Trifluoromethylnarcotine derivatives and preparation methods and applications thereof

Abstract

The present invention discloses a trifluoromethylnarcotine derivative, its preparation method, and application. The method aims to prepare N-trifluoromethylnarcotine using a four-step reaction consisting of m-chloroperbenzoic acid-mediated oxidation, ferrous sulfate-mediated reduction, thiofluoroformylation, and silver fluoride-mediated fluorination. Furthermore, 9′-halogenated and alkyl-substituted N-trifluoromethylnarcotine derivatives are prepared through a halogenation reaction and a photonickel-catalyzed reductive coupling reaction. The antitumor activity of these newly synthesized derivatives is investigated through multiple experiments.

Description

Technical Field

[0001] The present invention relates to the synthesis of a new class of N-trifluoromethylnarcotine derivatives and their application in the anti-tumor field, belonging to the field of medical technology. Background Art

[0002] Environmental pollution and changes in human lifestyles have led to a year-on-year increase in the incidence of malignant tumors, posing a serious threat to human health. The latest statistics released by the World Health Organization show that in 2020, there were 19.29 million new cases of malignant tumors worldwide and 9.96 million new deaths, with a mortality rate of 50%.

[0003] Small molecule drugs are one of the mainstays of combating malignant tumors. Commonly used anti-tumor drugs in clinical practice primarily include cytotoxic drugs and targeted drugs. However, cytotoxic drugs often exhibit significant side effects, severely impacting patients' quality of life. Targeted drugs, on the other hand, exhibit increasing drug resistance, creating a bottleneck in their clinical application. Therefore, the development of highly effective, low-toxic, and high-therapeutic-index anti-tumor drugs is urgently needed to address this challenge.

[0004] Noscapine is a phthalide tetrahydroisoquinoline alkaloid derived from the opium poppy. It has a simple structure, is abundant, and is inexpensive. It was first widely used clinically as an over-the-counter cough suppressant and can be taken orally. In 1998, it was discovered to exhibit moderate inhibitory activity against various malignant tumor cells, such as lung and colon cancer cells. Its mechanism of action is generally believed to be a tubulin inhibitor, binding to tubulin and disrupting microtubule homeostasis, causing tumor cells to arrest in the G2 / M phase of mitosis and undergo apoptosis, thus producing its anti-tumor effects. However, as a tubulin inhibitor, noscapine exhibits no significant side effects and, instead, effectively overcomes the widespread drug resistance to this class of anti-tumor drugs in clinical practice. It can also cross the blood-brain barrier, making it a promising anti-tumor drug lead.

[0005] The introduction of fluorine atoms, also known as fluorine substitution, not only effectively modulates the lipophilicity and acidity of drug molecules but also effectively improves their metabolic stability by blocking metabolic sites and reducing electron cloud density, thereby affecting their in vivo efficacy by influencing their pharmacokinetic properties. Furthermore, the introduction of fluorine atoms can also enable drug molecules to acquire additional dipole-dipole and hydrogen bonding interactions, thereby enhancing their affinity for target proteins and directly influencing their efficacy. Therefore, fluorine substitution has become a common strategy in drug design.

[0006] This study, dedicated to modifying the druggable structure of Noscapine, utilized a fluorine substitution strategy to replace the N-methyl group in Noscapine with a trifluoromethyl group. Combined with the introduction of diverse hydrophobic groups at the 9′ position, this led to the design and synthesis of a class of novel Noscapine derivatives. These derivatives, with their novel structures, generally exhibit superior antitumor activity to Noscapine and exhibit excellent chemical stability under neutral and alkaline conditions, laying the foundation for the development of new antitumor drugs. Summary of the Invention

[0007] The present invention aims to prepare N-trifluoromethylnarcotine by using a four-step reaction of m-chloroperbenzoic acid-mediated oxidation, ferrous sulfate-mediated reduction, thiofluoroformylation, and silver fluoride-mediated fluorination, and further prepare 9'-halogenated and alkyl-substituted N-trifluoromethylnarcotine derivatives through a halogenation reaction and a photo-nickel-co-catalyzed reductive coupling reaction, and study the anti-tumor activity of these newly synthesized derivatives.

[0008] The general structural formula of the compound of the present invention is as follows:

[0009]

[0010] In the general structural formula, R 1 The group represents a trifluoromethyl group;

[0011] In the general structural formula, R 2 The group is hydrogen, halogen, alkyl, azaalkyl, cycloalkyl, bridged cycloalkyl, oxacycloalkyl, azacycloalkyl, cycloalkylmethyl, oxacycloalkylmethyl, azacycloalkylmethyl; wherein:

[0012] The halogen is fluorine, chlorine, bromine, or iodine;

[0013] The alkyl group is a C2-C8 alkyl group or a deuterated alkyl group;

[0014] The azaalkyl group is a C2-C8 azaalkyl group or a deuterated azaalkyl group;

[0015] The cycloalkyl group is a C3-C10 cycloalkyl group or a deuterated cycloalkyl group;

[0016] The bridged cycloalkyl group is a C5-C12 bridged cycloalkyl group or a deuterated bridged cycloalkyl group;

[0017] The oxacycloalkyl group is a C3-C7 oxacycloalkyl group or a deuterated oxacycloalkyl group;

[0018] The azacycloalkyl group is a C3-C7 azacycloalkyl group or a deuterated azacycloalkyl group;

[0019] The cycloalkylmethyl group and the cycloalkyl group are C3-C10 cycloalkyl groups or deuterated cycloalkyl groups;

[0020] The oxacycloalkylmethyl group and the oxacycloalkyl group are C3-C7 oxacycloalkyl groups or deuterated oxacycloalkyl groups;

[0021] The azacycloalkylmethyl group and the azacycloalkyl group are C3-C7 azacycloalkyl groups or deuterated azacycloalkyl groups.

[0022] Furthermore, the compound has the following structure:

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029] Furthermore, the Narcotine derivatives of the present invention are obtained by the following preparation method:

[0030]

[0031] The present invention also provides a method for preparing the above derivative, which comprises the following steps:

[0032] 1) Synthesis of key intermediates: Oxidation of narcotine with m-CPBA to generate narcotine N-oxide intermediate I, followed by FeSO4 reduction to remove the nitrogen methyl group to obtain key intermediate II;

[0033] 2) Trifluoromethylation: Intermediate II is fluorinated using DAST as a fluorination reagent to obtain intermediate N-thiofluoroformylnarcotine III, which is further reacted with silver fluoride and desulfurized to produce N-trifluoromethylnarcotine S1;

[0034] 3) Halogenation reaction: Halogenate S1 with NCS and NBS to obtain compounds S2-S3 respectively.

[0035] 4) Photo-nickel synergistic catalytic coupling reaction: S3 is reductively coupled with alkyl bromide under the synergistic catalysis of photo-nickel to prepare S4-S22. DETAILED DESCRIPTION

[0036] Example 1: Synthesis of Compound S1

[0037] Narcotine (2.48 g, 6 mmol, 1.0 equiv) was dissolved in 62 mL of chloroform, and m-chloroperoxybenzoic acid (2.07 g, 12 mmol, 2.0 equiv) was added in portions at -5°C. The reaction was stopped after 5 h, 125 mL of glacial chloroform and 20 mL of glacial isopropanol were added to the system, and the system was washed with 70 mL of 10% glacial sodium hydroxide solution, 140 mL of ice water, and 70 mL of 10% hydrochloric acid aqueous solution in sequence, dried over anhydrous sodium sulfate, filtered, concentrated and dried by rotary evaporation. The crude product was dissolved in 57 mL of methanol, and ferrous sulfate heptahydrate (3.33 g, 12 mmol, 2.0 equiv) was added at -5°C. The reaction was continued for 12 h, and the methanol was removed by rotary evaporation. The crude product was dissolved in 125 mL of chloroform and washed with 0.1 mol / L ethylenediaminetetraacetic acid aqueous solution (3×60 mL) and 1 mol / L sodium hydroxide aqueous solution (2×60 mL). The mixture was stirred for 2 h at 4 °C for 3 h. ... 1 H NMR (400MHz, CDCl3) δ7.04 (d, J = 8.3Hz, 1H), 6.46 (d, J = 8.2Hz, 1H),6.35(s,1H),5.94(s,2H),5.75(d,J=4.5Hz,1H),5.05(d,J=4.5Hz,1H),4.09(s,3H), 4.00(s,3H),3.88(s,3H),3.11–3.05(m,1H),2.75–2.67(m,1H),2.44–2.38(m,1H),2.25– 2.29(m,1H). 19 F NMR(376MHz,CDCl3)δ-60.1.HRMS(ESI)Calcd.for C 22 H 20 F3NNaO7 + [(M+Na) + ]490.1090,found 490.1091.

[0038] Example 2: Synthesis of Compound S2

[0039] Compound S1 (47 mg, 0.1 mmol, 1.0 equiv) was dissolved in 1 mL of DCM, and NCS (13 mg, 0.1 mmol, 1.0 equiv) was added. The reaction was allowed to react for 3 h, and the mixture was extracted three times with water and dichloromethane. The mixture was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and dried, and purified by flash silica gel column chromatography (PE:EA=3:1) to obtain S2 (36 mg, 72%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.07 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H),6.04(d,J=1.6Hz,2H),5.69(d,J=4.8Hz,1H),5.02(d,J=4.8Hz,1H),4.10(s,3H),3.9 8(s,3H),3.89(s,3H),3.27–3.22(m,1H),2.70–2.61(m,1H),2.57–2.51(m,1H),2.45–2.38 (m,1H). 19 FNMR (376MHz,CDCl3)δ-60.2. 13 C NMR (100MHz, CDCl3) δ167.4,152.8, 148.4,145.8,140.0,138.8,127.3,118.9,118.6,117.5,116.7,107.3,101.7,78.9,62.5,59.6,52.2, 37.9,23.3.HRMS(ESI)Calcd.for C 22 H 19 ClF3NNaO7 + [(M+Na) + ]524.0700,found 524.0702.

[0040] Example 3: Synthesis of Compound S3

[0041] Compound S1 (47 mg, 0.1 mmol, 1.0 equiv) was dissolved in 1 mL of DCM and NBS (18 mg, 0.1 mmol, 1.0 equiv), and the mixture was reacted for 3 h. Water and dichloromethane were added, and the mixture was extracted three times. The mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and dried, and purified by flash silica gel column chromatography (PE:EA=3:1) to obtain S3 (38 mg, 70%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ7.07(d,J=8.2Hz,1H),6.56(d,J=8.2Hz,1H),6.03 (d,J=2.9Hz,2H),5.68(d,J=4.8Hz,1H),5.01(d,J=4.8Hz,1H),4.10(s,3H),3.98(s,3H), 3.89(s,3H),3.26–3.21(m,1H),2.68–2.60(m,1H),2.54–2.45(m,1H),2.45–2.39(m,1H). 19 F NMR(565MHz,CDCl3)δ-60.3.HRMS(ESI)Calcd.for C 22 H 19 BrF3NNaO7 + [(M+Na) + ]568.0195,found568.0200.

[0042] Example 4: Synthesis of Compound S4

[0043] Compound S3 (54 mg, 0.1 mmol, 1.0 equiv), ethyl bromide (22 μL, 0.3 mmol, 3.0 equiv), TTMSS (30.8 μL, 0.1 mmol, 1.0 equiv), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.12 mg, 1.0 μmol, 0.01 equiv) and anhydrous Na2CO3 (21 mg, 0.2 mmol, 2.0 equiv) were added to a dry reaction bottle equipped with a magnetic stirrer. The bottle was sealed with a septum-lined screw cap, evacuated and backfilled with nitrogen three times, and then 0.8 mL of DME solution was added via syringe and mixed evenly. NiCl2·glyme (2 mg, 10.0 μmol, 0.1 equiv) and dtbpy (2.7 mg, 10.0 μmol, 0.1 equiv) were added to another dry reaction vial, which was sealed with a septum nut. 0.4 mL of DME solution was added via syringe and mixed thoroughly. A long needle connected to a nitrogen balloon was inserted through the septum below the liquid level of the reaction vial, and then a short needle was inserted for ultrasonic bubbling degassing. After 5 minutes, 0.2 mL of the mixed solution was added to the reaction vial containing the sample vial via syringe, and ultrasonic bubbling degassing was continued through the long needle connected to the nitrogen balloon. After 10 minutes, the sealed reaction vial was illuminated with a 34 W blue LED and cooled by a fan to maintain the reaction temperature at 25°C. After 24 h, the reaction mixture was quenched by exposing it to air and extracted with ethyl acetate. The crude product was separated by silica gel column chromatography using a specific elution system (PE:EA = 3:1) to obtain S4 (12 mg, 24%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.02 (d, J = 8.2Hz, 1H), 6.47 (d,J=8.2Hz,1H),5.93(s,2H),5.71(d,J=4.8Hz,1H),5.07(d,J=4.8Hz,1H),4.09(s,3H), 3.95(s,3H),3.87(s,3H),3.13–3.07(m,1H),2.68–2.59(m,1H),2.56–2.51(m,2H),2.44– 2.38(m,2H),1.10(t,J=7.5Hz,3H). 13C NMR (150MHz, CDCl3) δ166.6,151.6,147.2,146.1, 139.1,137.0,132.6,126.6,118.1,117.5,117.2,116.9,116.4,114.1,99.7,78.4,61 .5,59.4,58.4,55.8,51.2,37.7,30.9,28.7,28.3,21.6,20.1,17.8,13.2,13.1,12.9. 19 F NMR(376MHz,CDCl3)δ -60.4.HRMS(ESI)Calcd.for C 24 H 24 F3NNaO7 + [(M+Na) + ]518.1403,found 518.1404.

[0044] Example 5: Synthesis of Compound S5

[0045] Ethyl bromide was replaced by propyl bromide in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S4 to give yellow solid S5 (12 mg, 22%). 1 H NMR (400MHz, CDCl3) δ7.01 (d, J = 8.3Hz, 1H), 6.46 (d, J = 8.2Hz, 1H),5.92(d,J=1.8Hz,2H),5.70(d,J=4.8Hz,1H),5.07(d,J=4.8Hz,1H),4.09(s,3H),3.95(s,3H),3.87(s,3H),3. 11–3.06(m,1H),2.63–2.57(m,1H),2.51–2.46(m,2H),2.42–2.36(m,2H),1.54–1.46(m,2H),0.94(t,J=7.4Hz,3H). 19 F NMR(376MHz,CDCl3)δ-60.4. HRMS(ESI)Calcd.for C 25 H 26 F3NNaO7 + [(M+Na) + ]532.1559,found 532.1558.

[0046] Example 6: Synthesis of Compound S6

[0047] Ethyl bromide was replaced by N-Boc-bromoethylamine at the same equivalent ratio. The remaining reagents and procedures were the same as those for the synthesis of S4 to give yellow solid S6 (26 mg, 43%).1 H NMR (600MHz, CDCl3) δ7.10 (d, J = 8.3Hz, 1H), 6.58 (d, J = 8.2 Hz,1H),5.91(dd,J=5.2,1.3Hz,2H),5.67(d,J=4.6Hz,1H),5.06(d,J=4.6Hz,1H),4.77(s,1 H),4.07(s,3H),3.91(s,3H),3.89(s,3H),3.29–3.22(m,2H),3.11–3.08(m,1H),2.78–2.65 (m,3H),2.56–2.48(m,2H),1.42(s,9H). 19 F NMR(565MHz,CDCl3)δ-60.7.HRMS(ESI)Calcd.for C 29 H 33 F3N2NaO9 + [(M+Na) + ]633.2306,found 633.2305.

[0048] Example 7: Synthesis of Compound S7

[0049] Ethyl bromide was replaced by 1-bromobutane in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S4 to give yellow solid S7 (13 mg, 25%). 1 H NMR (400MHz, CDCl3) δ7.00(d,J=8.3Hz,1H),6.44(d,J=8.2Hz,1H),5.93(d,J=2.0Hz,2H),5.71(d,J=4.8Hz,1H),5.07(d,J =4.8Hz,1H),4.09(s,3H),3.96(s,3H),3.87(s,3H),3.12–3.07(m,H),2.63–2.57(m,H),2.54–2.46(m,2H),2.41–2.35(m, 2H),1.48–1.40(m,2H),1.38–1.31(m,2H),0.93(t,J=7.2Hz,3H). 19 F NMR(376MHz,CDCl3)δ-60.4.HRMS(ESI)Calcd.for C 26 H 28 F3NNaO7 + [(M+Na) + ]546.1716,found 546.1717.

[0050] Example 8: Synthesis of Compound S8

[0051] Ethyl bromide was replaced by 1-bromo-4,4,4-trifluorobutane at the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S4 to give yellow solid S8 (22 mg, 38%). 1 H NMR (400MHz, CDCl3) δ7.00 (d, J = 8.3Hz, 1H), 6.41 (d, J=8.2Hz,1H),5.93(dd,J=6.6,1.3Hz,2H),5.69(d,J=4.7Hz,1H),5.07(d,J=4.7Hz,1H),4.08(s,3H),3.96(s,3 H),3.86(s,3H),3.14–3.09(m,1H),2.62–2.57(m,3H),2.43–2.33(m,2H),2.14–2.04(m,2H),1.79–1.71(m,2H). 19 F NMR(565MHz, CDCl3)δ-60.5,-66.1,-66.2, -66.2.HRMS(ESI)Calcd.for C 26 H 26 F6NO7 + [(M+H) + ]578.1613,found 578.1614.

[0052] Example 9: Synthesis of Compound S9

[0053] Ethyl bromide was replaced by N-Boc-3-aminopropyl bromide at the same equivalent ratio. The remaining reagents and operations were the same as those for the synthesis of S9 to give yellow solid S9 (23 mg, 36%). 1 H NMR (400MHz, CDCl3) δ7.08 (d, J = 8.2Hz, 1H), 6.47 (d, J=8.2Hz,1H),5.92(d,J=2.7Hz,2H),5.69(d,J=4.6Hz,1H),5.06(d,J=4.6Hz,1H),4.72(s,1H),4.07(s,3H),3.9 4(s,3H),3.87(s,3H),3.11–3.06(m,3H),2.63–2.48(m,3H),2.40–2.37(m,2H),1.71–1.65(m,2H),1.42(s,9H). 19 F NMR(565MHz,CDCl3)δ-60.5.HRMS(ESI)Calcd.for C 30 H 35 F3N2NaO9 + [(M+Na) +]647.2192,found 647.2191.

[0054] Example 10: Synthesis of Compound S10

[0055] Ethyl bromide was replaced with 1-bromo-2-methylbutane in the same equivalent ratio. The remaining reagents and procedures were the same as those for the synthesis of S10 to give yellow solid S10 (13 mg, 24%, dr = 3:1). Major diastereomers: 1 H NMR (400MHz, CDCl3) δ6.98 (d, J=8.3Hz, 1H), 6.43 (d, J=8.2Hz, 1H), 5.92 (dd, J= 7.2,1.4Hz,2H),5.72(d,J=4.7Hz,1H),5.08(d,J=4.8Hz,1H),4.09(s,3H),3.9 7(s,3H),3.86(s,3H),3.09–3.05(m,H),2.63–2.49(m,2H),2.41–2.22(m,3H), 1.42–1.36(m,1H),1.22–1.16(m,2H),0.94–0.89(m,3H),0.85(d,J=6.7Hz,3H). 19 F NMR(376MHz,CDCl3)δ-60.4.HRMS(ESI)Calcd.for C 27 H 30 F3NNaO7 + [(M+Na) + ]560.1872,found 560.1873.

[0056] Example 11: Synthesis of Compound S11

[0057] Ethyl bromide was replaced by 1-bromo-2,2-dimethylpropane at the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S4 to give yellow solid S11 (10 mg, 18%). 1 H NMR (600MHz, CDCl3) δ7.03 (d, J = 8.2Hz, 1H), 6.64 (d, J=8.2Hz,1H),5.88(d,J=8.3Hz,2H),5.64(d,J=5.0Hz,1H),5.08(d,J=5.0Hz,1H),4.08(s,3H),3.93(s,3 H),3.87(s,3H),2.99–2.95(m,1H),2.71–2.66(m,1H),2.61–2.53(m,2H),2.52–2.42(m,2H),0.94(s,9H). 19F NMR(376MHz,CDCl3)δ-61.1.HRMS(ESI)Calcd.ForC 27 H 30 F3NNaO7 + [(M+Na) + ]560.1872,found 560.1870.

[0058] Example 12: Synthesis of Compound S12

[0059] Ethyl bromide was replaced by 2-bromohexane at the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S4 to give yellow solid S12 (11 mg, 20%, dr = 1:1). 1 H NMR (400MHz, CDCl3) δ7.02 (d, J=8.2Hz, 0.5H), 6.96 (d, J=8.2Hz,0.5H),6.51(d,J=8.2Hz,0.5H),6.38(d,J=8.2Hz,0.5H),5.94–5.90(m,2H),5.7 3(d,J=4.8Hz,0.5H),5.68(d,J=5.0Hz,0.5H),5.07(d,J=5.0Hz,0.5H),5.10(d,J=4.8Hz, 0.5H),4.09–4.08(m,3H),3.99–3.95(m,3H),3.88–3.85(m,3H),3.12–3.07(m,1H),2.86–2.81(m,1H),2.68– 2.55(m,1H),2.49–2.22(m,2H),1.85–1.70(m,1H),1.56–1.53(m,1H),1.34–1.29(m,7H),0.93–0.80(m,3H). 19 F NMR(565MHz,CDCl3)δ-60.4,-60.6.HRMS(ESI)Calcd.for C 28 H 32 F3NNaO7 + [(M+Na) + ]574.2029,found 574.2031.

[0060] Example 13: Synthesis of Compound S13

[0061] Ethyl bromide was replaced by cyclobromobutane in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S4 to give yellow solid S13 (11 mg, 21%). 1H NMR (400MHz, CDCl3) δ7.04(d,J=8.2Hz,1H),6.53(d,J=8.2Hz,1H),5.93(s,2H),5.68(d,J=4.8Hz,1H),5.04(d,J=4.8Hz,1H),4.09(s,3H),3 .94(s,3H),3.88(s,3H),3.56–3.47(m,1H),3.10–3.04(m,1H),2.62– 2.54(m,1H),2.52–2.33(m,4H),2.27–2.22(m,2H),1.96–1.84(m,2H). 19 F NMR(565MHz,CDCl3)δ-60.6.HRMS(ESI)Calcd.for C 26 H 26 F3NNaO7 + [(M+Na) + ]544.1559,found 544.1558.

[0062] Example 14: Synthesis of Compound S14

[0063] Ethyl bromide was replaced by tert-butyl 3-bromoazetidine-1-carboxylate in the same equivalent ratio. The remaining reagents and procedures were the same as those in the synthesis of S4 to give yellow solid S14 (18 mg, 29%). 1 H NMR (400MHz, CDCl3) δ7.07(d,J=8.3Hz,1H),6.63(s,1H),5.95(d,J=1.5Hz,2H),5.64(d,J=4.7Hz,1H),5.02(d,J=4.8Hz,1H),4.25–4.14 (m,2H),4.08(s,3H),3.92(s,3H),3.89(s,3H),3.47–3.37(m,2H),3.34–3.27(m,2H),3.15–3.11(m,1H),2.58–2.35(m,2H),1.46(s,9H). 19 F NMR(376MHz, CDCl3)δ-55.9,-57.2,-59.2,-59.9,-60.4,-60.7,-61.7.HRMS(ESI)Calcd.for C 30 H 33 F3N2NaO9 + [(M+Na) + ]645.2036,found 645.2039.

[0064] Example 15: Synthesis of Compound S15

[0065] Ethyl bromide was replaced by cyclopentane bromide at the same equivalent ratio. The remaining reagents and procedures were the same as those for the synthesis of S4 to give yellow solid S15 (11 mg, 20%). 1 H NMR (600MHz, CDCl3) δ7.04(d,J=8.3Hz,1H),6.56(d,J=8.2Hz,1H),5.91(d,J=1.2Hz,2H),5.67(d,J=5.0Hz,1H),5.05(d,J=5.0Hz,1H),4.09(s,3H),3.93 (s,3H),3.88(s,3H),3.13–3.09(m,1H),3.05–3.02(m,1H),2.72–2.67(m,1H),2.53–2.46(m,2H),1.84–1.82(m,8H). 19 F NMR(565MHz,CDCl3)δ-60.6.HRMS(ESI)Calcd.forC 27 H 28 F3NNaO7 + [(M+Na) + ]558.1716,found 558.1714.

[0066] Example 16: Synthesis of Compound S16

[0067] Ethyl bromide was replaced by tert-butyl 3-bromopyrrolidine-1-carboxylate in the same equivalent ratio. The remaining reagents and procedures were the same as those for the synthesis of S4 to give yellow solid S16 (16 mg, 25%, dr = 3:2). 1 H NMR(400MHz, CDCl3)δ7.10–7.06(7.03 –7.01)(m,1H),6.72–6.65(6.40–6.38)(m,1H),5.92(s,2H),5.72–5.71(5.63–5.62)(m,1H),5.06–5.02(m,1H),4.11–4.08(m,3H),4.0 4–3.96(m,1H),3.91–3.85(m,5H),3.65–3.46(m,3H),3.37–3.29(m,2H),3.20–3.13(m,1H),2.76–2.70(m,1H),2.64–2.51(m,1H),2.49 –2.20(m,2H),2.04–1.95(m,1H),1.48(s,9H). 19 F NMR(565MHz,CDCl3)δ-60.3,-60.8, -60.8,-61.0.HRMS(ESI)Calcd.for C31 H 35 F3N2NaO9 + [(M+Na) + ]659.2192,found 659.2194.

[0068] Example 17: Synthesis of Compound S17

[0069] Ethyl bromide was replaced by cyclohexyl bromide in the same equivalent ratio. The remaining reagents and procedures were the same as those in the synthesis of S4 to give yellow solid S17 (13 mg, 24%). 1 H NMR (600MHz, CDCl3) δ7.02(d,J=8.3Hz,1H),6.51(d,J=8.2Hz,1H),5.91(dd,J=3.8,1.4Hz,2H),5.69(d,J=4.9Hz,1H),5.0 6(d,J=4.9Hz,1H),4.08(s,3H),3.93(s,3H),3.88(s,3H),3.12–3.08(m,1H),2.68–2.64(m,1H),2.62–2.58(m,1H),2.47– 2.43(m,2H),1.87–1.81(m,4H),1.72–1.71(m,1H),1.62–1.60(m,1H),1.33–1.22(m,4H). 19 F NMR(565MHz,CDCl3)δ-60.6.HRMS(ESI)Calcd.for C 28 H 30 F3NNaO7 + [(M+Na) + ]572.1872,found 572.1871.

[0070] Example 18: Synthesis of Compound S18

[0071] Ethyl bromide was replaced with tert-butyl 4-(bromopiperidine)-1-carboxylate in the same equivalent ratio. The remaining reagents and procedures were the same as those in the synthesis of S4 to give yellow solid S18 (19 mg, 30%). 1H NMR (400MHz, CDCl3) δ7.05 (d, J = 8.3Hz, 1H), 6.60(s,1H),5.89(s,2H),5.66(d,J=4.1Hz,1H),5.05(d,J=4.8Hz,1H),4.25–4.22(m,2H),4.07(s,3H),3. 90–3.88(m,8H),3.15–3.10(m,1H),2.77–2.68(m,4H),2.54–2.50(m,2H),2.11–2.01(m,2H),1.48(s,9H). 19 F NMR(376MHz, CDCl3)δ-55.3,-55.9,-59.1,-60.8. HRMS(ESI)Calcd.For C 32 H 37 F3N2NaO9 + [(M+Na) + ]673.2349,found 673.2352.

[0072] Example 19: Synthesis of Compound S19

[0073] Ethyl bromide was replaced by 4-bromotetrahydropyran in the same equivalent ratio. The remaining reagents and procedures were the same as those in the synthesis of S4 to give yellow solid S19 (14 mg, 25%). 1 H NMR (400MHz, CDCl3) δ7.05 (d, J = 8.3Hz, 1H), 6.61 (d, J = 8.3Hz, 1H), 5.92 (s, 2H), 5.67 (d, J = 4.8Hz, 1H), 5.06 (d, J = 4.8Hz, 1H),4.08(s,3H),4.06–4.04(m,2H),3.91(s,3H),3.89(s,3H),3.49–3.40(m,2H),3.17–3.11(m,1H),2.91–2.85(m,1H), 2.74–2.68(m,1H),2.62–2.50(m,2H),2.33–2.23(m,2H),1.53–1.46(m,2H). 19 F NMR(376MHz,CDCl3)δ-60.8.HRMS(ESI)Calcd.for C 27 H 28 F3NNaO8 + [(M+Na) + ]574.1665,found574.1663.

[0074] Example 20: Synthesis of Compound S20

[0075] Ethyl bromide was replaced by 2-bromobicyclo[2.2.1]heptane at the same equivalent ratio. The remaining reagents and procedures were the same as those for the synthesis of S4 to give yellow solid S20 (13 mg, 23%, dr = 1:1). 1 H NMR(600MHz, CDCl3)δ7.05–7.03(m,1H), 6.59(d,J=8.2Hz,0.5H),6.45(d,J=8.2Hz,0.5H),5.90–5.86(m,2H),5.75(d,J=4.8Hz,0.5H),5 .64(d,J=4.8Hz,0.5H),5.04–5.05(m,1H),4.10(s,1.5H),4.08(s,1.5H),3.96(s,1.5H),3.91(s ,1.5H),3.88(s,3H),3.15–3.06(m,1H),2.69–2.56(m,2H),2.48–2.23(m,4H),1.94–1.84(m,1H) ,1.77–1.75(m,1H),1.71–1.62(m,2H),1.49–1.39(m,2H),1.13–0.99(m,1H),0.89–0.87(m,1H). 19 F NMR(565MHz,CDCl3)δ-60.3,-60.9.HRMS(ESI)Calcd.forC 29 H 30 F3NNaO7 + [(M+Na) + ]584.1872,found 584.1873.

[0076] Example 21: Synthesis of Compound S21

[0077] Ethyl bromide was replaced with tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate at the same equivalent ratio. The remaining reagents and procedures were the same as those for the synthesis of S4 to give yellow solid S21 (21 mg, 33%, dr = 1:1). 1H NMR (400MHz, CDCl3) δ7.07– 7.03(m,1H),6.59(d,J=8.3Hz,0.5H),6.42(d,J=8.3Hz,0.5H),5.92(d,J=5.3Hz,2H),5.71–5.65(m,1H),5.09–5.05(m,1H),4.08 (s,3H),3.96–3.93(m,3H),3.87(s,3H),3.49–3.25(m,6H),3.10–2.97(m,2H),2.61–2.59(m,3H),2.46–2.31(m,2H),1.48(s,9H). 19 F NMR(376MHz,CDCl3)δ-60.5,-60.7.HRMS(ESI)Calcd.for C 32 H 37 F3N2NaO9 + [(M+Na) + ]673.2349,found 673.2350.

[0078] Example 22: Synthesis of Compound S22

[0079] Ethyl bromide was replaced by 2-(bromomethyl)tetrahydropyran at the same equivalent ratio, and the remaining reagents and procedures were the same as those for the synthesis of S4 to give a yellow solid S22 (15 mg, 28%, dr = 1:1). 1 H NMR (400MHz, CDCl3) δ7.05–7.02(m,1H),6.56–6.52(m,1H),5.94–5.92(m,2H),5.69–5.67(m,1H),5.07–5.06(m,1H),4.09(s,3H),4.08–3. 98(m,1H),3.96–3.95(m,3H),3.88(s,3H),3.76–3.64(m,2H),3.10–3 .03(m,1H),2.82–2.65(m,3H),2.53–2.43(m,2H),1.97–1.85(m,4H). 19 F NMR(376MHz,CDCl3)δ -60.5.HRMS(ESI)Calcd.for C 27 H 28 F3NNaO8 + [(M+Na) + ]574.1665,found 574.1666.

[0080] Example 23: Synthesis of Compound S23

[0081] Ethyl bromide was replaced by bromomethylcyclohexane in the same equivalent ratio. The remaining reagents and procedures were the same as those for the synthesis of S4 to give S23 (12 mg, 22%) as a yellow solid. 1 H NMR (600MHz, CDCl3) δ6.90(d,J=8.3Hz,1H),6.32(d,J=8.2Hz,1H),5.86–5.84(m,2H),5.64(d,J=4.9Hz,1H),5.01(d,J= 4.9Hz,1H),4.02(s,3H),3.91(s,3H),3.79(s,3H),3.01–2.97(m,1H),2.54–2.48(m,1H),2.36–2.24(m,4H),1.66–1.58 (m,4H),1.38–1.33(m,1H),1.19–1.10(m,4H),0.95–0.83(m,2H). 19 F NMR(565MHz,CDCl3)δ-60.4.HRMS(ESI)Calcd.for C 29 H 32 F3NNaO7 + [(M+Na) + ]586.2029,found 586.2024.

[0082] Example 24: Antitumor Pharmacology Experiment of Narcotine Derivatives

[0083] The synthetic Narcotine derivatives of the present invention have anti-tumor activity, and the pharmacological test results are as follows:

[0084] The CCK-8 method was used to perform the corresponding cell proliferation inhibitory activity analysis. The specific operation is as follows:

[0085] 1. Cell lines: Kasumi-1, SNU-1, Jeko-1, Raji, SNK6, Hela

[0086] 2. Culture medium

[0087] RPMI 1640 + 10% FBS

[0088] RPMI 1640 + 20% FBS

[0089] DMEM + 10% FBS

[0090] 3. Other materials

[0091] Full-wavelength multifunctional microplate reader: Model Varioskan Flash, manufacturer Thermo Scientific, imported 384-well plate, etc.

[0092] 4. Experimental method: This experiment uses the CCK-8 method. Cells and drugs are added to a 384-well plate, with a volume of 60uL per well and a cell concentration of 2×10 5 Each drug concentration is 10uM. After spreading, shake to make it even and not stick to the wall (for adherent cells, the cells need to be spread in advance and placed in the incubator so that the confluence reaches 30%-50% when the drug is added the next day); after spreading, place it in a 37°C, 5% CO2 incubator for 48 hours; after 48 hours, add 5uL of CCK-8 solution to each well, incubate in the incubator for 2-6 hours, and measure the OD with a multifunctional microplate reader. 450 The absorbance value was measured and the inhibitory activity of the cells was calculated according to the formula. The results of the inhibitory activity of solid tumor cell lines in vitro are shown in Table 1:

[0093] Table 1 Antiproliferative activity of narcotine derivatives against solid tumor cell lines

[0094]

[0095]

[0096] The results of in vitro hematological tumor cell line inhibitory activity are shown in Table 2:

[0097] Table 2 Antiproliferative activity of Narcotine derivatives against hematological tumor cell lines

[0098]

[0099]

Claims

1. Compounds represented by the general formula: in, R 1 Selected from trifluoromethyl; R 2 is selected from hydrogen, halogen, alkyl, azaalkyl, cycloalkyl, bridged cycloalkyl, oxacycloalkyl, azacycloalkyl, cycloalkylmethyl, oxacycloalkylmethyl, azacycloalkylmethyl; Where, The halogen is fluorine, chlorine, bromine, or iodine; The alkyl group is a C2-C8 alkyl group or a C2-C8 deuterated alkyl group; The azaalkyl group is a C2-C8 azaalkyl group or a C2-C8 deuterated azaalkyl group; The cycloalkyl group is a C3-C10 cycloalkyl group or a C3-C10 deuterated cycloalkyl group; The bridged cycloalkyl group is a C5-C12 bridged cycloalkyl group or a C5-C12 deuterated bridged cycloalkyl group; The oxacycloalkyl group is a C3-C7 oxacycloalkyl group or a C3-C7 deuterated oxacycloalkyl group; The azacycloalkyl group is a C3-C7 azacycloalkyl group or a C3-C7 deuterated azacycloalkyl group; The cycloalkylmethyl group and the cycloalkyl group are C3-C10 cycloalkyl groups or C3-C10 deuterated cycloalkyl groups; The oxacycloalkylmethyl group and the oxacycloalkyl group are C3-C7 oxacycloalkyl groups or C3-C7 deuterated oxacycloalkyl groups; The azacycloalkylmethyl group and the azacycloalkyl group are C3-C7 azacycloalkyl group or C3-C7 deuterated azacycloalkyl group.

2. The compound according to claim 1, wherein Has the following structure:

3. Use of the compound according to any one of claims 1 to 2 in the preparation of anti-tumor drugs.

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