Nitrogen-containing quaternary carbon bicyclic hydantoin derivative and synthesis method thereof

Abstract

The invention discloses an aza-quaternary carbon bicyclic hydantoin derivative and a synthesis method thereof. The chemical structural formula of the derivative is as shown in formula 3. The synthesis method comprises the following steps: adding a compound isocyanate derivative as shown in a formula 1 and a compound 2, 3-dicarbonyl keto ester derivative as shown in a formula 2 into an organic solvent as reaction raw materials, heating and stirring to react under the condition of nitrogen and the action of a catalyst, tracking the reaction by TLC until the reaction is complete, and purifying to obtain the product. The aza-quaternary carbon center-containing bicyclic hydantoin molecules are efficiently synthesized in one pot through cyclization dearomatization / 1, 2-rearrangement reaction, and the method is easy and convenient to operate, low in cost, mild in reaction condition, free of generation of by-products, wide in substrate application range, suitable for large-scale industrial production and suitable for industrial production. Technical support and material basis are provided for development of bicyclic hydantoin medicine molecules, and the application prospect is good. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a nitrogen-containing heteroquaternary carbon bicyclic hydantoin derivative and a synthesis method thereof. Background Art

[0002] Bicyclic hydantoin derivatives are widely present in drug molecules and biologically active natural products. Due to their unique molecular structure, they have different physiological and pharmaceutical activities, such as antibacterial and anticancer activities. They can also be used as cholesterol homeostasis regulators, 5-HT 1A Receptor ligand, presynaptic 5-HT 1A Agonists, etc. Therefore, the synthesis of nitrogen-containing quaternary carbon bicyclic hydantoin derivatives has attracted great interest from chemists.

[0003]

[0004] Most of the synthetic methods reported so far for nitrogen-containing quaternary carbon bicyclic hydantoin derivatives start from intramolecular cyclization 1,2-rearrangement reaction, through metal activation of alkynyl, nucleophilic cyclization and other steps. For example:

[0005] (1) The copper (I) catalytic mode was used to realize the cyclization rearrangement reaction of 22-propargyl alcohol compounds to construct nitrogen-containing quaternary carbon bicyclic hydantoin derivatives (Yan, B.; Zhou, Y.; Zhang, H.; Chen J.; Liu, Y. J. Org. Chem. 2007, 72, 7783). The reaction formula is as follows:

[0006]

[0007] (2) The cyclization rearrangement reaction of pyridine 2-propargyl alcohol compounds was carried out using platinum (II) catalysis mode 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) Using protic solvents to achieve the cyclization rearrangement reaction of quinoline 2-propargyl alcohol compounds to construct nitrogen-containing heteroquaternary carbon bicyclic hydantoin derivatives (Heller, ST; Kiho, T.; Narayan, AR; Sarpong, R. Angew. Chem. Int. Ed. 2013, 52, 11129), the reaction formula is as follows:

[0010]

[0011] (4) The cyclization rearrangement reaction of 2-substituted pyridine compounds and diarylcyclopropenones was used to construct nitrogen-containing quaternary carbon bicyclic hydantoin derivatives (Liu, X.; Shi, X.; Zhou, J.; Huang, C.; Lin, Y.; Zhang, C.; Cao, H. Chem. Commun. 2023, 59, 4051). The reaction formula is as follows:

[0012]

[0013] It can be seen that the current synthesis methods of intermolecular cyclorearrangement reactions of nitrogen-containing quaternary carbon indole bicyclic hydantoin derivatives are very limited, and are basically concentrated on the synthesis of intramolecular cyclorearrangement methods of pyridine or quinoline containing alkynyl substituents. In addition, the above methods often have problems such as narrow substrate range, cumbersome synthesis routes, and metal waste. Intermolecular cyclodearomatization / 1,2-rearrangement reaction is one of the most direct means to construct nitrogen-containing quaternary carbon bicyclic hydantoin derivatives, and it can greatly broaden the substrate range and has high research value. However, this type of synthesis method has been reported less, resulting in a large gap in the research of the chemical properties and biological activities of related compounds, which is one of the bottleneck problems restricting the creation of nitrogen-containing quaternary carbon bicyclic hydantoin derivative drugs. Therefore, the development of efficient and universal intermolecular cyclorearrangement synthesis methods for nitrogen-containing quaternary carbon bicyclic hydantoin derivatives has very important application value and research significance. Summary of the invention

[0014] The present invention aims to provide a nitrogen-containing quaternary carbon bicyclic hydantoin derivative and a synthesis method thereof. The method is simple to operate, low in cost, mild in reaction conditions, free of by-products, has a wide range of substrate applications, is suitable for industrial large-scale production, and provides technical support and material basis for the development of bicyclic hydantoin drug molecules.

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

[0016]

[0017] In formula 3, R1 is selected from one of oxygen atom and sulfur atom; R2 is selected from one of ethyl, allyl, benzyl, p-methoxyphenyl and p-chlorophenyl; R3 is selected from one of trifluoromethyl, ester, amide and phenyl; R4 is selected from one of 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 heteroquaternary carbon bicyclic hydantoin derivatives, which specifically comprises the following steps: adding the isocyanate derivative of the compound of formula 1 and the 2,3-dicarbonyl ketoester derivative of the compound of formula 2 as reaction raw materials into an organic solvent, heating and stirring the reaction under nitrogen and the action of a catalyst, tracking the reaction by TLC until it is complete, and purifying the product;

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

[0020] Preferably, the molar ratio of the 2,3-dicarbonyl ketoester derivative of the compound of formula 2, the isocyanate derivative of the compound 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 the compound of formula 2, the isocyanate derivative of the compound of formula 1, and the catalyst is 1:1.5:0.1.

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

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

[0024] Preferably, the organic solvent is selected from one of toluene, chlorobenzene, fluorobenzene and tetrahydrofuran; the ratio of the volume of the organic solvent to the molar amount of the 2,3-dicarbonyl ketoester derivative of the compound 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 the present invention is as follows:

[0029]

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

[0031] (1) The present invention directly constructs a nitrogen-containing heteroquaternary carbon bicyclic hydantoin molecular skeleton by a cyclodearomatization / 1,2-migration reaction involving an isocyanate derivative 1 and a 2,3-dicarbonyl ketoester derivative 2 catalyzed by triphenylphosphine. At the same time, the ester group and the acyl group can be used as excellent functional groups to achieve a variety of transformations, thereby realizing a bimolecular cyclorearrangement reaction to construct such compounds.

[0032] (2) The present invention avoids the use of metal catalysts and adopts an organic catalytic mode, so that the reaction process will not cause heavy metal residues and reduce the synthesis cost;

[0033] (3) The present invention efficiently synthesizes dicyclic hydantoin molecules containing nitrogen-containing quaternary carbon centers in one pot through cyclodearomatization / 1,2-rearrangement reaction. The method is simple to operate, low in cost, mild in reaction conditions, no by-products are generated, and the substrate has a wide range of applicability. It is suitable for large-scale industrial production, provides technical support and material basis for the development of dicyclic hydantoin drug molecules, and has good application prospects. DETAILED DESCRIPTION

[0034] The present invention is further described in detail below in conjunction with embodiments.

[0035] In the following examples, unless otherwise specified, isocyanate derivatives, pyridine 2,3-dicarbonyl ketoester derivatives, and other reagents can be purchased from the market or obtained according to known literature reports; the experimental methods are usually carried out under conventional 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 method of 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), and the characterization results of 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-Oxo-2-(4-(phenylethynyl)pyridin-2-yl)acetic acid ethyl ester (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-Oxo-2-(quinolin-2-yl)acetic acid ethyl ester (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 of 2-benzyl-1,3-dioxo-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxylic acid methyl ester (3a) is as follows:

[0048]

[0049] Add isocyanate derivative 1a and catalyst to an organic solvent, add 2,3-dicarbonyl ketoester derivative 2a under stirring, heat and stir to react under nitrogen, track the reaction until completion by TLC, evaporate the solvent to obtain a crude product, and then purify by column chromatography to obtain the target product 3a. The molar ratio of the 2,3-dicarbonyl ketoester derivative of the compound of formula 2, the isocyanate derivative of the compound of formula 1, and the catalyst is 1:(1-2):(0.1-0.5); the reaction temperature is 100-120°C, and the reaction time is 12-72h; the reaction conditions and yields are shown in Table 1.

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

[0051]

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

[0053] From the data in Table 1, it can be concluded that the optimal reaction conditions are: 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°C, and the reaction time is 36 hours.

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

[0055] Isocyanate compound 1a (0.15mmol), triphenylphosphine (0.01mmol), 2,3-dicarbonyl ketoester derivative 2a (0.1mmol) were added to a dry reaction tube, wherein the ratio of the three was 1.5:0.1:1, and toluene (1.0mL) was added to the mixture. The reaction system was stirred at 120°C for 36h under nitrogen, and after TLC monitoring, the solvent was removed to obtain a crude product, which was then purified by column chromatography (volume ratio of petroleum ether / ethyl acetate was 8 / 1) to obtain the target product (yield 88%). The structural characterization data of the 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 of 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 example, except that 2b is used to replace the structural formula 2a in Example 1, the remaining steps are the same as in Example 1, and the yield is 81%. Product spectrum 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 of ethyl 2-benzyl-1,3-dioxo-7-(phenylethynyl)-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxylate (3c) is as follows:

[0063]

[0064] In this example, except that 2c is used to replace the structural formula 2a in Example 1, the remaining operation steps are the same as in Example 1, and the yield is 85%. Product spectrum 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 of ethyl 2-benzyl-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylate (3d) is as follows:

[0067]

[0068] In this example, except that 2d is used to replace the structural formula 2a in Example 1, and the reaction time is 12h instead of 36h in Example 1, the remaining operation steps are the same as in Example 1, and the yield is 95%. Product spectrum 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 of ethyl 2-ethyl-1,3-dione-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylate (5e) is as follows:

[0071]

[0072] In this example, except that 1e is used to replace the structural formula 1a in Example 1, 2d is used to replace the structural formula 2a in Example 1, and the reaction time is 12h instead of 36h in Example 1, the remaining operation steps are the same as in Example 1, and the yield is 91%. Product spectrum 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 of ethyl 2-(4-methoxyphenyl)-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylate (3f) is as follows:

[0075]

[0076] In this example, except that 1f is used to replace the structural formula 1a in Example 1, 2d is used to replace the structural formula 2a in Example 1, the reaction temperature is 130°C instead of 120°C 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, and the yield is 62%. Product spectrum 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 of ethyl 2-(4-chlorophenyl)-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylate (3 g) is as follows:

[0079]

[0080] In this example, 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°C instead of 120°C in Example 1, and the reaction time is 16h instead of 36h in Example 1, the remaining operating steps are the same as those 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 of ethyl 2-allyl-1,3-dioxo-2,3-dihydroimidazo[1,5-a]quinoline-3a(1H)-carboxylate (3h) is as follows:

[0083]

[0084] In this example, except that 1h is used to replace the structural formula 1a in Example 1, 2d is used to replace the structural formula 2a in Example 1, and the reaction time is 16h instead of 36h in Example 1, the other operating steps are the same as those 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 of 2-benzyl-3a-(trifluoromethyl)imidazo[1,5-a]quinoline-1,3(2H,3aH)-dione (3i) is as follows:

[0087]

[0088] In this example, except that 2e is used to replace the structural formula 2a in Example 1, and the reaction temperature is 130° C. instead of 120° C. in Example 1, the remaining operating steps are the same as those in Example 1. 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 of 2-benzyl-10b-phenylimidazo[5,1-a]isoquinoline-1,3(2H,10bH)-dione (3j) is as follows:

[0091]

[0092] In this example, except that 2f is used to replace the structural formula 2a in Example 1, and the reaction temperature is 130° C. instead of 120° C. in Example 1, the remaining operating steps are the same as those in Example 1. 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] Embodiment 11

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

[0095]

[0096] In this example, except that 2g is used to replace the structural formula 2a in Example 1, the remaining operating steps are the same as 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 of 2-benzyl-1-oxo-3-thioxo-2,3-dihydroimidazo[1,5-a]pyridine-8a(1H)-carboxylic acid methyl ester (3l) is as follows:

[0099]

[0100] In this example, except that 1b is used to replace the structural formula 1a in Example 1, and the reaction temperature is 130° C. instead of 120° C. in Example 1, the remaining operating steps are the same as those 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 bicyclic hydantoin structures, they have potential antibacterial and presynaptic 5-HT 1A Agonist activity.

Claims

1. A nitrogen-containing quaternary carbon bicyclic hydantoin derivative, characterized in that: Its chemical structure is shown in Formula 3: In formula 3, R1 is selected from one of oxygen atom and sulfur atom; R2 is selected from one of ethyl, allyl, benzyl, p-methoxyphenyl and p-chlorophenyl; R3 is selected from one of trifluoromethyl, ester, amide and phenyl; R4 is selected from one of aryl, alkyl, alkynyl and hydrogen.

2. A method for synthesizing the nitrogen-containing quaternary carbon bicyclic hydantoin derivatives according to claim 1, characterized in that: The specific steps are: adding the isocyanate derivative of the compound of formula 1 and the 2,3-dicarbonyl ketoester derivative of the compound of formula 2 as reaction raw materials into an organic solvent, heating and stirring to react under nitrogen and the action of a catalyst, tracking the reaction by TLC until completion, and purifying to obtain the product; Wherein, the structural formula of the isocyanate derivative of the compound of formula 1 is In Formula 1, R1 is selected from one of oxygen atom and sulfur atom, and R2 is selected from one of ethyl, allyl, benzyl, p-methoxyphenyl and p-chlorophenyl. The structural formula of the 2,3-dicarbonyl ketoester derivative of the compound of Formula 2 is In Formula 2, R3 is one of trifluoromethyl, ester, amide, and phenyl; R4 is one of aryl, alkyl, alkynyl, and hydrogen.

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

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

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5. The method for synthesizing a nitrogen-containing quaternary carbon bicyclic hydantoin derivative according to claim 2 or 3, characterized in that: The reaction temperature is 100-120°C and the reaction time is 12-72h.

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

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

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

9. The method for synthesizing a nitrogen-containing quaternary carbon bicyclic hydantoin derivative according to claim 2 or 3, characterized in that: The catalyst is selected from one of trifluoromethanesulfonic acid, triphenylphosphine and diphenylethylphosphine.

10. The method for synthesizing a nitrogen-containing quaternary carbon bicyclic hydantoin derivative according to claim 9, characterized in that: The catalyst is triphenylphosphine.

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