A palladium-catalyzed chiral [5+4] indole-9-membered ring derivative

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, discloses a [5+4] indole and azepine nine-membered ring chiral derivative constructed by palladium catalysis, and also provides a method for preparing the [5+4] indole and azepine nine-membered ring chiral derivative by intermolecular reaction, wherein the preparation method is simple to operate, mild in reaction and high in yield. The indole and mesocyclic chiral derivative constructed by palladium catalysis provided by the present invention has excellent antibacterial activity and broad market application prospects.

Description

Technical Field

[0001] The invention relates to the technical field of medicinal chemistry, in particular to a [5+4] indole azepine nine-membered ring chiral derivative. Background Art

[0002] Heterocyclic compounds are cyclic molecules containing at least one heteroatom, such as oxygen, nitrogen and other elements. They are present in large quantities in natural products with biological activity and appear as the core skeletons of various pharmaceutically important active molecules. Among them, the indole heterocyclic skeleton with a chiral center is a key component of drug molecules. It has high biological activity and occupies a place in drugs in multiple therapeutic areas such as antihypertension, antiproliferation, antiviral, and antitumor. Studies have shown that there have been many reports on the synthesis of aza-nine-membered ring compounds through intramolecular cyclization reactions, but there are few reports on the synthesis of chiral indole heterocyclic nine-membered ring skeletons through intermolecular reactions. Therefore, it is still of strategic significance to develop new indole heterocyclic chiral compounds. Summary of the invention

[0003] In view of the problems in the prior art, the present invention provides a [5+4] indole aza nine-membered ring chiral derivative constructed by palladium catalysis, and a preparation method and use thereof.

[0004] The technical solution adopted by the present invention to solve the technical problem is: a [5+4] indole azepine nine-membered ring chiral derivative constructed by palladium catalysis, the general formula of the chiral derivative is:

[0005]

[0006] Among them, R 1 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, and heterocyclic group;

[0007] R 2 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, and heterocyclic group;

[0008] Preferably, the optional structures of the chiral derivative include but are not limited to:

[0009]

[0010] Furthermore, the present invention also provides a method for preparing a [5+4] indole azepine nine-membered ring chiral derivative constructed by palladium catalysis, the method comprising the following steps: adding 5 mol% eq Pd2(dba)3 to a 25 mL sealed tube dried in a glove box; .CHCl3 and 15 mol%eq chiral ligand L2, seal the lid, take out from the glove box, add 2mL dry mesitylene under argon atmosphere, and stir the resulting suspension at 60°C for 30 minutes for coordination, then cool the reactant to room temperature, add 1.0eq azadiene substrate 1 and 2.0eq vinyl cyclic carbonate 2 under argon atmosphere, and stir the reaction mixture at room temperature for 2 hours. The reaction is completed by monitoring by thin layer chromatography, and then the reaction mixture is directly purified by column chromatography to obtain the target product 3, which is the chiral derivative. The reaction formula is:

[0011]

[0012] Furthermore, the present invention provides R 1 The preparation method of the azadiene substrate 1a having a phenyl group comprises the following steps:

[0013] Step 1: Weigh 9.53 g of indole into a round-bottom flask, add 10.85 mL of TsN3, react at 60 °C for 14 h under condensation reflux conditions, the color changes to a dark red-brown liquid accompanied by solids, add a small amount of anhydrous methanol and stir until solids precipitate, filter and dry, and weigh to obtain a pink solid I;

[0014] Step 2: Weigh 1.2 g of I into a washed round-bottom flask covered with a rubber stopper, add 4 mL of dry DCM, 0.65 mL of benzaldehyde, and 1.3 mL of BF3·Et2O in sequence under argon, react at room temperature under argon atmosphere, and turn into a yellow solid after 1 h. Add a small amount of anhydrous methanol and sonicate until solid particles precipitate, filter and dry to obtain a light yellow solid II;

[0015] Step 3: Weigh 0.1eq Pd(OAc)2 and 0.15eq ligand L1 into a sealed tube, add 10mL dry dichloromethane under argon atmosphere, react at 40°C for 30min, and the coordination is successful when the color changes from red to yellow; add 1eq II, 3eq propylene bromide, and 2eq potassium tert-butoxide into the sealed tube under argon atmosphere, react at 40°C for 2h, monitor the reaction by thin layer chromatography, use petroleum ether / ethyl acetate system as the developing solvent, and the ratio of petroleum ether to ethyl acetate is 6:1. After the reaction is completed, concentrate and dry under reduced pressure, and purify by column chromatography, use petroleum ether:ethyl acetate = 10:1 as the eluent, and 300mL of dichloromethane to obtain the azadiene substrate 1a;

[0016] The reaction formula for preparing azadiene substrate 1a is:

[0017]

[0018] Furthermore, a [5+4] indole-aza nine-membered ring chiral derivative constructed by palladium catalysis was used for antibacterial purposes.

[0019] The present invention provides a [5+4] indole aza nine-membered ring chiral derivative which is constructed by palladium catalysis and synthesized by intermolecular reaction, and a method for preparing the chiral derivative. The chiral derivative has good antibacterial effect, and the preparation method is simple, the reaction is mild, the yield is high, and the market application prospect is broad. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Single crystal structure of the product of Example 3. DETAILED DESCRIPTION

[0021] In order to make the technical means, creative features, objectives and effects of the present invention easy to understand, the present invention is further described below in conjunction with specific embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0022] Unless otherwise specified, the reagents and testing equipment used in the present invention are conventional commercially available reagents and equipment.

[0023] A [5+4] indole azepine nine-membered ring chiral derivative constructed by palladium catalysis, wherein the general formula of the chiral derivative is:

[0024]

[0025] Among them, R 1 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, and heterocyclic group;

[0026] R 2 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, and heterocyclic group;

[0027] The optional structures of the chiral derivatives include but are not limited to:

[0028]

[0029] A method for preparing a [5+4] indole azepine nine-membered ring chiral derivative constructed by palladium catalysis, the method comprising the following steps: adding 5 mol% eq Pd2(dba)3 to a 25 mL sealed tube dried in a glove box; .CHCl3 and 15 mol%eq chiral ligand L2, seal the lid, take out from the glove box, add 2mL dry mesitylene under argon atmosphere, and stir the resulting suspension at 60°C for 30 minutes for coordination, then cool the reactant to room temperature, add 1.0eq azadiene substrate 1 and 2.0eq vinyl cyclic carbonate 2 under argon atmosphere, and stir the reaction mixture at room temperature for 2 hours. The reaction is completed by monitoring by thin layer chromatography, and then the reaction mixture is directly purified by column chromatography to obtain the target product 3, which is the chiral derivative. The reaction formula is:

[0030]

[0031] Example 1

[0032] The [5+4] indole azepine nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-4,7-diphenyl-1-toluenesulfonyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (carbonate is used when synthesizing the substrate)

[0033]

[0034] White solid, yield 85%, er 96:4;

[0035] 1 H NMR(600MHz, CDCl3)δ(ppm):7.61(d,J=7.8Hz,2H),7.45(d,J=8.4Hz,2H),7.37–7.33(m,4H),7.26–7.23(m ,2H),7.22–7.21(m,3H),7.18–7.17(m,2H),7.05(d,J=8.4Hz,1H),6.94(t,J=6.6Hz,1H),6.85(d,J=8.4Hz ,2H),6.57(t,J=7.8Hz,1H),6.08–6.01(m,1H),5.24(d,J=10.2Hz,1H),5.11(d,J=16.2Hz,1H),4.98(dd,J =16.2,6.0Hz,1H),4.94(s,1H),4.85–4.79(m,2H),4.46(d,J=12.6Hz,1H),3.93–3.88(m,2H),2.10(s,3H).

[0036] 13C NMR (151MHz, CDCl3) δ (ppm): 144.1, 141.9, 140.0, 139.9, 136.6, 135.6, 133.8, 129.6, 128.4, 128.0, 127.7, 127 .6,127.2,127.1,126.7,126.4,124.0,123.3,122.2,119.9,117.1,110.9,110.7,69.8,63.2,48.7,45.2,21.3.

[0037] This embodiment provides R 1 The preparation method of the azadiene substrate 1a having a phenyl group comprises the following steps:

[0038] Step 1: Weigh 9.53 g of indole into a round-bottom flask, add 10.85 mL of TsN3, react at 60 °C for 14 h under condensation reflux conditions, the color changes to a dark red-brown liquid accompanied by solids, add a small amount of anhydrous methanol and stir until solids precipitate, filter and dry, and weigh to obtain a pink solid I;

[0039] Step 2: Weigh 1.2 g of I into a washed round-bottom flask covered with a rubber stopper, add 4 mL of dry DCM, 0.65 mL of benzaldehyde, and 1.3 mL of BF3·Et2O in sequence under argon, react at room temperature under argon atmosphere, and turn into a yellow solid after 1 h. Add a small amount of anhydrous methanol and sonicate until solid particles precipitate, filter and dry to obtain a light yellow solid II;

[0040] Step 3: Weigh 0.1eq Pd(OAc)2 and 0.15eq ligand L1 into a sealed tube, add 10mL dry dichloromethane under argon atmosphere, react at 40°C for 30min, and the coordination is successful when the color changes from red to yellow; add 1eq II, 3eq propylene bromide, and 2eq potassium tert-butoxide into the sealed tube under argon atmosphere, react at 40°C for 2h, monitor the reaction by thin layer chromatography, use petroleum ether / ethyl acetate system as the developing solvent, and the ratio of petroleum ether to ethyl acetate is 6:1. After the reaction is completed, concentrate and dry under reduced pressure, and purify by column chromatography, use petroleum ether:ethyl acetate = 10:1 as the eluent, and 300mL of dichloromethane to obtain the azadiene substrate 1a;

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

[0042]

[0043] Example 2

[0044] The [5+4] indole aza nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-7-(3-fluorophenyl)-4-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (carbonate and 3-fluoroindole were used in the synthesis of the substrate (indole was used in all other embodiments not described here)).

[0045]

[0046] White solid, yield 86%, er 97:3;

[0047] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.62 (d, J = 8.4Hz, 2H), 7.47 (d, J = 6.6Hz, 2H), 7.37–7.31 (m, 4H), 7.25–7.22 (m, 1H), 7 .18–7.14(m,1H),7.00(d,J=7.8Hz,1H),6.97(d,J=7.8Hz,1H),6.94(d,J=7.2Hz,1H),6.93–6.86(m,4H),6.62(t,J =7.8Hz,1H),6.04–5.97(m,1H),5.21(d,J=10.2Hz,1H),5.07(d,J=17.4Hz,1H),4.96(s,1H),4.91(dd,J=16.8,6. 0Hz,1H),4.82(dd,J=15.0,7.8Hz,1H),4.79–4.75(m,1H),4.45(d,J=13.2Hz,1H),3.91–3.85(m,2H),2.14(s,3H).

[0048] 13 C NMR (151MHz, CDCl3) δ (ppm): 162.5 (C–F, 1 J C–F =244.3Hz),144.3,143.0(C–F, 3 J C–F =7.2Hz),141.6,139.7,136.5,135.6,133.7,129.7,129.0(C–F, 3 J C–F =7.2Hz),128.4,128.1,127.7,127.4,126.3,123.7,123.4,122.7,121.8,120.1,117.1,114.0(C–F, 2 J C–F=23.1Hz),113.5(C–F, 2 J C–F =20.2Hz),110.8,110.5,69.3,63.2,48.7,45.2,21.3.

[0049] Example 3

[0050] The [5+4] indole aza nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-7-(3-bromophenyl)-4-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (carbonate and 3-bromoindole were used in the synthesis of the substrate (indole was used in all other embodiments not described here)).

[0051]

[0052] White solid, yield 88%, ee>99:1;

[0053] 1 H NMR(600MHz, CDCl3)δ(ppm):7.62(d,J=7.8Hz,2H),7.55(s,1H),7.46(d,J=9.0Hz,1H),7.40–7.37(m,2H) ,7.27–7.23(m,5H),7.21–7.19(m,2H),7.06(d,J=8.4Hz,1H),6.95(t,J=7.8Hz,1H),6.88(d,J=7.8Hz,2H ),6.53(t,J=7.8Hz,1H),6.08–6.02(m,1H),5.24(d,J=10.2Hz,1H),5.12(d,J=17.4Hz,1H),4.98(dd,J=1 6.8, 6.0Hz, 1H), 4.88 (s, 1H), 4.85–4.80 (m, 2H), 4.40 (d, J = 12.6Hz, 1H), 3.91–3.87 (m, 2H), 2.14 (s, 3H).

[0054] 13 C NMR (151MHz, CDCl3) δ (ppm): 144.3, 142.1, 140.8, 139.7, 136.5, 135.6, 133.7, 130.9, 129.9, 129.7, 129.5, 128.4, 12 7.64,127.59,127.0,126.8,124.9,123.4,122.5,122.2,120.0,117.1,110.73,110.66,69.9,63.0,48.4,45.2,21.4.

[0055] The single crystal data of the product of Example 3 are as follows Figure 1 And as shown in Table 1.

[0056] Table 1 Single crystal data of the product of Example 3

[0057]

[0058] Example 4

[0059] The [5+4] indole aza nine-membered ring chiral derivative of this embodiment is (S,Z)-12-allyl-7-(2-fluorophenyl)-4-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (carbonate and 2-fluoroindole were used in the synthesis of the substrate (indole was used in all other embodiments not described here)).

[0060]

[0061] White solid, yield 77%, er 93:7;

[0062] 1 H NMR(600MHz, CDCl3)δ(ppm):7.72(d,J=7.8Hz,2H),7.67(t,J=7.2Hz,1H),7.37(d,J=8.4Hz,1H),7.33–7.32(m,2H),7 .30–7.24(m,5H),7.21(d,J=7.8Hz,1H),7.09(t,J=7.2Hz,1H),6.99(t,J=7.2Hz,1H),6.95(d,J=8.4Hz,2H),6.92(t, J=9.6Hz,1H),6.34(t,J=8.4Hz,1H),6.09–6.02(m,1H),5.24(d,J=10.8Hz,1H),5.15–5.12(m,2H),5.05(dd,J=16.8, 6.0Hz,1H),4.88–4.84(m,1H),4.76(dd,J=14.4,7.8Hz,1H),4.46(d,J=12.0Hz,1H),3.98–3.94(m,2H),2.22(s,3H).

[0063] 13 C NMR (151MHz, CDCl3) δ (ppm): 160.7 (C–F, 1 J C–F=251.6Hz),144.0,142.5,140.0,136.5,135.5,134.8,133.7,129.6,129.4(C–F, 3 J C–F =2.9Hz),128.9(C–F, 3 J C–F =8.6Hz),128.1,127.8,127.77,127.3(C–F, 2 J C–F =13.0Hz),126.4,124.2,123.22,123.19,123.17,121.6,120.0,117.1,115.4(C–F, 2 J C–F =21.7Hz), 110.8, 110.1, 67.0, 63.7, 48.4, 45.3, 21.4. Example 5

[0064] The [5+4] indole aza nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-4-phenyl-7-o-tolyl-1-toluenesulfonyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (carbonate and 2-methylindole were used in the synthesis of the substrate (indole was used in the other embodiments not described here)).

[0065]

[0066] White solid, yield 49%, er 95:5;

[0067] 1H NMR (600MHz, CDCl3) δ (ppm): 7.58 (d, J = 8.4Hz, 2H), 7.53 (d, J = 7.2Hz, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.28–7.22 (m, 7H), 7.16 ( t,J=7.8Hz,1H),7.07(t,J=7.8Hz,1H),7.00–6.97(m,2H),6.80(d,J=8.4Hz,2H),6.32(t,J=7.2Hz,1H),6.08–6.01(m,1H) ,5.22(d,J=11.4Hz,1H),5.12(d,J=16.8Hz,1H),5.05(dd,J=16.2,6.0Hz,1H),4.89–4.85(m,1H),4.84(s,1H),4.70(dd,J =14.4,8.4Hz,1H),4.50(d,J=12.6Hz,1H),4.05(dd,J=14.4,8.4Hz,1H),3.89(d,J=13.2Hz,1H),2.18(s,3H),1.63(s,3H).

[0068] 13 C NMR (151MHz, CDCl3) δ (ppm): 143.9, 143.0, 140.0, 138.0, 137.1, 136.1, 135.6, 134.3, 133.6, 130.6, 129.6, 128.9, 128.2, 127 .9,127.5,127.4,126.2,125.6,124.9,124.5,123.2,122.6,119.9,117.2,111.5,110.7,71.8,64.2,48.5,45.4,21.4,20.4.

[0069] Example 6

[0070] The [5+4] indole azepine nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-4-phenyl-7-o-tolyl-1-toluenesulfonyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (carbonate and N-methylindole were used in the synthesis of the substrate (indole was used in the other embodiments not described here)).

[0071]

[0072] White solid, yield 50%, er 93:7;

[0073] 1H NMR (600MHz, CDCl3) δ (ppm): 7.62 (d, J = 8.4Hz, 2H), 7.44 (d, J = 6.6Hz, 2H), 7.36–7.32 (m, 4H) ,7.28–7.25(m,3H),7.22–7.17(m,5H),7.03(d,J=7.2Hz,1H),6.94(t,J=8.4Hz,1H),6.87(d ,J=8.4Hz,2H),6.57(t,J=8.4Hz,1H),4.97(s,1H),4.92(dd,J=15.6,7.8Hz,1H),4.45(d,J= 12.0Hz,1H),3.94(d,J=13.2Hz,1H),3.89(dd,J=14.4,9.0Hz,1H),3.74(s,3H),2.12(s,3H).

[0074] 13 C NMR (151MHz, CDCl3) δ (ppm): 144.1, 142.1, 140.1, 139.9, 136.8, 136.1, 135.9, 129.7, 128.3, 128.0, 127.64, 1 27.58,127.02,126.97,126.6,126.4,123.9,123.2,122.1,119.8,110.6,110.0,69.8,63.2,48.4,29.4,21.3.

[0075] Example 7

[0076] The [5+4] indole and azepine nine-membered ring chiral derivative of this embodiment is (R, Z)-12-allyl-4-(4-fluorophenyl)-7-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (4-F carbonate was used when synthesizing the substrate).

[0077]

[0078] White solid, yield 76%, er 94:6;

[0079] 1H NMR (600MHz, CDCl3) δ (ppm): 7.60 (d, J = 8.4Hz, 2H), 7.45–7.42 (m, 2H), 7.35 (d, J = 8.4Hz, 1H), 7 .24–7.21(m,4H),7.18–7.17(m,2H),7.04–7.01(m,3H),6.93(t,J=7.2Hz,1H),6.84(d,J=8.4Hz ,2H),6.52(t,J=8.4Hz,1H),6.04–5.98(m,1H),5.21(d,J=10.2Hz,1H),5.08(d,J=16.8Hz,1H) ,4.94–4.90(m,2H),4.82–4.76(m,2H),4.40(d,J=12.6Hz,1H),3.91–3.85(m,2H),2.10(s,3H).

[0080] 13 C NMR (151MHz, CDCl3) δ (ppm): 162.5 (C–F, 1 J C–F =247.2Hz),161.7,144.1,140.8,139.9,136.5,135.9,135.88,135.6,135.5,133.7,129.6,128.0(C–F, 3 J C–F =7.2Hz),127.6(C–F, 3 J C–F =2.9Hz),127.1,127.0,126.7,123.9,123.3,122.1,119.9,117.0,115.2(C–F, 2 J C–F =21.7Hz),110.9,110.7,69.8,63.2,48.6,45.2,21.3.

[0081] Example 8

[0082] The [5+4] indole and azepine nine-membered ring chiral derivative of this embodiment is (R, Z)-12-allyl-4-(4-chlorophenyl)-7-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (4-chlorocarbonate was used when synthesizing the substrate).

[0083]

[0084] White solid, yield 91%, er 94:6;

[0085] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.59 (d, J = 7.8Hz, 2H), 7.41 (d, J = 9.0Hz, 2H), 7.35 (d, J = 7.8Hz, 1H), 7.32 (d,J=8.4Hz,2H),7.25–7.22(m,4H),7.18–7.17(m,2H),7.02(d,J=7.8Hz,1H),6.93(t,J=6.6Hz,1H),6 .85(d,J=7.2Hz,2H),6.56(t,J=8.4Hz,1H),6.05–5.99(m,1H),5.22(d,J=10.2Hz,1H),5.08(d,J=17.4 Hz,1H),4.95–4.91(m,2H),4.83–4.76(m,2H),4.40(d,J=12.6Hz,1H),3.91–3.85(m,2H),2.11(s,3H).

[0086] 13 C NMR (151MHz, CDCl3) δ (ppm): 144.2, 140.7, 139.8, 138.3, 136.5, 135.6, 135.5, 133.9, 133.7, 129.6, 128 .5,127.6,127.0,126.8,123.9,123.4,122.1,120.0,117.1,110.9,110.7,69.9,63.0,48.6,45.2,21.3.

[0087] Example 9

[0088] The [5+4] indole and azepine nine-membered ring chiral derivative of this embodiment is (R, Z)-12-allyl-4-(3-fluorophenyl)-7-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (3-fluorocarbonate was used when synthesizing the substrate).

[0089]

[0090] White solid, yield 91%, er 95:5;

[0091] 1H NMR (600MHz, CDCl3) δ (ppm): 7.61 (d, J = 8.4Hz, 2H), 7.35 (d, J = 8.4Hz, 1H), 7.32–7.29 (m, 1H), 7.24– 7.22(m,5H),7.20–7.18(m,2H),7.08–7.05(m,1H),7.03–6.99(m,2H),6.93(t,J=7.2Hz,1H),6.87(d ,J=7.8Hz,2H),6.53(t,J=7.8Hz,1H),6.06–6.00(m,1H),5.23(d,J=10.2Hz,1H),5.09(d,J=16.8Hz ,1H),4.96–4.93(m,2H),4.83–4.78(m,2H),4.41(d,J=13.2Hz,1H),3.91–3.86(m,2H),2.12(s,3H).

[0092] 13 C NMR (151MHz, CDCl3) δ (ppm): 162.8 (C–F, 1 J C–F =244.3Hz),144.3,142.2(C–F, 3 J C–F =8.6Hz),140.9,139.8,136.6,135.6,133.7,129.8(C–F, 3 J C–F =8.8Hz),129.7,128.2,127.7,127.0,126.8,123.9,123.4,122.1,122.0,121.9,120.0,117.1,114.8(C–F, 2 J C–F =21.7Hz),113.5(C–F, 2 J C–F =23.1Hz),110.8,110.7,69.9,63.0,48.5,45.2,21.3.

[0093] Example 10

[0094] The [5+4] indole and azepine nine-membered ring chiral derivative of this embodiment is (R, Z)-12-allyl-4-(2-fluorophenyl)-7-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (2-fluorocarbonate was used when synthesizing the substrate).

[0095]

[0096] White solid, yield 97%, er 94:6;

[0097] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.66 (d, J = 8.4Hz, 2H), 7.36 (d, J = 8.4Hz, 1H), 7.29–7.21 (m, 5H), 7.21–7.18 (m, 2H) ,7.05–7.00(m,3H),6.94–6.91(m,3H),6.73(t,J=7.8Hz,1H),6.32(t,J=8.4Hz,1H),6.07–6.01(m,1H),5.23(d ,J=10.2Hz,1H),5.10(d,J=17.4Hz,1H),5.04(s,1H),4.98(dd,J=16.2,6.0Hz,1H),4.83–4.79(m,1H),4.77(dd ,J=15.0,7.2Hz,1H),4.35(d,J=12.0Hz,1H),3.95(dd,J=14.4,8.4Hz,1H),3.87(d,J=12.0Hz,1H),2.20(s,3H).

[0098] 13 C NMR (151MHz, CDCl3) δ (ppm): 159.6 (C–F, 1 J C–F =247.2Hz),144.1,139.9,139.0,136.8,135.6,133.7,131.0,130.4(C–F, 3 J C–F =3.0Hz),129.7,129.4(C–F, 3 J C–F =8.6Hz),128.6(C–F, 2 J C–F =14.5Hz),127.8,127.6,127.0,126.7,123.9,123.8,123.3,122.2,119.9,117.1,115.7(C–F, 2 J C–F =21.7Hz),110.7,110.6,70.0,63.8,48.1,45.3,21.4.

[0099] Embodiment 11

[0100] The [5+4] indole and azepine nine-membered ring chiral derivative of this embodiment is (R, Z)-12-allyl-4-(2-bromophenyl)-7-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (2-bromocarbonate was used when synthesizing the substrate).

[0101]

[0102] White solid, yield 99%, er 87:13;

[0103] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.65 (d, J = 7.8Hz, 2H), 7.53 (d, J = 7.2Hz, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.28–7.23 (m, 6 H),7.16–7.09(m,2H),7.01(d,J=8.4Hz,1H),6.93–6.90(m,3H),6.25(d,J=6.0Hz,1H),6.09–6.02(m,2H),5.25( d,J=10.2Hz,1H),5.16(d,J=17.4Hz,1H),5.03(s,1H),5.00(dd,J=16.8,6.0Hz,1H),4.85–4.82(m,1H),4.75(dd ,J=15.6,7.8Hz,1H),4.36(d,J=12.0Hz,1H),3.96(dd,J=15.6,9.0Hz,1H),3.86(d,J=12.6Hz,1H),2.23(s,3H).

[0104] 13 C NMR (151MHz, CDCl3) δ (ppm): 144.1, 144.0, 141.8, 139.8, 137.0, 135.7, 135.6, 133.7, 132.5, 130.7, 130.2, 129.8, 129.1, 1 27.9,127.7,127.0,126.82,126.77,123.8,123.4,122.2,121.5,119.9,117.3,110.7,110.4,70.3,63.6,48.0,45.3,21.4.

[0105] Example 12

[0106] The [5+4] indole and azepine nine-membered ring chiral derivative of this embodiment is (R, Z)-12-allyl-4-(4-ethylphenyl)-7-phenyl-1-tosyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (4-ethyl carbonate was used when synthesizing the substrate).

[0107]

[0108] White solid, yield 78%, er 97:3;

[0109] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.62 (d, J = 8.4Hz, 2H), 7.42 (d, J = 7.8Hz, 2H), 7.37 (d, J = 8.4Hz, 1H), 7.27–7.25 (m, 1H ),7.24–7.19(m,7H),7.06(d,J=7.8Hz,1H),6.95(t,J=8.4Hz,1H),6.86(d,J=8.4Hz,2H),6.58(t,J=7.8Hz,1H),6. 08–6.02(m,1H),5.24(d,J=10.2Hz,1H),5.12(d,J=17.4Hz,1H),4.99(dd,J=17.4,7.2Hz,1H),4.96(s,1H),4.86– 4.80(m,2H),4.47(d,J=12.6Hz,1H),3.92–3.88(m,2H),2.70(q,J=7.8Hz,2H),2.11(s,3H),1.29(t,J=7.8Hz,3H).

[0110] 13 C NMR (151MHz, CDCl3) δ (ppm): 144.1, 144.0, 141.6, 140.0, 137.1, 136.5, 135.6, 133.8, 129.6, 127.8, 127.7, 127.5 ,127.1,126.6,126.3,124.0,123.3,122.1,119.9,117.0,110.9,110.7,69.7,63.1,48.8,45.2,28.5,21.3,15.5.

[0111] Example 13

[0112] The [5+4] indole aza nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-9-methoxy-4,7-diphenyl-1-toluenesulfonyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (carbonate and 5-bromoindole were used in the synthesis of the substrate (indole was used in all other embodiments not described here)).

[0113]

[0114] White solid, yield 68%, er 95:5;

[0115] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.62 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.4Hz, 2H), 7.37–7.31 (m, 3H), 7.25–7.19 (m, 6H), 6.90 (dd,J=9.0,3.0Hz,1H),6.86(d,J=8.4Hz,2H),6.58(t,J=7.8Hz,1H),6.45(d,J=3.0Hz,1H),5.98–6.06(m,1H),5.23(d ,J=10.2Hz,1H),5.09(d,J=17.4Hz,1H),4.96(s,1H),4.93(dd,J=17.4,6.6Hz,1H),4.83(dd,J=15.0,7.8Hz,1H),4.77 –4.73(m,1H),4.48(d,J=12.0Hz,1H),3.97(d,J=12.0Hz,1H),3.91(dd,J=14.4,9.0Hz,1H),3.52(s,3H),2.12(s,3H).

[0116] 13 C NMR (151MHz, CDCl3) δ (ppm): 153.7, 144.1, 141.8, 139.8, 136.5, 135.6, 133.9, 130.6, 129.6, 128.3, 128.0, 127.7, 127.6,127.2,127.1,126.7,126.3,124.3,116.9,114.1,111.6,110.3,103.1,69.8,63.1,55.4,48.7,45.3,21.3.

[0117] Embodiment 14

[0118] The [5+4] indole and azepine nine-membered ring chiral derivative of this embodiment is (R, Z)-4-(1,1'-biphenyl-4-yl)-12-allyl-7-phenyl-1-toluenesulfonyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (4-phenyl carbonate was used when synthesizing the substrate).

[0119]

[0120] White solid, yield 85%, er 96:4;

[0121] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.65 (d, J = 7.8Hz, 2H), 7.62–7.59 (m, 4H), 7.58–7.56 (m, 2H), 7.49–7.46 (m, 2H), 7.39–7 .36(m,2H),7.25–7.23(m,1H),7.22–7.20(m,3H),7.19–7.17(m,2H),7.06(d,J=7.8Hz,1H),6.94(t,J=8.4Hz,1H),6. 85(d,J=7.8Hz,2H),6.66(t,J=7.2Hz,1H),6.07–6.01(m,1H),5.23(d,J=10.2Hz,1H),5.10(d,J=16.8Hz,1H),4.99–4 .95(m,2H),4.85(dd,J=15.6,7.8Hz,1H),4.83–4.79(m,1H),4.50(d,J=13.2Hz,1H),3.95–3.89(m,2H),2.09(s,3H).

[0122] 13 C NMR (151MHz, CDCl3) δ (ppm): 144.1, 141.3, 140.6, 140.4, 139.9, 138.6, 136.5, 135.64, 135.61, 133.8, 129.7, 128.8, 127.7, 127 .6,127.5,127.1,127.01,126.95,126.8,126.7,124.0,123.3,122.2,119.9,117.1,110.9,110.7,69.8,63.1,48.8,45.2,21.3.

[0123] Embodiment 15

[0124] The [5+4] indole azepine nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-4-(3,4-dimethoxyphenyl)-7-phenyl-1-toluenesulfonyl-2,5,7,12-tetrahydro-1H-[1,5]oxaza[4,3-b]indole (3,4-dimethoxycarbonate was used when synthesizing the substrate)

[0125]

[0126] White solid, yield 77%, er 91:9;

[0127] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.58 (d, J = 8.4Hz, 2H), 7.35 (d, J = 8.4Hz, 1H), 7.24–7.21 (m, 1H), 7.21–7.17 (m, 6H ),7.11(d,J=8.4Hz,1H),7.03(d,J=8.4Hz,1H),6.92(t,J=6.6Hz,1H),6.85(d,J=8.4Hz,1H),6.83(d,J=7.2Hz ,2H),6.58(t,J=7.8Hz,1H),6.05–5.98(m,1H),5.21(d,J=10.2Hz,1H),5.07(d,J=17.4Hz,1H),4.95–4.92(m, 2H), 4.83 (dd, J=14.4, 7.2Hz, 1H), 4.79–4.76 (m, 1H), 4.42 (d, J=12.6Hz, 1H), 3.92–3.85 (m, 8H), 2.07 (s, 3H).

[0128] 13 C NMR (151MHz, CDCl3) δ (ppm): 148.9, 148.5, 144.0, 141.2, 140.0, 136.3, 135.6, 135.3, 133.8, 132.9, 129.6, 127.6, 127.5, 127 .0,126.7,125.8,123.9,123.3,122.0,119.90,118.99,117.0,111.1,110.7,109.4,69.7,63.4,55.9,55.8,48.9,45.2,21.3.

[0129] Example 16

[0130] The [5+4] indole azepine nine-membered ring chiral derivative of this embodiment is (R,Z)-12-allyl-4-naphthalen-2-yl-7-phenyl-1-toluenesulfonyl-2,5,7,12-tetrahydro-1H-[1,5]oxazolo[4,3-b]indole (the synthetic substrate uses 2-naphthalene carbonate)

[0131]

[0132] White solid, yield 72%, er 95:5;

[0133] 1 H NMR (600 MHz, CDCl3) δ (ppm): 8.03 (s, 1H), 7.88–7.85 (m, 2H), 7.84 (d, J = 9.0Hz, 1H), 7.63–7.61 (m, 3H), 7.54–7.50 (m, 2H), 7.40 (d, J = 7.8 Hz,1H),7.28–7.26(m,1H),7.21–7.18(m,5H),7.10(d,J=7.8 Hz,1H),6.97(t,J=7.2 Hz,1H),6.81(d,J=7.2 Hz,2H),6.76(t,J=8.4 Hz,1H),6.11–6.05(m,1H),5.27(d,J=10.2 Hz,1H),5.15(d,J=16.2Hz,1H),5.04(dd,J=16.2,6.0 Hz,1H),4.96(s,1H),4.92(dd,J=15.0,7.8 Hz,1H),4.87–4.84(m,1H),4.61(d,J=13.2 Hz, 1H), 4.02 (d, J = 12.6 Hz, 1H), 3.96 (dd, J = 15.0, 9.0 Hz, 1H), 2.04 (s, 3H).

[0134] 13 C NMR(151 MHz, CDCl3)δ(ppm):144.1,141.6,139.8,136.9,136.5,135.70,135.67,133.8,133.4,132.9,129.6,128.3,127.9,127.7,127.6,127.5 2,127.47,127.2,126.7,126.3,126.2,125.9,123.99,123.97,123.4,122.2,119.9,117.1,110.9,110.8,70.0,63.2,48.8,45.3,21.3.

[0135] The beneficial effects of the present invention are specifically described below through test examples.

[0136] Test Example 1, Anti-tumor research, Antibacterial activity test of [5+4] indole and azepine nine-membered ring chiral derivatives:

[0137] 1. Experimental purpose:

[0138] The agar plate two-fold dilution method was used to determine the MIC values ​​of the test compounds (compounds 7, 8, and 9) against clinically isolated pathogenic bacteria (including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-sensitive Staphylococcus epidermidis (MSSE) Gram-positive bacteria and Gram-negative bacteria such as Klebsiella pneumoniae (ESBLs+), Klebsiella pneumoniae (ESBLs-), Escherichia coli (ESBLs+), Escherichia coli (ESBLs-), Escherichia coli standard strain (ATCC25922), and Staphylococcus aureus standard strain (ATCC29213), about 1-3 strains, totaling about 24 strains) collected from hospitals in Chengdu area in the past 2-3 years.

[0139] 2. Experimental basis:

[0140] The minimum inhibitory concentration (MIC) was determined using the agar two-fold dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI).

[0141] 3. Experimental methods:

[0142] Add 1mL of the test drug solution to a sterile plate, then add 14mL of melted 50℃ MHA medium, mix well, and make the final drug concentration in each plate be 128, 64, 32, 16, 8μg / mL, respectively; after cooling, inoculate bacteria with a multi-point inoculator, the inoculation amount is about 104CFU / mL, cover the plate, place it in an incubator, 36±1℃, incubate for 20-24h. After the incubation, observe with the naked eye, and the lowest sample concentration in the plate where no bacteria grow is its minimum inhibitory concentration (MIC). At the same time, set up a blank bacteria control without any sample.

[0143] 4. Experimental results: The MIC values ​​of compounds 7, 8, and 9 against the standard strain of Escherichia coli (ATCC25922) were 128 μg / mL.

[0144] Show activity to it.

[0145] The compound prepared by the present invention can effectively inhibit the standard strain of Escherichia coli (ATCC25922) and has good antibacterial activity. Other compounds also have antibacterial effects, and the experimental methods and final effects are the same. In order to reduce repetitive content, the experimental contents of other compounds are no longer listed one by one.

[0146] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, based on the above content of the present invention, according to the common technical knowledge and customary means in the art, other various forms of modification, replacement or change can be made without departing from the above basic technical ideas of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A [5+4] indole azepine nine-membered ring chiral derivative constructed by palladium catalysis, characterized in that: The general formula of the chiral derivative is: Among them, R 1 It is one of phenyl, halogen-substituted phenyl and naphthyl; R 2 It is one of phenyl, halogen-substituted phenyl and naphthyl.

2. The structure of the [5+4] indole azepine nine-membered ring chiral derivative is selected from the following:

3. The method for preparing a [5+4] indole azepine nine-membered ring chiral derivative constructed by palladium catalysis as claimed in claim 1, characterized in that: The following steps are involved: Add 5 mol%eq Pd2(dba)3 to a 25 mL sealed tube dried in the glove box . CHCl3 and 15 mol%eq chiral ligand L2, seal the lid, take out from the glove box, add 2 mL of dry mesitylene under argon atmosphere, and stir the resulting suspension at 60°C for 30 minutes for coordination, then cool the reactant to room temperature, add 1.0 eq of azadiene substrate 1 and 2.0 eq of vinyl cyclic carbonate 2 under argon atmosphere, and stir the reaction mixture at room temperature for 2 hours. The reaction is completed by monitoring by thin layer chromatography, and then the reaction mixture is directly purified by column chromatography to obtain the corresponding target product 3, which is the chiral derivative, and the reaction formula is:

4. The preparation method according to claim 3, characterized in that: The azadiene substrate 1 has R 1 is phenyl, the azadiene substrate 1 is substrate 1a, and the preparation method thereof specifically comprises the following steps: Step 1: Weigh 9.53 g of indole into a round-bottom flask, add 10.85 mL of TsN3, react at 60 °C for 14 h under condensation reflux conditions, the color changes to a dark red-brown liquid accompanied by solids, add a small amount of anhydrous methanol and stir until solids precipitate, filter and dry, and weigh to obtain a pink solid I; Step 2: Weigh 1.2 g of I and add it to a washed round-bottom flask covered with a rubber stopper. Add 4 mL of dry DCM, 0.65 mL of benzaldehyde, and 1.3 mL of BF3·Et2O in sequence under argon. React at room temperature under argon atmosphere. After 1 h, it turns into a yellow solid. Add a small amount of anhydrous methanol and sonicate until solid particles precipitate. Filter and dry to obtain a light yellow solid II. Step 3: Weigh 0.1eq Pd(OAc)2 and 0.15eq ligand L1 into a sealed tube, add 10mL dry dichloromethane under argon atmosphere, react at 40°C for 30min, and the coordination is successful when the color changes from red to yellow; add 1eq II, 3eq propylene bromide, and 2eq potassium tert-butoxide into the sealed tube under argon atmosphere, react at 40°C for 2h, monitor the reaction by thin layer chromatography, use petroleum ether / ethyl acetate system as the developing solvent, and the ratio of petroleum ether to ethyl acetate is 6:

1. After the reaction is completed, concentrate and dry under reduced pressure, and purify by column chromatography, use petroleum ether:ethyl acetate = 10:1 as the eluent, and 300mL of dichloromethane to obtain the azadiene substrate 1a; The reaction formula for preparing azadiene substrate 1a is:

5. Use of the [5+4] indole azepine nine-membered ring chiral derivative constructed by palladium catalysis as claimed in claim 1 or 2 in the preparation of anti-Escherichia coli drugs.

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