Synthesis method of gem-diamine compound

Abstract

The invention discloses a synthetic method of a gem-diamine compound. The synthetic method comprises the following steps of: preparing a gem-diamine compound; the method comprises the following steps: reacting an amide N-OTs compound a with an amine compound b in an organic solvent system in the presence of alkali to generate a target compound c; the reaction formula is shown in the specification. The method has the advantages of simple operation, easily available raw materials, low cost, low toxicity, strong compatibility, diversified product structures, mild reaction conditions, easy realization of large-scale production and the like, and has important significance on rapid synthesis and application of gem-diamine compounds.

Description

Technical Field

[0001] This invention relates to a method for synthesizing geminal diamine compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] Gem-diamine compounds are important structural units in which two amino groups or their derivatives are attached to the same carbon atom. They are widely found in natural products, pharmaceutical active molecules, and functional materials. [1] For example, mofolinamide, a geminal diamine compound, is an important anti-tuberculosis drug that not only shows significant efficacy against various forms of tuberculosis, but also exhibits superior anti-tuberculosis activity compared to the classic drug pyrazinamide in infected human macrophages. [2] Gem-diamine compounds exhibit excellent reactivity and coordination ability, and have broad application prospects in fields such as new material development, medicinal chemistry, and green catalysis.

[0003] Currently, methods for synthesizing geminal diamine compounds have significant limitations. For example, Glase et al. used a two-step lead-mediated oxidation-amination strategy to synthesize geminal diamine benzamide derivatives. [3] This method first uses N-(3-methylbenzoyl)glycine as a starting material, refluxed in toluene under the catalysis of lead tetraacetate and copper acetate, to generate the key intermediate [(3-methylbenzoyl)amino]methylacetate via oxidative decarboxylation. Subsequently, this intermediate undergoes nucleophilic substitution with a substituted piperidine in acetonitrile in the presence of triethylamine to construct a geminal diamine skeleton. This method was a traditional strategy for constructing such structures in the past, but its disadvantages include: the need to use highly toxic and environmentally harmful lead tetraacetate as an oxidant, which does not conform to the principles of green synthesis; cumbersome operation steps; and the requirement to prepare a halogenated intermediate beforehand, resulting in poor atom economy and step economy. Subsequently, Kappe and Cantillo et al. developed an electrochemical decarboxylation acetylation process. [4] This process uses acetic acid as a solvent and sodium acetate as a base, achieving decarboxylation and acetylation directly through anodic oxidation under mild conditions. This method uses electrons as a clean "reagent," with only CO2 and H2 as byproducts, resulting in high atom economy. Compared to lead-based methods, the electrochemical process significantly outperforms other green indicators such as atom economy and reaction quality efficiency, while avoiding the use of heavy metals, demonstrating excellent sustainability and industrialization potential. Lian et al. employed an electrochemical dehydroimineation method. [5]This study achieved the direct coupling of N-methylbenzylamine and phthalimide, synthesizing a series of phthalimide-protected geminiamine compounds. The reaction was carried out under isothermal and isostatic conditions in a platinum electrode pair, acetonitrile / methanol mixed solvent, and tetrabutylammonium perchlorate electrolyte system, without the need for external oxidants, demonstrating the advantages of green synthesis and high regioselectivity. The drawback of this strategy is that it is mainly limited to N-methyl-substituted benzylamine substrates and relies on noble metal electrodes, limiting its application range and operational convenience. Li et al. used a copper-catalyzed oxidative coupling method to achieve a one-pot reaction of N-arylglycine ethyl ester and enamide, simultaneously constructing quinoline and geminiamine derivatives. [6] This study used Cu(OTf)₂ as a catalyst in an oxygen atmosphere and acetonitrile solvent to react the same imine intermediate with the double bond of an enamide and its cleaved amide fragment, demonstrating high atom economy and synthetic efficiency. The process involves a multi-step sequence of amine oxidation, Povarov cyclization, deamidation aromatization, and nucleophilic addition of the amide to the imine. The drawbacks of this strategy are the long reaction time, the need for strict control of the oxygen atmosphere, and the unbalanced substrate ratio, which to some extent affects the simplicity and versatility of the operation.

[0004] In summary, previous synthetic methods for geminal diamines have significant limitations in terms of cost, safety, selectivity, operational complexity, high toxicity, and environmental impact. Therefore, there is an urgent need to develop a novel synthetic paradigm for the concise and modular construction of structurally diverse geminal diamines.

[0005] References

[0006] [1] Xu Z.; Chen Z.; Liu S.; Gao J.; Lei J.; Li M.; Zhang Y.; Gan Z.;Yu L.; Liu SX; Jin Y. Transition photocatalyst-free synthesis of geminaldiamines via a sandwich-like photoactive donor–acceptor–donor complex [J]. Green. Chem, 2025, 27: 8126-8132.

[0007] [2] Chung W. J.; Kornilov A.; Brodsky B. H.; Higgins M.; Sanchez T.;Heifets L. B.; Cynamon M. H.; Welch J. Inhibition of M. tuberculosis in vitroin monocytes and in mice by aminomethylene pyrazinamide analogs [J].Tuberculosis, 2008, 88: 410-419。

[0008] [3] Patel M. V.; Kolasa T.; Mortell K.; Matulenko M. A.; Hakeem A.A.; Rohde J. J.; Nelson S. L.; Cowart M. D.; Nakane M.; Miller L. N.; UchicM. E.; Terranova M. A.; El-Kouhen O. F.; Donnelly-Roberts D. L.; Namovic M.T.; Hollingsworth P. R.; Chang R.; Martino B. R.; Wetter J. M.; Marsh K. C.;Martin R.; Darbyshire J. F.; Gintant G.; Hsieh G. C.; Moreland R. B.;Sullivan J. P.; Brioni J. D.; Stewart A. O. Discovery of 3-Methyl-N-(1-oxy-3′, 4′, 5′, 6′-tetrahydro-2′H-[2, 4′-bipyridine]-1′-ylmethyl)benzamide (ABT-670), an Orally Bioavailable Dopamine D4 Agonist for the Treatment ofErectile Dysfunction [J]. J. Med. Chem, 2006, 49: 7450-7465。

[0009] [4] Köckinger M.; Hanselmann P.; Roberde D. M.; Geotti-Bianchini P.; Kappe C. O.; Cantillo D. Sustainable electrochemical decarboxylative acetylation of aminoacids in batch and continuous flow [J]. Green Chem, 2021, 23: 2382-2390。

[0010] [5] Lian F.; Sun C.; Xu K.; Zeng C. Electrochemical Dehydrogenative Imidation of N-Methyl-Substituted Benzylamines with Phthalimides for the Direct Synthesis of Phthalimide-Protected gem-Diamines [J]. Org. Lett, 2019, 21: 1237-1241。

[0011] [6] Li X.M.; Tang L.; Qian Z.M.; He Y.H.; Guan Z. Copper Catalysis: One-Pot Simultaneous Synthesis of Quinolines and gem-Diamine Derivatives [J]. Tetrahedron Lett, 2020, 61: 152346。

[0012] [7] Ortiz Jr G.X.; Hemric B.N.; Wang Q. Direct and selective 3-amidation of indoles using electrophilic N-[(benzenesulfonyl)oxy]amides [J]. Org. Lett., 2017, 19: 1314-1317。 Summary of the Invention

[0013] To address the aforementioned problems in existing technologies, this invention provides a novel method for synthesizing geminal diamine compounds. This method offers advantages such as simple operation, readily available raw materials, low cost, low toxicity, strong compatibility, diverse product structures, mild reaction conditions, and ease of large-scale production, making it significant for the rapid synthesis of geminal diamine compounds.

[0014] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0015] The present invention provides a method for synthesizing geminal diamine compounds, wherein amide N-OTs compound a reacts with amine compound b in an organic solvent system and in the presence of a base to generate target compound c;

[0016] The reaction formula is shown below:

[0017]

[0018] in:

[0019] R 1 Selected from C1-C6 alkyl groups, substituted or unsubstituted aryl groups, , Any one of the following; the substituents used for substitution are selected from one or more of the following: C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkynyl, heteroatoms (N, S, O).

[0020] R 2 Selected from hydrogen and C1-C8 alkyl groups;

[0021] The amine fragment attached to the α-position of amide N in target compound c (i.e., R in target compound c) 3 R 4 The structural segments consisting of the N atom and its attachment are selected from substituted or unsubstituted pyrrole rings, piperidine rings, piperazine rings, aniline, , , , , , , Any one of them; that is, R at this time 3 R 4 Forming a ring.

[0022] In addition, R 3 and R 4 Also independently selected from C1-C8 alkyl groups, Any one of them.

[0023] Furthermore, R 1 Selected from C1-C6 alkyl, phenyl, , , , , , , , , , , , , , , , , Any one of them; R 5 It is selected from any one of methyl, methoxy, tert-butyl, chlorine, bromine, fluorine, cyano, trifluoromethyl, methyl formate, and alkynyl.

[0024] Furthermore, the amine fragment attached to the α-position of amide N in target compound c (R in compound c) 3 R 4 (and the structural fragment composed of its connected N atoms) is selected from , , , , , , , , , , , , , , , , , , , , , Any one of them; in addition, R 3 and R 4 Also selected from C1 to C8 alkyl groups, Any one of them.

[0025] Furthermore, target compound c is selected from any one of the following compounds with the following structures:

[0026]

[0027]

[0028] The alkali is selected from any one of Et3N, DIPEA, DBU, tBuONa, and Cs2CO3, with Et3N being more preferred.

[0029] The solvent is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile, with dimethyl sulfoxide being more preferred.

[0030] Furthermore, the molar ratio of amide N-OTs compound a to amine compound b is 1:1 to 3, more preferably 1:1.5; the molar ratio of amide N-OTs compound a to base is 1:1 to 3, more preferably 1:2.

[0031] Furthermore, depending on the reaction substrate with different structures, the reaction temperature is 80~120℃, with 80℃ being the preferred temperature.

[0032] Furthermore, depending on the different structures of the reaction substrates, the reaction time is 3 to 12 hours.

[0033] The method for synthesizing geminal diamine compounds of the present invention specifically includes the following steps:

[0034] N-OTs amide compound a and a base were added to a reaction vessel, along with an appropriate amount of solvent and amine compound b. The reaction was carried out at 80-120°C. After the reaction was completed, the target compound c was obtained by separation and purification by column chromatography or recrystallization.

[0035] Compared with the prior art, the present invention has the following significant advantages:

[0036] This method innovatively uses an amide N-OTs compound a to react with an amine compound b to generate a geminal diamine compound c.

[0037] The raw materials used in this method are all inexpensive, readily available, or easily prepared compounds, and the reaction conditions are mild and the operation is simple. This makes the method highly compatible, with a wide substrate range, greatly improving the structural diversity of geminal diamine compounds, which is beneficial for large-scale industrial production. Detailed Implementation

[0038] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. These embodiments are only for further illustrating the present invention and are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the raw materials and reagents used in the embodiments are commercially available.

[0039] Example 1: Preparation of N-OTs amide compound a1

[0040]

[0041] N-methylhydroxylamine hydrochloride (4.18 g, 50 mmol, 1.0 equiv.) and NaHCO3 (8.40 g, 100 mmol, 2.0 equiv.) were added to a reaction vessel. Under nitrogen protection, THF / H2O (80 / 8 mL) was added, and stirring was started. Compound 1 (6.4 mL, 55 mmol, 1.1 equiv.) was slowly added dropwise. The reaction was carried out at room temperature for 17 h. After the reaction was complete, the mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 5:1) to obtain N-hydroxy-N-methylbenzamide (5.2 g, 69%) as a yellow oily liquid. Then, N-hydroxy-N-methylbenzamide (4.54 g, 30 mmol, 1 equiv.) was... Add the product to a reaction vessel, add dichloromethane (100 mL), then add triethylamine (4.6 mL, 33 mmol, 1.1 equiv.), and finally slowly add p-toluenesulfonyl chloride (6.29 g, 33 mmol, 1.1 equiv.) at 0 °C. Raise the temperature to room temperature and react for 4 h. After the reaction is complete, wash the reaction solution with water and saturated brine, dry it with anhydrous Na2SO4, filter it, concentrate it under reduced pressure, and separate and purify it by recrystallization to obtain a1 (7.33 g, 80%), which is a white solid.

[0042] Using the above preparation method, a2-a11 were obtained by simply replacing the different reaction raw materials.

[0043] Test results:

[0044] Compound a1: 80% yield, white solid; 1 H NMR (400 MHz, CDCl3) δ 7.60(d, J = 8.1 Hz, 2H), 7.43-7.38 (m, 1H), 7.36-7.31 (m, 2H), 7.29 (d, J = 7.4Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 3.55 (s, 3H), 2.39 (s, 3H); 13 C NMR (101MHz, CDCl3) δ 171.2, 146.2, 132.4, 131.4, 130.2, 129.8, 129.2, 128.4, 128.1,40.5, 21.8; FTIR (neat) ν max1694, 1596, 1378, 1292, 1192, 1182, 735, 704, 661cm -1 HRMS (ESI / [M+H]) + m / z calcd. for C 15 H 15 NO4S + 306.0795, found [M+H] + :306.0792.

[0045] Compound a2: 47% yield, white solid; 1 H NMR (400 MHz, CDCl3) δ 7.65(d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.10(d, J = 8.0 Hz, 2H), 3.52 (s, 3H), 2.38 (d, J = 8.5 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 171.4, 146.1, 142.1, 130.5, 129.7, 129.5, 129.3, 128.8, 128.7, 40.9,21.9, 21.6; FTIR (neat) ν max 1694, 1377, 1296, 1191, 1183, 895, 747 cm -1 HRMS(ESI / [M+H]) + m / z calcd. for C 16 H 18 NO4S + 320.0952, found [M+H] + : 320.0944.

[0046] Compound a3: 63% yield, white solid; 1 H NMR (400 MHz, CDCl3) δ 7.58(d, J = 7.6 Hz, 2H), 7.26 (s, 4H), 7.11 (d, J = 7.9 Hz, 2H), 3.53 (s, 3H), 2.36 (s, 3H), 1.30 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.3, 155.0, 146.0,130.3, 129.7, 129.5, 129.2, 128.4, 125.0, 40.7, 35.0, 31.2, 21.8; FTIR (neat)ν max 1660, 1382, 1191, 1178, 748, 712, 686 cm -1 HRMS (ESI / [M+H]) + m / z calcd.for C 19 H 23 NO4S + 362.1421, found [M+H] + : 362.1420.

[0047] Compound a4: 53% yield, white solid; 1 ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 8.3 Hz, 2H), 7.29–7.20 (m, 4H), 7.16 (d, J = 8.2 Hz, 2H), 3.56 (s, 3H), 2.40 (s, 3H). This compound is known and the data match previously reported in the literature. [7] .

[0048] Compound a5: 63% yield, white solid; 1 H NMR (400 MHz, CDCl3) δ 7.53(d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.16(d, J = 8.2 Hz, 2H), 3.56 (s, 3H), 2.41 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ170.0, 146.5, 131.3, 131.3, 130.2, 130.2, 129.9, 129.2, 126.0, 40.0, 21.9; FTIR (neat) ν max 1692, 1380, 1295, 1194, 1171, 895, 748 cm -1 HRMS (ESI / [M+H]) +)m / z calcd. for C 15 H 15 BrNO4S + 383.9900, found [M+H] + : 374.0669.

[0049] Compound a6: 51% yield, white solid; 1 H NMR (400 MHz, CDCl3) δ 7.47(dd, J = 10.8, 8.4 Hz, 4H), 7.39 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 3.61 (s, 3H), 2.38 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 169.5, 146.6,136.0, 132.7 (q, J = 32.8 Hz), 130.0, 129.9, 129.1, 128.9, 124.9 (q, J = 3.7Hz), 123.6 (q, J = 272.6 Hz), 39.6, 21.8; 19 F NMR (565 MHz, CDCl3) δ −63.1; FTIR (neat) ν max 1656, 1388, 1323, 1164, 1122, 1064, 740, 717, 670 cm -1 HRMS(ESI / [M+H]) + m / z calcd. for C 16 H 15 F3NO4S + 374.0669, found [M+H] + : 374.0660.

[0050] Compound a7: 52% yield, white solid; 1 H NMR (400 MHz, CDCl3) δ7.91–7.88 (m, 2H), 7.53–7.49 (m, 2H), 7.36–7.32 (m, 2H), 7.11 (d, J = 8.0 Hz,2H), 3.94 (s, 3H), 3.55 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ170.1, 166.2, 146.6, 136.6, 132.3, 130.1, 129.9, 129.2, 129.1, 128.4, 52.6,39.9, 21.8; FTIR (neat) ν max 1726, 1698, 1376, 1278, 1192, 901, 656 cm -1 HRMS(ESI / [M+H]) + m / z calcd. for C 17 H 18 NO6S + 364.0849, found [M+H] + : 364.0845.

[0051] Compound a8: 81% yield, white solid; 1 H NMR (400 MHz, CDCl3) δ 7.50(s, 1H), 7.49–7.44 (m, 2H), 7.35–7.31 (m, 1H), 7.25–7.19 (m, 2H), 7.14 (d, J= 8.1 Hz, 2H), 3.59 (s, 3H), 3.10 (s, 1H), 2.41 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 169.9, 146.7, 134.4, 132.8, 132.0, 129.9, 129.8, 129.2, 128.4,127.9, 122.5, 82.5, 78.5, 39.9, 21.9; FTIR (neat) ν max 3238, 1652, 1378, 1193,1166, 808, 741, 699, 660 cm -1 HRMS (ESI / [M+H]) + m / z calcd. for C 17 H 15 NO4S + 330.0795, found [M+H] + : 330.0793.

[0052] Compound a9: 60% yield, pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.69(s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 2.4, 1.5 Hz, 1H), 7.67 (d, J= 8.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 3.63 (s, 3H), 2.41 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 166.4, 146.7, 146.6, 146.2, 145.5, 143.0, 130.4, 130.1,129.2, 40.4, 21.9; FTIR (neat) ν max 1697, 1368, 1188, 1176, 1017, 763, 679,654 cm -1 HRMS (ESI / [M+H]) + m / z calcd. for C 13 H 13 N3O4S + 308.0700, found [M+H] + :308.0695.

[0053] Compound a10: 55% yield, white solid; 1 H NMR (400 MHz, CDCl3)δ 8.10 (d, J = 2.2 Hz, 1H), 8.01 (dd, J = 8.8, 2.3 Hz, 1H), 7.63 (d, J = 8.3Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.9 Hz, 1H), 3.89 (d, J = 6.5Hz, 2H), 3.51 (s, 3H), 2.38 (s, 3H), 2.32 (s, 3H), 2.19 (dt, J = 13.5, 6.8Hz, 1H), 1.08 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 166.9, 164.6,162.6, 160.7, 146.9, 132.6, 131.9, 129.8, 129.6, 129.2, 125.6, 119.6, 115.4,112.8, 103.1, 75.8, 39.2, 28.2, 21.8, 19.1, 17.5; FTIR (neat) ν max 1663, 1280,1175, 1013, 729, 690cm -1 HRMS (ESI / [M+H]) + m / z calcd. for C 24 H 25 N3O5S2 + :500.1308, found [M+H] + : 500.1303.

[0054] Compound a11: 66% yield, white solid; 1 H NMR (600 MHz, CDCl3) δ7.88 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 7.37 (d, J= 8.0 Hz, 2H), 7.27 (d, J = 6.6 Hz, 1H), 7.13 (dd, J = 8.9, 2.6 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 4.03 (q, J = 6.9 Hz, 1H), 3.90 (s, 3H), 3.11 (s, 3H),2.45 (s, 3H), 1.34 (d, J = 6.9 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 157.8,146.8, 134.7, 133.8, 130.9, 130.3, 129.5, 129.4, 129.0, 127.3, 126.6, 126.3,119.1, 105.6, 55.4, 42.4, 38.9, 21.9, 19.2; IR (ATR) ν max 2989, 1715, 1382,1180, 1051, 812, 760, 661 cm -1 HRMS (ESI / [M+H])+ m / z calcd. for C 22 H 24 NO5S + :414.1370, found [M+H] + : 414.1377.

[0055] The following examples illustrate some implementations in the optimization process, and compare them to show that the optimal conditions for the reaction are Et3N as the base, dimethyl sulfoxide as the solvent, and reaction at 80 °C.

[0056] Example 2: Preparation of compound c1

[0057]

[0058] N-methyl-N-OTs benzamide a1 (61 mg, 0.2 mmol, 1.0 equiv.) was added to a reaction vessel, followed by DMSO (2 mL), piperidine b1 (29.5 µL, 0.3 mmol, 1.5 equiv.), and Et3N (55.6 µL, 0.4 mmol, 2.0 equiv.). The reaction was carried out at 80 °C for 4 h. After the reaction was completed, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1:1 with 2% Et3N) to obtain benzoylene diamine compound c1 (36 mg, 82%) as a white solid.

[0059] Example 3: Preparation of compound c1

[0060]

[0061] N-methyl-N-OTs benzamide a1 (61 mg, 0.2 mmol, 1.0 equiv.) was added to a reaction vessel, followed by DMSO (2 mL), piperidine b1 (29.5 µL, 0.3 mmol, 1.5 equiv.), and DBU (27 µL, 0.4 mmol, 2.0 equiv.). The reaction was carried out at 80 °C for 4 h. After the reaction was completed, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1:1 with 2% Et3N) to obtain benzoyl diamine compound c1 (28 mg, 65%) as a white solid.

[0062] Example 4: Preparation of compound c1

[0063]

[0064] N-methyl-N-OTs benzamide a1 (61 mg, 0.2 mmol, 1.0 equiv.) was added to a reaction vessel, followed by DMSO (2 mL), piperidine b1 (29.5 µL, 0.3 mmol, 1.5 equiv.), and DIPEA (69.7 µL, 0.4 mmol, 2.0 equiv.). The reaction was carried out at 80 °C for 4 h. After the reaction was completed, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1:1 with 2% Et3N) to obtain benzoyl diamine compound c1 (25 mg, 57%) as a white solid.

[0065] Example 5: Preparation of compound c1

[0066]

[0067] N-methyl-N-OTs benzamide a1 (61 mg, 0.2 mmol, 1.0 equiv.) was added to a reaction vessel, followed by DMF (2 mL), piperidine b1 (29.5 µL, 0.3 mmol, 1.5 equiv.), and Et3N (55.6 µL, 0.4 mmol, 2.0 equiv.). The reaction was carried out at 80 °C for 4 h. After the reaction was completed, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1:1 with 2% Et3N) to obtain benzoyl diamine compound c1 (23 mg, 53%) as a white solid.

[0068] Example 6: Preparation of compound c1

[0069]

[0070] N-methyl-N-OTs benzamide a1 (61 mg, 0.2 mmol, 1.0 equiv.) was added to a reaction vessel, followed by MeCN (2 mL), piperidine b1 (29.5 µL, 0.3 mmol, 1.5 equiv.), and Et3N (55.6 µL, 0.4 mmol, 2.0 equiv.). The reaction was carried out at 80 °C for 4 h. After the reaction was completed, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1:1 with 2% Et3N) to obtain benzoylene diamine compound c1 (26 mg, 60%) as a white solid.

[0071] Example 7: Preparation of compound c1

[0072]

[0073] N-methyl-N-OTs benzamide a1 (61 mg, 0.2 mmol, 1.0 equiv.) was added to a reaction vessel, followed by DMSO (2 mL), piperidine b1 (29.5 µL, 0.3 mmol, 1.5 equiv.), and Et3N (55.6 µL, 0.4 mmol, 2.0 equiv.). The reaction was carried out at 120 °C for 4 h. After the reaction was completed, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1:1 with 2% Et3N) to obtain benzoyl diamine compound c1 (5 mg, 11%) as a white solid.

[0074] Example 8: Preparation of compound c1

[0075]

[0076] N-methyl-N-OTs benzamide a1 (61 mg, 0.2 mmol, 1.0 equiv.) was added to a reaction vessel, followed by DMSO (2 mL), piperidine b1 (29.5 µL, 0.3 mmol, 1.5 equiv.), and Et3N (55.6 µL, 0.4 mmol, 2.0 equiv.). The reaction was carried out at 60 °C for 4 h. After the reaction was completed, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1:1 with 2% Et3N) to obtain benzoyl diamine compound c1 (28 mg, 65%) as a white solid.

[0077] The same method as in Example 2 was used below, except that reactant a and reactant b were replaced accordingly, to obtain compounds c2-c35 respectively.

[0078] Test results:

[0079] Compound c1: white solid (36 mg, 82%). 1 H NMR (600 MHz, CDCl3)δ 7.84-7.73 (m, 2H), 7.53-7.47 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H), 6.65 (s,1H), 4.29 (d, J = 6.2 Hz, 2H), 2.59 (t, J = 5.4 Hz, 4H), 1.60 (p, J = 5.7 Hz, 4H), 1.44 (p, J = 6.7, 6.3 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 168.0, 134.4,131.8, 128.7, 127.1, 62.6, 51.6, 25.8, 24.1; HRMS (ESI / [M + Na] + m / z calcd.for C 13 H 18 N2NaO + 241.1311, found [M + Na] + : 241.1305.

[0080] Compound c2: white solid (41 mg, 88%). 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.74 (t, J = 6.3Hz, 1H), 4.24 (d, J = 6.3 Hz, 2H), 2.55 (t, J = 5.5 Hz, 4H), 2.37 (s, 3H), 1.57 (q, J = 5.7 Hz, 4H), 1.41 (q, J = 6.0 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ167.8, 142.0, 131.5, 129.2, 127.0, 62.4, 51.5, 25.8, 24.1, 21.4; HRMS (ESI / [M+H] + m / z calcd. for C 14 H 21 N2O + 233.1648, found [M+H] + : 233.1646.

[0081] Compound C3: white solid (48 mg, 81%). 1 H NMR (600 MHz, CDCl3) δ 7.68-7.64 (m, 2H), 7.57-7.52 (m, 2H), 6.78 (s, 1H), 4.23 (d, J = 6.2Hz, 2H), 2.55 (t, J = 5.4 Hz, 4H), 1.57 (p, J = 5.6 Hz, 4H), 1.43 (q, J = 6.4Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 166.9, 133.1, 131.8, 128.6, 126.3, 62.6,51.5, 25.7, 24.0; HRMS (ESI / [M+H] + m / z calcd. for C 13 H 18 BrN2O + 297.0597, found [M+H] + : 297.0599.

[0082] Compound C4: white solid (34 mg, 61%). 1 H NMR (600 MHz, CDCl3) δ 8.10 (dt, J = 8.8, 4.9 Hz, 2H), 7.86 (dt, J = 8.7, 4.6 Hz, 2H), 6.75(s, 1H), 4.29 (d, J = 5.0 Hz, 2H), 3.94 (d, J = 3.8 Hz, 4H), 2.64–2.53 (m,4H), 1.61 (dt, J = 11.7, 5.3 Hz, 4H), 1.50-1.40 (m, 2H); 13 C NMR (151 MHz, CDCl3) δ 167.0, 166.3, 138.2, 132.8, 129.9, 127.0, 62.6, 52.4, 51.5, 25.7,24.0; HRMS (ESI / [M+H] + m / z calcd. for C 15 H 21 N2O3 + 277.1547, found [M+H] + :277.1545.

[0083] Compound C5: white solid (49 mg, 90%). 1 H NMR (600 MHz, CDCl3) δ 7.56 (dd, J = 8.5, 1.9 Hz, 2H), 7.29-7.23 (m, 2H), 6.49 (s, 1H), 4.10 (dt, J = 6.4, 1.7 Hz, 2H), 2.40 (t, J = 5.4 Hz, 4H), 1.41 (p, J = 5.6Hz, 4H), 1.25 (dq, J = 10.0, 6.1 Hz, 2H), 1.15 (d, J = 1.7 Hz, 9H)

[0084] ; 13 C NMR (151 MHz, CDCl3) δ 167.7, 155.2, 131.3, 126.8, 125.5, 62.4,51.4, 34.9, 31.1, 25.7, 24.0; HRMS (ESI / [M+H] + m / z calcd. for C 17H 27 N2O + :275.2118, found [M+H] + : 275.2116.

[0085] Compound C6: white solid (29 mg, 60%). 1 H NMR (600 MHz, CDCl3)δ 7.90 (d, J = 1.8 Hz, 1H), 7.81-7.77 (m, 1H), 7.61-7.58 (m, 1H), 7.39 (td, J= 7.8, 3.4 Hz, 1H), 6.83 (t, J = 6.4 Hz, 1H), 4.26 (dd, J = 6.2, 3.3 Hz, 2H), 3.12 (d, J = 1.8 Hz, 1H), 2.58 (q, J = 7.0, 5.2 Hz, 4H), 1.58 (p, J = 5.6 Hz,4H), 1.44 (h, J = 8.5, 7.4 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 167.0, 135.0,134.6, 130.6, 128.7, 127.5, 122.6, 82.6, 78.3, 62.5, 51.5, 25.7, 24.0; HRMS(ESI / [M+H] + m / z calcd. for C 15 H 19 N2O + :243.1492, found [M+H] + : 243.1495.

[0086] Compound C7: White solid (35 mg, 70%). 1 H NMR (600 MHz, CDCl3)δ 7.75-7.73 (m, 2H), 7.40-7.38 (m, 2H), 6.92 (s, 1H), 4.24 (d, J = 6.1 Hz, 2H), 2.56 (t, J = 5.4 Hz, 4H), 1.57 (p, J = 5.6 Hz, 4H), 1.43 (t, J = 6.0 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 167.0, 138.0, 132.7, 128.9, 128.6, 62.6, 51.6,25.8, 24.1; HRMS (ESI / [M+H] + m / z calcd. for C 13 H 18 ClN2O + 253.1102, found [M+H] + : 253.1104.

[0087] Compound C8: white solid (38 mg, 66%). 1 H NMR (600 MHz, CDCl3) δ 7.93-7.90 (m, 2H), 7.70 (t, J = 7.9 Hz, 2H), 6.90 (t, J = 6.3 Hz,1H), 4.29 (d, J = 6.1 Hz, 2H), 2.60 (t, J = 6.1 Hz, 4H), 1.61 (q, J = 5.7 Hz, 4H), 1.45 (p, J = 5.9 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 166.7, 137.6, 133.6,128.0, 127.7, 125.8 (q, J = 3.8 Hz), 62.7, 51.7, 25.8, 24.1; 19 F NMR (564 MHz, CDCl3) δ -63.0; HRMS (ESI / [M+H] + m / z calcd. for C 14 H 18 F3N2O + 287.1366, found[M+H] + : 287.1363.

[0088] Compound C9: White solid (57 mg, 88%). 1H NMR (600 MHz,CDCl3) δ 7.70 (dd, J = 11.6, 8.7 Hz, 2H), 7.66 (d, J = 1.8 Hz, 1H), 7.38 (dd,J = 8.5, 1.9 Hz, 1H.), J = , 7.5. 1H), 7.11 (d, J = 2.5 Hz,1H), 5.93-5.78 (m, 1H), 3.99 (dd, J = 6.4, 5.1 Hz, 2H), 3.91 (d, J = 1.9 Hz, 3H), 3, J, 3.71 (H2 = 1.9 Hz, 3H), 3, J.71 (q = Hz). 5.6, 4.7 Hz, 4H), 1.59 (dd, J =7.2, 3.5 Hz, 3H), 1.47 (p, J = 5.6 Hz, 4H), 1.33 (p, J = 5.8 Hz, 2H); 13 C NMR(151 MHz, CDCl3) δ 174.9, 157.7, 136.4, 133.8, 129.2, 129.0, 127.6, 127.6,126.3, 126.2, 555.3, 102.2, 51.2, 47.2, 25.6, 24.0, 18.4; HRMS(ESI / [M+H] + ) m / z calcd. for C 20 H 27 N2O2 + : 327.2067, found [M+H] + : 327,2066。

[0089] Charcoal (23 mg, 50%). 1 H NMR (600 MHz, CDCl3)δ 7.40 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.25-7.18 (m, 2H), 6.31(s, 1H), J 2, 6 = 6.4 (d, J = 5.5 Hz, 4H), 2.47 (s, 3H),1.64 (p, J = 5.7 Hz, 4H), 1.47 (q, J = 5.9 Hz, 2H); 1313C NMR (151 MHz, CDCl3) δ 170.5, 136.2, 136.1, 131.1, 130.1, 126.6, 125.8, 62.0, 51.3, 25.6, 23.9, 20.0; HRMS (ESI / [M+H] + ) m / z calcd. for C 14 H 21 N2O + : 233.1648, found [M+H] + : 233.1646。

[0090] Compound c11: White solid (44 mg, 53%). 1 1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 13.7 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.30 (t, J = 6.2 Hz, 1H), 4.26 (d, J = 6.1 Hz, 2H), 3.88 (d, J = 6.4 Hz, 3H), 2.99 (d, J = 4.8 Hz, 1H), 2.74 - 2.69 (m, 4H), 2.57 (t, J = 5.3 Hz, 4H), 2.18 (dt, J = 13.3, 6.6 Hz, 2H), 1.60 (t, J = 5.7 Hz, 5H), 1.44 (s, 2H), 1.07 (d, J = 6.7 Hz, 7H); 13 [[ID=,18]]13C NMR (151 MHz, CDCl3) δ 164.8, 162.4, 162.1, 157.2, 156.5, 132.6, 132.0, 126.0, 115.6, 112.7, 103.0, 62.7, 51.6, 28.2, 25.8, 24.1, 19.2, 17.6; HRMS (ESI / [M+H] + ) m / z calcd. for C 22 H 31 N4O2S + : 415.2162, found [M+H] + : 415.2163。

[0091] Compound C12: colorless oily liquid (27 mg, 55%). 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.4Hz, 2H), 6.71 (br s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 2.89 (ddd, J = 10.8, 6.2,3.6 Hz, 2H), 2.53-2.34 (m, 3H), 2.08 (s, 1H), 1.94-1.84 (m, 2H), 1.75-1.65(m, 2H); 13 C NMR (101 MHz, CDCl3) δ 168.0, 134.3, 131.9, 128.8, 127.1, 87.0,69.4, 62.2, 49.2, 31.4, 26.6; HRMS (ESI / [M + H] + m / z calcd. for C 15 H 19 N2O + :243.1492, found [M + H] + : 243.1491.

[0092] Compound C13: white solid (35 mg, 80%). 1 H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 6.9 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7Hz, 2H), 6.70 (d, J = 6.5 Hz, 1H), 4.28 (dd, J = 6.3, 1.8 Hz, 2H), 3.73-3.67(m, 4H), 2.64-2.60 (m, 4H); 13 C NMR (151 MHz, CDCl3) δ 168.0, 134.0, 131.7,128.5, 126.9, 66.7, 61.8, 50.4; HRMS (ESI / [M+H] + m / z calcd. for C 12 H 17 N2O2 +:221.1285, found [M+H] + : 221.1282.

[0093] Compound C14: white solid (35 mg, 71%). 1 H NMR (600 MHz, CDCl3) δ 7.81–7.78 (m, 2H), 7.50 (td, J = 7.3, 1.3 Hz, 1H), 7.45-7.41 (m,2H), 6.72 (s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.31 (d, J = 1.2 Hz, 3H), 3.23 (tt, J = 8.3, 3.9 Hz, 1H), 2.88 (dt, J = 10.8, 4.8 Hz, 2H), 2.46-2.39 (m,2H), 1.96-1.88 (m, 2H), 1.66-1.56 (m, 2H); 13 C NMR (151 MHz, CDCl3) δ 168.0,134.3, 131.8, 128.7, 127.1, 61.9, 55.7, 48.2, 30.7; HRMS (ESI / [M+H] + m / zcalcd. for C 14 H 21 N2O2 + 249.1598, found [M+H] + : 249.1600.

[0094] Compound C15: colorless oily liquid (26 mg, 52%). 1 H NMR (600MHz, CDCl3) δ 7.47 (d, J = 7.0 Hz, 2H), 7.38-7.34 (m, 1H), 7.32 (t, J = 7.3Hz, 2H), 3.37 (d, J = 6.3 Hz, 2H), 3.10 (s, 1H), 2.83 (d, J = 10.1 Hz, 2H), 1.68 (d, J = 13.0 Hz, 4H), 1.40 (d, J = 7.0 Hz, 1H), 1.37–1.30 (m, 2H), 1.02(q, J = 14.2, 13.6 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 136.6, 129.3, 128.8,127.5, 127.4, 67.5, 51.6, 37.8, 28.4, 24.4; HRMS (ESI / [M + K] + m / z calcd.for C 14 H 21 N2O2 + 249.1598, found [M + H] + : 249.1601.

[0095] Compound C16: white solid (42 mg, 72%). 1 H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 7.0 Hz, 2H), 7.54-7.50 (m, 1H), 7.45 (t, J = 7.7 Hz,2H), 7.32-7.27 (m, 2H), 7.20 (dt, J = 9.1, 6.1 Hz, 3H), 6.68 (d, J = 6.7 Hz,1H), 4.38 (dd, J = 6.3, 2.6 Hz, 2H), 3.12 (dd, J = 11.6, 3.4 Hz, 2H), 2.54-2.47 (m, 1H), 2.43 (t, J = 11.8 Hz, 2H), 1.89 (d, J = 13.2 Hz, 2H), 1.79 (q,J = 12.5 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 168.0, 146.0, 134.3, 131.9,128.8, 128.6, 127.1, 126.9, 126.4, 62.2, 51.4, 42.4, 33.3; HRMS (ESI / [M+H] + )m / z calcd. for C 19 H 23 N2O + 295.1805, found [M+H] + : 295.1807.

[0096] Compound C17: Brown oily liquid (22 mg, 55%). 1H NMR (600 MHz, CDCl3) δ 7.78 (dd, J = 8.2, 1.4 Hz, 2H), 7.51-7.47 (m, 1H), 7.43-7.39 (m,2H), 6.86-6.75 (m, 1H), 4.39 (d, J = 6.1 Hz, 2H), 3.44 (d, J = 2.4 Hz, 2H), 2.44 (s, 3H), 2.30-2.27 (m, 1H); 13 C NMR (151 MHz, CDCl3) δ 167.9, 134.4,131.8, 128.7, 127.1, 73.3, 60.7, 43.8, 39.1; HRMS (ESI / [M+H] + ) m / z calcd. forC 12 H 15 N2O + 203.1179, found [M+H] + : 203.1181.

[0097] Compound C18: white solid (50 mg, 81%). 1 H NMR (600 MHz, CDCl3) δ 7.83-7.79 (m, 2H), 7.54-7.49 (m, 1H), 7.44 (dd, J = 8.4, 7.0 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.86-6.82 (m, 2H), 6.69 (t, J = 6.3 Hz, 1H), 4.39(d, J = 6.3 Hz, 2H), 3.18-3.13 (m, 4H), 2.81 (dd, J = 6.0, 3.9 Hz, 4H), 2.27(s, 3H); 13 C NMR (151 MHz, CDCl3) δ 168.0, 149.1, 134.2, 131.8, 129.6, 129.5,128.6, 127.0, 116.6, 61.6, 50.2, 49.7, 20.4; HRMS (ESI / [M+H] + ) m / z calcd. forC 19 H 24 N3O +310.1914, found [M+H] + : 310.1917.

[0098] Compound C19: white solid (47 mg, 56%). 1 H NMR (600 MHz, CDCl3) δ 7.79 (dd, J = 7.4, 1.8 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.43 (t, J= 7.6 Hz, 2H), 7.33 (dd, J = 7.8, 5.5 Hz, 4H), 7.26-7.20 (m, 4H), 7.17 (t, J= 7.4 Hz, 1H), 6.71 (t, J = 6.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.20 (s,1H), 2.68 (t, J = 4.9 Hz, 4H), 2.41 (s, 4H); 13 C NMR (151 MHz, CDCl3) δ 168.1,142.1, 141.3, 134.2, 132.7, 131.9, 129.2, 128.8, 128.8, 128.7, 127.9, 127.3,127.1, 61.6, 51.6, 50.4; HRMS (ESI / [M+H] + m / z calcd. for C 25 H 27 ClN3O + :420.1837, found [M+H] + : 420.1834.

[0099] Compound C20: white solid (32 mg, 65%). 1 H NMR (600 MHz, CDCl3) δ 7.80–7.76 (m, 2H), 7.51-7.48 (m, 1H), 7.44-7.40 (m, 2H), 6.68 (d, J =6.8 Hz, 1H), 4.28 (dd, J = 6.3, 2.2 Hz, 2H), 3.67-3.59 (m, 2H), 2.77-2.72 (m,2H), 2.04 (t, J = 10.8 Hz, 2H), 1.14 (dd, J = 6.3, 2.2 Hz, 6H); 13 C NMR (151MHz, CDCl3) δ 168.1, 134.2, 131.9, 128.7, 127.1, 71.8, 61.6, 56.3, 19.2; HRMS(ESI / [M+H] + ) m / z calcd. for C 14 HN2O2 + : 249.1598, found [M+H] + : 249.1600。

[0100] Compound c21: White solid (47 mg, 81%). 1 H NMR (600 MHz,CDCl3) δ 7.77 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.7Hz, 2H), 6.70 (s, 1H), 4.27 (dd, J = 6.3, 1.9 Hz, 2H), 4.10 (qd, J = 7.1, 1.9Hz, 2H), 2.94 (d, J = 11.7 Hz, 2H), 2.30 (t, J = 11.5 Hz, 2H), 2.24 (t, J =11.2 Hz, 1H), 1.93-1.87 (m, 2H), 1.76-1.67 (m, 2H), 1.22 (td, J = 7.1, 1.9Hz, 3H); 13 C NMR δ 175.0, 168.0, 134.3, 131.8, 128.7, 127.1, 62.1, 60.5, 50.1,40.9, 28.2, 14.3; HRMS (ESI / [M+H] + ) m / z calcd. for C​16 H 23 N2O3 + 291.1703, found[M+H] + : 291.1701.

[0101] Compound C22: white solid (39 mg, 71%). 1 H NMR (600 MHz, CDCl3) δ 7.83-7.79 (m, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.43 (dd, J = 8.3, 7.1Hz, 2H), 7.03 (s, 1H), 4.56 (dd, J = 13.3, 6.6 Hz, 1H), 4.31 (dd, J = 13.3,5.3 Hz, 1H), 3.74 (s, 3H), 3.40 (dd, J = 7.7, 4.2 Hz, 1H), 3.13 (dt, J =11.1, 5.2 Hz, 1H), 2.54 (dt, J = 11.8, 6.0 Hz, 1H), 1.84 (dddd, J = 29.8,16.9, 13.0, 8.2, 3.9 Hz, 2H), 1.66-1.51 (m, 3H), 1.39 (dd, J = 10.4, 7.0 Hz,1H); 13 C NMR (151 MHz, CDCl3) δ 174.5, 167.8, 134.3, 131.7, 128.7, 127.1,62.3, 61.0, 52.2, 48.9, 29.5, 25.2, 22.3; HRMS (ESI / [M+H] + ) m / z calcd. forC 15 H 21 N2O3 + 277.1547, found [M+H] + : 277.1549.

[0102] Compound C23: colorless oily liquid (29 mg, 61%). 1H NMR (400 MHz,CDCl3) δ 7.79 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.5Hz, 2H), 6.71 (br s, J = 16 (H3), 4. 3.08 (t, J = 13.1 Hz,2H), 2.93 (t, J = 7.0 Hz, 2H), 2.27 (tt, J = 14.4, 7.0 Hz, 2H); 13 C NMR (101MHz, CDCl3) δ 168.3, 134.1, 132.0, 129.7 (t, J = 248.3 Hz), 128.8, 58.7 (t, J= 29.7 Hz), 57.7, 8, J = 3.0 (t 24.6 Hz); 19 F NMR (377MHz CDCl3) δ − 93.2; HRMS (ESI / [M + Na] + ) m / z calcd. for C 12 H 14 F2N2NaO + :263.0966, found [M + Na] + : 263.0967。

[0103] Charcoal (52 mg, 60%). 1H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 7.0 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6Hz, 2H), 7.34 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 7.09–7.05 (m,2H), 7.01 (dd, J = 7.7, 2.0 Hz, 1H), 6.86 (ddd, J = 8.3, 5.2, 3.3 Hz, 1H), 6.76 (t, J = 6.3 Hz, 1H), 6.53-6.49 (m, 1H), 4.43 (d, J = 6.3 Hz, 2H), 3.13(s, 4H), 2.87 (t, J = 4.7 Hz, 4H), 2.34 (s, 3H), 2.30 (s, 3H); 13 C NMR (151MHz, CDCl3) δ 167.9, 148.9, 142.2, 139.1, 136.0, 134.4, 134.0, 131.7, 131.6,128.6, 127.7, 127.3, 127.0, 126.2, 125.4, 124.4, 119.72, 61.6, 51.3, 50.4,21.1, 20.5; HRMS (ESI / [M + H] + m / z calcd. for C 26 H 30 N3OS + :432.2104, found [M +H] + : 432.2106.

[0104] Compound C25: white solid (32 mg, 61%). 1 H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7Hz, 2H), 6.64 (t, J = 6.4 Hz, 1H), 4.36 (d, J = 6.3 Hz, 2H), 2.68 (s, 8H),1.62 (dq, J = 6.8, 3.4 Hz, 1H), 0.48-0.36 (m, 4H);13 C NMR (151 MHz, CDCl3) δ168.0, 134.2, 131.9, 128.7, 127.1, 61.7, 53.1, 50.0, 38.5, 5.9; HRMS (ESI / [M+H] + m / z calcd. for C 15 H 22 N3O + 260.1757, found [M+H] + : 260.1755.

[0105] Compound C26: white solid (51 mg, 77%). 1 H NMR (600 MHz, CDCl3) δ 7.80 (dd, J = 8.3, 1.4 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.43 (t, J= 7.7 Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 6.75 (t, J= 6.3 Hz, 1H), 4.37 (d, J = 6.4 Hz, 2H), 3.18–3.12 (m, 5H), 2.81-2.75 (m,4H); 13 C NMR (151 MHz, CDCl3) δ 168.2, 149.9, 134.2, 131.9, 129.0, 128.7,127.1, 124.8, 117.5, 61.6, 50.0, 49.2; HRMS (ESI / [M+H] + ) m / z calcd. forC 18 H 21 ClN3O + 330.1368, found [M+H] + : 330.1370.

[0106] Compound C27: white solid (42 mg, 59%). 1H NMR (600 MHz, CDCl3) δ 7.79-7.75 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 6.65 (t, J = 6.6 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 2.92–2.85 (m, 4H),2.70–2.62 (m, 4H); 13 C NMR (151 MHz, CDCl3) δ 168.2, 134.2, 131.9, 128.7,127.1, 63.0, 52.3, 28.0; HRMS (ESI / [M+H] + m / z calcd. for C 12 H 17 N2OS + :237.1056, found [M+H] + : 237.1055.

[0107] Compound C28: colorless oily liquid (27 mg, 59%). 1 H NMR (400 MHz, CDCl3) δ 7.83−7.76 (m, 2H), 7.53−7.46 (m, 1H), 7.42 (dd, J = 8.2, 6.6 Hz, 2H), 6.67 (t, J = 6.4 Hz, 1H), 4.67 (s, 2H), 4.35 (d, J = 6.3 Hz, 2H), 2.65 (t, J = 5.7 Hz, 4H), 2.26 (t, J = 5.7 Hz, 4H); 13 C NMR (101 MHz, CDCl3) δ168.0, 145.6, 134.4, 131.8, 128.7, 127.1, 108.6, 61.9, 52.2, 34.5; HRMS (ESI / [M + Na] + m / z calcd. for C 14 H 18 N2NaO + 253.1311, found [M + Na] + : 253.1311.

[0108] Compound C29: white solid (33 mg, 55%). 1 H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.7Hz, 2H), 6.71 (s, 1H), 4.30 (dd, J = 6.4, 2.3 Hz, 2H), 3.71 (s, 4H), 3.08-2.97 (m, 2H), 2.53 (s, 4H), 2.30 (t, J = 11.8 Hz, 2H), 2.19 (t, J = 11.2 Hz,1H), 1.85 (d, J = 12.1 Hz, 2H), 1.55 (q, J = 12.1 Hz, 2H); 13 C NMR (151 MHz, CDCl3) 13 C NMR (151 MHz, Chloroform-d) δ 168.0, 134.2, 131.9, 128.8, 127.1,67.3, 61.8, 61.8, 50.1, 49.8, 27.9; HRMS (ESI / [M+H] + m / z calcd. for C 17 H 26 N3O2 + 304.2020, found [M+H] + : 304.2023.

[0109] Compound C30: white solid (56 mg, 67%). 1 H NMR (600 MHz, CDCl3) δ 7.82−7.78 (m, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.32 (dd, J = 8.4, 5.4 Hz, 4H), 6.95 (t, J = 8.7 Hz, 4H), 6.62 (t, J =6.3 Hz, 1H), 5.29 (s, 1H), 4.34 (d, J = 6.2 Hz, 2H), 4.22 (s, 1H), 2.68 (s,4H), 2.40 (s, 4H); 13C NMR (151 MHz, CDCl3) δ 168.03, δ 161.95 (d, J = 245.4Hz), 138.1, 134.2, 131.9, 129.3 (d, J = 7.9 Hz), 128.8, 127.1, 115.6 (d, J =21.2 Hz), 74.4, 61.6, 51.5, 50.4, 31.6; 19 F NMR (564 MHz, CDCl3) δ-115.5; HRMS(ESI / [M+H] + m / z calcd. for C 26 H 27 F2N2O + 421.2086, found [M+H] + : 421.2088.

[0110] Compound C31: white solid (43 mg, 81%). 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7Hz, 2H), 6.62 (s, 1H), 4.44 (d, J = 6.5 Hz, 2H), 3.23-3.16 (m, 4H), 3.07 (t,J = 5.3 Hz, 4H); 13 C NMR (151 MHz, CDCl3) δ 168.4, 133.8, 132.2, 128.8, 127.2,61.2, 51.6, 48.6; HRMS (ESI / [M+H] + m / z calcd. for C 12 H 17 N2O3S + 269.0954, found[M+H] + : 269.0956.

[0111] Compound C32: colorless oily liquid (35 mg, 51%). 1H NMR (600MHz, CDCl3) δ 7.80 (d, J = 7.4 Hz, 3H), 7.52 (d, J = 8.2 Hz, 1H), 7.43 (dd, J= 12.2, 8.2 Hz, 5H), 7.30 (d, J = 8.6 Hz, 2H), 6.83 (t, J = 6.2 Hz, 1H), 4.37(d, J = 6.3 Hz, 2H), 2.91-2.77 (m, 4H), 2.09 (td, J = 13.1, 4.7 Hz, 2H), 1.76(d, J = 11.6 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 168.2, 132.2, 132.0, 128.8,128.6, 127.5, 127.2, 126.2, 70.8, 61.9, 46.5, 38.2; HRMS (ESI / [M+H] + m / zcalcd. for C 19 H 22 ClN2O2 + 345.1364, found [M+H] + : 345.1366.

[0112] Compound C33: Brown oily liquid (19 mg, 41%). 1 H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 7.7 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.6Hz, 2H), 7.20 (t, J = 7.7 Hz, 2H), 6.79 (t, J = 7.3 Hz, 1H), 6.73 (d, J = 8.0Hz, 2H), 4.93 (d, J = 5.5 Hz, 2H); 13 C NMR (151 MHz, CDCl3) δ 168.2, 145.8,134.1, 131.9, 129.7, 128.7, 127.1, 119.0, 113.7, 50.4; HRMS (ESI / [M+H] + m / zcalcd. for C 14 H 15 N2O +227.1179, found [M+H] + : 227.1182.

[0113] Compound C34: Brown oily liquid (21 mg, 41%). 1 H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 7.7 Hz, 2H), 7.46 (dt, J = 7.4, 4.4 Hz, 1H), 7.41-7.35(m, 2H), 6.81-6.75 (m, 2H), 6.70 (d, J = 8.4 Hz, 2H), 4.86 (d, J = 5.5 Hz,2H), 3.73 (s, 3H); 13 C NMR (151 MHz, CDCl3) δ 192.7, 134.1, 131.8, 128.8,128.7, 127.5, 127.3, 127.1, 115.2, 55.8; HRMS (ESI / [M+H] + ) m / z calcd. forC 15 H 17 N2O2 + 257.1285, found [M+H] + : 257.1288.

[0114] Compound C35: white solid (21 mg, 50%). 1 H NMR (600 MHz, CDCl3)δ 9.41 (d, J = 1.5 Hz, 1H), 8.78 (d, J = 2.5 Hz, 1H), 8.55 (t, J = 2.0 Hz,1H), 8.25 (s, 1H), 4.37 (d, J = 6.6 Hz, 2H), 3.73 (t, J = 4.7 Hz, 4H), 2.67 (t, J = 4.7 Hz, 4H); 13 C NMR (151 MHz, CDCl3) δ 163.9, 147.7, 144.8, 144.1,142.8, 66.8, 61.4, 50.4; HRMS (ESI / [M+H] + m / z calcd. for C 10 H 15 N4O2 +: 223.1190,found [M+H] + : 223.1191。

Claims

1. A method for synthesizing a geminal diamine compound, characterized in that: In an organic solvent system and in the presence of a base, amide N-OTs compound a reacts with amine compound b to generate target compound c; The reaction formula is shown below: ； in: R 1 Selected from C1-C6 alkyl groups, substituted or unsubstituted aryl groups, , Any one of the following; the substituent used for substitution is selected from one or more of the following: C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkynyl, heteroatom; R 2 Selected from hydrogen and C1-C8 alkyl groups; R in target compound c 3 R 4 The structural segments formed by the N atom attached to the ring are selected from substituted or unsubstituted pyrrole rings, piperidine rings, piperazine rings, aniline, etc. , , , , , , Any one of them; or, R 3 and R 4 Alkyl groups selected independently from C1 to C8, Any one of them.

2. The synthesis method according to claim 1, characterized in that: R 1 Selected from C1-C6 alkyl, phenyl, , , , , , , , , , , , , , , , , Any one of them; R 5 It is selected from any one of methyl, methoxy, tert-butyl, chloro, bromine, fluorine, cyano, trifluoromethyl, methyl formate, and alkynyl; R in target compound c 3 R 4 The structural fragment composed of the N atom and its bonded N atom is selected from , , , , , , , , , , , , , , , , , , , , , Any one of them; or, R 3 and R 4 Alkyl groups selected from C1 to C8 respectively Any one of them.

3. The synthesis method according to claim 1 or 2, characterized in that: The target compound c is selected from any one of the compounds with the following structures: ； 。 4. The synthesis method according to claim 1, characterized in that: The alkali is selected from any one of Et3N, DIPEA, DBU, tBuONa, and Cs2CO3.

5. The synthesis method according to claim 4, characterized in that: The base is Et3N.

6. The synthesis method according to claim 1, characterized in that: The solvent is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile.

7. The synthesis method according to claim 1, characterized in that: The molar ratio of amide N-OTs compound a to amine compound b is 1:1~3; the molar ratio of amide N-OTs compound a to base is 1:1~3.

8. The synthesis method according to claim 1, characterized in that: The reaction temperature is 80~120℃, and the reaction time is 3~12 h.

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