Chiral imide derivatives, processes for their preparation and use thereof

Abstract

The application discloses a chiral imide derivative and a preparation method and application thereof. A simple synthesis method of NHC catalyzed imine and MBH carbonate is designed, and a chiral imide derivative is efficiently constructed by one-step method. Biological activity evaluation is carried out on the compounds, and the inhibition rates of all the compounds on three tumor cells, human lung cancer cells A549, human colon cancer cells LOVO and SW620, are enhanced with the increase of concentration, wherein, the compounds 3g, 3i, 3j and 3o show better inhibition effect on the three tumor cells, the inhibition rate of the compound 3g on the A549 cells reaches 50% at a concentration of 12.5 μg / ml, and the inhibition rates of the compounds 3i, 3j and 3o on the A549 cells are all above 70% at a concentration of 50.0 μg / ml, and the inhibition rate of the compound 3j on the A549 cells reaches 85.8%, so the compound 3j has the value of further development and research.

Description

Technical Field

[0001] This invention relates to the field of chemical technology, and in particular to a chiral imide derivative, its preparation method, and its application. Background Technology

[0002] N-heterocyclic carbenes (NHCs) are a class of small organic molecules with unique structures and powerful functions. They have become a research hotspot in the field of asymmetric catalysis in recent decades. Due to the advantages of chiral small organic molecule catalysts, such as low toxicity, mild reaction conditions, relatively stable chemical properties, and simple preparation methods, asymmetric organic catalysis has become one of the most promising research directions in organic chemistry. After decades of in-depth exploration, researchers have made significant progress in various branches of small organic molecule catalysis, such as enamine catalysis, imine catalysis, and... A series of classic reaction modes have been established in fields such as acid / base catalysis, Lewis acid / base catalysis, phase transfer catalysis, and photocatalysis. Among them, nitrogen-heterocyclic carbenes (NHCs) catalysts are a class of powerful small organic molecule catalysts. After more than half a century of development, a series of classic catalytic activation modes have been established in the field of NHC catalysis. In ongoing research, these catalysts can be applied to the efficient preparation of functional molecules with different biological and pharmaceutical activities, including bioactive small molecules, pharmaceutical and pesticide intermediates. Therefore, the research and development of this project is not only of great scientific significance for the development of novel organocatalysis, but also promotes the development of the pharmaceutical industry.

[0003] Chiral imides are widely found in natural products, pharmaceuticals, and biological intermediates, and possess broad-spectrum biological activities, such as antitumor and antibacterial activity. In addition, chiral imides can also serve as chiral auxiliaries and polymer precursors. Therefore, the rapid construction and bioactivity evaluation of chiral imides and their derivatives are of great significance. Summary of the Invention

[0004] The purpose of this invention is to provide a chiral imide derivative, its preparation method, and its application.

[0005] The present invention is achieved as follows: a chiral imide derivative having a structure as shown in general formula (I):

[0006]

[0007] In the formula, R1 is a benzene ring or a 2-4 substituted benzene ring; R2 is a benzene ring, a 2-4 substituted benzene ring, or a 1-naphthalene ring; R1 is a benzene ring, a 2-4 substituted benzene ring, or a 1-naphthalene ring.

[0008] The preparation method and synthetic route of chiral imide derivatives are as follows:

[0009]

[0010] In the formula, R1 is a benzene ring or a 2-4 substituted benzene ring; R2 is a benzene ring, a 2-4 substituted benzene ring, or a 1-naphthalene ring; R1 is a benzene ring, a 2-4 substituted benzene ring, or a 1-naphthalene ring.

[0011] The structures of NHC and (DHQD)2PYR are as follows:

[0012]

[0013] The application of the chiral imide derivative in the preparation of in vitro antitumor drugs, wherein the tumor is human lung cancer cells A549, human colon cancer cells LOVO or SW620.

[0014] By employing the above-mentioned technical approach, we designed a simple method for the one-step, efficient synthesis of chiral imine derivatives via NHC-catalyzed synthesis of imine and MBH carbonate. The bioactivity of these compounds was evaluated. The inhibitory rates of all compounds against three types of tumor cells—human lung cancer A549, human colon cancer LOVO, and SW620—increased with increasing concentration. Compounds 3g, 3i, 3j, and 3o showed particularly good inhibitory effects on all three tumor cell types. The inhibition rate against A549 cells reached 50% at a concentration of 12.5 μg / ml, and remained above 70% at 50.0 μg / ml. Compound 3j achieved an even higher inhibition rate of 85.8% against A549 cells, demonstrating its potential for further development and research. Attached Figure Description

[0015] Figure 1 This is a schematic diagram illustrating the synthesis principle of the present invention.

[0016] Figures 2-9 The proton, carbon, and HPLC spectra of the synthetic reaction products 3a and 3b of this invention are shown.

[0017] Figures 10-17 The 1H NMR, 1C NMR, and HPLC spectra of the synthesized products 4a and 4b of this invention are shown. Detailed Implementation

[0018] Embodiments of the present invention:

[0019] Examples of methods for preparing chiral imide derivatives are as follows, including the following steps:

[0020] (I) Synthesis of the reaction substrate imine 1a

[0021] (1) Synthesis of intermediate I

[0022] The reaction route is as follows:

[0023]

[0024] The reaction apparatus was placed under ice bath conditions. PhSO2Na (25 mmol, 1.5 equiv) was added to the reactor in sequence, followed by benzamide (25 mmol, 1.5 equiv) and 250 ml of acetonitrile solvent. Nitrogen protection was maintained. Stirring was continued under ice bath conditions. Then, benzaldehyde (16.7 mmol, 1.0 equiv) was added dropwise to the system. TMSCl (33.3 mmol, 2.0 eq) was slowly added to the apparatus. Stirring was continued at room temperature for 16 hours. After the reaction was completed, 250 ml of water was added to the reaction system and stirring was continued for 30 minutes. The mixture was filtered and dried to obtain a white solid intermediate I; (2) Synthesis of substrate imine 1a

[0025] In a 50 ml round-bottom flask, Cs2CO3 (10 mmol, 5.0 equiv.), Na2SO4 (10 mmol, 5.0 equiv.), and intermediate I (2 mmol, 1.0 equiv.) prepared in step (1) were added sequentially. After purging with nitrogen, CH2Cl2 (30 mL) solvent was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, petroleum ether (~40 mL) was added to the reaction system. The mixture was filtered through diatomaceous earth, and the diatomaceous earth was washed with petroleum ether (2 x 50 mL). The organic solvents were combined, and the reaction substrate imine 1a was obtained as a white solid under reduced pressure.

[0026] (II) Synthesis of reaction substrate 2a

[0027] (3) Synthesis of intermediate II

[0028] The reaction route is as follows:

[0029]

[0030] In a 50 mL round-bottom flask, benzaldehyde (5 mol, 1.0 equiv.), methyl acrylate (10 mmol, 2.0 equiv.), and DABCO (5 mol, 1.0 equiv.) were added sequentially. The reaction mixture was stirred at room temperature for 3 days. After the reaction was complete, 25 mL of H₂O and EtOAc (3 x 10 mL) were added to the mixture. The organic layers were combined, dried over anhydrous MgSO₄, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to obtain reaction intermediate II.

[0031] (4) Synthesis of reaction substrate 2a

[0032] The intermediate II (2 mmol, 1.0 equiv.) obtained in step (3) was placed in a 50 ml round-bottom flask, and then CH2Cl2 (25 ml), DMAP (10 mmol%, 0.1 equiv.) and (Boc)2O (2.4 mmol, 1.2 equiv.) were added. The mixture was stirred at room temperature for 30 minutes. TLC was used to track the reaction until intermediate I disappeared completely. The mixture was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 50:1) to obtain reaction substrate 2a.

[0033] Examples of the synthesis of 3a are as follows:

[0034]

[0035] The preparation method of chiral imide derivative 3a includes the following steps:

[0036] Add imine 1a (0.1 mmol, 1.0 equiv) and the pre-catalyst salt NHC-A (0.02 mmol, 0.2 equiv) sequentially to a dry vial equipped with a magnetic stir bar. MS (50.0 mg), K2CO3 (0.1 mmol, 1.0 equiv), (DHQD)2PYR (0.01 mmol, 0.1 equiv.), 2a (0.15 mmol, 1.5 equiv.), and DCE (1.0 mL). The reaction mixture was then stirred at 50 °C for 48 h until 1a was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 5:1) to obtain the desired product 3a. 3a was then purified by... 1 H NMR, 13 Its structure was confirmed by C NMR spectroscopy and HRMS.

[0037] Examples of the synthesis of 4a are as follows:

[0038]

[0039] The preparation method of chiral imide derivative 4a includes the following steps:

[0040] Add imine 1a (0.1 mmol, 1.0 equiv) and the pre-catalyst salt NHC-A (0.02 mmol, 0.2 equiv) sequentially to a dry vial equipped with a magnetic stir bar. MS (50.0 mg), K2CO3 (0.1 mmol, 1.0 equiv), (DHQD)2PYR (0.01 mmol, 0.1 equiv.), 2b (0.15 mmol, 1.5 equiv.), and DCE (1.0 mL). The reaction mixture was then stirred at 50 °C for 48 h until 1a was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 5:1) to obtain the desired product 4a. 4a was purified by... 1 H NMR, 13 Its structure was confirmed by C NMR spectroscopy and HRMS.

[0041] In step (1), the molar ratio of benzaldehyde, PhSO2Na, benzamide, and TMSCl is 1:1.5:1.5:2.0.

[0042] The molar ratio of intermediate I, Cs2CO3, and Na2SO4 in step (2) is 1.0:5.0:5.0.

[0043] The molar ratio of benzaldehyde, methyl acrylate, and DABCO in step (3) is 1.0:2.0:1.0.

[0044] The molar ratio of intermediate II, (Boc)2O, and DMAP in step (4) is 1.0:2.0:0.1.

[0045] The preparation method of reaction product 3a is as follows:

[0046] The synthetic route is as follows: Imine 1a (0.1 mmol, 1.0 equiv) and pre-catalyst salt NHC-A (0.02 mmol, 0.2 equiv) were added sequentially to a dry vial equipped with a magnetic stir bar. MS (50.0 mg), K2CO3 (0.1 mmol, 1.0 equiv), (DHQD)2PYR (0.01 mmol, 0.1 equiv.), 2a (0.15 mmol, 1.5 equiv.), and DCE (1.0 mL). The reaction mixture was then stirred at 50 °C for 48 h until 1a was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 5:1) to obtain the desired product 3a. 3a was then purified by... 1 HNMR, 13 Its structure was confirmed by C10 NMR spectroscopy and HRMS. Yield: 90% yield, white solid. mp: 111-112℃, [α] D 25= +74.1 (c = 1.0 in CHCl3)

[0047] 1 H NMR (400MHz, CDCl3): δ7.60-7.57(m,2H),7.38-7.35(m,6H),7.29(t,J=7.4Hz,1H),7.19(t,J=7.4Hz,2H) ,7.11-7.07(m,4H),6.93(t,J=1.8Hz,1H),6.54(d,J=0.9Hz,1H),5.71(d,J=1.5Hz,1H),3.73(s,3H).

[0048] 13 C NMR (100MHz, CDCl3): δ173.5,166.5,139.1,137.7,137.4,131.7,129.5,129.1,128.8,128.6,128.1,128.0,61.6,52.1.

[0049] HRMS (ESI,m / z):calcd.For C 25 H 22 NO4[M+H] + :400.1543,found:400.1542;

[0050] HPLC analysis :94%ee, [CHIRALPAK ODH column; 0.5mL / min; solvent system: i-PrOH / hexane=5:95; retention times: 24.2min (minor), 41.6min (major)].

[0051] The preparation method of reaction product 3b in Example 2 is as follows:

[0052] The synthetic route is as follows: Imine 1b (0.1 mmol, 1.0 equiv) and pre-catalyst salt NHC-A (0.02 mmol, 0.2 equiv) were added sequentially to a dry vial equipped with a magnetic stir bar. MS (50.0 mg), K2CO3 (0.1 mmol, 1.0 equiv), (DHQD)2PYR (0.01 mmol, 0.1 equiv.), 2a (0.15 mmol, 1.5 equiv.), and DCE (1.0 mL). The reaction mixture was then stirred at 50 °C for 48 h until 1a was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 5:1) to obtain the desired product 3b. 3b was purified by... 1 H NMR, 13 Its structure was confirmed by CNMR and HRMS. Yield: 89% yield, colorless oily liquid. [α] D 25 = +40.3 (c = 1.0 in CHCl3).

[0053] 1 H NMR (400MHz, CDCl3): δ7.61-7.53(m,2H),7.44-7.19(m,7H),7.17-7.07(m,3H),6.97-6.8 6(m,2H),6.71-6.64(m,1H),6.56(t,J=0.9Hz,1H),5.78(d,J=1.4Hz,1H),3.73(s,3H).

[0054] 13 C NMR (100MHz, CDCl3): δ173.2,168.2,166.5,160.0,157.5,138.8,137.3,136.7,133.1,133.0,132.0,129.9, 129.9,129.6,129.1,128.7,128.5,128.1,128.0,125.8,125.6,123.9,123.9,115.9,115.7,61.2,52.1.

[0055] HRMS (ESI,m / z):calcd.For C 25 H 21 FNO4[M+H] + :418.1449,found:418.1451;

[0056] HPLC analysis: 92%ee, [CHIRALPAK ODH column; 0.5mL / min; solvent system: i-PrOH / hexane=5:95; retention times: 26.0min (minor), 35.4min (major)].

[0057] Chiral imides and their derivatives prepared using this method are shown in Table 1:

[0058] Table 1. Structures of synthesized chiral imides and their derivatives

[0059]

[0060]

[0061] The preparation method of reaction product 4a in Example 3 is as follows:

[0062] The synthetic route is as follows: Imine 1a (0.1 mmol, 1.0 equiv) and pre-catalyst salt NHC-A (0.02 mmol, 0.2 equiv) were added sequentially to a dry vial equipped with a magnetic stir bar. MS (50.0 mg), K2CO3 (0.1 mmol, 1.0 equiv), (DHQD)2PYR (0.01 mmol, 0.1 equiv.), 2b (0.15 mmol, 1.5 equiv.), and DCE (1.0 mL). The reaction mixture was then stirred at 50 °C for 48 h until 1a was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 5:1) to obtain the desired product 4a. 4a was purified by... 1 HNMR, 13 Its structure was confirmed by C10 NMR spectroscopy and HRMS. Yield: 80% yield, colorless oily liquid. [α] D 25 = +182.8 (c = 1.0 in CHCl3)

[0063] 1 H NMR (400MHz, CDCl3): δ7.77(d,J=7.4Hz,1H),7.42-7.40(m,4H),7.27-7.14(m,5H),7.11 -7.04(m,5H),6.48(d,J=0.5Hz,1H),5.52(d,J=1.2Hz,1H),3.70(s,3H),2.42(s,3H).

[0064] 13 C NMR (100MHz, CDCl3): δ173.6,166.4,138.2,137.4,136.4,136.3,131.6,130.5,129.6,129.0,128.9,128.1,128.0,126.4,58.6,52.1,19.2.

[0065] HRMS (ESI,m / z):calcd.For C 26 H 24 NO4[M+H] + :414.1700, found:414.1703;

[0066] HPLC analysis :87%ee, [CHIRALPAK ODH column; 0.5mL / min; solvent system: i-PrOH / hexane=10:90; retention times: 13.2min (minor), 23.1min (major)].

[0067] The preparation method of reaction product 4b in Example 4 is as follows:

[0068] The synthetic route is as follows: Imine 1a (0.1 mmol, 1.0 equiv) and pre-catalyst salt NHC-A (0.02 mmol, 0.2 equiv) were added sequentially to a dry vial equipped with a magnetic stir bar. MS (50.0 mg), K2CO3 (0.1 mmol, 1.0 equiv), (DHQD)2PYR (0.01 mmol, 0.1 equiv.), 2c (0.15 mmol, 1.5 equiv.), and DCE (1.0 mL). The reaction mixture was then stirred at 50 °C for 48 h until 1a was completely consumed (monitored by TLC). The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 5:1) to give the desired product 4b. 4b was purified by... 1 H NMR, 13 Its structure was confirmed by CNMR and HRMS. Yield: 91%, white solid. mp: 65-66℃. [α] D 25 = +6.1 (c = 1.0 in CHCl3).

[0069] 1 H NMR (400MHz, CDCl3): δ7.59 (dd, J=7.6, 1.5Hz, 1H), 7.44-7.42 (m, 4H), 7.28-7.17 (m, 4H), 7.12-7.08 (m, 4H), 6.9 8(td,J=7.5,0.9Hz,1H),6.84(d,J=8.2Hz,1H),6.54(s,1H),5.84(d,J=1.0Hz,1H),3.77(s,3H),3.72(s,3H).

[0070] 13 C NMR (100MHz, CDCl3): δ173.4,166.4,156.7,138.5,137.4,131.5,130.5,129.3,128.9,128.4,128.0,125.7,120.6,110.5,56.3,55.3,52.1.

[0071] HRMS (ESI,m / z):calcd.For C 26 H 24 NO5[M+H] + :430.1649, found:430.1650;

[0072] HPLC analysis :94%ee, [CHIRALPAK ODH column; 0.5mL / min; solvent system: i-PrOH / hexane=20:80; retention times: 13.1min (minor), 34.4min (major)].

[0073] The chiral imides and their derivatives prepared using this method are shown in Table 2:

[0074] Table 2. Structures of synthesized chiral imides and their derivatives

[0075]

[0076]

[0077] Construction of chiral imide derivatives and their in vitro antitumor activity studies

[0078] The antitumor activity of the prepared partial chiral imide derivatives against human lung cancer cells A549, human colon cancer cells LOVO, and SW620 was preliminarily evaluated using the MTT assay. All five cell types in logarithmic growth phase were seeded into 96-well plates at a cell density of approximately 3 × 10⁻⁶ cells / well. 3 The drug concentrations were set at 12.5, 25.0, and 50.0 μg / mL per well. After 72 h of incubation, 10 μL of MTT was added to each well, and the cells were incubated at 37 °C for 4 h. The absorbance (OD value) of each well was measured at 568 nm using a microplate reader, and the cell inhibition rate of each test compound was calculated.

[0079] The results showed that the inhibitory rates of all compounds against the three types of tumor cells increased with increasing concentration. Among them, compounds 3g, 3i, 3j, and 3o showed good inhibitory effects on the three types of tumor cells, with an inhibition rate of 50% against A549 cells at a concentration of 12.5 μg / ml, and inhibition rates of over 70% at a concentration of 50.0 μg / ml. Compound 3j showed an even higher inhibition rate of 85.8% against A549 cells, indicating its value for further development and research.

[0080] Table 3. Inhibitory effects of compounds 3a-3j on different tumor cells.

[0081]

[0082] The foregoing has shown and described the basic principles and main features of the present invention, as well as its advantages. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a chiral imide derivative, characterized in that: The synthesis route is as follows: ， In the formula, R1 is a benzene ring or a 2-4 substituted benzene ring; R2 is a benzene ring, a 2-4 substituted benzene ring, or a 1-naphthalene ring; R3 is a benzene ring, a 2-4 substituted benzene ring, or a 1-naphthalene ring. The structures of NHC-A and (DHQD)2PYR are as follows: 。 2. The use of the chiral imide derivative as described in claim 1 in the preparation of in vitro antitumor drugs, characterized in that: The tumors described are human lung cancer cells A549, human colon cancer cells LOVO, or SW620.

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