A nitrogen-containing heteroquaternary carbon bicyclic hydantoin derivative and a method for synthesizing the same

Abstract

The application discloses a nitrogen-containing hetero-quaternary carbon bicyclic hydantoin derivative and a synthesis method thereof, and a chemical structural formula of the derivative is shown as formula 3; the synthesis method is as follows: compound isocyanate derivatives of formula 1 and compound 2,3-dicarbonyl ketone acid ester derivatives of formula 2 are taken as reaction raw materials and are added into an organic solvent, and then heating and stirring reaction is carried out under the conditions of nitrogen and under the action of a catalyst, and the reaction is tracked to completion by TLC, and then purification is carried out to obtain the derivative.The nitrogen-containing hetero-quaternary carbon center bicyclic hydantoin molecule is efficiently synthesized through cyclization de- aromatization / 1,2-rearrangement reaction in one pot, the method has the advantages of simple operation, low cost, mild reaction condition, no by-product generation, wide substrate application range, and is suitable for industrial large-scale production, provides technical support and material basis for development of the bicyclic hydantoin drug molecule, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative and its synthesis method. Background Technology

[0002] Bicyclic hydantoin derivatives are widely found in drug molecules and bioactive natural products. Due to their unique molecular structure, they possess different physiological and pharmacological activities, such as antibacterial and anticancer activities. They can also act as cholesterol homeostasis regulators and 5-HT inhibitors. 1A Receptor ligands, presynaptic 5-HT 1A Agonists, etc. Therefore, the synthesis methods of nitrogen-containing heterocyclic carbon bicyclic hydantoin derivatives have attracted great interest from chemists.

[0003]

[0004] Most reported synthetic methods for nitrogen-containing heterocyclic bicyclic hydantoin derivatives start from intramolecular cyclization 1,2-rearrangement reactions, proceeding through steps such as metal activation of the alkynyl group and nucleophilic cyclization. For example:

[0005] (1) Using copper (I) catalysis, cyclization rearrangement of 22-propynyl alcohols was carried out to construct nitrogen-containing heterocyclic bicyclic hydantoin derivatives (Yan, B.; Zhou, Y.; Zhang, H.; Chen J.; Liu, Y. J. J. J. G. Chem. 2007, 72, 7783). The reaction formula is as follows:

[0006]

[0007] (2) Cyclization rearrangement of pyridine-propargyl alcohols was carried out using platinum(II) catalysis to construct nitrogen-containing heteroquaternary carbon bicyclic hydantoin derivatives (Smith, CR; Bunelle, EM; Rhodes, AJ; Sarpong, R. Org. Lett. 2007, 9, 1169). The reaction formula is as follows:

[0008]

[0009] (3) Nitrogen-containing heterocyclic bicyclic hydantoin derivatives were constructed by cyclization rearrangement of quinoline-2-propargyl alcohol compounds using proton-type solvents (Heller, ST; Kiho, T.; Narayan, AR; Sarpong, R. Angew. Chem. Int. Ed. 2013, 52, 11129). The reaction formula is as follows:

[0010]

[0011] (4) Nitrogen-containing heterocyclic bicyclic hydantoin derivatives were constructed by cyclization rearrangement reaction of 2-substituted pyridine compounds with diarylcyclopropenones (Liu, X.; Shi, X.; Zhou, J.; Huang, C.; Lin, Y.; Zhang, C.; Cao, H. Chem. Commun. 2023, 59, 4051), and the reaction formula is as follows:

[0012]

[0013] Therefore, the current synthetic methods for intermolecular cyclization rearrangement reactions of nitrogen-containing heteroquaternary carbon-indinocyclohexane derivatives are very limited, and are mainly concentrated on the synthesis of intramolecular cyclization rearrangement methods for pyridines or quinolines with alkynyl substituents. Furthermore, these methods often suffer from narrow substrate scope, cumbersome synthetic routes, and metal waste. Intermolecular cyclization dearomatization / 1,2-rearrangement reactions are one of the most direct means of constructing nitrogen-containing heteroquaternary carbon-indinocyclohexane derivatives, and can greatly broaden the substrate scope, possessing high research value. However, such synthetic methods are rarely reported, resulting in significant gaps in the study of the chemical properties and biological activities of related compounds, which is one of the bottleneck problems restricting the development of nitrogen-containing heteroquaternary carbon-indinocyclohexane derivative drugs. Therefore, developing efficient and universal intermolecular cyclization rearrangement synthetic methods for nitrogen-containing heteroquaternary carbon-indinocyclohexane derivatives has significant application value and research significance. Summary of the Invention

[0014] The purpose of this invention is to provide a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative and its synthesis method. This method is simple to operate, low in cost, mild in reaction conditions, produces no byproducts, has a wide range of applicable substrates, and is suitable for large-scale industrial production, providing technical support and material basis for the development of bicyclic hydantoin drug molecules.

[0015] To achieve the above objectives, the technical solution adopted by the present invention is: a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative, the chemical structural formula of which is shown in Formula 3:

[0016]

[0017] In Formula 3, R1 is selected from oxygen atom and sulfur atom; R2 is selected from ethyl, allyl, benzyl, p-methoxyphenyl, and p-chlorophenyl; R3 is selected from trifluoromethyl, ester, amide, and phenyl; and R4 is selected from aryl, alkyl, alkynyl, and hydrogen.

[0018] To achieve the purpose of the invention, the present invention also provides a method for synthesizing the above-mentioned nitrogen-containing heterocyclic carbon bicyclic hydantoin derivatives. The specific steps are as follows: the isocyanate derivative of Formula 1 and the 2,3-dicarbonyl ketoester derivative of Formula 2 are added to an organic solvent as reaction raw materials, and the reaction is heated and stirred under nitrogen and catalyst conditions. The reaction is monitored by TLC until complete, and the product is purified.

[0019] The structural formula of the isocyanate derivative of compound 1 is as follows: In Formula 1, R1 is selected from oxygen atom and sulfur atom, and R2 is selected from ethyl, allyl, benzyl, p-methoxyphenyl, and p-chlorophenyl; the structural formula of the 2,3-dicarbonyl ketoester derivative of Formula 2 is as follows: In Formula 2, R3 is selected from trifluoromethyl, ester, amide, and phenyl; R4 is selected from aryl, alkyl, alkynyl, and hydrogen.

[0020] Preferably, the molar ratio between the 2,3-dicarbonyl ketoester derivative of Formula 2, the isocyanate derivative of Formula 1, and the catalyst is 1:(1.5-2):(0.1-0.5).

[0021] Preferably, the molar ratio of the 2,3-dicarbonyl ketoester derivative of Formula 2, the isocyanate derivative of Formula 1, and the catalyst is 1:1.5:0.1.

[0022] Preferably, the reaction temperature is 100-120℃ and the reaction time is 12-72h.

[0023] Preferably, the reaction temperature is 120℃ and the reaction time is 36h.

[0024] Preferably, the organic solvent is selected from toluene, chlorobenzene, fluorobenzene, and tetrahydrofuran; the volume ratio of the organic solvent to the molar amount of the 2,3-dicarbonyl ketoester derivative of Formula 2 is 1 mL: 0.1 mmol.

[0025] Preferably, the solvent is toluene.

[0026] Preferably, the catalyst is selected from one of trifluoromethanesulfonic acid, triphenylphosphine, and diphenylethylphosphine.

[0027] Preferably, the catalyst is triphenylphosphine.

[0028] The synthetic reaction route involved in this invention is shown below:

[0029]

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) This invention directly constructs a nitrogen-containing heterocyclic bicyclic hydantoin molecular skeleton through a cyclization-dearomatization / 1,2-migration reaction involving isocyanate derivative 1 and 2,3-dicarbonyl ketoester derivative 2 catalyzed by triphenylphosphine. At the same time, the ester group and acyl group are excellent functional groups that can achieve a variety of transformations, realizing the construction of such compounds through bimolecular cyclization rearrangement reaction.

[0032] (2) This invention avoids the use of metal catalysts and adopts an organic catalytic mode. The reaction process does not cause heavy metal residues and reduces the synthesis cost.

[0033] (3) This invention has synthesized a bicyclic hydantoin molecule with a nitrogen-containing heterocyclic carbon center in one pot through cyclization-dearomatization / 1,2-rearrangement reaction. This method is simple to operate, low in cost, mild in reaction conditions, has no by-products, and has a wide range of substrates. It is suitable for large-scale industrial production and provides technical support and material basis for the development of bicyclic hydantoin drug molecules. It has good application prospects. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to the embodiments.

[0035] In the following examples, unless otherwise stated, isocyanate derivatives, pyridine 2,3-dicarbonyl ketoester derivatives, and other reagents are commercially available or obtained in accordance with known literature; the experimental methods described are generally performed under standard conditions or conditions recommended by the manufacturer.

[0036] The 2,3-dicarbonyl ketoester derivative 2 used in the following examples was synthesized according to the methods described in the references (Shang R, Yang Z-W, Wang Y, Zhang SL, Liu L, J. Am. Chem. Soc. 2010, 132, 14391–14393; Roy S, Das S.K., Chattopadhyay B, Angew. Chem. Int. Ed. 2018, 57, 2238–2243). The characterization results of the unreported compounds 2b, 2c, and 2d are as follows:

[0037] N-Methoxy-N-methyl-2-oxo-2-(pyridin-2-yl)acetamide (2b)

[0038]

[0039] 1H NMR (400MHz, Chloroform-d) δ8.77–8.74(m,1H),8.13–8.08(m,1H),7.90(td,J=7.7,1.7Hz,1H),7.55–7.50(m,1H),3.63(s,3H),3.38(s,3H). 13 C NMR (101MHz, Chloroform-d) δ191.3,168.1,150.8,149.9,137.2,128.0,122.7,61.9,31.5.

[0040] 2-O-2-(4-(phenylethynyl)pyridin-2-yl)ethyl acetate (2c)

[0041]

[0042] 1 H NMR (400MHz, Chloroform-d) δ8.72(d,J=5.1Hz,1H),8.17(s,1H),7.61–7.54(m,3H),7.44–7.36(m,3H),4.49(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ187.3,165.1,150.5,149.9,133.3,132.2,129.8,129.7,128.7,125.4,121.7,96.1,85.8,62.4,14.2.

[0043] 2-O-2-(quinolin-2-yl)ethyl acetate (2d)

[0044]

[0045] 1 H NMR(400MHz,Chloroform-d)δ8.34(d,J=8.5Hz,1H),8.19(d,J=8.5Hz,1H),8.13(d,J=8.5Hz,1H),7.90(d ,J=8.0Hz,1H),7.80(t,J=7.7Hz,1H),7.70(t,J=7.2Hz,1H),4.56(q,J=7.1Hz,2H),1.47(t,J=7.1Hz,3H). 13C NMR (101MHz, Chloroform-d) δ188.3,165.8,150.0,147.5,137.6,131.0,130.6,130.1,129.7,127.9,118.6,62.2,14.3.

[0046] Example 1

[0047] The synthetic route for methyl 2-benzyl-1,3-dioxo-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxylic acid (3a) is as follows:

[0048]

[0049] Isocyanate derivative 1a and a catalyst were added to an organic solvent, followed by 2,3-dicarbonyl ketoester derivative 2a under stirring. The reaction was heated and stirred under nitrogen atmosphere, and the reaction was monitored by TLC until complete. The solvent was removed by evaporation to obtain the crude product, which was then purified by column chromatography to obtain the target product 3a. The molar ratio of the 2,3-dicarbonyl ketoester derivative of Formula 2, the isocyanate derivative of Formula 1, and the catalyst was 1:(1-2):(0.1-0.5); the reaction temperature was 100-120℃, and the reaction time was 12-72 h. The reaction conditions and yields are shown in Table 1.

[0050] Table 1 Effects of different types of catalysts, temperatures, and solvents on yield a

[0051]

[0052] Note: a In Table 1, the isocyanate content of all compounds in reaction formula 1 is 0.1 mmol. b The reaction yield is the separation yield.

[0053] The optimal reaction conditions can be determined from the data in Table 1 as follows: the solvent is toluene, the catalyst is PPh3, the molar ratio of 2-carbonyl ketoester derivatives, isocyanate derivatives and catalyst PPh3 is 1:1.5:0.1, the reaction temperature is 120℃, and the reaction time is 36 hours.

[0054] The steps for obtaining product formula 3a under optimal reaction conditions in Example 1 are as follows:

[0055] Three starting materials—isocyanate compound 1a (0.15 mmol), triphenylphosphine (0.01 mmol), and 2,3-dicarbonyl ketoester derivative 2a (0.1 mmol)—were added to a dry reaction tube in a ratio of 1.5:0.1:1. Toluene (1.0 mL) was then added to the mixture. The reaction system was stirred at 120 °C for 36 h under nitrogen atmosphere. After the reaction was confirmed to be complete by TLC, the solvent was removed by rotary evaporation to obtain the crude product. This crude product was then purified by column chromatography (petroleum ether / ethyl acetate volume ratio of 8 / 1) to obtain the target product (yield 88%). The structural characterization data of product formula 3a obtained under the optimal reaction conditions in Example 1 are as follows:

[0056] 1 H NMR(400MHz,Chloroform-d)δ7.39–7.28(m,5H),6.88(d,J=7.3Hz,1H),6.21–6.17( m,1H),6.01(d,J=9.3Hz,1H),5.63(t,J=6.6Hz,1H),4.74–4.66(m,2H),3.75(s,3H). 13 C NMR (101MHz, Chloroform-d) δ167.5,166.9,154.2,135.1,128.9,128.5,128.3,125.0,122.4,115.8,109.8,67.3,54.1,43.1.

[0057] Example 2

[0058] The synthetic route for 2-benzyl-N-methoxy-N-methyl-1,3-dione-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxamide (3b) is as follows:

[0059]

[0060] In this embodiment, except that 2b is used instead of structural formula 2a in Example 1, the other operating steps are the same as in Example 1. Yield: 81%. Product spectral analysis: 1 H NMR(400MHz,Chloroform-d)δ7.45–7.39(m,2H),7.36–7.27(m,3H),6.84(d,J=7.1Hz,1H),6.21(dd,J =9.3,5.5Hz,1H),5.97–5.92(m,1H),5.73–5.66(m,1H),4.74–4.62(m,2H),3.39(s,3H),3.15(s,3H). 13C NMR (101MHz, Chloroform-d) δ168.2,165.6,154.9,135.3,129.1,128.8,128.3,124.3,122.4,117.5,111.6,67.6,61.1,43.0,33.8.

[0061] Example 3

[0062] The synthetic route for 2-benzyl-1,3-dioxo-7-(phenylethynyl)-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxylic acid ethyl ester (3c) is as follows:

[0063]

[0064] In this embodiment, except that 2c is used instead of structural formula 2a in Example 1, the other operating steps are the same as in Example 1. Yield: 85%. Product spectral analysis: 1 H NMR(400MHz,Chloroform-d)δ7.48–7.42(m,2H),7.39–7.27(m,8H),6.95(dd,J=7.3,1.2Hz,1H),6.30(t,J =1.3Hz,1H),5.71(dd,J=7.3,1.3Hz,1H),4.75–4.68(m,2H),4.22(q,J=7.1Hz,2H),1.22(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ166.8,165.9,153.8,135.0,131.9,129.1,128.9,128.6 ,128.5,128.3,122.4,122.3,120.7,118.9,111.9,91.6,86.3,67.7,63.8,43.1,14.0.

[0065] Example 4

[0066] The synthetic route for 2-benzyl-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylic acid ethyl ester (3d) is as follows:

[0067]

[0068] In this embodiment, except that 2d is used instead of structural formula 2a in Example 1, and the reaction time is 12h instead of 36h in Example 1, the other operating steps are the same as in Example 1. Yield: 95%. Product spectral analysis: 1H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.0Hz,1H),7.44–7.27(m,6H),7.21–7.13(m,2H),6.68 (d,J=9.5Hz,1H),6.27(d,J=9.5Hz,1H),4.76(s,2H),4.21–4.09(m,2H),1.17(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ167.0,165.8,154.4,135.3,131.9,129.7,128.9,1 28.6,128.24,128.18,127.9,125.6,125.0,121.9,119.9,68.3,63.5,43.3,14.0.

[0069] Example 5

[0070] The synthetic route for 2-ethyl-1,3-dione-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylic acid ethyl ester (5e) is as follows:

[0071]

[0072] In this embodiment, except that 1e replaces structural formula 1a in Example 1, 2d replaces structural formula 2a in Example 1, and the reaction time is 12h instead of 36h in Example 1, the remaining operating steps are the same as in Example 1. Yield: 91%. Product spectral analysis: 1 HNMR(400MHz,Chloroform-d)δ7.84(d,J=8.3Hz,1H),7.39–7.33(m,1H),7.21–7.12(m,2H),6.68(d ,J=9.5Hz,1H),6.27(d,J=9.5Hz,1H),4.19(q,J=7.1Hz,2H),3.72–3.60(m,2H),1.31–1.19(m,6H). 13 C NMR (101MHz, Chloroform-d) δ167.0,165.9,154.5,131.9,129.7,128.0,127.8,125.5,125.0,121.9,120.0,68.1,63.4,34.8,14.0,13.3.

[0073] Example 6

[0074] The synthetic route for 2-(4-methoxyphenyl)-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylic acid ethyl ester (3f) is as follows:

[0075]

[0076] In this embodiment, except that 1f replaces structural formula 1a in Example 1, 2d replaces structural formula 2a in Example 1, the reaction temperature is 130℃ instead of 120℃ in Example 1, and the reaction time is 16h instead of 36h in Example 1, the remaining operating steps are the same as in Example 1. Yield: 62%. Product spectral analysis: 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=8.0Hz,1H),7.41–7.37(m,1H),7.36–7.30(m,2H),7.25–7.17(m,2H),7.02– 6.95(m,2H),6.76(d,J=9.5Hz,1H),6.36(d,J=9.5Hz,1H),4.24(q,J=7.1Hz,2H),3.83(s,3H),1.26(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ166.4,165.9,159.8,153.8,131.9,129.8,128.2, 127.9,127.8,125.7,125.1,123.7,122.1,120.1,114.6,68.1,63.6,55.6,14.1.

[0077] Example 7

[0078] The synthetic route for ethyl 2-(4-chlorophenyl)-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylate (3g) is as follows:

[0079]

[0080] In this embodiment, except that 1g is used instead of structural formula 1a in Example 1, 2d is used instead of structural formula 2a in Example 1, the reaction temperature is 130℃ instead of 120℃ in Example 1, and the reaction time is 16h instead of 36h in Example 1, the other operating steps are the same as in Example 1, and the yield is 46%. 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J=8.0Hz,1H),7.50–7.37(m,5H),7.26–7.16(m,2H ),6.77(d,J=9.4Hz,1H),6.36(d,J=9.5Hz,1H),4.27–4.21(m,2H),1.26(t,J=7.1Hz,3H). 13C NMR(101MHz,Chloroform-d)δ166.0,165.7,153.2,134.6,131.7,129.9,129. 7,129.6,128.4,128.0,127.5,125.9,125.1,122.1,119.9,68.1,63.8,14.1.

[0081] Example 8

[0082] The synthetic route for ethyl 2-allyl-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylate (3h) is as follows:

[0083]

[0084] In this embodiment, except that 1h is used instead of structural formula 1a in Example 1, 2d is used instead of structural formula 2a in Example 1, and 16h is used instead of 36h in Example 1, the other operating steps are the same as in Example 1, and the yield is 92%. 1 H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.0Hz,1H),7.37(td,J=8.0,7.6,2.0Hz,1H),7.22–7.12(m,2H),6.70(d,J =9.5Hz,1H),6.28(d,J=9.5Hz,1H),5.91–5.78(m,1H),5.32–5.19(m,2H),4.23–4.15(m,4H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ166.8,165.9,154.2,131.8,130.4,129.7,128.1,127.8,125.6,125.0,121.9,119.9,118.4,68.2,63.5,41.6,14.0.

[0085] Example 9

[0086] The synthetic route for 2-benzyl-3a-(trifluoromethyl)imidazo[1,5-a]quinoline-1,3(2H,3aH)-dione (3i) is as follows:

[0087]

[0088] In this embodiment, except that 2e is used instead of structural formula 2a in Example 1, and the temperature is 130℃ instead of 120℃ in Example 1, the other operating steps are the same as in Example 1, and the yield is 48%. 1H NMR (400MHz, Chloroform-d) δ7.81–7.75(m,1H),7.44–7.28(m,6H),7.24–7.16(m,2H),6.87(d,J=9.6Hz,1H),6.06(d,J=9.6Hz,1H),4.83–4.71(m,2H). 13 C NMR(101MHz,Chloroform-d)δ165.7,154.8,134.8,132.4,132.2,130.3,129.0,128.6,128 .5,128.3,126.0,124.3,122.37,122.35(d,J=290.3Hz),114.8,65.7(d,J=30.9Hz),43.5. 19 FNMR(376MHz,Chloroform-d)δ-79.1.

[0089] Example 10

[0090] The synthetic route for 2-benzyl-10b-phenylimidazo[5,1-a]isoquinoline-1,3(2H,10bH)-dione (3j) is as follows:

[0091]

[0092] In this embodiment, except that 2f is used instead of structural formula 2a in Example 1, and the operating temperature is 130℃ instead of 120℃ in Example 1, the other operating steps are the same as in Example 1, and the yield is 61%. 1 H NMR(400MHz,Chloroform-d)δ8.21(d,J=7.6Hz,1H),7.42–7.23(m,10H),7.22–7.17(m,2H),7.15(d,J=7 .4Hz,1H),6.99(d,J=7.3Hz,1H),6.10(d,J=7.3Hz,1H),4.76(d,J=14.5Hz,1H),4.71(d,J=15.4Hz,1H). 13 CNMR(101MHz,Chloroform-d)δ171.4,153.3,137.6,135.6,130.7,128.92,128.86,1 28.81,128.77,128.6,128.2,127.8,126.6,125.8,125.0,120.8,114.2,66.4,42.9.

[0093] Example 11

[0094] The synthetic route for ethyl 2-benzyl-7-methyl-1,3-dioxo-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxylate (3k) is as follows:

[0095]

[0096] Except for replacing structural formula 2a in Example 1 with 2g, the other operating steps in this embodiment are the same as in Example 1, and the yield is 61%. 1 H NMR(400MHz,Chloroform-d)δ7.42–7.27(m,5H),6.83(d,J=7.3Hz,1H),5.72(s,1H),5.48( d,J=7.3Hz,1H),4.75–4.63(m,2H),4.20–4.14(m,2H),1.86(s,3H),1.18(t,J=6.9Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.9,166.7,154.2,135.3,133.9,128.8,128.5,128.2,121.6,113.6,111.1,67.8,63.3,42.9,20.7,14.0.

[0097] Example 12

[0098] The synthetic route for methyl 2-benzyl-1-oxo-3-thio-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxylic acid (3l) is as follows:

[0099]

[0100] In this embodiment, except that 1b is used instead of structural formula 1a in Example 1, and the operating temperature is 130℃ instead of 120℃ in Example 1, the other operating steps are the same as in Example 1, and the yield is 75%. 1 H NMR(400MHz,Chloroform-d)δ7.44–7.37(m,2H),7.35–7.27(m,4H),6.27–6.23(m,1H),6.15– 6.08(m,1H),5.80–5.72(m,1H),5.11(d,J=14.7Hz,1H),5.02(d,J=14.7Hz,1H),3.75(s,3H). 13 C NMR (101MHz, Chloroform-d) δ180.9,168.1,165.7,135.1,128.7,128.5,128.1,125.4,124.5,117.2,111.6,69.1,54.3,45.1.

[0101] Since the synthesized compounds all contain a bicyclic hydantoin structure, they possess potential antibacterial and presynaptic 5-HT properties. 1A Agonist activity.

Claims

1. A method for synthesizing a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative, characterized in that, The specific steps are as follows: the isocyanate derivative of Formula 1 and the 2,3-dicarbonyl ketoester derivative of Formula 2 are added to an organic solvent as reaction raw materials, and the reaction is heated and stirred under nitrogen and the catalyst triphenylphosphine. The reaction is monitored by TLC until it is complete, and the product is purified. The structural formula of the isocyanate derivative of compound 1 is as follows: In Formula 1, R1 is selected from oxygen atom and sulfur atom, and R2 is selected from ethyl, allyl, benzyl, p-methoxyphenyl, and p-chlorophenyl; the structural formula of the 2,3-dicarbonyl ketoester derivative of Formula 2 is as follows: In Formula 2, R3 is one of trifluoromethyl, ester, amide, or phenyl; R4 is one of aryl, alkyl, alkynyl, or hydrogen. The chemical structural formula of the nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative is shown in Formula 3: .

2. The method for synthesizing a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative according to claim 1, characterized in that, The molar ratio between the 2,3-dicarbonyl ketoester derivative of Formula 2, the isocyanate derivative of Formula 1, and the catalyst is 1:(1.5-2):(0.1-0.5).

3. The method for synthesizing a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative according to claim 2, characterized in that, The molar ratio of the compound 2,3-dicarbonyl ketoester derivative of Formula 2, the isocyanate derivative of Formula 1, and the catalyst is 1:1.5:0.

1.

4. A method for synthesizing a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative according to claim 1 or 2, characterized in that, The reaction temperature is 100-120 ℃, and the reaction time is 12-72 h.

5. The method for synthesizing a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative according to claim 4, characterized in that, The reaction temperature was 120 °C and the reaction time was 36 h.

6. A method for synthesizing a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative according to claim 1 or 2, characterized in that, The organic solvent is selected from toluene, chlorobenzene, fluorobenzene, and tetrahydrofuran; the volume ratio of the organic solvent to the molar amount of the 2,3-dicarbonyl ketoester derivative of Formula 2 is 1 mL: 0.1 mmol.

7. The method for synthesizing a nitrogen-containing heterocyclic carbon bicyclic hydantoin derivative according to claim 6, characterized in that, The solvent is toluene.

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