A method for preparing biologically active benzoindolizine derivatives

Abstract

The present invention provides a method for preparing a biologically active benzoindolizine derivative, and relates to the technical field of indolizine derivatives that can be used as medicines. The present invention provides a method for preparing a benzoindolizine derivative, which is prepared by a [3+2] cycloaddition reaction of an N-isoquinoline ylide salt and an aromatic acetylene. The biologically active benzoindolizine derivative prepared by the present invention is constructed in one step without the participation of transition metals, a direct and efficient [3+2] cycloaddition reaction, simple and easy to operate, a wide range of application of reaction substrates, good regioselectivity, high yield, a simple and efficient method, and environmental friendliness. The preparation method is as follows.

Description

Technical Field

[0001] The present invention relates to the technical field of indolizine derivatives which can be used as medicines, and in particular to a method for preparing a biologically active benzoindolizine derivative. Background Art

[0002] Indolizine derivatives are widely used in the fields of biology, pesticides, medicine and luminescent materials, and are essential for the production of drugs, dyes and organic luminescent materials. For example, it is an effective component in pigments, herbicides, potential phospholipase inhibitors, anti-leishmania and antiviral drugs; in addition, it also exhibits anti-mycobacterial activity; it is a key intermediate in the synthesis of alkaloids with important physiological activities. In recent years, studies have confirmed that the biological activity of indolizine derivatives also plays a positive role in human anti-tumor, anti-bacterial, anti-viral, anti-mite, anti-inflammatory, anti-arrhythmic, anti-hypertension and other aspects.

[0003] Indolizine is an important family of N-heterocyclic compounds with a variety of biological activities, such as anti-HIV, anti-inflammatory, anti-tuberculosis, antibacterial and anti-tumor. In addition, molecules containing indolizine are also used in biomarkers, electroluminescent materials and fluorescent dyes. Therefore, in the past decade, some synthetic methods have been developed to construct benzoindolizine derivatives. However, their synthetic methods are mostly complex multi-step reactions with low synthetic efficiency.

[0004] Patent CN 102276601 B discloses a method for preparing an indolizine derivative. It uses an alkyl glyoxylate, an α-bromoacetophenone derivative and pyridine as raw materials, and refluxes in an organic solvent in the presence of sodium carbonate for 12-24 hours, and then obtains the indolizine derivative through water washing, extraction, concentration, column chromatography or recrystallization purification. However, the yield of the product is low and is not suitable for large-scale promotion. The reaction formula is as follows:

[0005]

[0006] Patent CN 114014858 A discloses a method for preparing polysubstituted indolizine derivatives, wherein the method directly prepares polysubstituted indolizine derivatives by reacting N-substituted pyridinium salts prepared from halogenated compounds and pyridine derivatives, quinoline derivatives or isoquinoline with electron-deficient olefins in the presence of nitrite. However, the yield of the product is not high.

[0007] The [3+2] cycloaddition reaction is an important organic synthesis reaction that is often used to construct new ring structures. In this reaction, a double bond undergoes an addition reaction with a nucleophile to form a new three-membered ring compound. This process is often described as an addition reaction of a double bond with a nucleophile of two carbon atoms, so it is also called "[3+2] cycloaddition". In organic synthesis, the [3+2] cycloaddition reaction is widely used to construct ring structures containing heteroatoms such as nitrogen, oxygen, and sulfur, as well as to construct a variety of useful compounds such as cyclopropane, epoxides, and cyclohexanone. This reaction plays an important role in the synthesis of complex molecules and drugs because it can efficiently construct complex ring structures, and the reaction conditions are usually mild and applicable to a variety of substrates.

[0008] However, the preparation of such compounds from N-isoquinoline ylide salts and aromatic alkynes through an efficient [3+2] cycloaddition reaction as the basic raw materials has not been disclosed. Therefore, it is of great significance to develop a simple and efficient synthesis method.

[0009] In summary, the present invention discloses a [3+2] cycloaddition reaction of N-isoquinoline ylide salt and aromatic alkyne, which obtains a series of biologically active benzoindolizine derivatives with good yield and wide substrate range. Summary of the invention

[0010] In view of the above problems, the present invention provides a highly efficient and direct [3+2] cycloaddition reaction of N-isoquinoline ylide salt and aromatic alkyne without the participation of transition metal. The reaction is prepared with the participation of a catalyst, and a series of biologically active benzoindolizine derivatives are finally obtained with moderate to good yields and a wide substrate range through continuous [3+2] cycloaddition reaction and decarboxylation process, which is suitable for large-scale promotion.

[0011] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0012] The present invention provides a method for preparing a benzoindolizine derivative, which is prepared by reacting an N-isoquinoline ylide salt with an aromatic alkyne through a [3+2] cycloaddition reaction, and the expression is:

[0013]

[0014] R includes but is not limited to hydrogen, halogen, substituted or unsubstituted aryl, alkyl, heteroalkyl;

[0015] The substituted substituents include but are not limited to C 1-12 Alkyl, C 1-12 heteroalkyl or halogen;

[0016] The heteroatoms of the heteroalkyl group include, but are not limited to, O, S, and N.

[0017] Preferably, R includes but is not limited to hydrogen, halogen, substituted or unsubstituted C 1-12 The aromatic group, C 1-12 Alkyl, C 1-12 of heteroalkyl;

[0018] The substituted substituents include but are not limited to C 1-6 Alkyl, C 1-6 heteroalkyl or halogen;

[0019] The heteroatoms of the heteroalkyl group include, but are not limited to, O, S, and N.

[0020] More preferably, R includes but is not limited to hydrogen, F, Cl, Br, substituted or unsubstituted C 1-6 The aromatic group, C 1-6 Alkyl, C 1-6 of heteroalkyl;

[0021] The substituted substituents include but are not limited to C 1-3 Alkyl, C 1-3 heteroalkyl, F, Cl, Br;

[0022] The heteroatoms of the heteroalkyl group include, but are not limited to, O, S, and N.

[0023] More preferably, R includes but is not limited to hydrogen, methyl, phenyl, methoxy, and Br.

[0024] Preferably, Formula II includes but is not limited to the following structures:

[0025]

[0026] Unless otherwise specified, the term "alkyl" as used herein includes branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, including all isomers. Common abbreviations for alkyl groups, such as methyl, can be represented by "Me" or CH3, ethyl, can be represented by "Et" or CH2CH3, propyl, can be represented by "Pr" or CH2CH2CH3, butyl, can be represented by "Bu" or CH2CH2CH2CH3, etc. For example, "C 1-4 "C1-C4 alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms, including all isomers. 1-4 Alkyl includes n-, iso-, sec- and tert-butyl, n- and iso-propyl, ethyl and methyl. 1-10 "Alkyl" and the like have similar meanings.

[0027] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

[0028] The term "heteroalkyl" refers to an alkyl group (wherein alkyl is as defined herein) wherein one or more carbon atoms are independently replaced by one or more heteroatoms (eg, nitrogen, oxygen, phosphorus and / or sulfur atoms).

[0029] The term "aryl" refers to aromatic mono- and polycyclic carbon ring systems wherein the individual carbon rings in the polycyclic system are fused or linked to each other by single bonds. Typical aryl groups include phenyl, naphthyl and biphenylene.

[0030] The aryl group in the term "substituted aryl" is as defined above. When the substituent of the substituted aryl group is not specified, the substituent may be selected from the following groups, including but not limited to: halogen, C1-C 20 Alkyl, CF3, NH2, N(C1-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -O(C1-C6 alkyl), C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C6 alkyl)S(O) 0-2 -, Aryl-S(O) 0-2 -, (C0-C6 alkyl) S (O) 0-2 (C0-C6 alkyl)-, (C0-C6 alkyl)C(O)NH-, H2N-C(NH)-, -O(C1-C6 alkyl)CF3, (C0-C6 alkyl)C(O)-, (C0-C6 alkyl)OC(O)-, (C0-C6 alkyl)2NC(O)-(C0-C6 alkyl)O(C1-C6 alkyl)-, (C0-C6 alkyl)C(O) 1-2 (C0-C6 alkyl)-, (C0-C6 alkyl)OC(O)NH-, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halogen-aryl, halogen-aralkyl, halogen-heterocycle, halogen-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl. The term "substituted phenyl" has a similar definition.

[0031] Preferably, the [3+2] cycloaddition reaction is carried out in the presence of a catalyst. Further preferably, the catalyst includes but is not limited to at least one of K2CO3, Na2CO3, NaHCO3, Cs2CO3, Li2CO3, and triethylamine. More preferably, the catalyst is selected from K2CO3.

[0032] Preferably, the molar ratio of the N-isoquinoline ylide salt to the aromatic alkyne is 1:1-2. Further preferably, the molar ratio of the N-isoquinoline ylide salt to the aromatic alkyne is 1:1.5.

[0033] Preferably, the molar ratio of the catalyst to the N-isoquinoline ylide salt is 1-3: 1. Further preferably, the molar ratio of the catalyst to the N-isoquinoline ylide salt is 1.5:1.

[0034] Preferably, the [3+2] cycloaddition reaction is carried out in the presence of a solvent. Further preferably, the solvent includes but is not limited to at least one of tetrahydrofuran, ethyl acetate, 1,4-dioxane, and acetonitrile. More preferably, the solvent is ethyl acetate.

[0035] Preferably, the reaction temperature of the [3+2] cycloaddition reaction is 60-100°C, and the reaction time is 8-16h. Further preferably, the reaction temperature of the [3+2] cycloaddition reaction is 80°C, and the reaction time is 12h.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] The bioactive benzoindolizine derivatives prepared by the present invention are constructed in one step through a direct and efficient [3+2] cycloaddition reaction without the participation of transition metals, are simple and easy to operate, have a wide range of applicable reaction substrates, good regional selectivity, high yield, a simple and efficient method, are environmentally friendly, and are suitable for large-scale promotion. DETAILED DESCRIPTION

[0038] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0039] Embodiment 1:

[0040] 86.1 mg (0.3 mmol) of N-isoquinoline ylide salt shown below and 45.9 mg (0.45 mmol) of phenylacetylene substrate were added to a reaction tube with a stirring bar, followed by 62.1 mg (0.45 mmol) of K2CO3 additive, and then ethyl acetate (2 ml) solvent was added to dissolve it. The mixture was stirred at 80°C for 12 hours, and then spin-dried and separated by silica gel chromatography to obtain the target product with a yield of 85%.

[0041]

[0042] 1H NMR (400MHz, CDCl3) δ9.30(d,J=7.6Hz,1H),8.11(d,J=7.8Hz,1H),7.68(d,J=7.3Hz,1H),7.52(t,J =7.5Hz,4H),7.45-7.35(m,3H),7.02(d,J=8.8Hz,2H),4.22(q,J=7.1Hz,2H),1.10(t,J=7.1Hz,3H).

[0043] 13 C NMR (100MHz, CDCl3) δ162.11,136.98,136.83,134.20,130.08,128.18,127.69,127. 56,127.16,126.91,125.38,124.89,123.22,113.21,112.63,103.90,59.99,13.98.

[0044] HR-GC-MS m / z calcd.C 21 H 17 NO2[M] + :315.1259,found:315.1260.

[0045] Embodiment 2:

[0046] 86.1 mg (0.3 mmol) of N-isoquinoline ylide salt shown below and 52.2 mg (0.45 mmol) of phenylacetylene substrate were added to a reaction tube with a stirring bar, followed by 62.1 mg (0.45 mmol) of additive K2CO3, and then ethyl acetate (2 ml) solvent was added to dissolve it, stirred at 80°C for 12 hours, and then spin-dried and separated by silica gel chromatography to obtain the target product with a yield of 81%.

[0047]

[0048] 1 H NMR (400MHz, CDCl3) δ9.28(d,J=7.6Hz,1H),8.11(d,J=7.7Hz,1H),7.67(d,J=7.5Hz,1H),7.51(p,J=6.8Hz,2H),7. 43(d,J=7.8Hz,2H),7.23(t,2H),7.01(d,J=7.1Hz,2H),4.24(q,J=7.1Hz,2H),2.43(s,3H),1.14(t,J=7.1Hz,3H).

[0049] 13C NMR (100MHz, CDCl3) δ162.16,137.03,136.86,134.19,133.75,129.97,128.31,128.18,127 .65,127.55,126.89,125.45,124.90,123.24,113.16,112.50,103.93,60.00,21.41,14.11.

[0050] HR-GC-MS m / z calcd.for C 22 H 19 NO2[M] + :329.1416,found:329.1411.

[0051] Embodiment 3:

[0052] 86.1 mg (0.3 mmol) of N-isoquinoline ylide salt shown below and 52.2 mg (0.45 mmol) of phenylacetylene substrate were added to a reaction tube with a stirring bar, followed by 62.1 mg (0.45 mmol) of additive K2CO3, and then ethyl acetate (2 ml) solvent was added to dissolve it. The mixture was stirred at 80°C for 12 hours, and then spin-dried and separated by silica gel chromatography to obtain the target product with a yield of 86%.

[0053]

[0054] 1 H NMR (400MHz, CDCl3) δ9.31(d,J=7.0Hz,1H),8.10(d,J=7.4Hz,1H),7.68(d,J=7.3Hz,1H),7.52(p,J=6.4Hz,2H),7. 24(d,J=11.3Hz,4H),7.03(d,J=7.1Hz,1H),6.93(s,1H),4.08(q,J=6.1Hz,2H),2.18(s,3H),0.90(t,J=6.9Hz,3H).

[0055] 13 C NMR (100MHz, CDCl3) δ161.91,137.10,136.54,136.18,134.18,129.65,129.15,128.09,127.57,127 .44,127.15,126.82,125.23,124.86,124.82,123.14,113.92,112.37,103.46,59.61,20.33,13.57.

[0056] HR-GC-MS m / z calcd.for C 22 H 19 NO2[M] + :329.1416,found:329.1411.

[0057] Embodiment 4:

[0058] 86.1 mg (0.3 mmol) of N-isoquinoline ylide salt shown below and 68.4 mg (0.45 mmol) of phenylacetylene substrate were added to a reaction tube with a stirring bar, followed by 62.1 mg (0.45 mmol) of K2CO3 additive, and then ethyl acetate (2 ml) solvent was added to dissolve it. The mixture was stirred at 80°C for 12 hours, and then separated by silica gel chromatography to obtain the target product with a yield of 80%.

[0059]

[0060] 1 H NMR (400MHz, CDCl3) δ9.34(d,J=7.6Hz,1H),8.15(d,J=7.6Hz,1H),7.99(s,1H),7.93-7.84(m,3H),7.72-7.6 4(m,2H),7.59-7.47(m,4H),7.13(s,1H),7.05(d,J=7.6Hz,1H),4.20(q,J=7.1Hz,2H),1.03(t,J=7.1Hz,3H).

[0061] 13 C NMR (100MHz, CDCl3) δ162.12,136.86,134.39,134.33,133.16,132.67,129.00,128.46,128.23,128.15, 127.77,127.67,126.96,126.75,126.12,125.95,125.42,124.91,123.29,112.76,104.19,60.05,14.10.

[0062] HR-GC-MS m / z calcd.for C 25 H 19 NO2[M] + :365.1416,found:365.1410.

[0063] Embodiment 5:

[0064] 86.1 mg (0.3 mmol) of N-isoquinoline ylide salt shown below and 59.4 mg (0.45 mmol) of phenylacetylene substrate were added to a reaction tube with a stirring bar, followed by 62.1 mg (0.45 mmol) of additive K2CO3, and then ethyl acetate (2 ml) solvent was added to dissolve it. The mixture was stirred at 80°C for 12 hours, and then spin-dried and separated by silica gel chromatography to obtain the target product with a yield of 86%.

[0065]

[0066] 1 H NMR(400MHz, CDCl3)δ9.28(d,J=7.6Hz,1H),8.11(d,J=7.7Hz,1H),7.70-7.65(m,1H),7.56-7.43(m,4H) ,7.01(t,J=3.9Hz,2H),6.95(d,J=8.6Hz,2H),4.24(q,J=7.1Hz,2H),3.88(s,3H),1.15(t,J=7.1Hz,3H).

[0067] 13 C NMR (100MHz, CDCl3) δ162.19,159.03,136.77,134.24,131.24,129.12,128.22,127.66, 127.57,126.90,125.50,124.88,123.25,113.07,112.47,103.90,60.01,55.49,14.19.

[0068] HR-GC-MS m / z calcd.for C 22 H 19 NO3[M] + :345.1365,found:345.1366.

[0069] Embodiment 6:

[0070] 86.1 mg (0.3 mmol) of N-isoquinoline ylide salt shown below and 58.5 mg (0.45 mmol) of phenylacetylene substrate were added to a reaction tube with a stirring bar, followed by 62.1 mg (0.45 mmol) of additive K2CO3, and then ethyl acetate (2 ml) solvent was added to dissolve it, stirred at 80°C for 12 hours, and then spin-dried and separated by silica gel chromatography to obtain the target product with a yield of 80%.

[0071]

[0072] 1H NMR (400MHz, CDCl3) δ9.21(d,J=7.7Hz,1H),8.03(d,J=7.8Hz,1H),7.59(d,J=7.6Hz,1H),7.48-7.31(m,4H),7.21-7.13( m,1H),6.93(d,J=9.4Hz,1H),4.15(q,J=7.1Hz,2H),2.65(q,J=7.7Hz,2H),1.22(t,J=7.6Hz,3H),1.04(t,J=7.1Hz,3H).

[0073] 13 C NMR (100MHz, CDCl3) δ162.19,143.32,137.08,134.19,133.98,130.02,128.18,127.67,127.56 ,127.11,126.90,125.45,124.91,123.25,113.19,112.51,103.92,60.00,28.83,15.90,14.04.

[0074] HR-GC-MS m / z calcd.for C 23 H 21 NO2[M] + :343.1572,found:343.1570.

[0075] Embodiment 7:

[0076] 86.1 mg (0.3 mmol) of N-isoquinoline ylide salt shown below and 81.0 mg (0.45 mmol) of phenylacetylene substrate were added to a reaction tube with a stirring bar, followed by 62.1 mg (0.45 mmol) of K2CO3 additive, and then ethyl acetate (2 ml) solvent was added to dissolve it. The mixture was stirred at 80°C for 12 hours, and then the target product was separated by silica gel chromatography with a yield of 83%.

[0077]

[0078] 1 H NMR(400MHz, CDCl3) δ9.30(d,J=7.5Hz,1H),7.88(d,J=8.3Hz,1H),7.63(dd,J=19.5,8.0Hz,3H),7.46 -7.38(m,4H),7.32-7.23(m,1H),7.03(d,J=7.6Hz,1H),4.39(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H).

[0079] 13 C NMR (100MHz, CDCl3) δ161.50,136.24,131.87,130.69,130.37,128.72,127.40,127. 21,125.57,124.86,123.62,122.48,121.45,118.76,115.73,113.22,60.29,14.67.

[0080] HR-GC-MS(m / z):calcd for C 21 H 16 BrNO2[M] + :393.0364,found:393.0365.

[0081] Test example: Cytotoxicity test

[0082] Cancer is a group of diseases characterized by the uncontrolled growth of abnormal cells in the body, which often form tumors. These tumors can be benign (do not invade surrounding tissue) or malignant (invade surrounding tissue and may spread to other sites). Cancer is a multifactorial disease that includes genetic, environmental, and lifestyle factors.

[0083] In order to explore the application of ester-containing benzoindolizine in terms of biological activity, the MTT colorimetric method was used to study the effects of the above compounds on the growth of Hep-G2 liver cancer cells.

[0084] The test results are as follows:

[0085] Compound No. <![CDATA[IC 50 (μM)]]> I 105.21 II 88.41 III 130.63 IV 67.55 V 24.40 VI 45.56 VII 30.25

[0086]

[0087] From the above results, it can be seen that compounds V and VII have obvious inhibitory effects on Hep-G2 liver cancer cells (the half-maximal inhibitory concentrations are 24.40 μM and 30.25 μM, respectively).

[0088] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a benzoindolizine derivative, characterized in that: It is prepared by [3+2] cycloaddition reaction of N-isoquinoline ylide salt and aromatic alkyne, and the formula is: R is selected from hydrogen, halogen, alkyl, methoxy; Or formula II is selected from The [3+2] cycloaddition reaction is carried out in the presence of a catalyst; the catalyst is selected from K2CO3; The molar ratio of the N-isoquinoline ylide salt to the aromatic alkyne is 1:1-2; The molar ratio of the catalyst to the N-isoquinoline ylide salt is 1-3:

1.

2. The preparation method according to claim 1, characterized in that: R is selected from hydrogen, F, Cl, Br, C 1-6 of alkyl.

3. The preparation method according to claim 1, characterized in that: R is selected from hydrogen, methyl, methoxy, and Br.

4. The preparation method according to claim 1, characterized in that: Formula II is selected from the following structures:

5. The preparation method according to claim 1, characterized in that: The [3+2] cycloaddition reaction is carried out in the presence of a solvent.

6. The preparation method according to claim 5, characterized in that: The solvent is selected from at least one of tetrahydrofuran, ethyl acetate, 1,4-dioxane and acetonitrile.

7. The preparation method according to claim 1, characterized in that: The reaction temperature of the [3+2] cycloaddition reaction is 60-100° C., and the reaction time is 8-16 h.

8. The preparation method according to claim 7, characterized in that: The reaction temperature of the [3+2] cycloaddition reaction is 80° C. and the reaction time is 12 h.

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