A benzazepine bridged ring derivative and a method for preparing the same

Abstract

The application relates to the technical field of pharmaceutical chemistry, and discloses a benzazepine bridged ring derivative and a preparation method thereof. The preparation method comprises the following steps: adding a substrate (1.0 eq), a sulfur-substituted benzylpropyl aldehyde (1.5 eq), a base DABCO (0.2 eq) and dry acetonitrile (2.0 mL) into a reaction test tube, mixing the mixture at normal temperature for 24 hours, concentrating and purifying after the reaction is completed to obtain a hemiacetal product 3. Then the hemiacetal product, chloroform (0.5 mL) and H2O (100 muL) are added into the reaction test tube, and stirring is carried out at 60 DEG C for 72 hours. The reaction is monitored to be completed through thin layer chromatography, then the reaction mixture is directly purified through column chromatography to obtain a corresponding target product. The preparation method has the advantages of simple operation, mild reaction and high yield. The derivative provided by the application has good antibacterial activity, and has a wide market application prospect.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a bridged ring derivative and its preparation method. Background Technology

[0002] Bridged ring compounds are widely found in natural products and synthetic drugs. Studies have shown that compounds containing this skeleton possess a variety of important biological and pharmaceutical activities. Substituent modification, derivatization of structural analogs, and further re-evaluation of biological activities have become research hotspots. Introducing nitrogen atoms into bridged ring compounds is an excellent method for modifying drug skeletons, which can not only increase efficacy but also alter various physicochemical properties of drugs. However, the synthesis methods for these compounds are limited or require stringent conditions.

[0003] How to easily prepare benzo[a]azapyridine with high yield Bridged ring derivatives are currently a research challenge. Summary of the Invention

[0004] To address the problems in the prior art, the present invention provides a benzo[a]azapyridine... Bridged ring derivatives.

[0005] The technical solution adopted by this invention to solve its technical problem is: a benzo[a]azapyridine Bridged ring derivatives, wherein the general formula of the derivatives is:

[0006]

[0007] Wherein, R1 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, C5-C6 heterocyclic group, and C4-C6 alkyl group;

[0008] R2 is one of phenyl, halogen-substituted phenyl, or alkyl-substituted phenyl;

[0009] Preferably, the optional structures of the derivative include, but are not limited to:

[0010]

[0011]

[0012] The present invention also provides a benzo[a]aza A method for preparing a bridged ring derivative includes the following steps: 1.0 eq of substrate 1, 1.5 eq of sulfur-substituted phenylpropanal 2, 0.2 eq of base DABCO, and 2.0 mL of dry acetonitrile are added to a reaction tube. The mixture is reacted at room temperature for 24 hours. After the reaction is complete, the mixture is concentrated and purified to obtain a hemiacetal product 3. Then, hemiacetal product 3, 0.5 mL of chloroform, and 100 μL of H2O are added to the reaction tube, and the mixture is stirred at 60 °C for 72 hours. The reaction mixture is then directly purified by column chromatography to obtain the corresponding target product 4, which is the benzo[a]aza ... Bridged ring derivatives, used to prepare the benzo[a]aza The reaction formula for the bridged ring derivative is:

[0013]

[0014] Furthermore, the preparation method of sulfur-substituted phenylpropionaldehyde 2 in the above method is as follows:

[0015] Step 1: In a round-bottom flask, add 1 eq of substituted cinnamic acid and 3 eq of lithium aluminum hydride in tetrahydrofuran solvent. React under reflux for 4 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, quench with water. Extract the reaction solution three times with ethyl acetate and concentrate under reduced pressure to obtain a colorless oil. In a round-bottom flask, add 3 eq of pyridine chlorochromate oxidant and dichloromethane solvent. Stir at room temperature for 3 h. After the reaction is complete, filter the mixture and concentrate under reduced pressure. Column chromatography yields the product of oxidized phenylpropionaldehyde.

[0016] Step 2: In a round-bottom flask, add 1 eq of substituted phenylpropanal or existing substituted phenylpropanal and 1.11 eq of N-chlorosuccinimide and 20% L-proline in dichloromethane. React at room temperature for 4 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, concentrate the reaction solution and filter it to obtain a yellow oil by column chromatography.

[0017] Step 3: Add 1.6 eq potassium carbonate and 5% IMes 2HCl to the sealing tube, replace with argon gas, then add dichloromethane. Add 1 eq α-chloroaldehyde and 1.5 eq EtSH obtained in the previous step to the sealing tube. React at room temperature for 24 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, filter the reaction solution, concentrate it, and then precipitate by column chromatography to obtain oily substrate 2, which is the sulfur-substituted phenylpropanal 2. The reaction formula is:

[0018] ;

[0019] R2 = halogen-substituted phenyl, alkane-substituted phenyl, C5-C6 heterocyclic group, C4-C6 alkyl group.

[0020] Furthermore, the present invention also provides a method for preparing the above-mentioned substrate 1, the steps of which are as follows:

[0021] Step 1: In a round-bottom flask, add 1 eq of substituted o-nitrobenzoic acid and 1.5 eq of lithium aluminum hydride solvent tetrahydrofuran. React at room temperature for 4 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, extract the reaction solution three times with ethyl acetate and concentrate under reduced pressure to obtain a colorless oil. In a round-bottom flask, add 3 eq of pyridine chlorochromate oxidant and dichloromethane solvent. Stir at room temperature for 3 h. After the reaction is complete, filter the mixture and concentrate under reduced pressure. Column chromatography yields the product oxidized to an aldehyde.

[0022] Step 2: In a round-bottom flask, add 1 eq of substituted o-nitrobenzaldehyde and 1.01 eq of p-toluenesulfonylhydrazine to anhydrous EtOH, and react under reflux for 4 h. Monitor the spotting on the plate using thin-layer chromatography. After the reaction is complete, concentrate the reaction solution and filter to obtain a yellow solid.

[0023] Step 3: Add 1 eq of the yellow solid intermediate obtained in the previous step and 6.7 eq of reduced iron powder to 15 ml of acetic acid and 15 ml of anhydrous ethanol. Add a few drops of hydrochloric acid and heat under reflux for 1 h. Monitor the spotting on the plate using thin-layer chromatography. After the reaction is complete, filter the reaction solution and adjust the pH to weakly alkaline with saturated Na2CO3. Extract with water and ethyl acetate, dry with anhydrous MgSO4, concentrate and pass through a column to obtain the yellow substituted reduced product.

[0024] Step 4: Add 1 eq of the yellow solid obtained in the previous step to 3.7 eq of triethyl orthoformate and heat under reflux at 80°C for 1 h. Monitor the spotting on the plate using thin-layer chromatography. After the reaction is complete, add diethyl ether to solidify and then recrystallize with acetonitrile to obtain substrate 1.

[0025] The reaction formula for preparing substrate 1 is:

[0026]

[0027] R1 = a halogen-substituted phenyl or an alkane-substituted phenyl.

[0028] Preferably, a benzo[a]aza Bridged ring derivatives, used for antibacterial purposes.

[0029] This invention provides a new class of compounds, benzo[a]aza Bridged ring derivatives exhibit good antibacterial effects, and a method for preparing these derivatives is provided. This method is simple, mild, and yields high results, and has broad market application prospects. Attached Figure Description

[0030] Figure 1 Single crystal structure of the product of Example 1. Detailed Implementation

[0031] To make the technical means, creative features, achieved objectives, and effects of this invention readily understandable, the invention is further described below in conjunction with specific embodiments. However, this should not be construed as limiting the scope of the above-described subject matter of this invention to the following examples. All technologies implemented based on the above-described content of this invention fall within the scope of this invention.

[0032] Unless otherwise specified, all reagents and testing equipment used in this invention are conventional commercially available reagents and equipment.

[0033] Example 1

[0034] The benzo[a]aza in this embodiment The bridged ring derivative is (2R)-10-benzyl-10-(ethylthio)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (thioethyl is used to replace phenylpropionaldehyde when synthesizing the substrate)

[0035]

[0036] This derivative was synthesized from substrate 1 and sulfur-substituted phenylpropionaldehyde. First, substrate 1 was prepared, and the specific steps are as follows:

[0037] Step 1: In a round-bottom flask, add 1 eq of substituted o-nitrobenzoic acid and 1.5 eq of lithium aluminum hydride solvent tetrahydrofuran. React at room temperature for 4 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, extract the reaction solution three times with ethyl acetate and concentrate under reduced pressure to obtain a colorless oil. In a round-bottom flask, add 3 eq of pyridine chlorochromate oxidant and dichloromethane solvent. Stir at room temperature for 3 h. After the reaction is complete, filter the mixture and concentrate under reduced pressure. Column chromatography yields the product oxidized to an aldehyde.

[0038] Step 2: In a round-bottom flask, add 1 eq of substituted o-nitrobenzaldehyde and 1.01 eq of p-toluenesulfonylhydrazine to anhydrous EtOH, and react under reflux for 4 h. Monitor the spotting on the plate using thin-layer chromatography. After the reaction is complete, concentrate the reaction solution and filter to obtain a yellow solid.

[0039] Step 3: Add 1 eq of the yellow solid intermediate obtained in the previous step and 6.7 eq of reduced iron powder to 15 ml of acetic acid and 15 ml of anhydrous ethanol. Add a few drops of hydrochloric acid and heat under reflux for 1 h. Monitor the spotting on the plate using thin-layer chromatography. After the reaction is complete, filter the reaction solution and adjust the pH to weakly alkaline with saturated Na2CO3. Extract with water and ethyl acetate, dry with anhydrous MgSO4, concentrate and pass through a column to obtain the yellow substituted reduced product.

[0040] Step 4: Add 1 eq of the yellow solid obtained in the previous step to 3.7 eq of triethyl orthoformate and heat under reflux at 80°C for 1 h. Monitor the spotting on the plate using thin-layer chromatography. After the reaction is complete, add diethyl ether to solidify and then recrystallize with acetonitrile to obtain substrate 1.

[0041] The reaction formula for preparing substrate 1 is:

[0042]

[0043] R1 = a halogen-substituted phenyl or an alkane-substituted phenyl.

[0044] Then, substrate 2, namely sulfur-substituted phenylpropionaldehyde 2, is prepared. The specific steps are as follows:

[0045] Step 1: In a round-bottom flask, add 1 eq of substituted cinnamic acid and 3 eq of lithium aluminum hydride in tetrahydrofuran solvent. React under reflux for 4 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, quench with water. Extract the reaction solution three times with ethyl acetate and concentrate under reduced pressure to obtain a colorless oil. In a round-bottom flask, add 3 eq of pyridine chlorochromate oxidant and dichloromethane solvent. Stir at room temperature for 3 h. After the reaction is complete, filter the mixture and concentrate under reduced pressure. Column chromatography yields the product of oxidized phenylpropionaldehyde.

[0046] Step 2: In a round-bottom flask, add 1 eq of substituted phenylpropanal or existing substituted phenylpropanal and 1.11 eq of N-chlorosuccinimide and 20% L-proline in dichloromethane. React at room temperature for 4 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, concentrate the reaction solution and filter it to obtain a yellow oil by column chromatography.

[0047] Step 3: Add 1.6 eq potassium carbonate and 5% IMes 2HCl to the sealing tube, replace with argon gas, then add dichloromethane. Add 1 eq α-chloroaldehyde and 1.5 eq EtSH obtained in the previous step to the sealing tube. React at room temperature for 24 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, filter the reaction solution, concentrate it, and then precipitate by column chromatography to obtain oily substrate 2, which is the sulfur-substituted phenylpropanal 2. The reaction formula is:

[0048]

[0049] R2 = halogen-substituted phenyl, alkane-substituted phenyl, C5-C6 heterocyclic group, C4-C6 alkyl group.

[0050] Finally, benzo[a]aza The bridged ring derivative was prepared by the following steps: 1.0 eq of substrate 1, 1.5 eq of sulfur-substituted phenylpropanal 2, 0.2 eq of base DABCO, and 2.0 mL of dry acetonitrile were added to a reaction tube. The mixture was reacted at room temperature for 24 hours. After the reaction was completed, the mixture was concentrated and purified to obtain hemiacetal product 3. Then, hemiacetal product 3, 0.5 mL of chloroform, and 100 μL of H2O were added to the reaction tube, and the mixture was stirred at 60 °C for 72 h. The reaction mixture was then directly purified by column chromatography to obtain the corresponding target product 4, which is the benzo[a]azapyridine. Bridged ring derivatives, used to prepare the benzo[a]aza The reaction formula for the bridged ring derivative is:

[0051]

[0052] Benzoazae prepared The bridged ring derivative is (2R)-10-benzyl-10-(ethylthio)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (thioethyl is used to replace phenylpropionaldehyde when synthesizing the substrate)

[0053]

[0054] White solid, yield 75%;

[0055] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.91 (s, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.41-7.35 (m, 4H), 7.33-7. 30(m,1H),6.93-6.91(m,3H),6.66(t,J=7.8Hz,1H),6.55(t,J=7.2Hz,1H),5.57(d,J=8.4Hz, 1H),5.25(s,1H),5.00(d,J=5.6Hz,1H),4.42(d,J=4.8Hz,1H),3.04(d,J=13.8Hz,1H),2.74 (d,J=13.8Hz,1H),2.47-2.37(m,1H),2.26(s,3H),2.21-2.15(m,1H),0.97(t,J=7.8Hz,3H).

[0056] 13C NMR (151MHz, CDCl3) δ (ppm): 167.9, 144.4, 140.6, 135.1, 134.7, 131.1, 128.9, 128.8, 12 8.4,128.1,127.6,127.5,121.1,118.9,113.4,74.1,64.3,53.3,37.0,23.8,21.5,14.0.

[0057] The single-crystal data of the product in Example 1 are as follows: Figure 1 As shown in Table 1.

[0058] Table 1 Single crystal data of the product from Example 1

[0059]

[0060]

[0061] Example 2

[0062] (2R)-10-(ethio)-10--(4-methylbenzyl)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (p-methylthioethyl-substituted phenylpropionaldehyde is used as the substrate in the synthesis).

[0063]

[0064] White solid, yield 60%;

[0065] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.89 (s, 1H), 7.48 (d, J = 7.2Hz, 2H), 7.28 (d, J = 7.2Hz, 2H), 7.17 ( d,J=7.2Hz,2H),6.92(d,J=6.6Hz,3H),6.66(t,J=7.8Hz,1H),6.54(t,J=7.8Hz,1H),5.57(d,J =7.8Hz,1H),5.23(s,1H),5.00(s,1H),4.40(s,1H),3.00(d,J=14.5Hz,1H),2.70(d,J=13.8H z,1H),2.48-2.42(m,1H),2.36(s,3H),2.24(s,3H),2.23-2.18(m,1H),0.98(t,J=6.6Hz,3H).

[0066] 13C NMR (151MHz, CDCl3) δ (ppm): 167.8, 144.3, 140.5, 137.0, 134.6, 131.9, 130.8, 129.0, 128.8, 1 28.6,128.0,127.5,121.0,118.8,113.3,73.9,64.2,53.2,36.3,23.6,21.4,21.1,14.2,13.9.

[0067] Example 3

[0068] (2R)-10-(ethio)-10--(3-methylbenzyl)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (3-methylthioethyl is used to replace phenylpropanal when synthesizing the substrate).

[0069]

[0070] White solid, yield 81%;

[0071] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.89 (s, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.27-7.24 (m, 1H), 7.20 (d, J = 7.2Hz, 2H),7.13(d,J=7.2Hz,1H),6.93-6.92(m,3H),6.66(t,J=6.0Hz,1H),6.55(t,J=7.8Hz,1H),5.57(d,J= 7.2Hz,1H),5.24(s,1H),5.02(d,J=4.2Hz,1H),4.38(d,J=4.2Hz,1H),3.01(d,J=13.8Hz,1H),2.70(d, J=14.4Hz,1H),2.46-2.41(m,1H),2.39(s,3H),2.26(s,3H),2.21-2.15(m,1H),0.97(t,J=7.2Hz,3H).

[0072] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.8, 144.2, 140.5, 137.9, 134.9, 134.7, 131.7, 128.8, 128.7, 12 8.2,128.1,128.0,127.5,121.1,118.8,113.3,73.9,64.2,53.1,36.8,23.7,21.5,21.4,13.9.

[0073] Example 4

[0074] (2R)-10-(ethio)-10--(4-methoxybenzyl)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (4-methoxythioethyl is used to replace phenylpropanaldehyde when synthesizing the substrate).

[0075]

[0076] White solid, yield 50%;

[0077] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.89 (s, 1H), 7.48 (d, J = 8.4Hz, 2H), 7.31 (d, J = 9.6Hz, 2H), 6.93 -6.90(m,5H),6.66(t,J=6.6Hz,1H),6.54(t,J=6.6Hz,1H),5.57(d,J=7.8Hz,1H),5.22(s,1 H),4.98(d,J=4.2Hz,1H),4.39(d,J=4.2Hz,1H),3.82(s,3H),2.99(d,J=14.4Hz,1H),2.68( d,J=13.2Hz,1H),2.47-2.40(m,1H),2.26(s,3H),2.22-2.15(m,1H),0.98(t,J=7.8Hz,3H).

[0078] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.8, 158.9, 144.3, 140.5, 134.6, 132.0, 128.8, 128.6, 128.0 ,127.5,127.0,121.0,118.8,113.7,113.3,73.9,64.1,55.2,53.3,36.0,23.6,21.4,13.9.

[0079] Example 5

[0080] (2R)-10-(3-chlorobenzyl)-10-(ethio)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (3-chlorothioethyl is used to replace phenylpropanal when synthesizing the substrate).

[0081]

[0082] White solid, yield 67%;

[0083] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.88 (s, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.41 (s, 1H), 7.31-7.27 (m, 3H),6.93(t,J=9.6Hz,3H),6.68(t,J=9.0Hz,1H),6.56(t,J=7.8Hz,1H),5.60(d,J=7.8Hz,1 H),5.24(s,1H),4.98(d,J=4.8Hz,1H),4.43(d,J=6.4Hz,1H),3.01(d,J=13.8Hz,1H),2.72( d,J=14.4Hz,1H),2.43-2.37(m,1H),2.26(s,3H),2.20-2.14(m,1H),0.98(t,J=7.8Hz,3H).

[0084] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.6, 144.4, 140.3, 137.1, 134.5, 134.1, 131.1, 129.5, 129.0, 12 8.9,128.8,128.0,127.6,127.6,120.8,118.9,113.4,74.0,64.0,53.0,36.7,23.8,21.4,13.8.

[0085] Example 6

[0086] (2R)-10-(3-bromobenzyl)-10-ethylthio)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (3-bromothioethyl is used to replace phenylpropanal when synthesizing the substrate).

[0087]

[0088] White solid, yield 53%;

[0089] 1H NMR (600MHz, CDCl3) δ (ppm): 8.88 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.47-7.45 (m, 1H), 7.33 (d,J=7.8Hz,1H),7.24(d,J=7.6Hz,1H),6.94-6.90(m,3H),6.68(t,J=7.2Hz,1H),6.56(t,J=7.8Hz,1H ),5.60(d,J=7.2Hz,1H),5.23(s,1H),4.97(d,J=3.6Hz,1H),4.43(d,J=4.2Hz,1H),3.00(d,J=14.4Hz, 1H), 2.71 (d, J = 14.4Hz, 1H), 2.43-2.26 (m, 1H), 2.26 (s, 3H), 2.19-2.14 (m, 1H), 0.98 (t, J = 7.8Hz, 3H).

[0090] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.6, 144.4, 140.3, 137.3, 134.5, 134.0, 130.5, 129.8, 129.5, 12 8.9,128.8,128.0,127.6,122.3,120.8,118.9,113.4,73.9,63.9,53.0,36.7,23.8,21.4,13.8.

[0091] Example 7

[0092] (2R)-10-(ethio)-10-propyl-3-tolyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (pentanal, which is substituted with thioethyl during substrate synthesis).

[0093]

[0094] White solid, yield 62%;

[0095] 1H NMR (600MHz, CDCl3) δ (ppm): 8.68 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 6.91 (d, J = 7.8Hz, 2H), 6.88 (d,J=6.6Hz,1H),6.67(t,J=7.8Hz,1H),6.54(t,J=7.8Hz,1H),5.62(d,J=7.2Hz,1H),5.12(d ,J=4.8Hz,1H),5.10(s,1H),4.56(d,J=4.8Hz,1H),2.47-2.40(m,1H),2.39-2.33(m,1H),2.2 5(s,3H),1.55-1.49(m,2H),1.42-1.33(m,2H),1.09(t,J=7.2Hz,3H),0.95(t,J=7.2Hz,3H).

[0096] 13 C NMR (151MHz, CDCl3) δ (ppm): 170.6, 143.9, 140.0, 135.1, 128.9, 128.8, 128.6, 1 27.7,120.0,119.1,113.6,73.7,66.0,57.4,30.4,22.4,21.4,20.1,14.4,13.3.

[0097] Example 8

[0098] (2R)-10-Butyl-10-(ethio)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (thioethyl-substituted hexanal is used as the substrate in the synthesis).

[0099]

[0100] White solid, yield 56%;

[0101] 1H NMR (600MHz, CDCl3) δ (ppm): 8.68 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 6.90 (d, J = 8.4Hz, 2H), 6.88 (d,J=5.4Hz,1H),6.67(t,J=8.4Hz,1H),6.54(t,J=7.8Hz,1H),5.62(d,J=8.4Hz,1H),5.12( d,J=3.6Hz,1H),5.09(s,1H),4.57(d,J=4.8Hz,1H),2.47-2.40(m,1H),2.39-2.33(m,1H),2 .25(s,3H),1.56-1.49(m,3H),1.41-1.33(m,2H),1.29-1.17(m,1H),0.95(t,J=7.2Hz,3H).

[0102] 13 C NMR (151MHz, CDCl3) δ (ppm): 168.1, 144.1, 140.3, 134.6, 128.8, 128.7, 128.0, 127.9, 120.8, 118.8, 113.6, 74.9, 62.7, 52.6, 30.1, 26.4, 23.7, 22.8, 21.4, 14.4, 13.9. Example 9

[0103] (2R)-10-(ethio)-10-pentyl-3-tolyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (thioethyl is used to replace heptanal when synthesizing the substrate).

[0104]

[0105] White solid, yield 53%;

[0106] 1H NMR (600MHz, CDCl3) δ (ppm): 8.68 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 6.90 (d, J = 8.4Hz, 2H), 6.88 (d, J = 7.8Hz, 1H), 6 .67(t,J=7.2Hz,1H),6.54(t,J=8.4Hz,1H),5.62(d,J=8.4Hz,1H),5.12(d,J=3.0Hz,1H),5.09(s,1H),4.58(d,J =4.8Hz,1H),2.46-2.40(m,1H),2.39-2.33(m,1H),2.25(s,3H),1.59-1.57(m,1H),1.56-1.52(m,2H),1.50-1.4 8(m,1H),1.37-1.34(m,1H),1.34-1.31(m,2H),1.31-1.28(m,1H),1.08(t,J=7.8Hz,3H),0.92(t,J=6.6Hz,3H).

[0107] 13 C NMR (151MHz, CDCl3) δ (ppm): 168.1, 144.1, 140.3, 134.6, 128.8, 128.7, 128.0, 127.90, 120.8,118.8,113.6,74.9,62.7,52.6,31.9,30.4,24.0,23.7,22.5,21.4,14.5,14.0.

[0108] Example 10

[0109] (2R)-10-(benzo[d][1,3]dioxo-5-ylmethyl)-10-ethylthio)-3-tolyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (the substrate is synthesized using phenanthrenethioethyl instead of phenylpropionaldehyde).

[0110]

[0111] White solid, yield 50%;

[0112] 1H NMR (600MHz, CDCl3) δ (ppm): 8.87 (s, 1H), 7.48 (d, J = 7.8Hz, 2H), 6.93-6.90 (m, 4H), 6.85 (d, J = 9. 6Hz,1H),6.81(d,J=7.2Hz,1H),6.67(t,J=7.2Hz,1H),6.55(t,J=7.8Hz,1H),5.97(s,2H),5.58(d ,J=7.8Hz,1H),5.21(s,1H),5.01(d,J=3.6Hz,1H),4.41(d,J=4.2Hz,1H),2.96(d,J=14.4Hz,1H), 2.65(d,J=14.4Hz,1H),2.45-2.40(m,1H),2.26(s,3H),2.22-2.16(m,1H),0.98(t,J=7.2Hz,3H).

[0113] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.7, 147.5, 146.9, 144.3, 140.5, 134.6, 128.8, 128.7, 128.5, 128.0 ,127.6,124.1,121.0,118.8,113.3,111.3,108.1,101.0,73.9,64.0,53.3,36.5,23.7,21.4,13.9.

[0114] Example 11

[0115] (2R)-10-(ethio)-10-thiophene-2-ylmethyl)-3-tolyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (thiophene thioethyl is used to replace phenylpropanal when synthesizing the substrate).

[0116]

[0117] White solid, yield 51%;

[0118] 1H NMR (600MHz, CDCl3) δ (ppm): 8.85 (s, 1H), 7.48 (d, J = 8.4Hz, 2H), 7.27-7.26 (m1H), 7.06 (d, J = 2.4Hz, 1H),7.02-7.00(q,J=3.0Hz,1H),6.93-6.89(m,3H),6.68(t,J=7.8Hz,1H),6.55(t,J=7.2Hz,1H),5. 61(d,J=8.4Hz,1H),5.22(s,1H),5.09(d,J=3.6Hz,1H),4.50(d,J=4.2Hz,1H),3.24(d,J=16.2Hz,1H ),3.06(d,J=15.6Hz,1H),2.50-2.45(m,1H),2.36-2.31(m,1H),2.26(s,3H),1.05(t,J=7.8Hz,3H).

[0119] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.5, 144.3, 140.3, 136.2, 134.5, 128.8, 128.8, 128.5, 12 8.0,127.7,126.6,125.6,120.8,118.9,113.4,74.2,63.2,53.1,31.8,23.8,21.4,14.0.

[0120] Example 12

[0121] (2R)-10-benzyl-10-(p-toluenethio)-3-toluenesulfonyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (p-methylthiophenol is used instead of phenylpropionaldehyde when synthesizing the substrate).

[0122]

[0123] Semi-solid, yield 53%;

[0124] 1H NMR (600MHz, CDCl3) δ (ppm): 8.85 (s, 1H), 7.55 (d, J = 7.2Hz, 2H), 7.47 (d, J = 8.4Hz, 2H), 7.42-7.40 (m,2H),7.35(d,J=7.8Hz,1H),7.15(d,J=9.0Hz,2H),6.96-6.93(m,3H),6.80(d,J=9.0Hz,2H),6.7 2(t,J=6.6Hz,1H),6.62(t,J=7.8Hz,1H),5.64(d,J=7.8Hz,1H),5.05(s,1H),4.91(d,J=4.8Hz,1H ),4.47(d,J=4.8Hz,1H),3.80(s,3H),3.07(d,J=15.0Hz,1H),2.50(d,J=15.0Hz,1H),2.27(s,3H).

[0125] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.4, 160.7, 144.3, 140.5, 137.4, 135.0, 134.6, 131.0, 128.9, 128.8, 128.4,128.2,127.9,127.4,121.2,120.4,119.0,114.8,113.6,73.5,64.8,55.9,55.3,35.9,21.4.

[0126] Example 13

[0127] (2R)-10-benzyl-10-(ethio)-6-methyl-3-tolyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (3-methyl dipole is used when synthesizing the substrate).

[0128]

[0129] White solid, yield 53%;

[0130] 1H NMR (600MHz, CDCl3) δ (ppm): 8.91 (s, 1H), 7.48 (d, J = 7.8Hz, 2H), 7.41-7.40 (m, 2H), 7.35-7.38 (m, 2H) ,7.31(t,J=7.2Hz,1H),6.89(d,J=7.2Hz,2H),6.82(d,J=7.2Hz,1H),6.56(d,J=6.6Hz,1H),6.50(t,J= 7.8Hz,1H),5.23(s,1H),5.06(d,J=3.6Hz,1H),4.29(d,J=4.2Hz,1H),3.05(d,J=13.2Hz,1H),2.74(d ,J=14.4Hz,1H),2.43-2.37(m,1H),2.23(s,3H),2.19-2.12(m,1H),1.61(s,3H),0.95(t,J=7.2Hz,3H)

[0131] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.7, 143.9, 139.0, 135.1, 134.4, 131.0, 130.2, 128.6, 128.3, 127.4, 127.3, 125.9, 120.8, 120.5, 118.9, 73.9, 64.1, 53.3, 36.8, 23.6, 21.3, 16.6, 14.0. Example 14

[0132] (2R)-10-benzyl-10-(ethio)-8-methoxy-3-tolyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (5-methoxydipolar is used when synthesizing the substrate).

[0133]

[0134] White solid, yield 52%;

[0135] 1H NMR (600MHz, CDCl3) δ (ppm): 8.90 (s, 1H), 7.50 (d, J = 8.3Hz, 2H), 7.40-7.35 (m, 4H), 7.33-7.30 (m, 1H),6.96(d,J=8.4Hz,2H),6.53(d,J=2.4Hz,1H),6.27(dd,J=8.4,3.0Hz,1H),5.51(d,J=8.4Hz,1 H),5.19(s,1H),5.00(d,J=4.2Hz,1H),4.20(d,J=4.2Hz,1H),3.69(s,3H),3.03(d,J=13.8Hz,1H) ,2.73(d,J=13.8Hz,1H),2.45-2.40(m,1H),2.29(s,3H),2.24-2.19(m,1H),0.99(t,J=7.8Hz,3H).

[0136] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.8, 153.0, 144.2, 135.0, 134.8, 134.1, 131.0, 128.8, 128.3 ,128.0,127.4,122.0,114.5,114.4,113.2,74.5,64.0,55.8,53.5,36.9,23.6,21.4,13.9.

[0137] Example 15

[0138] (2R)-10-benzyl-10-(ethio)-7-fluoro-3-tolyl-1,2,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (using 4-F dipoles in substrate synthesis)

[0139]

[0140] White solid, yield 80%;

[0141] 1H NMR (600MHz, CDCl3) δ (ppm): 8.90 (s, 1H), 7.49 (d, J = 7.8Hz, 2H), 7.40-7.35 (m, 4H), 7.32 (t, J =6.0Hz,1H),7.01(d,J=7.8Hz,2H),6.88-6.86(m,1H),6.25(t,J=8.4Hz,1H),5.27(d,J=7.8H z,1H),5.24(s,1H),4.98(d,J=4.8Hz,1H),4.50(d,J=4.8Hz,1H),3.03(d,J=14.4Hz,1H),2.7 3(d,J=13.8Hz,1H),2.45-2.40(m,1H),2.32(s,3H),2.19-2.14(m,1H),0.99(t,J=7.2Hz,3H).

[0142] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.7, 163.36 (d, 1 J C-F =244.3Hz), 144.9, 142.2(d, 5 J C-F =6.2Hz),134.9,134.5,130.9,128.9,128.7(d, 4 J C-F =10.1Hz),128.3,128.0,127.4,117.1,105.3(d, 3 J C-F =21.7Hz), 100.1(d, 2 J C-F =26.0Hz), 73.4, 63.5, 53.3, 36.8, 23.7, 21.3, 13.8. Example 16

[0143] (2R)-10-benzyl-3-((4-(tert-butyl)phenyl)sulfonyl)-10-(ethio)-1,3,5-tetrahydro-4H-2,5-methylbenzo[e][1,2,4]triaza -4-Formaldehyde (synthetic substrate using tBu benzenesulfonyl hydrazine)

[0144]

[0145] White solid, yield 50%;

[0146] 1H NMR (600MHz, CDCl3) δ (ppm): 8.93 (s, 1H), 7.55 (d, J = 8.4Hz, 2H), 7.41 (d, J = 7.2Hz, 2H), 7.37 (t, J = 6.6Hz, 2H ),7.32(t,J=7.2Hz,1H),7.18(d,J=7.8Hz,2H),6.92(d,J=6.0Hz,1H),6.64(t,J=7.8Hz,1H),6.52(t,J=7.2 Hz,1H),5.62(d,J=7.8Hz,1H),5.26(s,1H),5.01(d,J=4.2Hz,1H),4.46(s,1H),3.05(d,J=14.4Hz,1H),2.7 5(d,J=14.4Hz,1H),2.44-2.39(m,1H),2.20-2.15(m,1H),1.58(s,3H),1.25(s,9H),0.97(t,J=7.8Hz,3H).

[0147] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.8, 156.8, 140.7, 135.0, 134.6, 131.0, 129.6, 128.3, 128.0, 127.6, 127.3, 4 125.4,120.9,118.7,113.0,73.9,64.2,53.1,36.9,35.0,30.9,23.7,13.9.

[0148] Benzaza Antibacterial activity test of bridged ring derivatives:

[0149] (1) Experimental objective:

[0150] The agar plate dilution method was used to determine the effects of the test compounds (compounds 31 and 32) on clinically isolated pathogenic bacteria (including susceptible Escherichia coli) collected from hospitals in Chengdu over the past 2-3 years. — ), enzyme-producing Escherichia coli (E. coli) + ), susceptible Klebsiella pneumoniae (lung E) — ), enzyme-producing Klebsiella pneumoniae (lung E) + The MIC values ​​of susceptible Staphylococcus aureus (MSSA), drug-resistant Staphylococcus epidermidis (MRSE), susceptible Staphylococcus epidermidis (MSSE), drug-resistant Staphylococcus aureus (MRSA), Escherichia coli standard strain (ATCC25922), and Staphylococcus aureus standard strain (ATCC29213), with approximately 1-3 strains of each type, totaling approximately 24 strains.

[0151] (2) Experimental basis:

[0152] The minimum inhibitory concentration (MIC) was determined using the agar double dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI).

[0153] (3) Experimental methods:

[0154] Add 1 ml of the test drug solution to a sterile Petri dish, followed by 14 ml of melted 50°C MHA medium. Mix well to achieve final drug concentrations of 128, 64, 32, 16, and 8 μg / ml in each dish, respectively. After cooling, inoculate bacteria using a multi-point inoculation device at an inoculation density of approximately 10⁴ CFU / ml. Cover the dishes and incubate at 36±1°C for 20–24 hours. After incubation, visually inspect the Petri dishes. The lowest concentration at which no bacterial growth is observed is the minimum inhibitory concentration (MIC). A blank control without any sample is also included.

[0155] (4) Experimental results: Compounds 2, 6, 9, and 15 showed an activity against the standard strain of Escherichia coli (ATCC25922) with a MIC value of 128 μg / ml.

[0156] The compounds prepared in this invention can effectively inhibit the standard strain of Escherichia coli (ATCC25922) and exhibit good antibacterial activity. Other compounds also show antibacterial activity; the experimental methods and final results are the same. To avoid repetition, the experimental details for other compounds will not be listed individually.

[0157] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. For those skilled in the art, based on the above description and according to common technical knowledge and practices, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A benzo[a]azapyridine Bridged ring derivatives, characterized in that, The benzozazepine The structure of the bridged ring derivative is selected from:

2. A benzo[a]azapyridine A method for preparing bridged ring derivatives, characterized in that, The reaction mixture includes the following steps: 1.0 eq of substrate 1, 1.5 eq of sulfur-substituted phenylpropanal 2, 0.2 eq of base DABCO, and 2.0 mL of dry acetonitrile are added to a reaction tube and mixed. The mixture is then reacted at room temperature for 24 hours. After the reaction is complete, the mixture is concentrated and purified to obtain hemiacetal product 3. Hemiacetal product 3, 0.5 mL of chloroform, and 100 μL of H2O are then added to the reaction tube and stirred at 60 °C for 72 hours. The reaction mixture is then directly purified by column chromatography to obtain the target product 4, which is the benzo[a]azapyridine. Bridged ring derivatives Preparation of the benzozazepine The reaction formula for the bridged ring derivative is:

3. A benzo[a]azapyridine according to claim 2 A method for preparing bridged ring derivatives, characterized in that, The The preparation method specifically includes the following steps: Step 1: Add 1 eq to the round-bottom flask 3 eq of lithium aluminum hydride was reacted in tetrahydrofuran solvent under reflux for 4 h. Thin-layer chromatography was used to monitor the reaction, and the reaction was quenched with water after completion. The reaction solution was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a colorless oil. This oil was then added to a round-bottom flask with 3 eq of pyridine chlorochromate as the oxidant and dichloromethane as the solvent. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and column chromatography was used to obtain the product of phenylpropanal oxidation. Step 2: Add 1 eq to the round-bottom flask. 1.11 eq of N-chlorosuccinimide and 20% L-proline were reacted in dichloromethane at room temperature for 4 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated and filtered to obtain the final product by column chromatography. Step 3: Add 1.6 eq of potassium carbonate and 5% IMes·HCl to the sealing tube, replace the argon gas, and then add dichloromethane. The 1 eq of potassium carbonate obtained in the previous step... Add 1.5 eq EtSH to the sealing tube and react at room temperature for 24 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, filter the reaction solution, concentrate it, and then precipitate it by column chromatography to obtain oily substrate 2, which is the [substrate name missing]. The reaction formula is:

4. A benzo[a]azapyridine according to claim 2 A method for preparing bridged ring derivatives, characterized in that: The The preparation method specifically includes the following steps: Step 1: Add 1 eq to the round-bottom flask 1.5 eq of lithium aluminum hydride solvent tetrahydrofuran was reacted at room temperature for 4 h, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was extracted three times with ethyl acetate and concentrated under reduced pressure to obtain a colorless oil. This oil was then transferred to a round-bottom flask, and 3 eq of pyridine chlorochromate oxidant and dichloromethane solvent were added. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and column chromatography was performed to obtain... Step 2: Add 1 eq to the round-bottom flask. 1.01 eq of p-toluenesulfonylhydrazine was reacted in anhydrous EtOH under reflux for 4 h. Thin-layer chromatography was used to monitor the reaction. After the reaction was complete, the reaction solution was concentrated and filtered to obtain... Step 3: Combine the 1eq obtained in the previous step 6.7 eq of reduced iron powder was added to 15 ml of acetic acid and 15 ml of anhydrous ethanol. A few drops of hydrochloric acid were added, and the mixture was heated under reflux for 1 h. The reaction was monitored by thin-layer chromatography. After the reaction was complete, the reaction solution was filtered and the pH was adjusted to weakly alkaline with saturated Na2CO3. The solution was extracted with water and ethyl acetate, dried over anhydrous MgSO4, concentrated, and then passed through a column chromatography to obtain... Step 4: Take the 1eq obtained in the previous step Add 3.7 eq of triethyl orthoformate and heat under reflux at 80 °C for 1 h. Monitor the reaction on a thin-layer chromatography plate. After the reaction is complete, add diethyl ether to solidify the mixture, and then recrystallize with acetonitrile to obtain the desired product. preparation The reaction formula is:

5. A benzo[a]azapyridine according to claim 1 Bridged ring derivatives or a benzo[a]azapyridine as described in claim 2 Benzo[a]azapyridine prepared by the method of preparing bridged ring derivatives Bridged ring derivatives, characterized in that, The benzozazepine Bridged ring derivatives are used for antibacterial purposes.

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