Synthesis method of amino-protected alkyl trifluoromethyl quinoline structure and anti-tumor application of amino-protected alkyl trifluoromethyl quinoline structure

Abstract

The invention discloses an amino-protected alkyl trifluoromethyl quinoline structure in the field of organic synthesis and medicinal chemistry, trifluoropropene quinoline (A) and redox active ester (B) are used as raw materials, dimethyl sulfoxide is used as a solvent, dihydropyridine is used as an electron donor, and trifluoromethyl alkyl quinoline (C) is synthesized at high yield under visible light irradiation. The method comprises the following steps: taking trifluoromethyl alkyl quinoline (C) as a raw material, removing Boc under an acidic condition to obtain exposed amino alkyl trifluoromethyl quinoline (D), and reacting the compound (D) with benzyl chloroformate, benzenesulfonyl chloride or trifluoroacetic acid to obtain substituted trifluoromethyl alkyl quinoline (E). The specific reaction formula is as follows: # imgabs0. The compound provided by the invention has excellent anti-tumor activity and shows low toxicity to normal cells, so that the compound has an application prospect in preparation of anti-tumor drugs.

Description

Technical Field

[0001] The invention relates to the fields of organic synthesis and medicinal chemistry, and in particular to a synthesis method of an amino-protected alkyl trifluoromethyl quinoline structure and its anti-tumor application. Background Art

[0002] Tumors are one of the factors that seriously endanger human health and are currently the second leading cause of morbidity and mortality in the world. Anti-tumor treatments mainly include surgery, radiotherapy, chemotherapy, immunotherapy, etc. Chemotherapy is one of the most effective means of treating malignant tumors, and cisplatin is a classic chemotherapy drug for liver cancer. Platinum chemotherapy resistance is a key factor in poor prognosis and recurrence of liver cancer cells. Tumor cells that develop resistance to one chemotherapy drug will rapidly induce acquired tolerance to other chemotherapy drugs, ultimately leading to multidrug resistance. DNA damage repair and avoidance of apoptosis are the main factors that cause tumor cells to develop resistance to platinum drugs. Therefore, the development of new drugs or treatment strategies to alleviate or overcome platinum drug resistance in the treatment of liver cancer is a clinical problem that urgently needs to be solved.

[0003] Using the advantageous pharmacophore skeleton to construct heterocyclic small molecule pharmacological compounds is an economical and effective new drug synthesis strategy. Quinoline, as a multifunctional pharmacophore, is a multifunctional scaffold in medicinal chemistry and has broad pharmacological application prospects in anti-cancer, anti-inflammatory, antibacterial, and antiviral drugs. Therefore, how to use the quinoline multifunctional pharmacophore as a skeleton to prepare more anti-tumor compounds is of great significance for overcoming the toxicity and drug resistance problems of traditional platinum metal drugs. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention designs a quinoline compound containing a trifluoromethyl alkyl group and its analogues which are highly effective, low toxic and have good targeting.

[0005] One of the purposes of the present invention is to provide a compound represented by the following general formula E, a pharmaceutically acceptable salt thereof, a prodrug molecule thereof, a stereoisomer thereof or a tautomer thereof:

[0006]

[0007] wherein the number of n is 2 or 3; R is benzyloxycarbonyl, benzenesulfonyl, or trifluoroacetyl;

[0008] Specifically, the compound of general formula E is one selected from the following compounds:

[0009]

[0010] The second object of the present invention is to provide a method for synthesizing the above-mentioned compound. The specific reaction formula is as follows:

[0011]

[0012] wherein the number of n is 2 or 3; R is benzyloxycarbonyl, benzenesulfonyl, or trifluoroacetyl;

[0013] Specifically, trifluoropropylenequinoline (A) and redox-active ester (B) are used as raw materials, dimethyl sulfoxide is used as a solvent, and dihydropyridine is used as an electron donor. Trifluoromethylalkylquinoline (C) is synthesized in high yield under visible light irradiation. Trifluoromethylalkylquinoline (C) is used as a raw material, and Boc is removed under acidic conditions to obtain exposed aminoalkyltrifluoromethylquinoline (D). Compound (D) is then reacted with benzyl chloroformate, benzenesulfonyl chloride or trifluoroacetic acid to obtain substituted trifluoromethylalkylquinoline (E).

[0014] Furthermore, the molar ratio of the compound of formula A to the compound of formula B is 1:1 to 3, preferably 1:2.

[0015] Furthermore, the compound of formula A and the compound of formula B are selected from the following groups:

[0016]

[0017] Furthermore, the reaction is carried out at 0 to 50°C, preferably 30°C.

[0018] Furthermore, the visible light is blue light, and the wavelength is preferably 430 to 490 nm.

[0019] The third object of the present invention is to provide the use of the compound, its pharmaceutically acceptable salt, its prodrug molecule, its stereoisomer or its tautomer in the preparation of anti-tumor drugs.

[0020] Furthermore, the tumor is liver cancer.

[0021] The working principle and beneficial effects of the present invention: The synthesis method of the present invention is simple, can react under light conditions and 0-50°C, is economical and efficient, and takes a short time, with a yield of up to 98%. The synthesized compound has been confirmed by activity tests to have significant anti-tumor activity and very low toxicity to normal cells. It has application in the preparation of anti-liver cancer drugs and has great development value.

[0022] Terminology: As used herein, the term "C 1-15 The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 15 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl or the like.

[0023] The term "C 1-15The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 15 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or the like.

[0024] The term "halogen" refers to fluorine, chlorine, bromine or iodine. DETAILED DESCRIPTION

[0025] The following is further described in detail through specific implementation methods:

[0026] The present invention provides a synthesis of a quinoline structure containing a trifluoromethyl alkyl group and its anti-tumor application, as follows:

[0027] With trifluoropropylenequinoline (A) and redox-active ester (B) as raw materials, dimethyl sulfoxide as solvent and dihydropyridine as electron donor, trifluoromethylalkylquinoline (C) is synthesized in high yield under visible light irradiation. With trifluoromethylalkylquinoline (C) as raw material, Boc is removed under acidic conditions to obtain exposed aminoalkyltrifluoromethylquinoline (D). Compound (D) is then reacted with benzyl chloroformate, benzenesulfonyl chloride or trifluoroacetic acid to obtain substituted trifluoromethylalkylquinoline (E).

[0028] The specific reaction formula is as follows:

[0029]

[0030] In the above reaction formula, R and n are as defined above.

[0031] In the reaction formula, compounds A and B are selected from the following groups:

[0032]

[0033] The compounds of formula A and formula B of the present invention can be prepared by commercially available methods or methods well known to those skilled in the art to which the present invention belongs. However, the specific conditions of the method, such as reactants, solvents, amounts of compounds used, reaction temperature, time required for reaction, etc., are not limited to the following explanation.

[0034] The compound of formula C prepared by the present invention can be further modified as needed to prepare various functional compounds.

[0035] The product obtained by the preparation method of the present invention can be separated and purified by a variety of methods, including recrystallization, column chromatography, etc. The above purification methods are all conventional methods in the art. For example, when performing recrystallization, a mixed solvent of a polar solvent and a non-polar solvent can be used, preferably a mixed solvent such as ethyl acetate-petroleum ether, ethanol-petroleum ether, etc. When using column chromatography, the developing solvent used can be a single solvent or a mixed solvent, such as petroleum ether or a mixed solvent of ethyl acetate-petroleum ether, etc.

[0036] The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0037] In the following examples, conventional post-treatment methods in the art were used for purification.

[0038] Example 1

[0039]

[0040] Compound B-1 (1.45 g, 4 mmol, 2.0 equiv.) and Hantzsch ester ((1.52 g, 6 mmol, 3.0 equiv.)) were added to a 100 mL reaction bottle. After argon replacement three times, DMSO (20.0 mL) and A (0.45 mg, 2 mmol) were added. Under blue light (430-490 nm), the mixture was stirred at 30 ° C for 24 h to obtain compound C-1 with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ8.89(dd,J=4.4Hz,1.6Hz,1H),8.14(d,J=8.4Hz,1H),8.11(d,J=8.8Hz,1H),7.70(s,1H),7.62(d,J=8.8Hz,1H),7.40(dd, J=8.4Hz,4.4Hz,1H),4.60(bs,1H),3.45–3.33(m,1H),3.04–2.97(m,2H ),2.10–2.00(m,1H),1.99–1.89(m,1H),1.38(s,9H),1.36–1.07(m,6H).

[0041] Step 1: Add compound C-1 (1.8 mmol) to a 50 mL eggplant-shaped bottle, add 4M HCl·Dioxane solution (18 mL) dropwise at 0°C, add MeOH (2 mL), stir for 30 min after slow addition, and then stir at room temperature for 4 h. The solvent was dried to obtain the hydrochloride, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, extracted with DCM to obtain the crude product, and purified by column chromatography to obtain compound D-1.

[0042] Step 2: Add DCM (2 mL) and Et3N (24.3 mg, 0.24 mmol, 1.2 equiv.) to a 25 mL reaction tube at 0°C, add D-1 (0.22 mmol, 1.1 equiv.) under stirring, slowly drop benzyl chloroformate (34.1 mg, 0.2 mmol), and after the addition, heat the mixture from 0°C to room temperature and stir until the reaction is complete. Quench with 1.0 M hydrochloric acid, extract with DCM 3 times, collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, and purify with column chromatography to obtain compound E-1 (yield 60%).

[0043] 1 H NMR (400MHz, CDCl3) δ8.90(d,J=2.8Hz,1H),8.15–8.09(m,2H),7.70(s,1H),7.62(d,J=8.8Hz,1H),7.39(dd,J=8.4Hz,4.0Hz,1H),7.34–7.25(m, 5H),5.11–5.03(m,1H),5.06(s,1H),5.00–4.92(m,1H),3.47–3.33(m,1H ),3.11(dd,J=13.2Hz,6.8Hz,2H),2.12–1.89(m,2H),1.45–1.05(m,6H).

[0044] Example 2

[0045]

[0046] Compound B-2 (2.8 g, 8 mmol, 2.0 equiv.) and Hantzsch ester (3.0 g, 12 mmol, 3.0 equiv.) were added to a 100 mL reaction tube, and DMSO (40 mL) and A (0.9 g, 4 mmol) were added after argon replacement three times. Under blue light (430-490 nm), the mixture was stirred at 30 ° C for 24 h to obtain compound C-2 with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ8.94(dd,J=4.4Hz,2.0Hz,1H),8.19(d,J=8.0Hz,1H),8.16(d,J=8.8Hz,1H),7.74(s,1H),7.66(d,J=8.8Hz,1H),7.46(d, J=8.4Hz,4.4Hz,1H),4.44(s,1H),3.49–3.36(m,1H),3.08–2.97(m,2H) ,2.16–1.94(m,2H),1.57–1.41(m,2H),1.37(s,9H),1.27–1.14(m,2H).

[0047] Step 1: Add compound C-2 (1.8 mmol) to a 50 mL eggplant-shaped bottle, add 4M HCl·Dioxane solution (18 mL) dropwise at 0°C, add MeOH (2 mL), stir for 30 min after slow addition, and then stir at room temperature for 4 h. The solvent was dried to obtain the hydrochloride, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, extracted with DCM to obtain the crude product, and purified by column chromatography to obtain compound D-2.

[0048] Step 2: Add DCM (2 mL) and Et3N (24.3 mg, 0.24 mmol, 1.2 equiv.) to a 25 mL reaction tube at 0°C, add D-2 (0.22 mmol, 1.1 equiv.) under stirring, slowly drop benzenesulfonyl chloride (35.3 mg, 0.2 mmol), and after the addition, heat the mixture from 0°C to room temperature and stir until the reaction is complete. Quench with 1.0 M hydrochloric acid, extract with DCM 3 times, collect the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, and purify with column chromatography to obtain compound E-2 (yield 65%).

[0049] 1 H NMR (400MHz, CDCl3) δ8.87 (dd, J=4.0Hz, 1.6Hz, 1H), 8.13 (d, J=8.0Hz, 1H), 8.05 (d, J=8.8Hz,1H),7.77(d,J=7.6Hz,2H),7.68(d,J=0.8Hz,1H),7.55(d,J=8.4Hz,1H),7 .52–7.46(m,1H),7.44–7.36(m,3H),5.44(t,J=6.2Hz,1H),3.40–3.27(m,1H),2.83 (dd,J=13.2Hz,6.8Hz,2H),2.00–1.84(m,2H),1.54–1.35(m,2H),1.21–1.04(m,2H).

[0050] Example 3

[0051]

[0052] Compound B-2 (2.8 g, 8 mmol, 2.0 equiv.) and Hantzsch ester (3.0 g, 12 mmol, 3.0 equiv.) were added to a 100 mmL reaction tube, and DMSO (40 mL) and A (0.9 g, 4 mmol) were added after argon replacement three times. Under blue light (430-490 nm), the mixture was stirred at 30 ° C for 24 h to obtain compound C-2 with a yield of 62%. 1H NMR (400MHz, CDCl3) δ8.94(dd,J=4.4Hz,2.0Hz,1H),8.19(d,J=8.0Hz,1H),8.16(d,J=8.8Hz,1H),7.74(s,1H),7.66(d,J=8.8Hz,1H),7.46(d, J=8.4Hz,4.4Hz,1H),4.44(s,1H),3.49–3.36(m,1H),3.08–2.97(m,2H) ,2.16–1.94(m,2H),1.57–1.41(m,2H),1.37(s,9H),1.27–1.14(m,2H).

[0053] Step 1: Add compound C-2 (1.8 mmol) to a 50 mL eggplant-shaped bottle, add 4M HCl·Dioxane solution (18 mL) dropwise at 0°C, add MeOH (2 mL), stir for 30 min after slow addition, and then stir at room temperature for 4 h. The solvent was dried to obtain the hydrochloride, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, extracted with DCM to obtain the crude product, and purified by column chromatography to obtain compound D-2.

[0054] Step 2: Add trifluoroacetic acid (22.8 mg, 0.2 mmol), EDCI (46.0 mg, 0.24 mmol, 1.2 equiv.), HOBt (32.4 mg, 0.24 mmol, 1.2 equiv.) to a 25 mL reaction tube, add ultra-dry DCM (2 mL), dropwise add Et3N (50.6 mg, 0.5 mmol, 2.5 equiv.), stir for half an hour, add D-2 (0.24 mmol, 1.2 equiv.), seal the reaction system, and stir until the reaction is complete. Compound E-3 is obtained with a yield of 60%.

[0055] 1 H NMR (400MHz, CDCl3) δ8.90(dd,J=4.4Hz,1.6Hz,1H),8.16(d,J=8.4Hz,1H),8.09(d,J=8.8Hz,1H),7.72(d,J=1.2Hz,1H),7.62(d,J=8.8Hz,1H), 7.43(dd,J=8.4Hz,4.4Hz,1H),6.86(s,1H),3.48–3.35(m,1H),3.26(q, J=6.8Hz,2H),2.15–1.95(m,2H),1.68–1.48(m,2H),1.32–1.14(m,2H)..

[0056] Activity test of trifluoromethyl alkylquinoline and its analogs

[0057] Cell lines and solvents

[0058] Human hepatocellular carcinoma Huh-7 cells;

[0059] Human lung cancer A549 cells;

[0060] Cells were cultured in RPMI1640 medium containing 10% fetal bovine serum;

[0061] Solvent: dimethyl sulfoxide (DMSO for short).

[0062] Implementation plan for detecting cell anti-tumor activity by CCK-8 staining

[0063] The cells with a live cell ratio of more than 90% were selected for the experiment. The cell proliferation inhibition test was performed using the EnoGeneCellTM Counting Kit-8 (abbreviated as CCK-8) cell viability detection kit. Human liver cancer Huh-7 cells and human lung cancer A549 cells in the logarithmic growth phase were taken, the culture medium was discarded, PBS was rinsed twice, trypsinized, centrifuged, the cells were resuspended in the culture medium, and 5×10 4 Each well was inoculated in parallel in a 96-well plate. The 96-well plate was placed in a 37°C, 5% CO2 incubator for 8 hours and then taken out. A 4μM culture solution of the compound to be tested was added to each well. A negative control group, a solvent control group, and a positive control group (the positive controls were sorafenib and cisplatin, respectively) were set up at the same time. Each group was repeated 3 times. After continuing to culture in a 37°C, 5% CO2 incubator for 48 hours, 10μL CCK-8 solution was added to each well. After the culture plate was incubated in the incubator, the absorbance value (OD value) at 450nm was measured with an enzyme marker. The experimental group and the control group were repeated 3 times to calculate the proliferation inhibition rate of each compound on human liver cancer cell Huh-7. The experimental results are shown in Table 1.

[0064] Table 1: Inhibition rate of proliferation of human liver cancer Huh-7 cells

[0065] Compound Huh-7 inhibition rate (%) E-1 32 E-2 42 E-3 33 Sorafenib 30

[0066] Table 2: Proliferation inhibition rate of human lung cancer A549 cells

[0067] Compound A549 inhibition rate (%) E-1 18 E-2 2 Cisplatin 38

[0068] The experimental results in Table 1 and Table 2 show that the compounds E-1, E-2 and E-3 of the present invention have significant in vitro anti-tumor activity and significant inhibitory activity against human liver cancer cell Huh-7. Therefore, the above compounds are suitable anti-tumor drug candidates.

[0069] The above is only an embodiment of the present invention, and the common knowledge such as the known specific structure and characteristics in the scheme is not described in detail here. It should be pointed out that for those skilled in the art, several deformations and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A compound represented by the following general formula E, a pharmaceutically acceptable salt thereof, a prodrug molecule thereof, a stereoisomer thereof or a tautomer thereof: in, The number of n is 2 or 3; R is benzyloxycarbonyl, benzenesulfonyl or trifluoroacetyl.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its prodrug molecule, its stereoisomer or its tautomer, characterized in that: The compound of general formula E is one selected from the following compounds:

3. The method for synthesizing the compound according to claim 1, characterized in that: The specific reaction formula is as follows: wherein the number of n is 2 or 3; R is benzyloxycarbonyl, benzenesulfonyl, or trifluoroacetyl; Trifluoropropylenequinoline (A) and redox-active ester (B) are used as raw materials, dimethyl sulfoxide is used as solvent, and dihydropyridine is used as electron donor to synthesize trifluoromethylalkylquinoline (C) in high yield under visible light irradiation; trifluoromethylalkylquinoline (C) is used as raw material, and Boc is removed under acidic conditions to obtain exposed aminoalkyltrifluoromethylquinoline (D), and compound (D) is then reacted with benzyl chloroformate, benzenesulfonyl chloride or trifluoroacetic acid to obtain substituted trifluoromethylalkylquinoline (E).

4. The synthesis method according to claim 2, characterized in that: The molar ratio of the compound of formula A to the compound of formula B is 1:1-3.

5. The synthesis method according to claim 3 or 4, characterized in that: The reaction is carried out at 0-50°C.

6. The synthesis method according to claim 5, characterized in that: Visible light is blue light.

7. Use of the compound according to claim 1 or 2, its pharmaceutically acceptable salt, its prodrug molecule, its stereoisomer or its tautomer in the preparation of anti-tumor drugs.

8. The use according to claim 7, characterized in that: The tumor is liver cancer or lung cancer.

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