A method for synthesizing an n-heterocyclic tetraalkane compound

Abstract

The application belongs to the field of chemical synthesis, and particularly relates to a synthesis method of N-heterocyclic tetraalkane compounds. Specifically, in the presence of a catalyst DMAP, without adding any transition metal catalyst and ligand, a compound of formula A is prepared with a compound of formula B, and a target product N-heterocyclic tetraalkane compound C is obtained with good selectivity and yield. The application has the advantages of low cost, good reaction functional group tolerance, high atomic economy and high reaction substrate universality.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, in particular to a synthesis method of N-heterocyclic tetra-cycloalkane compound. BACKGROUND

[0002] Nitrogen-containing heterocyclic compounds as an important class of small molecules have a wide range of applications in industry and life. Researchers have been committed to how to efficiently and simply build C-N bond. The classic Ullmann and Goldberg reaction is the most classic transition metal-catalyzed cross-coupling reaction, which requires the use of expensive catalysts or ligands, harsh reaction conditions, relatively low yield and poor selectivity:

[0003]

[0004] In 2014, Luo's group used N-hydroxy carbamate beta-keto carbonyl asymmetric catalytic alpha-amination (Angew. Chem. Int. Ed., 2014, 53, 4149-4153-ref-1). The reaction is achieved by the combination of chiral primary amine and copper catalyst under aerobic conditions. However, these methods for synthesizing chiral C-N bond products involve the use of copper catalyst or the use of strong organic acid HOTf, which poses a challenge to the functional group tolerance of the substrate.

[0005]

[0006] In 2017, Baran's group proposed that THF is used as a solvent, and a sulfone-containing tetra-tension ring substrate is subjected to nucleophilic addition with a lithium chloride complex of dibenzylamino magnesium chloride at room temperature to obtain an N-heterocyclic tetra-cycloalkane product (JACS., 2017, 139, 3209-3226-ref-2). The reaction has only a separation yield of 28%, and most of the reaction products are dimer and trimer compounds:

[0007]

[0008] In summary, in view of the problems in the synthesis of nitrogen-containing heterocyclic compounds by the above-mentioned process, it is of important research and practical significance to develop a high-selectivity catalytic N-heterocyclic tetra-cycloalkane compound. SUMMARY

[0009] The present application aims to overcome the deficiencies in the prior art, and provides a synthesis method of N-heterocyclic tetra-cycloalkane compound.

[0010] To achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0011] The present application first provides a compound of formula C, the structural formula of which is:

[0012]

[0013] wherein R1 and R2 together form a substituted aromatic heterocyclic group.

[0014] Another aspect of the present application provides a method for preparing the compound of formula C, which is prepared by reacting a compound of formula A with a compound of formula B in the presence of a catalyst to form a N-heterocyclic tetra-cyclic alkane compound of formula C,

[0015]

[0016] The compound of formula A can be selected from one of the following compounds,

[0017]

[0018] The catalyst is a pyridine catalyst such as DMAP, which is commercially available, i.e. 4-dimethylaminopyridine.

[0019] The ratio of the catalyst to the compound B is most preferably 25 umol: 0.5 mmol.

[0020] The reaction temperature can be 80-130°C, and is most preferably 110°C. The reaction time can be 10-30 hours, and is most preferably 16 hours.

[0021] The reaction solvent can be toluene, acetonitrile, acetone or tetrahydrofuran, and is most preferably super dry toluene.

[0022] The ratio of the amide compound A, the compound B and the solvent is most preferably 1.5 mmol: 0.5 mmol: 5 mL.

[0023] The preferred method for preparing the compound of formula C according to the present application comprises the following steps:

[0024] Step (1): First, compound B and DMAP are mixed and added to a pressure tube equipped with a magnetic stirrer, and then the secondary amine compound A and toluene are added. The reaction mixture is then heated to 110°C in an oil bath and stirred for 16 hours.

[0025] Step (2): After the reaction is complete, it is monitored by TLC, and compound B is completely reacted and a new spot is generated.

[0026] Step (3): The product is purified by flash column chromatography. Specifically, the eluent is used for purification, and the corresponding N-heterocyclic tetra-cyclic alkane compound C is obtained.

[0027] In the above step (3), the eluent is a mixture of n-hexane and ethyl acetate, and the volume ratio of n-hexane to ethyl acetate in the eluent is 5:1.

[0028] Compared with the prior art, the present application has the advantages that: the present application uses N-heterocyclic compounds as reaction substrate molecules, and for the first time uses 5 mol% of DMAP as a catalyst, in the catalytic system, the four-membered tension ring as the reaction substrate can react with most amides to obtain N-heterocyclic four-membered ring alkane products with good yield. The method has the advantages of low cost, good reaction functional group tolerance, simple operation, high atom economy, and high reaction substrate universality. DETAILED DESCRIPTION

[0029] To further illustrate the technical content, structural features, purposes and effects of the technical scheme, the following will be further described in combination with specific embodiments. The embodiments are implemented on the premise of the technical scheme of the present application, and give detailed implementation modes and specific operation processes, but the protection scope of the present application is not limited to the following examples.

[0030] To better illustrate the purposes, technical scheme and advantages of the present application, the following will further describe the present application in combination with specific embodiments.

[0031] Example 1

[0032]

[0033] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-1 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added, and the reaction was heated and stirred at 110°C oil bath for 16 h. TLC monitoring showed that compound B was completely reacted, and a new spot was generated, and fast column chromatography was carried out, and the eluent was n-hexane and ethyl acetate (volume ratio 5:1), to obtain N-heterocyclic four-membered ring alkane compound C-1, white solid. trans / cis = 1:1.6 by Crude 1HNMR, trans / cis = 1:1.5, 52% (the sum of the yields of two separated isomers: 87%)

[0034] 1H NMR (400 MHz, CDC13) δ 7.94 (d, J = 8.0 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.62 - 7.58 (m, 3H), 7.38 - 7.35 (m, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 4.88 - 4.78 (m, 1H), 3.84 (s, 2H), 3.76 - 3.67 (m, 1H), 3.09 - 3.01 (m, 2H), 2.85 - 2.79 (m, 2H).

[0035] 13C NMR (101 MHz, CDC13) δ 137.8, 136.2, 134.3, 129.7, 128.4, 126.9, 123.4, 122.9, 120.5, 118.8, 118.1, 109.9, 104.9, 50.4, 44.6, 32.0, 14.5.

[0036] HRMS (ESI) m / z: [M + Na]+ + Calculated for C 20 H 18 N2NaO2S 373.0981; Found 373.0981.

[0037] Example 2

[0038]

[0039] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-2 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated at 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. The product, N-heterocyclic tetra-cyclic alkane compound C-2, was obtained as a white solid by flash column chromatography using n-hexane and ethyl acetate (5:1 by volume) as eluent. 1 HNMR, trans / cis = 1:3.5 (total yield: 82% for isomers that could not be separated)

[0040] 1H NMR (400 MHz, CDC13) δ 7.98 (d, J = 7.2 Hz, 0.44H), 7.93 (d, J = 7.2 Hz, 1.51H), 7.69 (t, J = 7.6 Hz, 1H), 7.63 - 7.57 (m, 3H), 7.32 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 5.33 - 5.25 (m, 0.24H), 4.85 - 4.77 (m, 0.83H), 3.91 - 3.85 (m, 0.27H), 3.79 (s, 1.63H), 3.77 (s, 0.46H), 3.72 - 3.64 (m, 3.95H), 3.17 - 3.03 (m, 2H), 2.89 - 2.75 (m, 2H).

[0041] 13C NMR (101 MHz, CDC13) δ 172.5, 172.4, 138.0, 137.7, 136.1, 136.0, 134.2, 134.1, 129.6 (2C), 128.5, 128.4, 128.2 (2C), 123.6, 122.8, 122.3, 122.2, 120.0 (2C), 119.5, 119.3, 109.8, 109.5, 108.8, 108.4, 53.3, 52.1, 50.4, 47.5, 44.4, 32.0, 31.4, 31.3, 31.1.

[0042] HRMS (ESI) m / z: [M + Na]+ + Calculated for C 22 H 25 NNaO4S422.1397; Found 422.1403.

[0043] Example 3

[0044]

[0045] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-3 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added, and the reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. The product, N-heterocyclic tetra-cyclic alkane compound C-3, was obtained as a white solid after flash column chromatography with eluent of n-hexane and ethyl acetate (5:1, by volume). The yield was 67%, colorless oil, and a single isomer was separated.

[0046] 1H NMR (400 MHz, CDC13) δ 7.92 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 5.05 - 4.92 (m, 1H), 3.68 - 3.59 (m, 1H), 3.40 - 3.31 (m, 3H), 2.55 - 2.40 (m, 3H), 1.03 (d, J = 7.2 Hz, 3H), 0.84 (d, J = 7.2 Hz, 3H).

[0047] 13C NMR (101 MHz, CDC13) δ 177.4, 142.3, 137.9, 134.1, 129.5, 128.3, 128.1, 127.8, 124.7, 122.3, 110.4, 51.3, 50.9, 40.1, 31.1, 28.3, 28.2, 19.6, 18.0.

[0048] HRMS (ESI) m / z: [M + Na]+ + Calculated for C 21 H 23 NNaO3S392.1291; Found 392.1308.

[0049] Example 4

[0050]

[0051] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-4 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. Flash column chromatography was performed with eluent of n-hexane and ethyl acetate (volume ratio 5:1) to obtain N-heterocyclic tetra-cyclic alkane compound C-4 as a white solid. trans / cis = 1:2.3 by Crude 1H NMR, trans / cis = 1:2, 25% (sum of two separated isomers yield: 75%).

[0052] 1H NMR (400 MHz, CDC13) δ 7.92 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 4.0 Hz, 1H), 7.27 (d, J = 4.8 Hz, 1H), 4.99 - 4.91 (m, 1H), 3.90 - 3.83 (m, 1H), 3.01 - 2.90 (m, 4H).

[0053] 13C NMR (101 MHz, CDC13) δ 149.5 (d, J = 245 Hz), 137.8, 134.1, 129.6, 128.5, 127.3 (d, J = 14 Hz), 115.3 (d, J = 27 Hz), 53.5, 53.3, 31.0.

[0054] 19F NMR (376 MHz, CDC13) δ -176.7.

[0055] HRMS (ESI) m / z: [M + Na] Calcd for C + Calculated for C 13 H 13 N2FNaO2S303.0574; Found 303.0575.

[0056] Example 5

[0057]

[0058] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-5 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated at 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. Column chromatography was performed with n-hexane and ethyl acetate (5:1, by volume) as eluent to obtain the N-heterocyclic tetra-cyclic alkane compound C-5 as a white solid. trans / cis = 1:4 by Crude 1H NMR, trans / cis = 1:2.7, 40% (sum of the yields of two separated isomers: 55%)

[0059] 1H NMR (400 MHz, CDC13) δ 7.89 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 6.89 (d, J = 2.8 Hz, 1H), 4.95 - 4.86 (m, 1H), 3.91 (s, 3H), 3.72 - 3.63 (m, 1H), 3.04 - 2.97 (m, 2H), 2.87 - 2.81 (m, 2H).

[0060] 13C NMR (101 MHz, CDC13) δ 160.3, 138.7, 138.3, 133.9, 131.8, 129.5, 128.5, 112.1, 52.1, 50.7, 48.6, 31.2.

[0061] HRMS (ESI) m / z: [M + Na]+ + Calculated for C 15 H 16 N2NaO4S343.0723; Found 343.0722.

[0062] Example 6

[0063]

[0064] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-6 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. Column chromatography was performed with n-hexane and ethyl acetate (5:1 by volume) as eluent to obtain the N-heterocyclic tetra-ring alkane compound C-6 as a white solid.

[0065] dr = 1 : 1 by Crude 1H NMR, dr = 1 : 1.4, two isomers could not be separated, total yield: 74%.

[0066] 1H NMR (400 MHz, CDC13) dr = 1.4 δ 8.49 (s, 1H), 8.26 (s, 0.61H), 7.97 - 7.92 (m, 2.43H), 7.72 - 7.51 (m, 4.94H), 7.38 - 7.29 (m, 2.95H), 5.67 (s, 2H), 5.38 - 5.30 (m, 0.44H), 5.17 - 5.09 (m, 0.61H), 4.15 - 4.09 (m, 0.43H), 3.81 - 3.72 (m, 0.66H), 3.41 - 3.33 (m, 0.86H), 3.15 - 3.08 (m, 1.98H), 2.96 - 2.89 (m, 1.26H).

[0067] 13C NMR (101 MHz, CDC13) δ 160.1 (2C), 152.3, 152.2, 152.1, 152.0, 141.7, 140.2, 138.1, 137.5, 136.2, 134.4, 134.2, 130.4, 129.7 (2C), 128.6, 128.5 (3C), 128.3, 122.5, 121.6, 68.7, 68.6, 53.2, 50.5, 48.2, 42.6, 32.1, 30.4.

[0068] Example 7

[0069]

[0070] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-7 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. Flash column chromatography was performed with eluent of n-hexane and ethyl acetate (volume ratio 5:1) to obtain N-heterocyclic tetra-ring alkane compound C-7 as a white solid. trans / cis = 1:2.4 by Crude 1H NMR, trans / cis = 1:2.3, 27% (sum of the yield of two separated isomers: 90%)

[0071] 1H NMR (400 MHz, CDC13) δ 7.95 (d, J = 8.0 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 8.0 Hz, 2H), 7.12 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.46 (s, 2H), 3.97 - 3.90 (m, 1H), 3.12 - 2.97 (m, 4H).

[0072] 13C NMR (101 MHz, CDC13) δ 167.0, 145.4, 137.8, 134.1, 130.8, 129.6, 128.5, 127.2, 119.0, 118.9, 115.5, 68.8, 53.6, 48.4, 29.2.

[0073] HRMS (ESI) m / z: [M + Na] Calcd for C + Calculated for C 18 H 16 BrNNaO4S 443.9876; Found 443.9872.

[0074] Example 8

[0075]

[0076] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-8 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. Flash column chromatography was used to purify the product with eluent of n-hexane and ethyl acetate (volume ratio 5:1) to give N-heterocyclic tetra-cyclic alkane compound C-8 in 71% yield as a single isomer.

[0077] 1H NMR (400 MHz, CDC13) δ 7.81 (d, J = 7.2 Hz, 2H), 7.76 - 7.73 (m, 1H), 7.64 (t, J = 7.2 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.48 - 7.45 (m, 1H), 7.31 - 7.27 (m, 3H), 7.16 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.73 - 4.65 (m, 1H), 3.60 - 3.52 (m, 1H), 3.05 - 2.98 (m, 1H), 2.63 - 2.55 (m, 1H), 2.45 - 2.37 (m, 1H), 2.14 - 2.06 (m, 1H).

[0078] 13C NMR (101 MHz, CDC13) δ 168.4, 140.3, 139.7, 137.8, 137.1, 136.9, 133.9, 133.4, 132.2, 131.5, 131.4, 129.4, 129.2, 128.6, 128.5, 127.1, 126.1, 51.2, 49.3, 33.5, 29.0.

[0079] HRMS (ESI) m / z: [M + Na]+ + Calculated for C 23 H 19 NNaO3S2444.0699; Found 444.0694.

[0080] Example 9

[0081]

[0082] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-9 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. Column chromatography was performed with n-hexane and ethyl acetate (5:1 by volume) as eluent to obtain the N-heterocyclic tetra-cyclic alkane compound C-9 as a white solid. trans / cis = 1:1.1 by Crude 1H NMR, trans / cis = 1:1, 24% (sum of the yields of two separated isomers: 48%)

[0083] 11H NMR (400 MHz, CDC13) δ 8.01 - 7.89 (m, 2H), 7.74 - 7.65 (m, 1H), 7.65 - 7.55 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.27 - 7.25 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.99 - 4.66 (m, 1H), 4.11 - 3.84 (m, 1H), 3.45 - 3.20 (m, 2H), 2.98-2.07 (m, 2H).

[0084] 13 C NMR (101 MHz, CDC13) δ 180.30, 157.67, 152.19, 138.36, 137.48, 134.11, 129.53, 128.64, 128.34, 122.17, 116.38, 108.96, 53.12, 45.04, 28.18.

[0085] HRMS (ESI) m / z: [M + Na]+ + Calculated for C 18 H 14 BrNNaO4S 419.9719; Found 441.9719.

[0086] Example 10

[0087]

[0088] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-10 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added, and the reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted, and a new spot was generated. Column chromatography was performed with n-hexane and ethyl acetate (5:1 by volume) as eluent to obtain the N-heterocyclic four-membered ring alkane compound C-10, white solid, 55% of a single isomer was separated.

[0089] 1H NMR (400 MHz, CDC13) δ 8.01 - 7.89 (m, 2H), 7.74 - 7.65 (m, 1H), 7.65 - 7.55 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.27 - 7.25 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.99 - 4.66 (m, 1H), 4.11 - 3.84 (m, 1H), 3.45 - 3.20 (m, 2H), 2.98-2.07 (m, 2H).

[0090] 13C NMR (101 MHz, CDC13) δ 171.7, 138.2, 137.3, 134.0, 130.9 (2C), 130.0, 129.5, 128.3, 118.0, 116.3, 51.6, 45.5, 33.0, 31.1, 25.3.

[0091] HRMS (ESI) m / z: [M + Na]+ + Calculated for C 19 H 18 BrNNaO3S 442.0083; Found 442.0086.

[0092] Example 11

[0093]

[0094] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-11 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. The product, N-heterocyclic tetranuclear alkane compound C-11, was obtained by flash column chromatography using n-hexane and ethyl acetate (5:1 by volume) as eluent. The yield was 21% as a yellow solid.

[0095] 1 H NMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.97 - 7.88 (m, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.70 - 7.63 (m, 1H), 7.62 - 7.48 (m, 3H), 7.44 - 7.30 (m, 1H), 7.22 - 7.04 (m, 1H), 5.07 - 4.99 (m, 1H), 3.87 - 3.58 (m, 1H), 3.47 - 3.36 (m, 2H), 2.83 - 2.70 (m, 2H).

[0096] 13 C NMR (101 MHz, CDC13) δ 138.82, 137.94, 133.84, 133.74, 129.35, 128.29, 126.45, 124.65, 121.31, 120.94, 109.06, 77.32, 77.00, 76.68, 50.60, 47.38, 31.04.

[0097] HRMS (ESI) m / z: [M + H] + Calculated for C 17 H 17 N2O2S 313.1005; Found 313.1004.

[0098] Example 12

[0099]

[0100] In a sealed tube, compound B (0.5 mmol, 1.00 eq.) and DMAP (25 umol, 0.05 eq.) were added, and secondary amine compound A-12 (1.50 mmol, 3.00 eq.) and toluene (5 ml) were added. The reaction was heated to 110 °C in an oil bath with stirring for 16 h. TLC monitoring showed that compound B was completely reacted and a new spot was generated. Flash column chromatography was used to purify the product with eluent of n-hexane and ethyl acetate (volume ratio 5:1) to give N-heterocyclic four-membered ring alkane compound C-12 as a white solid. trans / cis = 1:3.3 by Crude 1H NMR, trans / cis = 1:3, 19% (sum of the yield of two separated isomers: 76%)

[0101] 1 H NMR (400 MHz, CDCl3) δ 8.03 - 7.95 (m, 2H), 7.71 - 7.63 (m, 2H), 7.63 - 7.55 (m, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.18 - 7.14 (m, 1H), 6.06 - 5.88 (m, 1H), 4.13 - 4.03 (m, 0H), 3.90 (s, 3H), 3.46 - 3.23 (m, 2H), 3.13 - 2.99 (m, 2H).

[0102] 13 C NMR (101 MHz, CDCl3) δ 162.61, 139.06, 138.01, 133.80, 129.38, 128.48, 127.76, 126.12, 125.43, 122.99, 121.03, 113.50, 111.12, 52.93, 51.98, 46.76, 31.11.

[0103] HRMS (ESI) m / z: [M + Na] + Calculated for C 20 H 19 NNaO4S 392.0927; Found 392.0927.

[0104] It should be noted that the above-mentioned embodiments are described herein by way of example only, not by way of limitation. Hence, modifications and alterations of the embodiments described herein, or of equivalent constructions or processes by those skilled in the art, which are not described explicitly herein, fall within the scope of the present application.

Claims

1. A process for the preparation of a compound of formula C, characterized by, The compound of formula A is reacted with the compound of formula B in the presence of a catalyst DMAP to obtain a N-heterocyclic tetra-cyclic alkane compound of formula C, wherein R1 and R2 form a substituted aromatic heterocyclic group, and the structural formula of the compound of formula A is selected from one of the following compounds, 2. The method of claim 1, wherein, The ratio of the catalyst to the compound B is 20 umol-60 umol: 0.15 mmol-20 mmol.

3. The method of claim 1, wherein, The reaction temperature is 80-130 °C.

4. The method of claim 1, wherein, The solvent is super dry toluene, acetonitrile, acetone or tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that, The ratio of the amide compound A, the compound B and the solvent is 0.5 mmol-50 mmol: 0.15 mmol-20 mmol: 2 mL-200 mL.

6. The method of claim 1, wherein, Preparation is carried out by the following steps: Step (1): first, compound B and DMAP are mixed and added to a pressure tube equipped with a magnetic stirrer, then the secondary amine compound A and toluene are added, and then the reaction mixture is heated to 110 °C in an oil bath and continues to be stirred for 16 h; Step (2): after the reaction is completed, it is monitored by TLC, compound B is completely reacted, and a new spot is generated; Step (3): the product N-heterocyclic tetra-cyclic alkane compound C is obtained by fast column chromatography.

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