 (s, 3H).

[0047] Example 3

[0048]

[0049] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-phenylformamide, and the remaining steps were the same as those in Example 1, to obtain the target product 2-(N-methylformamido)-N-phenylbenzamide with the structure as above, a white solid, with a yield of 53%.

[0050] cis / trans = 5.7:1

[0051] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.47 (s, 1H cis ), 10.35 (s, 1H trans ), 8.19 (s, 1H cis ), 8.18 (s, 1H trans ), 7.72–7.57 (m, 4H cis+trans ), 7.51–7.46 (m, 2H cis+trans ), 7.40–7.31 (m, 2H cis+trans ), 7.12–7.06 (m, 1H cis+trans ), 3.33 (s, 3H trans ), 3.13 (s, 3H cis ).

[0052] Example 4

[0053]

[0054] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of 2,2,2-trifluoro-N-phenylethanamide, and the remaining steps were the same as those in Example 1, to obtain the target product N-phenyl-2-(2,2,2-trifluoro-N-methylacetamido)benzamide with the structure as above, a white solid, with a yield of 58%.

[0055] cis / trans = 5.0:1

[0056] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.50 (s, 1H cis ), 10.46 (s, 1H trans ), 7.80 (dd, J = 7.5, 1.4 Hz, 1H cis ), 7.72 (d, J = 8.1 Hz, 1H trans ), 7.70 (d, J = 7.9 Hz, 2H cis+trans ), 7.69–7.65 (m, 1H cis+trans ), 7.64–7.61 (m, 1H cis ), 7.57 (d, J = 7.6 Hz, 1H cis ), 7.55–7.52 (m, 2H trans ), 7.36–7.31 (m, 2H cis+trans ), 7.11 (t, J = 7.4 Hz, 1H cis ), 7.08 (d, J = 7.4 Hz, 1H trans ), 3.46 (s, 3H trans ), 3.25 (s, 3H cis ).

[0057] Example 5

[0058]

[0059] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-(4-iodophenyl)cyclopropanecarboxamide, and the remaining steps were the same as in Example 1 to obtain the target product N-(4-iodophenyl)-2-(N-methylcyclopropanecarboxamido)benzamide with the structure as above, a white solid, and the yield was 53%.

[0060] cis / trans = 19.0:1

[0061] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.49 (d, J = 1.8 Hz, 1H cis ), 10.29 (d, J = 1.1 Hz, 1H trans ), 7.68 (d, J = 8.3 Hz, 3H cis+trans ), 7.63 (t, J = 7.7 Hz, 1H cis ), 7.53 (t, J = 7.5 Hz, 3H cis+trans ), 7.49 (d, J = 7.8 Hz, 1H cis ), 7.38 (t, J = 7.3 Hz, 1H trans), 7.32 (d, J = 7.9 Hz, 1H trans ), 3.48 (s, 3H trans ), 3.14 (d, J = 3.6 Hz, 3H cis ), 1.25 (d, J = 4.3 Hz, 1H cis+trans ), 0.70 (s, 1H cis+trans ), 0.52 (d, J = 7.0 Hz, 3H cis+trans ).

[0062] Example 6

[0063]

[0064] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of N-(2-oxo-2H-chromen-3-yl)acetamide, and the remaining steps were the same as in Example 1 to obtain the target product 2-(N-methylacetamido)-N-(2-oxo-2H-chromen-3-yl)benzamide with the structure as above, a white solid, with a yield of 52%.

[0065] cis / trans = 6.3:1

[0066] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.09 (s, 1H cis ), 9.42 (s, 1H trans ), 8.67 (s, 1H cis+trans ), 7.82–7.77 (m, 1H cis+trans ), 7.71 (dd, J = 7.6, 1.2 Hz, 1H cis+trans ), 7.63 (t, J = 7.7 Hz, 1H cis+trans ), 7.56–7.52 (m, 2H cis+trans ), 7.47–7.43 (m, 2H cis+trans ), 7.37 (t, J = 7.5 Hz, 1H cis+trans ), 3.39 (s, 3H trans ), 3.10 (s, 3H cis ), 2.16 (s, 3H trans ), 1.74 (s, 3H cis ).

[0067] Example 7

[0068]

[0069] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-N-(2,2,2-trifluoroethyl)acetamide, and the remaining steps were the same as in Example 1, to obtain the target product 2-(2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-N-methylacetamido)-N-(2,2,2-trifluoroethyl)benzamide, a white solid, with a yield of 36%.

[0070] cis / trans = 13.3:1

[0071] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 9.29 (t, J = 6.4 Hz, 1H cis ), 8.93 (t, J = 6.3 Hz, 1H trans ), 7.60–7.57 (m, 1H cis+trans ), 7.54 (dd, J = 7.6, 1.6 Hz, 1H cis+trans ), 7.52–7.49 (m, 1H cis ), 7.48–7.46 (m, 1H trans ), 7.46–7.44 (m, 1H cis ), 7.39–7.37 (m, 1H trans ), 7.27 (d, J = 4.8 Hz, 1H trans ), 7.26 (d, J = 5.1 Hz, 1H cis ), 6.78 (d, J = 5.1 Hz, 1H trans ), 6.74 (d, J = 5.1 Hz, 1H cis ), 4.09–4.00 (m, 1H cis+trans ), 3.75–3.67 (m, 1H cis+trans ), 3.53–3.44 (m, 2H cis+trans ), 3.34 (s, 3H trans ), 3.16–3.02 (m, 2H cis+trans ), 3.04 (s, 3H cis ), 2.84–2.82 (m, 4H trans ), 2.66–2.57 (m, 4H cis )。

[0072] Example 8

[0073]

[0074] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of N-hexylheptanamide, and the remaining steps were the same as in Example 1, to obtain the target product N-hexyl-2-(N-methylheptanamide)benzamide with the structure as above, a colorless transparent oil, with a yield of 37%.

[0075] cis / trans>20:1

[0076] 1 H NMR(600MHz,DMSO-d6):δ cis =8.36(t,J=5.6Hz,1H),7.53–7.49(m,1H),7.45–7.44(m,2H),7.32(d,J=7.7Hz,1H),3.15(dd,J=12.9,6.8Hz,2H),3.05(s,3H),1.96–1.91(m,1H),1.88–1.83(m,1H),1.45–1.35(m,4H),1.29–1.23(m,6H),1.19(dd,J=14.5,7.3Hz,2H),1.11–1.08(m,4H),0.86(t,J=7.0Hz,3H),0.80(t,J=7.3Hz,3H).

[0077] Example 9

[0078]

[0079] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of methyl benzoyl-glycinate, and the remaining steps were the same as in Example 1, to obtain the target product methyl (2-(N-methylbenzamido)benzoyl)glycinate with the structure as above, a white solid, with a yield of 62%.

[0080] cis / trans=11.5:1

[0081] 1 H NMR(600MHz,DMSO-d6):δ cis+trans =8.88(t,J=5.5Hz,1H cis ),8.80(s,1H trans ),7.49–7.47(m,1H cis+trans ),7.40(d,J=7.4Hz,2H cis+trans ),7.28–7.27(m,2H cis+trans ),7.21(t,J=7.2Hz,1H cis+trans ),7.15(t,J=7.4Hz,2H cis+trans ),7.04–7.02(m,1H cis+trans), 4.07 (dd, J = 17.2, 5.7 Hz, 1H cis+trans ), 3.95 (dd, J = 17.3, 5.5 Hz, 1H cis+trans ), 3.68 (s, 3H cis ), 3.61 (s, 3H trans ), 3.25 (s, 3H cis ), 3.18 (s, 3H trans ).

[0082] Example 10

[0083]

[0084] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of (2R,3S,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-azidotetrahydro-2H-pyran-3,4-diyl diacetate, and the remaining steps were the same as in Example 1 to obtain the target product (2R,3S,4R,5R,6R)-2-(acetoxymethyl)-6-azido-5-(2-(N-methylacetamido)benzamido)tetrahydro-2H-pyran-3,4-diyl diacetate with the structure as above, a white solid, and the yield was 61%.

[0085] cis / trans = 18.5:1

[0086] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.74 (d, J = 9.2 Hz, 1H cis ), 8.46 (d, J = 9.2 Hz, 1H trans ), 7.57 (t, J = 7.6 Hz, 1H cis+trans ), 7.52–7.49 (m, 1H cis+trans ), 7.39 (d, J = 7.8 Hz, 1H cis ), 7.35 (d, J = 7.6 Hz, 1H cis+trans ), 7.24 (d, J = 7.4 Hz, 1H trans ), 5.25 (t, J = 9.9 Hz, 1H trans ), 5.22–5.17 (m, 1H cis ), 4.98–4.97 (m, 1H cis+trans ), 4.96–4.94 (m, 1H cis ), 4.94–4.92 (m, 1H trans ), 4.21 (dd, J = 12.5, 4.9 Hz, 1H cis+trans), 4.10 (dd, J = 12.4, 2.0 Hz, 1H cis+trans ), 4.06–4.03 (m, 1H cis+trans ), 4.02–3.96 (m, 1H cis+trans ), 3.24 (s, 3H trans ), 3.06–3.02 (m, 3H cis ), 2.06 (s, 3H trans ), 2.04 (s, 3H cis+trans ), 2.00 (s, 3H cis ), 1.99 (s, 3H trans ), 1.98–1.97 (m, 3H cis ), 1.97 (s, 3H trans ), 1.68–1.63 (m, 3H cis ).

[0087] Example 11

[0088]

[0089] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of (2S,3S,4S,5S)-2-((3S,4R,5S,6S)-5-acetamido-4,6-diacetoxy-2-(acetoxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and the remaining steps were the same as in Example 1 to obtain the target product (3S,4S,5S,6S)-2-(acetoxymethyl)-6-(((3S,4R,5S,6S)-4,6-diacetoxy-2-(acetylmethyl)-5-(2-(N-methylacetamido)benzamido)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-3H-pyran-3,4,5-triyl triacetate having the structure above, a white solid, with a yield of 37%.

[0090] cis / trans = 15.7:1

[0091] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.84–8.78 (m, 1H cis+trans ), 7.56–7.53 (m, 1H cis +trans ), 7.48 (t, J = 7.4 Hz, 1H cis+trans ), 7.38–7.36 (m, 1H cis ), 7.34–7.33 (m, 1H trans), 7.26–7.25 (m, 1H cis ), 7.23–7.22 (m, 1H trans ), 5.98–5.96 (m, 1H cis ), 5.94 (d, J=3.4 Hz, 1H trans ), 5.23 (d, J=3.5 Hz, 1H cis+trans ), 5.22–5.15 (m, 2H cis+trans ), 4.86–4.83 (m, 1H cis+trans ), 4.75 (t, J=7.9 Hz, 1H cis+trans ), 4.40–4.36 (m, 1H cis+trans ), 4.32 (d, J=11.3 Hz, 1H cis+trans ), 4.26 (t, J=6.6 Hz, 1H cis+trans ), 4.08–4.03 (m, 3H cis+trans ), 3.98–3.95 (m, 1H cis+trans ), 3.93–3.89 (m, 1H cis+trans ), 3.03–3.01 (m, 3H trans ), 3.00–2.98 (m, 3H cis ), 2.17 (s, 3H trans ), 2.15 (s, 3H cis ), 2.11 (s, 3H cis ), 2.09 (s, 3H cis ), 2.05 (s, 3H trans ), 2.04–2.01 (m, 3H cis+trans ), 2.03 (s, 3H trans ), 2.02 (s, 6H cis+trans ), 1.90 (s, 3H cis+trans ), 1.64 (s, 3H cis+trans )。

[0092] Example 12

[0093]

[0094] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of the target product N-methyl-N-(2-(phenylcarbamoyl)phenyl)benzamide in Example 1, and the remaining steps were the same as in Example 1 to obtain the target product N-methyl-2-(N-methylbenzamido)-N-(2-(phenylcarbamoyl)phenyl)benzamide with the structure as above, a white solid, and the yield was 22%.

[0095] cis / trans = 2.8:1

[0096] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.67 (s, 1H trans ), 10.47 (s, 1H cis ), 7.80–7.68 (m, 3H cis+trans ), 7.54–7.05 (m, 14H cis+trans ), 7.01–6.81 (m, 1H cis+trans ), 3.39 (s, 1H cis +trans ), 3.30–3.11 (m, 5H cis+trans ).

[0097] Example 13

[0098]

[0099] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-phenylbenzothioamide, and the remaining steps were the same as in Example 1 to obtain the target product 2-(N-methylphenylthioamino)-N-phenylbenzamide with the structure as above, a yellow solid, and the yield was 46%.

[0100] cis / trans = 9.0:1

[0101] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.43 (s, 1H trans ), 10.23 (s, 1H cis ), 7.71 (d, J = 7.7 Hz, 2H cis+trans ), 7.55 (d, J = 7.0 Hz, 1H cis+trans ), 7.37–7.33 (m, 6H cis+trans ), 7.24 (t, J = 7.1 Hz, 1H cis+trans ), 7.20 (d, J = 7.5 Hz, 1H cis+trans ), 7.15–7.11 (m, 3H cis+trans ), 3.29 (s, 3H cis +trans ).

[0102] Example 14

[0103]

[0104] In Example 1, 1-methyl-2,1-benzisoxazole tetrafluoroborate used was replaced with an equimolar amount of 5-methoxy-1-methyl-2,1-benzisoxazole tetrafluoroborate, and the remaining steps were the same as those in Example 1, to obtain the target product 5-methoxy-2-(N-methylbenzamide)-N-phenylbenzamide with the structure as above, a white solid, with a yield of 85%.

[0105] cis / trans = 9.4:1

[0106] 1 H NMR(600MHz,DMSO-d6):δ cis+trans = 10.39(s,1H trans ),10.19(s,1H cis ),7.76(d,J = 5.8Hz,2H trans ),7.70(d,J = 7.9Hz,2H cis ),7.44–7.33(m,4H cis+trans ),7.24(t,J = 7.4Hz,1H cis ),7.20(s,1H trans ),7.16–7.11(m,4H cis+trans ),7.07(d,J = 2.8Hz,1H cis+trans ),6.93(dd,J = 8.7,2.9Hz,1H cis+trans ),3.86(s,3H trans ),3.76(s,3H cis ),3.25(s,3H cis ),3.20(s,3H trans ).

[0107] Example 15

[0108]

[0109] In Example 1, 1-methyl-2,1-benzisoxazole tetrafluoroborate used was replaced with an equimolar amount of 4-chloro-1-methylbenzo[c]isoxazole tetrafluoroborate, and the remaining steps were the same as those in Example 1, to obtain the target product 2-chloro-6-(N-methylbenzamide)-N-phenylbenzamide with the structure as above, a white solid, with a yield of 63%.

[0110] cis / trans>20:1

[0111] 1 H NMR(600MHz,DMSO-d6):δ cis= 10.76 (s, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.51–7.46 (m, 3H), 7.39 (t, J = 6.9 Hz, 2H), 7.27–7.24 (m, 4H), 7.15 (s, 1H), 7.07 (s, 1H), 3.28 (s, 3H).

[0112] Example 16

[0113]

[0114] In Example 1, the 1-methyl-2,1-benzisoxazolium tetrafluoroborate used was replaced with an equimolar amount of 6-bromo-1-methylbenzo[c]isoxazolium tetrafluoroborate, and the remaining steps were the same as in Example 1, to obtain the target product 4-bromo-2-(N-methylbenzamide)-N-phenylbenzamide with the structure as above, a white solid, with a yield of 66%.

[0115] cis / trans = 6.1:1

[0116] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.47 (s, 1H trans ), 10.20 (s, 1H cis ), 7.67 (d, J = 6.1 Hz, 2H cis+trans ), 7.58–7.56 (m, 2H cis+trans ), 7.48 (d, J = 6.7 Hz, 1H cis+trans ), 7.37–7.28 (m, 5H cis+trans ), 7.17–7.12 (m, 3H cis+trans ), 3.28 (s, 3H cis+trans ).

[0117] Example 17

[0118]

[0119] In Example 1, the 1-methyl-2,1-benzisoxazolium tetrafluoroborate used was replaced with an equimolar amount of 1-methylnaphtho[1,2-c]isoxazolium tetrafluoroborate, and the remaining steps were the same as in Example 1, to obtain the target product 1-(N-methylbenzamido)-N-phenyl-2-naphthamide with the structure as above, a white solid, with a yield of 45%.

[0120] cis / trans = 6.4:1

[0121] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans= 10.48 (s, 1H trans ), 10.16 (s, 1H cis ), 8.13–8.11 (m, 2H trans ), 8.06 (d, J = 8.2 Hz, 1H cis+trans ), 8.00 (t, J = 8.7 Hz, 2H cis ), 7.81–7.77 (m, 4H trans ), 7.73–7.70 (m, 3H cis+trans ), 7.64–7.60 (m, 2H cis ), 7.59–7.57 (m, 2H trans ), 7.51–7.50 (m, 2H trans ), 7.39–7.36 (m, 2H cis+trans ), 7.19 (dd, J = 8.2, 1.1 Hz, 2H cis ), 7.15–7.11 (m, 2H cis ), 6.98–6.95 (m, 2H cis ), 3.40 (s, 3H cis ), 3.30 (s, 3H trans ).

[0122] Example 18

[0123]

[0124] In Example 1, the 1-methyl-2,1-benzisoxazolium tetrafluoroborate used was replaced with an equimolar amount of 1-ethyl-2,1-benzisoxazolium tetrafluoroborate, and the remaining steps were the same as in Example 1 to obtain the target product N-ethyl-N-(2-(phenylcarbamoyl)phenyl)benzamide with the structure as above, a white solid, with a yield of 75%.

[0125] cis / trans > 20:1

[0126] 1 H NMR (600 MHz, DMSO-d6): δ cis = 10.38 (s, 1H), 7.74 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 6.6 Hz, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.37–7.30 (m, 4H), 7.23 (t, J = 7.1 Hz, 1H), 7.16–7.11 (m, 3H), 7.03 (d, J = 7.2 Hz, 1H), 4.21–4.15 (m, 1H), 3.35–3.31 (m, 1H), 1.11 (t, J = 6.9 Hz, 3H).

[0127] Example 19

[0128]

[0129] The 1-methyl-2,1-benzisoxazole tetrafluoroborate used in Example 1 was replaced with an equimolar amount of 3-(methoxycarbonyl)-1-methyl-2,1-benzisoxazole tetrafluoroborate, and the remaining steps were the same as in Example 1, to obtain the target product methyl 3-(N-methylbenzamido)-4-(phenylcarbamoyl)benzoate with the structure as above, a white solid, with a yield of 55%.

[0130] cis / trans = 4.9:1

[0131] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.60 (s, 1H trans ), 10.34 (s, 1H cis ), 8.10–7.70 (m, 5H cis+trans ), 7.46–7.14 (m, 8H cis+trans ), 3.84 (s, 3H cis+trans ), 3.32 (s, 3H cis+trans ).

[0132]

[0133] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-(4-methoxyphenyl)benzamide, and the remaining steps were the same as in Example 1, to obtain the target product N-(2-((4-methoxyphenyl)carbamoyl)phenyl)-N-methylbenzamide with the structure as above, a white solid, with a yield of 83%.

[0134] cis / trans = 10.3:1

[0135] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.27 (s, 1H trans ), 10.08 (s, 1H cis ), 7.61–7.46 (m, 4H cis+trans ), 7.37–7.12 (m, 7H cis+trans ), 6.93 (d, J = 8.7 Hz, 2H cis+trans ), 3.75 (s, 3H cis +trans ), 3.28 (s, 3H cis+trans ).

[0136] Example 21

[0137]

[0138] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-(2-bromophenyl)benzamide, and the remaining steps were the same as those in Example 1, to obtain the target product N-(2-((2-bromophenyl)carbamoyl)phenyl)-N-methylbenzamide with the structure as above, a white solid, with a yield of 58%.

[0139] cis / trans = 7.6:1

[0140] 1 H NMR(600MHz, DMSO-d6): δ cis+trans = 10.06(s, 1H cis+trans ), 7.74–7.62(m, 3H cis +trans ), 7.49–7.14(m, 10H cis+trans ), 3.35(s, 3H cis ), 3.23(s, 3H trans )

[0141] Example 22

[0142]

[0143] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of 3-benzamidothiophene, and the remaining steps were the same as those in Example 1, to obtain the target product N-methyl-N-(2-(thiophen-3-ylcarbamoyl)phenyl)benzamide with the structure as above, a white solid, with a yield of 74%.

[0144] cis / trans = 8.1:1

[0145] 1 H NMR(600MHz, DMSO-d6): δ cis+trans = 10.85(s, 1H trans ), 10.63(s, 1H cis ), 7.73(d, J = 2.2Hz, 1H cis+trans ), 7.52(d, J = 7.1Hz, 1H cis+trans ), 7.50–7.47(m, 2H cis+trans ), 7.37(t, J = 7.2Hz, 1H cis+trans ), 7.32(t, J = 7.6Hz, 2H cis+trans ), 7.24–7.17(m, 3H cis+trans), 7.12 (t, J = 7.5 Hz, 2H cis+trans ), 3.27 (s, 3H cis+trans ).

[0146] Example 23

[0147]

[0148] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-benzoylbenzamide, and the remaining steps were the same as in Example 1 to obtain the target product N-(2-(benzoylaminocarbonyl)phenyl)-N-methylbenzamide with the structure as above, a white solid, with a yield of 40%.

[0149] cis / trans = 6.0:1

[0150] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 11.49 (s, 1H cis+trans ), 7.92 (dd, J = 8.2, 1.0 Hz, 2H cis+trans ), 7.66–7.34 (m, 8H cis+trans ), 7.29–7.15 (m, 4H cis+trans ), 3.29 (s, 3H cis ), 3.21 (s, 3H trans ).

[0151] Example 24

[0152]

[0153] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of 3-methyl-N-phenylbenzamide, and the remaining steps were the same as in Example 1 to obtain the target product N,3-dimethyl-N-(2-(phenylaminocarbonyl)phenyl)benzamide with the structure as above, a white solid, with a yield of 60%.

[0154] cis / trans = 8.1:1

[0155] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.41 (s, 1H trans ), 10.12 (s, 1H cis ), 7.71 (d, J = 8.0 Hz, 2H cis+trans ), 7.53 (d, J = 7.0 Hz, 1H cis+trans ), 7.41 (t, J = 7.5 Hz, 1H cis+trans), 7.35 (t, J = 7.5 Hz, 3H cis+trans ), 7.26 (d, J = 8.0 Hz, 1H cis+trans ), 7.13–7.10 (m, 2H cis+trans ), 7.04 (d, J = 7.0 Hz, 2H cis+trans ), 6.99–6.96 (m, 1H cis+trans ), 3.29 (s, 3H cis ), 3.25 (s, 3H trans ), 2.29 (s, 3H trans ), 2.04 (s, 3H cis ).

[0156]

[0157] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of N-(4-(difluoromethoxy)phenyl)acetamide, and the remaining steps were the same as in Example 1, to obtain the target product N-(4-(difluoromethoxy)phenyl)-2-(N-methylacetamido)benzamide with the structure as above, a white solid, with a yield of 44%.

[0158] cis / trans = 10.1:1

[0159] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.56 (s, 1H cis ), 10.38 (s, 1H trans ), 7.72 (d, J = 8.7 Hz, 2H cis+trans ), 7.66 (d, J = 7.5 Hz, 1H cis ), 7.63–7.60 (m, 1H cis ), 7.55–7.52 (m, 1H cis +trans ), 7.46 (dd, J = 7.8, 0.8 Hz, 1H cis ), 7.39 (t, J = 7.5 Hz, 1H trans ), 7.32–7.29 (m, 3H trans ), 7.18–7.14 (m, 3H cis ), 7.05–7.04 (m, 2H trans ), 3.32 (s, 3H trans ), 3.07 (s, 3H cis ), 2.06 (s, 3H trans ), 1.72 (s, 3H cis ).

[0160] Example 26

[0161]

[0162] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide, and the remaining steps were the same as those in Example 1. The target product 2-(N-methylacetamido)-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide with the above structure was obtained as a white solid with a yield of 39%.

[0163] cis / trans = 11.5:1

[0164] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.60 (s, 1H cis ), 10.42 (s, 1H trans ), 7.71 (d, J = 8.2 Hz, 2H cis+trans ), 7.67–7.60 (m, 4H cis+trans ), 7.53 (t, J = 7.5 Hz, 1H cis ), 7.45 (d, J = 7.8 Hz, 1H cis ), 7.39 (t, J = 7.5 Hz, 1H trans ), 7.31 (d, J = 7.7 Hz, 1H trans ), 3.32 (s, 3H trans ), 3.07 (s, 3H cis ), 2.04 (s, 3H trans ), 1.72 (s, 3H cis ), 1.28 (s, 12H cis+trans )。

[0165] Example 27

[0166]

[0167] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of 2-cyano-N-phenylacetamide, and the remaining steps were the same as those in Example 1. The target product 2-(2-cyano-N-methylacetamido)-N-phenylbenzamide with the above structure was obtained as a white solid with a yield of 42%.

[0168] cis / trans = 1.5:1

[0169] 11H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.60 (s, 1H trans ), 10.40 (s, 1H cis ), 7.61 (d, J = 8.2 Hz, 2H trans ), 7.55 (d, J = 8.2 Hz, 2H cis ), 7.39–7.30 (m, 4H cis+trans ), 7.18 (t, J = 9.0 Hz, 1H trans ), 7.14 (t, J = 8.1 Hz, 1H cis ), 7.09 (t, J = 7.5 Hz, 1H trans ), 7.05 (t, J = 7.5 Hz, 1H cis ), 7.00 (d, J = 7.9 Hz, 1H cis+trans ), 6.00 (d, J = 5.1 Hz, 1H cis ), 5.97 (d, J = 6.7 Hz, 1H trans ), 4.54 (d, J = 5.1 Hz, 1H cis ), 4.34 (d, J = 6.7 Hz, 1H trans ), 3.08 (s, 3H cis ), 3.07 (s, 3H trans ).

[0170] Example 28

[0171]

[0172] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of 2-oxo-N,2-diphenylethanamide, and the remaining steps were the same as in Example 1 to obtain the target product 2-(N-methyl-2-oxo-2-phenylethanamido)-N-phenylbenzamide with the structure as above, a white solid, and the yield was 80%.

[0173] cis / trans > 20:1

[0174] 1 1H NMR (400 MHz, CDCl3): δ cis= 9.65 (s, 1H), 8.04 (dd, J = 8.3, 1.2 Hz, 2H), 7.75 (dd, J = 7.7, 1.5 Hz, 1H), 7.70–7.67 (m, 3H), 7.56–7.52 (m, 2H), 7.44–7.40 (m, 1H), 7.39–7.34 (m, 2H), 7.25–7.21 (m, 1H), 7.17–7.13 (m, 1H), 6.93 (dd, J = 7.8, 0.9 Hz, 1H), 3.38 (s, 3H).

[0175] Example 29

[0176]

[0177] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of 2-(naphthalen-2-yl)-2-oxo-N-phenylethanamide, and the remaining steps were the same as in Example 1, to obtain the target product 2-(N-methyl-2-(naphthalen-2-yl)-2-oxoacetamide)-N-phenylbenzamide with the structure as above, a white solid, with a yield of 87%.

[0178] cis / trans = 19.0:1

[0179] 1 H NMR (400 MHz, CDCl3): δ cis+trans = 9.73 (s, 1H cis ), 8.70 (s, 1H cis ), 8.46 (s, 1H trans ), 8.40 (s, 1H trans ), 8.04 (d, J = 8.1 Hz, 1H cis+trans ), 7.97–7.90 (m, 3H cis ), 7.82–7.80 (m, 3H trans ), 7.77–7.68 (m, 4H cis+trans ), 7.62 (t, J = 7.5 Hz, 1H cis ), 7.57 (d, J = 7.9 Hz, 1H trans ), 7.53–7.49 (m, 1H trans ), 7.44 (d, J = 8.1 Hz, 1H trans ), 7.42–7.35 (m, 3H cis+trans ), 7.22 (d, J = 7.5 Hz, 1H trans ), 7.16 (q, J = 7.8 Hz, 2H cis ), 6.96 (d, J = 7.8 Hz, 1H cis ), 3.43 (s, 3Hcis ), 3.38 (s, 3H trans ).

[0180] Example 30

[0181]

[0182] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of 2-oxo-N-phenylpropanamine, and the remaining steps were the same as in Example 1, to obtain the target product 2-(N-methyl-2-oxopropanamide)-N-phenylbenzamide with the structure as above, a white solid, with a yield of 43%.

[0183] cis / trans > 20:1

[0184] 1 H NMR (600 MHz, CDCl3): δ cis = 9.17 (s, 1H), 7.74 (dd, J = 7.4, 1.8 Hz, 1H), 7.57 (dd, J = 8.5, 0.9 Hz, 2H), 7.50–7.44 (m, 2H), 7.35–7.32 (m, 2H), 7.15–7.12 (m, 1H), 7.04 (dd, J = 7.5, 1.3 Hz, 1H), 3.23 (s, 3H), 2.48 (s, 3H).

[0185] Example 31

[0186]

[0187] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)quinoline-3-carboxamide, and the 1-methyl-2,1-benzisoxazolium tetrafluoroborate was replaced with an equimolar amount of 5,6-dimethoxy-1-methylbenzo[c]isoxazolium tetrafluoroborate, and the remaining steps were the same as in Example 1, to obtain the target product N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)-N-methylquinoline-2-carboxamide with the structure as above, a white solid, with a yield of 20%.

[0188] cis / trans > 20:1

[0189] 1 H NMR (600 MHz, DMSO-d6): δ cis= 9.78 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 7.21 (s, 1H), 6.98 (s, 1H), 6.65 (d, J = 8.9 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.70 (d, J = 0.9 Hz, 6H), 3.56 (s, 2H), 3.36 (s, 3H, N-Me, inadequate suppression of H2O peak), 2.83–2.80 (m, 2H), 2.72–2.67 (m, 6H).

[0190] Example 32

[0191]

[0192] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of (S)-N,N'-([1,1'-binaphthalene]-2,2'-diyl)diacetamide, and the remaining steps were the same as in Example 1 to obtain the target product (S)-N-(2'-acetamido-[1,1'-binaphthalene]-2-yl)-2-(N-methylacetamido)benzamide with the structure as above, a white solid, with a yield of 45%.

[0193] cis / trans = 19.0:1

[0194] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 9.72 (d, J = 24.4 Hz, 1H cis ), 9.27 (s, 1H trans ), 9.19 (s, 1H trans ), 9.11 (d, J = 26.3 Hz, 1H cis ), 8.15–8.11 (m, 1H cis+trans ), 8.08–8.02 (m, 2H cis +trans ), 8.00–7.98 (m, 1H cis+trans ), 7.90–7.79 (m, 2H cis+trans ), 7.50 (t, J = 7.5 Hz, 1H cis ), 7.45 (q, J = 7.0 Hz, 2H cis+trans), 7.38 (t, J = 7.7 Hz, 1H trans ), 7.31–7.24 (m, 4H cis+trans ), 7.14–7.10 (m, 2H trans ), 7.06–6.96 (m, 1H cis ), 6.92–6.89 (m, 2H cis ), 6.86 (d, J = 7.4 Hz, 1H trans ), 2.93 (s, 3H trans ), 2.90–2.65 (m, 3H cis ), 1.93 (s, 3H trans ), 1.72–1.70 (m, 3H cis ), 1.69 (s, 3H trans ), 1.56–1.33 (m, 3H cis )。

[0195] Example 33

[0196]

[0197] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of (S)-N-(2'-acetamido-[1,1'-binaphthalen]-2-yl)-2-(N-methylacetamido)benzamide, and the remaining steps were the same as in Example 1, to obtain the target product (S)-N,N'-([1,1'-binaphthalen]-2,2'-diyl)bis(2-(N-methylacetamido)benzamide) with the structure as above, a white solid, and the yield was 38%.

[0198] cis / trans = 18.3:1

[0199] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 9.90 (s, 1H cis ), 9.78 (s, 1H trans ), 9.75 (s, 1H cis ), 9.68 (s, 1H trans ), 8.13 (d, J = 8.8 Hz, 2H cis+trans ), 8.04 (d, J = 8.1 Hz, 2H cis+trans ), 7.85–7.77 (m, 2H cis+trans ), 7.52–7.43 (m, 4H cis+trans ), 7.33–7.23 (m, 6H cis+trans ), 7.19–7.11 (m, 2H cis +trans), 7.01–6.96 (m, 2H cis+trans ), 2.87–2.83 (m, 3H trans ), 2.80–2.62 (m, 3H trans ), 2.78–2.72 (m, 3H cis ), 2.64–2.45 (m, 3H cis ), 1.53 (s, 3H trans ), 1.51–1.46 (m, 3H cis ), 1.40–1.24 (m, 3H cis ), 1.34 (s, 3H trans ).

[0200] Example 34

[0201]

[0202] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of methyl benzoylalaninate, and the remaining steps were the same as in Example 1 to obtain the target product methyl (2-(N-methylbenzamido)benzoyl)alaninate with the structure as above, a white solid, with a yield of 51%.

[0203] cis / trans = 1.9:1

[0204] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.88 (d, J = 6.4 Hz, 1H trans ), 8.78 (d, J = 6.6 Hz, 1H cis ), 7.46 (d, J = 6.9 Hz, 2H cis ), 7.41 (d, J = 7.2 Hz, 2H trans ), 7.37 (d, J = 7.4 Hz, 1H cis +trans ), 7.29 (dd, J = 17.4, 7.4 Hz, 2H cis+trans ), 7.21 (t, J = 7.1 Hz, 1H cis+trans ), 7.14 (t, J = 6.8 Hz, 2H cis+trans ), 7.07 (d, J = 7.3 Hz, 1H cis ), 6.99 (d, J = 7.1 Hz, 1H trans ), 4.51–4.49 (m, 1H trans ), 4.44–4.39 (m, 1H cis ), 3.69 (s, 3H trans ), 3.66 (s, 3H cis), 3.24 (s, 3H cis ), 3.23 (s, 3H trans ), 1.39 (d, J = 7.0 Hz, 3H trans ), 1.36 (d, J = 7.3 Hz, 3H cis ).

[0205] Example 35

[0206]

[0207] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of ethyl benzoyl-glycyl-L-phenylalaninate, and the remaining steps were the same as in Example 1 to obtain the target product (2-(N-methylbenzamido)benzoyl)glycyl-L-phenylalaninate with the structure as above, a white solid, with a yield of 28%.

[0208] cis / trans > 20:1

[0209] 1 H NMR (600 MHz, DMSO-d6): δ cis = 8.53–8.51 (m, 1H), 8.48–8.45 (m, 1H), 7.48–7.47 (m, 1H), 7.39–7.83 (m, 2H), 7.29–7.19 (m, 8H), 7.15–7.13 (m, 2H), 7.01–6.99 (m, 1H), 4.50 (s, 1H), 4.07–4.04 (m, 2H), 3.97–3.91 (m, 1H), 3.84–3.76 (m, 1H), 3.22 (s, 3H), 3.04–2.94 (m, 2H), 1.12–1.09 (m, 3H).

[0210] Example 36

[0211]

[0212] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyl-decahydro-12H-3,12-epoxy[1,2]dioxolo[4,3-i]isochromen-10-yl 4-(((1R,4aS,10aR)-7-isopropyl-1,4-dimethyl-1,2,3,4,4a,9,10,10-octahydroanthracen-1-yl)methyl)amino)-4-oxobutyrate, and the remaining steps were the same as in Example 1, to obtain the target product (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyl-decahydro-12H-3,12-epoxy[1,2]dioxolane[4,3-i]isochroman-10-yl 4-((2-((((1S,4aR,10aS)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methyl)carbonyl)phenyl)(methyl)amino)-4-oxobutyrate having the structure as above, which was a white solid with a yield of 31%.

[0213] cis / trans>20:1

[0214] 1 1H NMR(600MHz,DMSO-d6):δ cis = 8.30(t,J = 6.2Hz,1H),7.54–7.51(m,1H),7.46–7.41(m,2H),7.37–7.34(m,1H),7.14(dd,J = 8.2,1.4Hz,1H),6.93(dd,J = 8.0,1.2Hz,1H),6.83–6.82(m,1H),5.60(dd,J = 9.7,1.4Hz,1H),5.52(d,J = 4.8Hz,1H),3.20–3.17(m,1H),3.10–3.04(m,1H),3.02–3.00(m,3H),2.85–2.73(m,3H),2.42–2.37(m,1H),2.30–2.15(m,6H),1.99(dd,J = 12.5,2.0Hz,1H),1.90–1.88(m,1H),1.82–1.79(m,1H),1.70–1.52(m,6H),1.45–1.30(m,6H),1.31–1.27(m,3H),1.23–1.17(m,2H),1.15(s,3H),1.14(s,3H),1.13(s,3H),0.95–0.92(m,1H),0.89–0.87(m,6H),0.75–0.73(m,3H).

[0215] Example 37

[0216]

[0217] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-N-(1-(2,6-dimethylphenoxy)propan-2-yl)-2-methylpropanamide, and the remaining steps were the same as in Example 1, to obtain the target product 2-(2-(4-(2,2-dichlorocyclopropyl)phenoxy)-N,2-dimethylpropanamido)-N-(1-(2,6-dimethylphenoxypropan-2-yl)benzamide having the structure above, as a white solid, with a yield of 50%.

[0218] cis / trans = 11.5:1

[0219] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.36 (s, 1H trans ), 8.31 (d, J = 7.9 Hz, 1H cis ), 7.54 (d, J = 6.2 Hz, 2H trans ), 7.46 (d, J = 5.9 Hz, 2H cis ), 7.38 (t, J = 7.0 Hz, 1H cis+trans ), 7.28 (d, J = 6.5 Hz, 2H cis ), 7.14 (d, J = 5.7 Hz, 2H trans ), 7.09 (s, 4H trans ), 7.01 (d, J = 7.2 Hz, 2H cis +trans ), 6.96–6.90 (m, 4H cis ), 4.34–4.29 (m, 1H cis+trans ), 3.73–3.58 (m, 2H cis+trans ), 3.37 (s, 3H cis ), 3.12 (s, 3H trans ), 3.05 (t, J = 9.3 Hz, 1H cis ), 2.98 (t, J = 8.3 Hz, 1H trans ), 2.23 (s, 6H cis ), 2.15 (s, 6H trans ), 2.12–2.04 (m, 2H cis+trans ), 1.63 (s, 3H trans ), 1.52 (s, 3H cis ), 1.37 (s, 6H trans), 1.30–1.27 (m, 6H cis ).

[0220] Example 38

[0221]

[0222] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-3,4-dimethoxybenzamide, and the remaining steps were the same as those in Example 1, to obtain the target product N-(2-(((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbonyl)phenyl)-3,4-dimethoxy-N-methylbenzamide with the structure as above, a white solid, and the yield was 45%.

[0223] cis / trans > 20:1

[0224] 1 H NMR (600 MHz, DMSO-d6): δ cis = 8.29 (s, 1H), 7.42–7.40 (m, 1H), 7.28–7.27 (m, 2H), 7.12 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 6.77–6.76 (m, 1H), 4.10 (s, 1H), 3.68 (s, 3H), 3.44 (s, 3H), 3.23 (s, 3H), 2.55 (t, J = 9.0 Hz, 1H), 2.05 (s, 3H), 2.01–1.96 (m, 2H), 1.69–1.30 (m, 14H), 1.20–1.03 (m, 5H), 0.77 (s, 3H), 0.70 (t, J = 10.8 Hz, 1H), 0.50 (s, 3H).

[0225] Example 39

[0226]

[0227] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of N-((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-(5-((3-methylbut-2-en-1-yl)oxy)-2-((E)-3-(4-((3-methylbut-2-en-1-yl)oxy)phenyl)acryloyl)phenoxy)acetamide, and the remaining steps were the same as in Example 1, to obtain the target product N-((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-(N-methyl-2-(5-((3-methylbut-2-en-1-yl)oxy)-2-((E)-3-(4-((3-methylbut-2-en-1-yl)oxy)phenyl)acryloyl)phenoxy)acetamide)benzamide with the structure as above, a white solid, with a yield of 33%.

[0228] cis / trans = 1.2:1

[0229] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.60 (d, J = 6.6 Hz, 1H cis ), 8.54 (d, J = 6.2 Hz, 1H trans ), 8.35 (d, J = 15.6 Hz, 1H cis ), 8.19 (d, J = 15.7 Hz, 1H trans ), 7.91 (d, J = 8.8 Hz, 1H cis +trans ), 7.83 (d, J = 8.8 Hz, 1H cis+trans ), 7.75 (d, J = 8.5 Hz, 1H cis ), 7.71 (d, J = 9.2 Hz, 1H trans ), 7.61 (d, J = 1.9 Hz, 1H cis ), 7.59 (d, J = 1.9 Hz, 1H trans ), 7.55–7.50 (m, 4H cis+trans ), 6.98–6.96 (m, 2H cis+trans ), 6.72–6.70 (m, 1H cis+trans ), 6.67–6.65 (m, 1H cis+trans ), 5.45–5.40 (m, 2H cis +trans ), 4.77 (d, J = 5.0 Hz, 1H trans), 4.74 (d, J = 4.8 Hz, 1H cis ), 4.59 (d, J = 6.6 Hz, 2H cis+trans ), 4.52–4.47 (m, 2H cis+trans ), 4.04–4.01 (m, 1H cis+trans ), 3.19 (s, 3H cis ), 3.18 (s, 3H trans ), 2.34 (t, J = 9.0 Hz, 1H trans ), 2.26 (t, J = 9.1 Hz, 1H cis ), 1.99 (s, 3H cis ), 1.96 (s, 3H trans ), 1.92–1.81 (m, 1H cis+trans ), 1.75 (s, 3H cis+trans ), 1.73 (s, 3H cis+trans ), 1.72 (s, 3H cis+trans ), 1.68 (s, 3H cis+trans ), 1.56–1.18 (m, 14H cis+trans ), 1.15–0.98 (m, 6H cis+trans ), 0.88–0.80 (m, 2H cis+trans ), 0.67 (s, 3H trans ), 0.66 (s, 3H cis ), 0.37 (s, 3H trans ), 0.35 (s, 3H cis ).

[0230] Example 40

[0231]

[0232] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of benzyl (6R,7R)-7-(2-acetoxybenzamide)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and the remaining steps were the same as in Example 1 to obtain the target product benzyl (6R,7R)-7-(2-(2-acetoxy-N-methylbenzamide)benzamide)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate with the structure shown above, a white solid, with a yield of 29%.

[0233] cis / trans = 3.2:1

[0234] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans＝9.68–9.63(m,1H cis ),9.52(d,J=7.7Hz,1H trans ),7.58(d,J=7.5Hz,2H cis+trans ),7.52–7.49(m,3H cis+trans ),7.40–7.34(m,6H cis+trans ),7.31–7.23(m,5H cis+trans ),7.08–7.04(m,1H cis+trans ),6.97–6.93(m,2H cis+trans ),6.81–6.77(m,1H cis+trans ),6.08–6.00(m,1H cis ),5.94–5.92(m,1H trans ),5.26–5.23(m,1H cis ),5.20(d,J=4.9Hz,1H trans ),3.79–3.60(m,2H cis+trans ),3.25–3.23(m,3H cis ),3.09(s,3H trans ),2.33(s,3H trans ),2.27(s,3H cis ).

[0235] Example 41

[0236]

[0237] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of N-((3s,5s,7s)-adamantan-1-yl)-6-(3-((3r,5r,7r)-adamantan-1-yl)-4-methoxyphenyl)-2-naphthamide, and the remaining steps were the same as in Example 1 to obtain the target product 6-(3-((3R,5R,7R)-adamantan-1-yl)-4-methoxyphenyl)-N-(2-(((3S,5S,7S)-adamantan-1-yl)carbonyl)phenyl)-N-methyl-2-naphthamide with the structure as above, a white solid, and the yield was 34%.

[0238] cis / trans > 20:1

[0239] 1 H NMR(600MHz,DMSO-d6):δ cis= 8.02 (d, J = 13.7 Hz, 2H), 7.86 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.75–7.71 (m, 2H), 7.55 (t, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.35 (d, J = 7.0 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 3.85 (s, 3H), 3.33 (s, 3H), 2.11–2.05 (m, 18H), 1.74 (s, 6H), 1.68 (s, 6H).

[0240] Example 42

[0241]

[0242] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of 2-butoxy-N-(2-(diethylamino)ethyl)quinoline-4-carboxamide, and the remaining steps were the same as in Example 1 to obtain the target product 2-butoxy-N-(2-(diethylamino)ethyl)carbamoyl)phenyl)-N-methylquinoline-4-carboxamide with the structure as above, a white solid, and the yield was 43%.

[0243] cis / trans = 2.6:1

[0244] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.46 (s, 1H trans ), 8.26 (s, 1H cis ), 7.93 (d, J = 8.2 Hz, 1H cis ), 7.84 (d, J = 8.3 Hz, 1H trans ), 7.75–7.56 (m, 3H cis+trans ), 7.50–7.37 (m, 2H cis +trans ), 7.24–7.01 (m, 3H cis+trans ), 4.45 (t, J = 6.5 Hz, 2H trans ), 4.30–4.20 (m, 2H cis ), 3.43–3.39 (m, 2H cis+trans ), 3.36 (s, 3H cis ), 3.09 (s, 3H trans ), 2.55 (s, 6H cis+trans ), 1.80–1.76 (m, 2H trans), 1.66–1.61 (m, 2H cis ), 1.52–1.46 (m, 2H trans ), 1.37–1.31 (m, 2H cis ), 1.00–0.94 (m, 7H cis+trans ), 0.89–0.87 (m, 2H cis+trans ).

[0245] Example 43

[0246]

[0247] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of ethyl (1-((2-methyl-1,1-dioxido-3-(pyridin-2-ylcarbonyl)-2H-benzo[e][1,2]thiazin-4-yl)oxy)ethyl) carbonate, and the remaining steps were the same as those in Example 1 to obtain the target product ethyl (1-((2-methyl-3-(methyl(2-(pyridin-2-ylcarbonyl)phenyl)carbonyl)-1,1-dioxido-2H-benzo[e][1,2]thiazin-4-yl)oxy)ethyl) carbonate having the structure as above, which was a white solid with a yield of 49%.

[0248] cis / trans > 20:1

[0249] 1 H NMR (600 MHz, DMSO-d6): δ cis = 10.95 (s, 1H), 8.36–8.34 (m, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.86–7.81 (m, 3H), 7.75–7.72 (m, 2H), 7.69–7.67 (m, 1H), 7.52–7.50 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.16–7.14 (m, 1H), 6.16 (d, J = 5.0 Hz, 1H), 3.95 (q, J = 7.0 Hz, 2H), 3.43 (s, 3H), 2.99 (s, 3H), 1.56 (d, J = 4.5 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H).

[0250] Example 44

[0251]

[0252] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide, and the remaining steps were the same as in Example 1 to obtain the target product N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(N-methyl-2-(2-oxopyrrolidin-1-yl)acetamide)benzamide with the structure as above. It was a white solid with a yield of 33%.

[0253] cis / trans = 8.2:1

[0254] 1 H NMR(600MHz,DMSO-d6):δ cis+trans = 10.39(s,1H cis ),10.08(s,1H trans ),7.80(d,J = 7.2Hz,1H cis ),7.77(d,J = 7.9Hz,1H trans ),7.71–7.68(m,1H cis ),7.66–7.63(m,1H cis ),7.61(dd,J = 7.7,1.4Hz,1H trans ),7.56(dd,J = 7.8,1.1Hz,1H cis ),7.50–7.47(m,1H trans ),7.36(dd,J = 7.9,0.9Hz,1H trans ),3.85(d,J = 16.6Hz,1H cis+trans ),3.60(d,J = 16.6Hz,1H cis +trans ),3.38–3.34(m,1H cis+trans ,inadequate suppression of H2O peak),3.28(s,3H trans ),3.17(s,1H cis+trans ),3.15(s,3H cis ),2.87(t,J = 6.1Hz,2H cis+trans ),2.69(s,2H cis+trans ),2.36(s,3H cis ),2.33(s,3H trans ),2.19(s,3H cis+trans ),2.18–2.12(m,2H cis+trans), 1.91–1.74 (m, 6H cis+trans ).

[0255] Example 45

[0256]

[0257] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxalylamide)methyl)acetamide, and the remaining steps were the same as in Example 1 to obtain the target product (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxalylamide-5-yl)methyl)-2-(N-methylacetamide)benzamide with the structure as above, a white solid, and the yield was 56%.

[0258] cis / trans = 11.5:1

[0259] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.86–8.84 (m, 1H cis ), 8.51 (t, J = 5.9 Hz, 1H trans ), 7.56–7.48 (m, 2H cis+trans ), 7.44–7.42 (m, 2H cis+trans ), 7.38 (d, J = 7.8 Hz, 1H cis ), 7.32 (t, J = 7.5 Hz, 1H trans ), 7.24 (d, J = 7.8 Hz, 1H trans ), 7.21–7.19 (m, 1H cis ), 7.07 (t, J = 9.4 Hz, 1H cis+trans ), 4.81–4.79 (m, 1H cis+trans ), 4.14 (t, J = 9.0 Hz, 1H cis ), 4.09 (t, J = 9.0 Hz, 1H trans ), 3.83–3.81 (m, 1H trans ), 3.79–3.75 (m, 1H cis ), 3.74–3.72 (m, 4H cis+trans ), 3.65–3.51 (m, 2H cis +trans ), 3.25 (s, 3H trans ), 3.04–3.00 (m, 3H cis ), 2.96–2.95 (m, 4H cis+trans ), 2.06 (s, 3H trans), 1.68–1.65 (m, 3H cis ).

[0260] Example 46

[0261]

[0262] The N-phenylbenzamide used in Example 1 was replaced with an equimolar amount of (S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide, and the remaining steps were the same as those in Example 1 to obtain the target product (S)-N-(2-(1-(4-ethoxy-3-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-2-(N-methylacetamido)benzamide having the structure above, which was a white solid with a yield of 45%.

[0263] cis / trans = 4.3:1

[0264] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 10.30 (s, 1H cis ), 10.02 (s, 1H trans ), 8.65 (d, J = 8.4 Hz, 1H trans ), 8.43 (dd, J = 11.1, 8.4 Hz, 1H cis ), 7.88 (d, J = 7.8 Hz, 1H cis ), 7.86–7.84 (m, 1H cis+trans ), 7.77 (d, J = 7.6 Hz, 1H trans ), 7.71–7.63 (m, 2H cis+trans ), 7.61 (t, J = 7.4 Hz, 1H cis ), 7.51 (dd, J = 7.8, 0.6 Hz, 1H cis ), 7.45 (t, J = 7.6 Hz, 1H trans ), 7.41 (d, J = 7.9 Hz, 1H trans ), 7.08 (s, 1H cis+trans ), 6.99–6.96 (m, 1H cis+trans ), 6.93 (d, J = 8.5 Hz, 1H cis+trans ), 5.79–5.75 (m, 1H cis+trans ), 4.36–4.30 (m, 1H cis+trans ), 4.15 (dd, J = 14.4, 3.3 Hz, 1H cis+trans), 4.01 (q, J = 7.0 Hz, 2H cis+trans ), 3.72 (s, 3H cis+trans ), 3.44 (s, 3H trans ), 3.08 (d, J = 3.4 Hz, 3H cis ), 3.02 (s, 3H trans ), 2.99 (d, J = 4.2 Hz, 3H cis ), 2.04 (s, 3H trans ), 1.75 (d, J = 10.0 Hz, 3H cis ), 1.31 (t, J = 7.0 Hz, 3H cis+trans ).

[0265] Example 47

[0266]

[0267] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, and the remaining steps were the same as in Example 1, to obtain the target product 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methyl-N-(2-(methylcarbamoyl)phenyl)benzamide with the structure as above, a white solid, with a yield of 66%.

[0268] cis / trans = 4.6:1

[0269] 1 H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.41 (d, J = 8.2 Hz, 1H trans ), 8.37 (d, J = 8.3 Hz, 1H cis ), 8.31 (d, J = 1.4 Hz, 1H trans ), 8.29 (d, J = 4.5 Hz, 1H trans ), 8.24 (d, J = 1.5 Hz, 1H cis ), 8.12–8.09 (m, 1H cis+trans ), 8.03 (dd, J = 8.2, 1.6 Hz, 1H cis ), 7.69 (t, J = 7.7 Hz, 1H trans ), 7.59–7.56 (m, 1H trans ), 7.55–7.52 (m, 1H cis+trans), 7.50 (dd, J = 9.8, 1.5 Hz, 1H trans ), 7.46–7.43 (m, 2H trans ), 7.42–7.40 (m, 1H cis+trans ), 7.37–7.34 (m, 1H cis ), 7.30–7.28 (m, 1H cis ), 7.22 (d, J = 7.9 Hz, 1H cis ), 7.18 (dd, J = 10.1, 1.6 Hz, 1H cis ), 7.00 (dd, J = 8.2, 1.7 Hz, 1H cis ), 3.28 (s, 3H cis ), 3.19 (s, 3H trans ), 2.75 (d, J = 4.6 Hz, 3H cis ), 2.74 (s, 3H trans ), 1.57 (s, 6H trans ), 1.39 (d, J = 9.3 Hz, 6H cis ).

[0270] Example 48

[0271]

[0272] In Example 1, the N-phenylbenzamide used was replaced with an equimolar amount of (2aR,4S,4aR,6R,9S,11S,12R,12aS)-4-((S)-2-acetoxypropionyloxy)-9-((2R,3S)-2-((S)-2-acetoxypropionyloxy)-3-benzamido-3-phenylpropionyloxy)-12-(benzoyloxy)-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-1,2a,3,4,4a,5,6,9,10,11,12,12b-dodecahydro-12aH-7,11-methanocyclododeca[3,4]benzo[1,2-b]oxazine-6,12a-diyl diacetate, and the remaining steps were the same as in Example 1, to obtain the target product (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-4-((S)-2-acetoxypropionyloxy)-9-((2R,3R)-2-((S)-2-acetoxypropionyloxy)-3-(2-(N-methylbenzamido)benzamido)-3-phenylpropionyloxy)-12-(benzoyloxy)-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-3,4,4a,5,6,9,10,11,12,12a-decahydro-1H-7,11-methanocyclododeca[3,4]benzo[1,2-b]oxazine-6,12b(2aH)-diyl diacetate, a white solid, with a yield of 30%.

[0273] cis / trans = 1.5:1

[0274] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 9.53 (d, J = 7.5 Hz, 1H trans ), 9.19 (d, J = 7.9 Hz, 1H cis ), 8.01 (t, J = 7.7 Hz, 2H cis+trans ), 7.77–7.67 (m, 3H cis+trans ), 7.60–7.03 (m, 13H cis +trans ), 6.89 (t, J = 7.1 Hz, 1H cis+trans ), 6.15 (s, 1H cis+trans ), 5.83 (s, 1H cis+trans ), 5.60–5.56 (m, 1H cis+trans ), 5.48 (s, 1H cis+trans ), 5.43–5.32 (m, 2H cis+trans ), 5.20 (d, J = 6.6 Hz, 1H trans ), 5.09 (d, J = 6.9 Hz, 1Hcis ), 4.99 (d, J = 8.7 Hz, 1H cis+trans ), 4.89 (q, J = 6.8 Hz, 1H cis+trans ), 4.78 (s, 1H trans ), 4.77 (s, 1H cis ), 4.08 (s, 2H cis+trans ), 3.72 (s, 1H cis+trans ), 3.31 (s, 3H cis ), 2.86 (s, 3H trans ), 2.43 (s, 1H cis+trans ), 2.36 (s, 3H cis+trans ), 2.10 (s, 3H cis+trans ), 2.06 (s, 3H cis +trans ), 2.04–1.96 (m, 3H cis+trans ), 1.85–1.80 (m, 1H cis+trans ), 1.71–1.69 (m, 7H cis+trans ), 1.51–1.40 (m, 4H cis+trans ), 1.26 (d, J = 6.8 Hz, 3H cis+trans ), 1.02–1.00 (m, 6H cis+trans ).

[0275] Using N-alkyl-2,1-benzoxazole tetrafluoroborate (II) and lactam (III) as reaction raw materials, TMEDA as the Lewis base, and PhOMe as the solvent, different substituted lactam aminoacylated amplification products were obtained under the protection of argon at 20 °C.

[0276] Example 49

[0277]

[0278] Add benzyl 4-oxoazetidine-2-carboxylate (41.0 mg, 0.2 mmol), 1-methyl-2,1-benzisoxazole tetrafluoroborate (66.3 mg, 0.3 mmol), TMEDA (0.6 mmol) and PhOMe (1 mL) to a 5 mL clean reaction flask. Then, under an argon atmosphere, place the reaction flask at 20 °C and stir the reaction. After the reaction system has reacted for 12 h, stop the reaction, distill off the solvent under reduced pressure, and separate the residue by column chromatography to obtain the target product benzyl 1-methyl-2,6-dioxo-1,2,3,4,5,6-hexahydrobenzo[b][1,5]diazaindene-4-carboxylate, a white solid, with a yield of 41%.

[0279] cis / trans = 13.3:1

[0280] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 8.48 (d, J = 7.1 Hz, 1H cis ), 8.23 (d, J = 6.2 Hz, 1H trans ), 7.61–7.58 (m, 1H trans ), 7.55–7.52 (m, 1H cis ), 7.47 (dd, J = 7.7, 2.6 Hz, 2H trans ), 7.43 (dd, J = 7.5, 1.5 Hz, 1H trans ), 7.39–7.33 (m, 5H cis+trans ), 7.25 (dd, J = 7.5, 1.8 Hz, 2H cis ), 7.20 (dd, J = 7.7, 1.4 Hz, 1H cis ), 5.17–5.09 (m, 2H trans ), 5.03 (q, J = 12.4 Hz, 2H cis ), 4.37–4.33 (m, 1H cis ), 4.11–4.08 (m, 1H trans ), 3.15 (s, 3H cis ), 3.09 (s, 3H trans ), 2.65–2.55 (m, 2H cis+trans ).

[0281] Example 50

[0282]

[0283] The benzyl 4-oxoazetidine-2-carboxylate used in Example 49 was replaced with an equimolar amount of 1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one, and the remaining steps were the same as in Example 49 to obtain the target product 5-methyl-7,8,9,14-tetrahydro-5H-dibenzo[b,f][1,5]diazacycloundecane-6,15-dione with the structure as above, a white solid, and the yield was 81%.

[0284] cis / trans = 13.3:1

[0285] 1 1H NMR (600 MHz, DMSO-d6): δ cis+trans = 9.79 (s, 1H cis ), 9.29 (s, 1H trans ), 7.66 (dd, J = 7.5, 1.6 Hz, 1Hcis ), 7.53 (d, J = 7.5 Hz, 1H trans ), 7.46 (d, J = 7.6 Hz, 1H cis ), 7.41 (t, J = 7.5 Hz, 1H trans ), 7.37–7.35 (m, 1H trans ), 7.32–7.29 (m, 1H cis ), 7.28–7.25 (m, 1H cis ), 7.24–7.22 (m, 2H trans ), 7.18–7.12 (m, 3H cis+trans ), 7.11–7.08 (m, 1H cis ), 3.28 (s, 3H trans ), 3.13 (s, 3H cis ), 2.62–2.57 (m, 1H cis+trans ), 2.40–2.38 (m, 1H cis+trans ), 2.28–2.23 (m, 1H cis+trans ), 1.66 (dd, J = 14.7, 3.7 Hz, 1H cis+trans ), 1.55–1.51 (m, 1H cis+trans ), 1.41–1.36 (m, 1H cis+trans ).

[0286] Example 51

[0287]

[0288] Replace the benzyl 4-oxoazetidine-2-carboxylate used in Example 49 with an equimolar amount of pivaloyl-protected rifamycin S, and perform the remaining steps in the same manner as in Example 49 to obtain the target product (1) having the structure shown above 2 (1S,7E,9E,11S,12S,13R,14S,15S,16S,17S,18R,19E)-16-acetoxy-12,14-dihydroxy-18-methoxy-1 2 ,1 4 ,5,7,11,13,15,17-octamethyl-1 1 ,1 6 ,1 9 ,3,6-pentaoxo-11,12,16,19-tetrahydro-21-oxa-2,5-diaza-1(7,2)-naphtho[2,1-b]furan-4(1,2)-benzocycloeicosane-7,9,19-triene-1 5 -yl tert-butyrate, a yellow solid, with a yield of 33%.

[0289] cis / trans = 3.3:1

[0290] 1 1H NMR (600 MHz, CDCl3): δ cis+trans = 8.83–8.75 (m, 1H cis+trans ), 7.65–7.47 (m, 3H cis +trans ), 7.38 (t, J = 7.3 Hz, 1H cis+trans ), 7.30 (d, J = 8.0 Hz, 1H cis+trans ), 6.32–6.12 (m, 3H cis +trans ), 5.30–5.15 (m, 1H cis+trans ), 4.96–4.81 (m, 1H cis+trans ), 3.48 (s, 3H cis+trans ), 3.43 (d, J = 8.7 Hz, 1H cis+trans ), 3.36 (d, J = 9.6 Hz, 1H cis+trans ), 3.11 (s, 3H cis+trans ), 3.05 (d, J = 9.6 Hz, 1H cis+trans ), 2.35 (s, 1H cis+trans ), 2.27–2.23 (m, 3H cis+trans ), 2.11 (s, 3H cis ), 2.08 (s, 3H trans ), 2.01 (s, 3H trans ), 1.98 (s, 3H cis ), 1.87 (d, J = 6.6 Hz, 1H cis+trans ), 1.72–1.67 (m, 6H cis+trans ), 1.52–1.45 (m, 9H cis+trans ), 1.30–1.25 (m, 3H cis+trans ), 1.05–0.98 (m, 5H cis+trans ), 0.79 (t, J = 6.7 Hz, 3H cis+trans ), 0.47–0.37 (m, 3H cis+trans )。

[0291] Example 52

[0292]

[0293] Add the target product in Example 51 (1 2(S,7E,9E,11S,12S,13R,14S,15S,16S,17S,18R,19E)-16-acetoxy-12,14-dihydroxy-18-methoxy-1 2 ,1 4 ,5,7,11,13,15,17-octamethyl-1 1 ,1 6 ,1 9 ,3,6-pentaoxa-11,12,16,19-tetrahydro-21-oxa-2,5-diaza-1(7,2)-naphtho[2,1-b]furan-4(1,2)-benzocycloeicosane-7,9,19-triene-1 5 -yl tert-butyrate (273.9 mg, 0.3 mmol), 1-methyl-2,1-benzisoxazolium tetrafluoroborate (44.2 mg, 0.2 mmol), DIPEA (0.4 mmol) and CH2Cl2 (1 mL), then under an argon atmosphere, the reaction flask was placed at 40 °C and stirred in the dark. After the reaction system continued for 12 h, the reaction was stopped, the solvent was removed by distillation under reduced pressure in an ice-water bath, and the residue was separated by column chromatography to obtain the target product (1 2 (S,10E,12E,14S,15S,16R,17S,18S,19S,20S,21R,22E)-19-acetoxy-15,17-dihydroxy-21-methoxy-1 2 ,1 4 ,5,8,10,14,16,18,20-nonamethyl-1 1 ,1 6 ,1 9 ,3,6,9-hexaoxa-1 1 ,1 2 ,1 6 ,1 9 -tetrahydro-24-oxa-2,5,8-triaza-1(7,2)-naphtho[2,1-b]furan-4,7(1,2)-dibenzocyclotetracosane-10,12,22-triene-1 5 -yl tert-butyrate, red solid, yield 11%.

[0294] cis / trans = 1.6:1

[0295] 1 1H NMR (600 MHz, CDCl3): δ cis+trans = 10.65 (s, 1H trans ), 10.52 (s, 1H cis ), 7.94–7.91 (m, 1H cis+trans ), 7.43–7.35 (m, 3H cis+trans), 7.30 (d, J = 6.8 Hz, 1H cis+trans ), 7.12–7.00 (m, 1H cis +trans ), 6.81 (s, 1H cis+trans ), 6.48–6.44 (m, 1H cis+trans ), 6.16–6.14 (m, 1H cis+trans ), 6.02–5.95 (m, 2H cis+trans ), 5.71 (d, J = 15.6 Hz, 1H cis+trans ), 5.19 (dd, J = 38.0, 9.9 Hz, 1H cis+trans ), 4.92 (d, J = 10.7 Hz, 1H cis+trans ), 4.40 (s, 1H trans ), 4.25 (s, 1H cis ), 4.01 (dd, J = 29.2, 8.3 Hz, 1H cis +trans ), 3.55 (s, 1H cis+trans ), 3.32 (s, 3H cis+trans ), 3.24–3.21 (m, 3H cis+trans ), 3.14–3.11 (m, 3H cis+trans ), 3.08 (s, 1H cis+trans ), 2.39 (s, 1H cis+trans ), 2.23–2.17 (m, 3H cis+trans ), 2.13 (d, J = 7.0 Hz, 3H cis+trans ), 2.00 (s, 1H cis+trans ), 1.94 (s, 3H cis+trans ), 1.92–1.88 (m, 1H cis+trans ), 1.79–1.73 (m, 1H cis+trans ), 1.69 (s, 3H cis+trans ), 1.66–1.64 (m, 1H cis+trans ), 1.12 (d, J = 34.5 Hz, 12H cis+trans ), 1.06–1.02 (m, 1H cis+trans ), 0.86 (d, J = 6.9 Hz, 3H cis+trans ), 0.68 (s, 3H cis+trans ), 0.25–0.22 (m, 3H cis+trans )。

[0296] Afterwards, based on Examples 1 and 50 respectively, tests were carried out by changing different conditions, and the results are as follows:

[0297] Based on Example 1:

[0298]

[0299]

[0300] Based on Example 50:

[0301]

[0302] From the above results, it can be found that by selecting specific reagents, the present invention can effectively improve the yield of the reaction and can more effectively prepare the product.

[0303] The applicant declares that the present invention uses the above embodiments to illustrate the preparation method and application of oligopeptides and cyclic peptides based on inert amide bond insertion of the present invention. However, the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc. all fall within the protection scope and disclosure scope of the present invention.

[0304] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0305] In addition, it should be noted that in the above specific embodiments, the various specific technical features described can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not separately describe various possible combination methods.

Claims

1. A method for preparing oligoamides and cyclic peptides based on inert amide bond insertion, characterized in that: The preparation method comprises the following steps: The amide compound is mixed with 2,1-benzisoxazole salt and Lewis base to react, thereby obtaining the oligoamide or cyclic peptide; The structure of the oligoamide is shown in compound II', and the structure of the cyclic peptide is shown in compound III'; The reaction formula is shown in Formula I or II: In the formula, R 1 , R 2 , R 3 , R 4 Independently selected from any one of hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C1-C12 alkoxy, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted C4-C12 heteroaryl, the substituted group is selected from any one of C1-C12 alkyl, C1-C12 alkoxy, C5-C12 aryl, C4-C12 heteroaryl, hydroxyl, amino, acyl, amide, nitro, carboxyl, halogen, sulfone, sulfoxide, and ester; the substituted groups exist independently or any two adjacent groups are connected to form a ring structure; X - Selected from CF3SO2O - 、BF4 - or ClO4 - ; Y chooses O or S; n represents the number of atoms in the ring structure of the lactam compound III, and is an integer selected from 4-40.

2. The preparation method according to claim 1, characterized in that: The Lewis base includes an organic base and / or an inorganic base.

3. The preparation method according to claim 2, characterized in that: The organic base includes any one or a combination of at least two of triethylamine, potassium tert-butoxide, p-dimethylaminopyridine, N,N-diisopropylethylamine or tetramethylethylenediamine; Preferably, the inorganic base includes any one of sodium carbonate, cesium carbonate, potassium phosphate, potassium acetate, or a combination of at least two thereof.

4. The preparation method according to claim 2 or 3, characterized in that: The Lewis base is an organic base.

5. The preparation method according to claim 3 or 4, characterized in that: The product is oligoamide, and the organic base is triethylamine; Preferably, the product is a cyclopeptide and the organic base is tetramethylethylenediamine.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The product is an oligoamide, and the molar ratio of the amide compound to the 2,1-benzisoxazole salt is (1.2-1.5):1; Preferably, the product is a cyclic peptide, and the molar ratio of the amide compound to the 2,1-benzisoxazole salt is 1:(1.2-1.5).

7. The preparation method according to any one of claims 1 to 6, characterized in that The product is oligoamide, and the solvent of the reaction includes any one of acetonitrile, dichloromethane or chloroform or a combination of at least two of them, preferably dichloromethane.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The product is a cyclopeptide, and the solvent of the reaction includes any one of dichloromethane, toluene or anisole or a combination of at least two thereof, preferably anisole.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The reaction is carried out under an inert gas environment; Preferably, the reaction temperature is 10-70°C.

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of drug molecules.

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