A kind of amine fluoride curcumol derivative compound and its application and preparation method

Abstract

The present invention relates to the technical field of medical technology, and more specifically to an amine fluorinated curcuminol derivative compound, the structure of which is shown in general formula I: wherein in general formula I, the R group is selected from hydrogen atom, arylformyl, heteroarylformyl, arylsulfonyl, arylacetyl, arylacryloyl, alkanoyl, and carbamoyl; the amine fluorinated curcuminol derivative synthesized by the present invention has anti-tumor activity.

Description

Technical Field

[0001] The present invention relates to the technical field of medical technology, and more specifically to an amine fluoride curcuminol derivative compound and its application and preparation method. Background Art

[0002] Environmental pollution and changes in human lifestyles have led to an increase in the incidence of malignant tumors, which seriously threatens 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 and 9.96 million new deaths worldwide, with a mortality rate of 50%; while in my country, there were 4.57 million new cases of cancer and 3 million deaths, both ranking first in the world.

[0003] Small molecule chemical drugs are the main means to fight against malignant tumors. Commonly used anti-tumor drugs in clinical practice mainly include cytotoxic drugs and targeted drugs. However, cytotoxic drugs usually show strong toxic side effects, which seriously affect the quality of life of patients with malignant tumors. Targeted drugs show increasing drug resistance, which has become a bottleneck in their clinical application. Therefore, it is urgent to develop anti-tumor drugs with high efficiency, low toxicity and high therapeutic index to meet this challenge.

[0004] Traditional Chinese medicine, as a treasure of the Chinese nation, still bears the important function of serving the people's health to a large extent. The natural product molecules contained in traditional Chinese medicine are the material basis for its clinical treatment, especially the natural product molecules with the most important content. Therefore, finding drug leads from traditional Chinese medicine has become an effective way to develop new drugs and an inevitable requirement for the modernization of traditional Chinese medicine. Curcuma, also known as Wen Curcuma, is a herbaceous plant of the ginger family. It can be used to prepare spices, seasonings and other additives in food. It is also a traditional Chinese medicine. "Compendium of Materia Medica" records that "Curcuma, pungent, warm and non-toxic, its color is black, and it can break the blood in the air." Therefore, Curcuma can usually be used to promote blood circulation and relieve pain. In recent years, studies have shown that the extract of Curcuma zedoaria, volatiles of Curcuma oil, has certain anti-tumor activity. And curcumol, as the component with the highest content in Curcuma zedoaria volatiles, is the main material basis for its anti-tumor effect. Further studies have shown that curcumol can exert its anti-tumor effect by promoting the arrest of tumor cell cycle and the occurrence of apoptosis, and has shown a certain inhibitory effect on many tumor cells such as ovarian cancer, breast cancer, liver cancer, lung cancer, colorectal cancer, gastric cancer and nasopharyngeal cancer.

[0005] Fluorine atoms have the characteristics of small atomic radius, strongest electronegativity, and long half-life. The introduction of fluorine atoms can effectively improve the lipid solubility and metabolic stability of drug molecules, thereby enhancing the efficacy. Amino groups are also widely used in drug molecules. Molecules containing amino groups often show more diverse protein bonding characteristics and more reasonable pharmacokinetic properties. In view of this, we synthesized a series of curcuminol derivatives fluorinated with alkenylamines through three-step reactions, taking visible light-catalyzed olefin fluoroamination reaction as the core strategy. These derivatives contain both amino and fluorine functional groups, and show certain inhibitory activity against a variety of tumor cells, and are expected to be developed into highly effective and low-toxic anti-tumor drugs. Summary of the invention

[0006] The purpose of the present invention is to overcome the shortcomings of the prior art. The first aspect of the present invention provides an amine fluorinated curcuminol derivative compound, the structure of which is shown in general formula I:

[0007]

[0008] Wherein, in the general formula I, the R group is selected from hydrogen atom, arylformyl, heteroarylformyl, arylsulfonyl, arylacetyl, arylacryloyl, alkanoyl, carbamoyl.

[0009] As a preferred technical solution, the aromatic formyl group in the present invention is benzoyl, substituted benzoyl, naphthoyl, or substituted naphthoyl; the substituent in the substituted benzoyl group is selected from alkyl, halogen, ester, cyano, and alkoxy.

[0010] As a preferred technical solution, the heteroarylformyl group in the present invention is selected from pyridineformyl, substituted pyridineformyl, thenoyl, substituted thenoyl, furoyl, substituted furoyl, pyrazineformyl, substituted pyrazineformyl, pyrroyl, substituted pyrroyl, quinolineformyl, substituted quinolineformyl, isoquinolineformyl, substituted isoquinolineformyl, benzothiazoleformyl, substituted benzothiazoleformyl, indoleformyl, substituted indoleformyl, benzimidazoleformyl, substituted imidazoleformyl, benzoxazoleformyl, substituted benzoxazoleformyl, imidazoleformyl, substituted imidazoleformyl, oxazoleformyl, substituted oxazoleformyl, thiazoleformyl, substituted thiazoleformyl.

[0011] As a preferred technical solution, the aromatic sulfonyl group in the present invention is selected from benzenesulfonyl or substituted benzenesulfonyl; the substituent in the substituted benzenesulfonyl group is selected from alkyl and halogen.

[0012] As a preferred technical solution, the aromatic acetyl group in the present invention is selected from phenylacetyl or substituted phenylacetyl.

[0013] As a preferred technical solution, the aromatic acryloyl group in the present invention is selected from phenyl acryloyl group or substituted phenyl acryloyl group.

[0014] As a preferred technical solution, the alkyl group in the alkanoyl group of the present invention is selected from C1-C6 alkyl group or deuterated alkyl group; the carbamoyl group is selected from N-phenylcarbamoyl group or N-substituted phenylcarbamoyl group.

[0015] As a preferred technical solution, the structure of the compound in the present invention is selected from at least one of the structural formulas corresponding to the serial numbers S1-S24 in Table 1;

[0016] Table 1

[0017]

[0018]

[0019]

[0020]

[0021] The second aspect of the present invention provides an application of the amine fluoride curcuminol derivative compound for treating tumor-related diseases.

[0022] The third aspect of the present invention provides a method for preparing the amine fluoride curcuminol derivative compound, the steps comprising at least:

[0023] (1) Curcumol, compound II and Selectfluor undergo photocatalytic amine fluorination reaction to obtain compound II;

[0024] (2) Compound II was treated with zinc powder and potassium dihydrogen phosphate at room temperature to obtain the primary amino product S1;

[0025] The structural formula of the compound II is shown below:

[0026]

[0027] As a preferred technical solution, the method for preparing the amine fluorinated curcumin derivative compound described in the present invention also includes the step (3): subjecting compound S1 to a nucleophilic addition reaction with an acyl chloride, a sulfonyl chloride or an isocyanate to obtain an amine fluorinated curcumin derivative compound.

[0028] Beneficial effects of the present invention: The present invention synthesizes a series of curcumol derivatives through a semi-synthetic method based on the visible light-catalyzed olefin amine fluorination strategy. These derivatives show inhibitory activity against various malignant hematological tumors and malignant solid tumor cells, and can be used to prepare highly effective and low-toxic anti-tumor therapeutic drugs. DETAILED DESCRIPTION

[0029] The technical scheme of the present invention is described in detail below in conjunction with the embodiments, but the present invention is not limited to the scope of the embodiments. The experimental methods in the following embodiments without specifying specific conditions are selected according to conventional methods and conditions, or according to the product specifications. The reagents and raw materials used in the present invention are all commercially available.

[0030] The first aspect of the present invention provides an amine fluoride curcuminol derivative compound, the structure of the compound is shown in general formula I:

[0031]

[0032] Wherein, in the general formula I, the R group is selected from hydrogen atom, arylformyl, heteroarylformyl, arylsulfonyl, arylacetyl, arylacryloyl, alkanoyl, carbamoyl.

[0033] In some embodiments, the arylformyl group is benzoyl, substituted benzoyl, naphthoyl, or substituted naphthoyl; the substituent in the substituted benzoyl group is selected from alkyl, halogen, ester, cyano, and alkoxy.

[0034] In some embodiments, the heteroarylcarbonyl group is selected from pyridinylcarbonyl, substituted pyridinylcarbonyl, thenoylcarbonyl, substituted thenoylcarbonyl, furoyl, substituted furoyl, pyrazinecarbonyl, substituted pyrazinecarbonyl, pyrroyl, substituted pyrroyl, quinolinecarbonyl, substituted quinolinecarbonyl, isoquinolinecarbonyl, substituted isoquinolinecarbonyl, benzothiazolecarbonyl, substituted benzothiazolecarbonyl, indolecarbonyl, substituted indolecarbonyl, benzimidazolyl, substituted imidazolecarbonyl, benzoxazolecarbonyl, substituted benzoxazolecarbonyl, imidazolecarbonyl, substituted imidazolecarbonyl, oxazolecarbonyl, substituted oxazolecarbonyl, thiazolecarbonyl, substituted thiazolecarbonyl.

[0035] In some embodiments, the arylsulfonyl group is selected from benzenesulfonyl or substituted benzenesulfonyl; the substituent in the substituted benzenesulfonyl group is selected from alkyl and halogen.

[0036] In some embodiments, the arylacetyl group is selected from phenylacetyl or substituted phenylacetyl.

[0037] In some embodiments, the aromatic acryloyl group is selected from a phenyl acryloyl group or a substituted phenyl acryloyl group.

[0038] In some embodiments, the alkyl group in the alkanoyl group is selected from a C1-C6 alkyl group or a deuterated alkyl group; the carbamoyl group is selected from an N-phenylcarbamoyl group or an N-substituted phenylcarbamoyl group.

[0039] In some embodiments, the structure of the amine fluoride curcuminol derivative compound is selected from at least one of the structural formulas corresponding to sequence numbers S1-S24 in Table 1;

[0040] Table 1

[0041]

[0042]

[0043]

[0044]

[0045]

[0046] The second aspect of the present invention provides an application of the amine fluoride curcuminol derivative compound for treating tumor-related diseases.

[0047] In some embodiments, the curcumin amine fluoride derivative compounds described in the present invention are used for tumor-related diseases, including but not limited to ovarian cancer, breast cancer, liver cancer, lung cancer, colorectal cancer, gastric cancer, and nasopharyngeal cancer.

[0048] The third aspect of the present invention provides a method for preparing the amine fluoride curcuminol derivative compound, the steps comprising at least:

[0049] (1) Curcumol, compound II and Selectfluor undergo photocatalytic amine fluorination reaction to obtain compound II;

[0050] (2) Compound II is treated with zinc powder and potassium dihydrogen phosphate at room temperature to obtain the primary amino product S1.

[0051] In some preferred embodiments, the method for preparing the amine fluorinated curcuminol derivative compound further comprises step (3): subjecting compound S1 to a nucleophilic addition reaction with an acyl chloride, a sulfonyl chloride or an isocyanate to obtain the amine fluorinated curcuminol derivative compound.

[0052] In some preferred embodiments, the method for preparing the amine fluoride curcuminol derivative compound comprises the following steps:

[0053] (1) Curcumol, compound II and Selectfluor undergo photocatalytic amine fluorination reaction under the action of visible light to obtain compound III;

[0054] (2) Compound II is treated with zinc powder and potassium dihydrogen phosphate at room temperature to obtain the primary amino product compound S1;

[0055] (3) Compound S1 is subjected to a nucleophilic addition reaction with acyl chlorides, sulfonyl chlorides or isocyanates to obtain an amine fluoride curcuminol derivative compound.

[0056] The reaction formula of the preparation method of the amine fluoride curcuminol derivative compound described in the present invention is as follows:

[0057]

[0058] The Mes-Acr-Me described in the present invention is a visible light catalyst, and its Chinese name is 9-mesityl-10-methylacridine perchlorate, and its structure is as follows:

[0059]

[0060] The Selectfluor described in the present invention is a fluorination reagent, and its Chinese name is 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo-2.2.2-octane bis(tetrafluoroborate) salt, and its structure is as follows:

[0061]

[0062] The following describes it in conjunction with specific embodiments.

[0063] Example 1: Synthesis of Compound S1

[0064] 1) Synthesis of compound III:

[0065] Add Mes-Acr-Me (10.3 mg, 0.025 mmol), curcumol (118.2 mg, 0.5 mmol), compound II (220 mg, 0.75 mmol), Selectfluor (355 mg, 1.0 mmol), Na2HPO4 (212.5 mg, 1.5 mmol) and a clean stirring bar to a clean reaction tube. After nitrogen backfilling, add a mixed solvent of acetonitrile (3.5 ml) and water (1.75 ml), and react for 16 hours under a blue LED light. After the reaction is completed, add 25 mL of water, extract with dichloromethane (30 mL × 3), combine the organic phases, add anhydrous Na2SO4 to dry, filter and rotary evaporate to obtain a crude product, and then purify it through a silica gel column, the eluent is DCM: MeOH = 200: 1, and a light yellow solid of 113.5 mg is obtained, with a yield of 51%. 1HNMR(400MHz, CDCl3)δ=5.49–5.43(5.40–5.30)(m,1H),4.75(s,2H),3.49–3.34(m,2H),2.79(s,1 H),2.33–2.02(m,3H),1.97–1.73(m,4H),1.54–1.36(m,3H),1.30–1.18(m,2H),1.02–0.88(m,9H).

[0066] 2) Synthesis of compound S1:

[0067] Compound III (445 mg, 1 mmol) and THF (13 mL) were added to the reaction flask, followed by activated zinc powder (1.63 g, 25 mmol) and 1M KH2PO4 (2.67 mL) solution, and the reaction was continued at room temperature for 8 h. The reaction solution was filtered through diatomaceous earth. The filtrate was dried by rotary evaporation, extracted with saturated NaHCO3 solution (30 mL) and ethyl acetate (30 mL×3), and the organic phases were combined, dried by adding anhydrous Na2SO4, filtered, and rotary evaporated to obtain a crude product, which was then purified by silica gel column, with the eluent being DCM:MeOH=100:1, to obtain 184 mg of white solid S1, with a yield of 68%. 1 HNMR(400MHz, CDCl3)δ=3.35–3.04(m,1H),3.03–2.86(m,1H),2.77–2.49(m,1H),2.30–2.12(m,2H ),2.00–1.85(m,6H),1.77–1.63(m,2H),1.58–1.36(m,3H),1.28–1.20(m,1H),1.08–0.83(m,9H).

[0068] Example 2: Synthesis of Compound S2

[0069] At room temperature, compound S1 (0.12mmol, 33mg) was weighed and added to a 15mL reaction bottle containing a clean stirring bar, 4mL of dichloromethane solution was added, followed by diisopropylethylamine (DIPEA) (0.156mmol, 27.3μL), stirred for 10 minutes, and then benzoyl chloride (0.144mmol, 20.2mg) was added dropwise, and stirred for 3 hours. After the reaction was completed, 20mL of saturated brine and ethyl acetate (20mL×3) were used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain a crude product, which was purified by preparative silica gel plate (DCM:MeOH=180:1) to obtain 18mg of white solid S2, with a yield of 40%. 1H NMR (400MHz, CDCl3) δ = 7.83 (7.78) (d, J = 7.2Hz, 2H), 7.52 (7.45) (t, J = 7.3Hz, 3H) ,6.76–6.67(6.62–6.40)(m,1H),3.84–3.58(4.13–4.95)(3.46–3.33)(m,2H),2.7 8(s,1H),2.33–2.09(m,3H),2.03–1.82(m,3H),1.77–1.73(m,1H),1.61–1.46(m,2 H),1.43–1.36(m,1H),1.33–1.24(m,2H),1.06–0.87(m,9H); HRMS(ESI)Calcd.for C 22 H 30 FNaNO3[(M+Na) + ]398.2107,found398.2108.

[0070] Example 3: Synthesis of Compound S3

[0071] The benzoyl chloride in Example 2 was replaced by 4-methylbenzoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 28 mg of white solid S3 with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ = 7.72 (7.68) (d, J = 8.0Hz, 2H), 7.26–7.22 (m, 2H), 6.68–6 .62(6.50–6.41)(m,1H),4.15–3.94(3.79–3.56)(m,2H),2.75(s,1H),2.40(s,3 H),2.28–2.12(m,3H),2.01–1.83(m,3H),1.79–1.72(m,2H),1.55–1.49(m,1H) ,1.45–1.36(m,1H),1.33–1.26(m,2H),1.01–0.87(m,9H); HRMS(ESI)Calcd.for C 23 H 32 FNaNO3[(M+Na) + ]412.2264,found412.2262.

[0072] Example 4: Synthesis of Compound S4

[0073] The benzoyl chloride in Example 2 was replaced by 2-methylbenzoyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 22 mg of white solid S4 with a yield of 47%. 1HNMR(400MHz, CDCl3)δ=7.42–7.30(m,2H),7.26–7.17(m,2H),6.27–6.17 (6.16–6.08)(m,1H),3.84–3.49(m,2H),2.70(s,1H),2.46(s,3H),2.27–2 .18(m,2H),2.01–1.85(m,3H),1.79–1.70(m,3H),1.57–1.52(m,1H),1.45 –1.38(m,1H),1.35–1.19(m,2H),1.02–0.93(m,9H); HRMS(ESI)Calcd.for C 23 H 32 FNaNO3[(M+Na) + ]412.2264,found412.2265.

[0074] Example 5: Synthesis of Compound S5

[0075] The benzoyl chloride in Example 2 was replaced by 3-methylbenzoyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 18 mg of white solid S5 with a yield of 40%. 1 HNMR(400MHz, CDCl3)δ=7.67–7.51(m,2H),7.37–7.30(m,2H),6.70–6.61(6. 51–6.42)(m,1H),4.12–3.96(3.80–3.56)(m,2H),2.79(s,1H),2.40(s,3H),2 .29–2.13(m,3H),1.99–1.83(m,3H),1.75–1.72(m,1H),1.59–1.46(m,2H),1. 44–1.38(m,1H),1.34–1.27(m,2H),1.01–0.89(m,9H); HRMS(ESI)Calcd.forC 23 H 32 FNaNO3[(M+Na) + ]412.2264,found412.2265.

[0076] Example 6: Synthesis of Compound S6

[0077] The benzoyl chloride in Example 2 was replaced by 4-methoxybenzoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 26 mg of white solid S6 with a yield of 54%. 1H NMR (400MHz, CDCl3) δ = 7.80 (7.75) (d, J = 8.4Hz, 2H), 7.00–6.84 (m, 2H), 6. 67–6.58(6.49–6.35)(m,1H),4.13–3.95(3.77–3.57)(m,2H),3.85(s,3H), 2.80(s,1H),2.33–2.08(m,3H),2.01–1.83(m,3H),1.58–1.46(m,2H),1.44 –1.36(m,1H),1.35–1.17(m,3H),1.06–0.88(m,9H); HRMS(ESI)Calcd.forC 23 H 32 FNaNO4[(M+Na) + ]428.2213,found428.2214.

[0078] Example 7: Synthesis of Compound S7

[0079] The benzoyl chloride in Example 2 was replaced by 4-tert-butylbenzoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 22 mg of white solid S7 with a yield of 43%. 1 HNMR(400MHz, CDCl3)δ=7.77(7.72)(d,J=8.3Hz,2H),7.46(d,J=8.3Hz,2H),6.77–6.65(6.54–6.42)(m,1H),4.19–3.94(3.82–3.56)(m,2H),2.31 –2.11(m,3H),1.99–1.84(m,3H),1.78–1.65(m,3H),1.56–1.44(m,2H),1.33(s,9H),1.29–1.25(m,1H),1.03–0.90(m,9H); HRMS(ESI)Calcd.forC 26 H 38 FNaNO3[(M+Na) + ]454.2733,found454.2728.

[0080] Example 8: Synthesis of Compound S8

[0081] The benzoyl chloride in Example 2 was replaced by 4-fluorobenzoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 26 mg of light yellow oily liquid S8 with a yield of 55%. 1HNMR(400MHz, CDCl3)δ=7.91–7.83(7.82–7.75)(m,2H),7.18–7.03(m,2H),6.76–6.62(6.48–6.38)(m,1H),4.16–3.93(3.81–3.55)(m,2H),2.72 (s,1H),2.31–2.08(m,3H),2.01–1.82(m,3H),1.76–1.69(m,2H),1.56–1.35(m,3H),1.31–1.24(m,1H),1.02–0.89(m,9H); HRMS(ESI)Calcd.forC 22 H 29 F2NaNO3[(M+Na) + ]416.2013,found416.2014.

[0082] Example 9: Synthesis of Compound S9

[0083] The benzoyl chloride in Example 2 was replaced by 4-chlorobenzoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 32 mg of white solid S9 with a yield of 66%. 1 HNMR(400MHz, CDCl3)δ=7.78(7.73)(d,J=8.4Hz,2H),7.49–7.33(m,2H),6.86–6.75(6.61–6.42)(m,1H),4.18–3.91(3.84–3.49)(m,2H),2.92( s,1H),2.35–2.07(m,3H),1.96–1.83(m,3H),1.76–1.66(m,3H),1.51–1.40(m,2H),1.32–1.24(m,1H),1.01–0.91(m,9H); HRMS(ESI)Calcd.for C 22 H 29 ClFNaNO3[(M+Na) + ]432.1718,found432.1719.

[0084] Example 10: Synthesis of Compound S10

[0085] The benzoyl chloride in Example 2 was replaced by 4-bromobenzoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 13 mg of yellow oily liquid S10 with a yield of 24%. 1H NMR (400MHz, CDCl3) δ = 7.71 (7.66) (d, J = 8.4Hz, 2H), 7.62–7.49 (m, 2H), 6.7 8–6.71(6.59–6.36)(m,1H),4.17–3.94(3.83–3.51)(m,2H),2.75(s,1H),2. 35–2.03(m,3H),1.98–1.82(m,2H),1.79–1.70(m,2H),1.55–1.48(m,1H),1. 45–1.37(m,1H),1.33–1.24(m,3H),1.06–0.82(m,9H); HRMS(ESI)Calcd.for C 22 H 29 BrFNaNO3[(M+Na) + ]476.1213,found476.1216.

[0086] Example 11: Synthesis of Compound S11

[0087] The benzoyl chloride in Example 2 was replaced by methyl 4-(chlorocarbonyl)benzoate in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 30 mg of white solid S11 with a yield of 58%. 1 HNMR (400MHz, CDCl3) δ = 8.11 (d, J = 8.3Hz, 2H), 7.90 (7.84) (d, J = 8.3Hz, 2H) ,6.87–6.78(6.62–6.50)(m,1H),4.13–3.99(3.81–3.59)(m,2H),3.94(s,3H ),2.75(s,1H),2.33–2.09(m,3H),2.02–1.82(m,3H),1.76–1.69(m,2H),1. 58–1.36(m,3H),1.33–1.26(m,1H),1.02–0.88(m,9H); HRMS(ESI)Calcd.for C 24 H 32 FNaNO5[(M+Na) + ]456.2162,found456.2161.

[0088] Example 12: Synthesis of Compound S12

[0089] The benzoyl chloride in Example 2 was replaced by 4-cyanocarbonyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 21 mg of white solid S12 with a yield of 43%. 1HNMR(400MHz, CDCl3)δ=8.01–7.94(7.92–7.86)(m,2H),7.81–7.66(m,2H) ,6.68–6.53(6.47–6.36)(m,1H),4.15–3.92(3.82–3.55)(m,2H),2.88(2. 83)(s,1H),2.36–2.07(m,3H),2.04–1.80(m,4H),1.78–1.71(m,1H),1.61 –1.35(m,3H),1.33–1.28(m,1H),1.04–0.87(m,9H); HRMS(ESI)Calcd.forC 23 H 29 FNaN2O3[(M+Na) + ]423.2060,found423.2061.

[0090] Example 13: Synthesis of Compound S13

[0091] The benzoyl chloride in Example 2 was replaced by 2-phenylacetyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 5 mg of colorless liquid S13 with a yield of 10%. 1 HNMR(400MHz, CDCl3)δ=7.42–7.26(m,5H),5.77–5.70(5.65–5.55)(m,1H),3.61(s,2H),3.51–3.26(m,2H),2.59(s,1H) ),2.16–1.98(m,2H),1.90–1.75(m,3H),1.71–1.58(m,4H),1.49–1.32(m,3H),1.07–0.77(m,9H); HRMS(ESI)Calcd.for C 23 H 32 FNaNO3[(M+Na) + ]412.2264,found412.2263.

[0092] Example 14: Synthesis of Compound S14

[0093] The benzoyl chloride in Example 2 was replaced by cinnamoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 21 mg of white solid S14 with a yield of 44%. 1H NMR (400MHz, CDCl3) δ = 7.56 (d, J = 15.6Hz, 1H), 7.56–7.47 (m, 2H), 7.41–7.32 (m, 3H), 6.4 6(dd,J=15.6Hz,9.8Hz,1H),6.30–6.22(6.11–6.01)(m,1H),4.06–3.86(3.75–3.50)(m,2 H),2.95–2.75(m,1H),2.27–2.10(m,2H),1.99–1.81(m,3H),1.76–1.68(m,2H),1.56–1. 48(m,1H),1.45–1.37(m,1H),1.33–1.24(m,2H),1.03–0.87(m,9H); HRMS(ESI)Calcd.for C 24 H 32 FNaNO3[(M+Na) + ]424.2264,found424.2258.

[0094] Example 15: Synthesis of Compound S15

[0095] The benzoyl chloride in Example 2 was replaced by 3,5-dimethylbenzoyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 29 mg of white solid S15 with a yield of 60%. 1 HNMR(400MHz, CDCl3)δ=7.41(7.38)(s,2H),7.15(s,1H),6.63–6.54(6.51–6.37)(m,1H),4.16–3.91(3.83–3.53)(m,2H),2.70(s,1H) ),2.36(s,6H),2.28–2.16(m,2H),2.01–1.83(m,3H),1.76–1.65(m,3H),1.57–1.26(m,4H),1.03–0.88(m,9H); HRMS(ESI)Calcd.for C 24 H 34 FNaNO3[(M+Na) + ]426.2420,found412.2419.

[0096] Example 16: Synthesis of Compound S16

[0097] The benzoyl chloride in Example 2 was replaced by 3,4-dimethoxybenzoyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 21 mg of white solid S16 with a yield of 40%. 1H NMR(400MHz, CDCl3)δ=7.46–7.38(m,1H),7.33–7.26(m,1H),6.95–6.83(m,1H) ),6.73–6.65(6.48–6.38)(m,1H),4.15–4.02(3.79–3.56)(m,2H),4.01–3.85( m,6H),2.74(s,1H),2.78–2.13(m,2H),1.99–1.853(m,2H),1.77–1.67(m,3H), 1.56–1.34(m,3H),1.32–1.24(m,2H),1.05–0.83(m,9H); HRMS(ESI)Calcd.for C 24 H 35 FNO5[(M+H) + ]436.2499,found436.2450.

[0098] Example 17: Synthesis of Compound S17

[0099] The benzoyl chloride in Example 2 was replaced by 2-naphthoyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 33 mg of brown solid S17 with a yield of 65%. 1 HNMR(400MHz, CDCl3)δ=8.37(8.31)(s,1H),8.00–7.81(m,4H),7.61–7.48 (m,2H),6.88–6.78(6.70–6.57)(m,1H),4.20–4.00(3.88–3.62)(m,2H),2 .66(s,1H),2.29–2.17(m,2H),2.04–1.85(m,3H),1.78–1.71(m,2H),1.62 –1.50(m,2H),1.46–1.21(m,3H),1.04–0.89(m,9H); HRMS(ESI)Calcd.for C 26 H 32 FNaNO3[(M+Na) + ]448.2264,found448.2265.

[0100] Example 18: Synthesis of Compound S18

[0101] The benzoyl chloride in Example 2 was replaced by 2-furoyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 28 mg of white solid S18 with a yield of 65%. 1HNMR(400MHz, CDCl3)δ=7.50–7.41(m,1H),7.16–7.09(m,1H),6.80–6.73(6.7 2–6.62)(m,1H),6.54–6.47(m,1H),4.02–3.83(3.74–3.52)(m,2H),2.84(s,1H ),2.27–2.16(m,2H),1.97–1.85(m,2H),1.80–1.69(m,5H),1.53–1.47(m,1H), 1.43–1.35(m,1H),1.32–1.28(m,1H),1.01–0.89(m,9H); HRMS(ESI)Calcd.for C 20 H 28 FNaNO4[(M+Na) + ]388.1900, found 388.1899.

[0102] Example 19: Synthesis of Compound S19

[0103] The benzoyl chloride in Example 2 was replaced by 5-chloro-2-thiophenecarbonyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those in the synthesis of S2 to obtain 22 mg of white solid S19 with a yield of 44%. 1 HNMR (400MHz, CDCl3) δ = 7.39 (7.29) (d, J = 3.9Hz, 1H), 6.91 (d, J = 3.8Hz, 1H), 6.67–6.61(6.32–6.22)(m,1H),4.09–3.90(3.76–3.5)(m,2H),2.73(s,1H),2 .31–2.05(m,3H),1.97–1.81(m,3H),1.76–1.69(m,2H),1.54–1.48(m,1H),1 .44–1.37(m,1H),1.29–1.25(m,2H),1.01–0.89(m,9H); HRMS(ESI)Calcd.for C 20 H 27 FClNaNO3S[(M+Na) + ]438.1282,found438.1281.

[0104] Example 20: Synthesis of Compound S20

[0105] The benzoyl chloride in Example 2 was replaced by 4-bromo-2-pyridinecarbonyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 15 mg of white solid S20 with a yield of 27%. 1HNMR (400MHz, CDCl3) δ = 8.48 (8.39) (d, J = 5.2Hz, 1H), 8.35 (8.19) (dd, J = 6.2Hz, 1. 9Hz,1H),8.33–8.26(m,1H),7.62(7.45)(dd,J=5.2Hz,1.8Hz,1H),3.97–3.80(3.7 8–3.57)(m,2H),2.63(s,1H),2.28–2.10(m,2H),2.03–1.80(m,3H),1.78–1.67(m, 2H),1.57–1.35(m,3H),1.32–1.23(m,2H),1.04–0.87(m,9H); HRMS(ESI)Calcd.for C 21 H 28 BrFNaN2O3[(M+Na) + ]477.1165,found477.1168.

[0106] Example 21: Synthesis of Compound S21

[0107] The benzoyl chloride in Example 2 was replaced by pyrazinecarbonyl chloride in the same equivalent ratio, and the other reagents and operations were the same as those in the synthesis of S2 to obtain 15 mg of light yellow solid S21 with a yield of 34%. 1H NMR (400MHz, CDCl3) δ = 9.40 (9.39) (s, 1H), 8.77 (d, J = 2.4Hz, 1H), 8.59-8.50 (m, 1H), 8.20-8.08 (m, 1H), 4.02-3.84 (3.82-3.60) (m, 2H), 2.76 (s, 1H), 2.28-2.16 (m, 2H), 2.02-1.82 (m,3H),1.76–1.70(m,2H),1.55–1.48(m,1H),1.45–1.37(m,1H),1.34–1.27(m,3H),1.01 –0.86(m,9H);HRMS(ESI)Calcd.forC20H28FNaN3O3[(M+Na)+]400.2012,found400.2012.

[0108] Example 22: Synthesis of Compound S22

[0109] The benzoyl chloride in Example 2 was replaced by 4-methylbenzenesulfonyl chloride in the same equivalent ratio. The remaining reagents and operations were the same as those for the synthesis of S2 to obtain 9 mg of white solid S22 with a yield of 18%. 1HNMR(400MHz, CDCl3)δ=7.72(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),5.37–5.31(4.68–4.58)(m,1H),3.16–2.99(2.99–2.82)(m, 2H),2.56(s,1H),2.44(s,3H),2.27–2.02(m,3H),1.94–1.71(m,6H),1.50–1.38(m,3H),1.00–0.83(m,9H); HRMS(ESI)Calcd.for C 22 H 32 FNaNO4S[(M+Na) + ]448.1934,found448.1935.

[0110] Example 23: Synthesis of Compound S23

[0111] The benzoyl chloride in Example 2 was replaced by 4-bromobenzenesulfonyl chloride in the same equivalent ratio, and the remaining reagents and operations were the same as those in the synthesis of S2 to obtain 14 mg of white solid S23 with a yield of 24%. 1 HNMR(400MHz, CDCl3)δ=7.78–7.59(m,4H),5.26–5.19(4.82–4.74)(m,1H),4.49–4.31(m,1H),4.16–4.03(m,1H),3.19–3.04(2.99–2.88) (m,2H),2.66(s,1H),2.18–2.08(m,2H),2.06–2.03(m,1H),1.90–1.79(m,5H),1.46–1.40(m,2H),0.96–0.87(m,9H); HRMS(ESI)Calcd.for C 21 H 29 BrFNaNO4S[(M+Na) + ]512.0882, found 512.0889.

[0112] Example 24: Synthesis of Compound S24

[0113] Compound S1 (0.1mmol, 27mg) was weighed and added to a 10ml reaction bottle containing a clean stirring bar, 4mL of toluene solution was added, and then p-toluene isocyanate (0.1mmol, 13μL) was added and heated to reflux for 8 hours. After the reaction was completed, 20mL of saturated brine and ethyl acetate (20mL×3) were used for extraction, the organic phases were combined, anhydrous sodium sulfate was added for drying, and the crude product was obtained by rotary evaporation after filtration. It was purified by preparative silica gel plate (DCM:MeOH=30:1) to obtain 14mg of white solid S24 with a yield of 36%. 1 HNMR(400MHz, CDCl3)δ=7.24–7.18(m,2H),7.10–7.06(m,2H),5.59–5.57(5.38–5.35)(m,1H),3.49–3.23(m,3H),2.29(2.28) (s,3H),2.24–2.05(m,3H),1.91–1.78(m,3H),1.72–1.69(m,2H),1.50–1.21(m,5H),1.02–0.87(m,9H); HRMS(ESI)Calcd.for C 23 H 33 FNaN2O3[(M+Na) + ]427.2373,found427.2374.

[0114] Performance Testing

[0115] The amine fluorinated curcuminol derivative synthesized by the present invention has anti-tumor activity, and the corresponding cell proliferation inhibition activity analysis is carried out using the CCK-8 method, and the specific operation is as follows:

[0116] 1. Sample preparation: Dissolve with DMSO (Merck), add PBS (-) to make a 0.6 mM solution, and then dilute with PBS (-) containing DMSO to a 30 μM or 10 μM solution.

[0117] 2. Tumor cell lines

[0118] Jurkat, Raji, K562, MDA-MB-231, HCT116, Capan-1, Hela, U251, A549, Huh7.

[0119] 3. Culture medium

[0120] RPMI 1640+10%FBS+double antibody

[0121] 4. Other Materials

[0122] Full wavelength multifunctional microplate reader: VarioskanFlash model, Thermo scientific manufacturer, imported 96-well plate, etc.

[0123] 5. Experimental method: This experiment uses the CCK-8 method. Add 57 μL (59 μL) of 2×10 5 Cell suspension of 100 μL / mL was placed in a 37°C, 5% CO2 incubator. After 48 hours, 3 μL (1 μL) of sample solution was added to each well in turn, and three replicate wells were set up to make the compound concentration 30 μM (10 μM). Incubate for 48 hours at 37°C, 5% CO2. Then 5 μL of CCK-8 solution was added to each well and placed in an incubator for 2-4 hours. Then the OD value at 450nm was measured with a full-wavelength multifunctional microplate reader.

[0124] Among them, a) the drug concentration of the experimental group was 10 μM.

[0125] The results of in vitro non-solid tumor cell inhibitory activity are shown in Table 2:

[0126] Table 2 In vitro non-solid tumor cell inhibitory activity

[0127]

[0128]

[0129] The results of in vitro solid tumor cell inhibition activity are shown in Table 3; wherein, the administration concentration of a) the experimental group was 30 μM.

[0130] Table 3 In vitro solid tumor cell inhibitory activity

[0131]

[0132]

[0133]

[0134] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by any technician familiar with the technical field within the technical scope disclosed by the present invention should be covered within the protection scope of the present invention.

Claims

1. An amine fluoride curcuminol derivative compound, characterized in that: The structure of the compound is shown in general formula I: Wherein, in the general formula I, the structure of the compound is selected from one of the structural formulas corresponding to the following serial numbers; 2. A use of the amine fluoride curcuminol derivative compound as claimed in claim 1, characterized in that: Used in preparing drugs for treating malignant hematological tumors.

3. A method for preparing the amine fluoride curcumol derivative compound as claimed in claim 1, characterized in that: The steps include at least: (1) Curcumol, Compound II and Selectfluor undergo a photocatalytic amine fluorination reaction in the presence of a catalyst to obtain Compound III; the Selectfluor is 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo-2.2.2-octane bis(tetrafluoroborate); (2) Compound III was treated with zinc powder and potassium dihydrogen phosphate at room temperature to obtain the primary amino product S1; The structural formula of the compound II is shown below: (3): Compound S1 undergoes a nucleophilic addition reaction with an acyl chloride or a sulfonyl chloride to obtain an amine fluoride curcuminol derivative compound.

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