Method for synthesizing sulfonylated spiropyrimidine compound through electrochemical oxidation

Abstract

The invention discloses a method for synthesizing sulfonylated spiropyrimidine compounds through electrochemical oxidation, and belongs to the field of organic chemistry. In a non-separation electrolytic tank, a 1, 3-dimethyl-5-(propyl-2-alkyne-1-oxy) pyrimidine-2, 4 (1H, 3H)-diketone compound 1 and a sodium sulfinate compound 2 are used as raw materials, in the presence of potassium iodide, a constant-current electrolytic reaction is performed in an organic solvent, and a sulfonylated spiropyrimidine compound 3 is obtained; the method disclosed by the invention is mild in reaction condition, high in selectivity and environment-friendly, and provides a simple and effective synthesis way for sulfonylation of pyrimidine compounds.

Description

Technical Field

[0001] The invention relates to a method for preparing a sulfonylated spirocyclic pyrimidine compound, in particular to a method for synthesizing the sulfonylated spirocyclic pyrimidine compound by electrochemical oxidation, and belongs to the field of organic chemistry. Background Art

[0002] Spiropyrimidines are a class of pyrimidines connected to ring segments through helical carbon atoms. They have attracted extensive research attention due to their biological importance. Typical examples include spirobarbiturates, which are important spiropyrimidine analogs known for their diverse biological activities, have important biological significance, and have broad application prospects in the pharmaceutical and biomedical fields.

[0003] The synthesis of sulfonylated spirocyclic pyrimidine compounds is still insufficient, and only a few reports disclose the synthesis of spirofuranone. In 2004, Majumdar et al. reported an aminohydride-mediated intramolecular aromatic cyclization, which made the synthesis of 6-spiro-tetrahydrobenzofuran pyrimidine possible (Synthesis, 2004, 11, 1864-1868). Subsequently, the research team proved that AgSbF6 and FeCl3 were effective for the construction of dihydrofuran-tethered spiropyrimidine by 5-exo-tri-electrophilic cyclization of C5 propyloxypyrimidine molecules (Synthesis, 2013, 45, 3164-3172; New J.Chem., 2011, 35, 1355-1359). However, these methods usually require multiple steps, relatively harsh reaction conditions, use of additional equivalents of Lewis acid promoters, and the products lack structural diversity.

[0004] Therefore, it is necessary to further study and develop more general and efficient synthetic strategies, especially by using free radical cyclization procedures to expand their structural diversity and develop new green oxidation systems. Summary of the invention

[0005] In order to overcome the above technical defects, the present invention discloses a preparation method for synthesizing sulfonated spirocyclic pyrimidine compounds by electrochemical oxidation; the preparation method obtains sulfonated spirocyclic pyrimidine compounds under electric anode oxidation conditions and under the catalysis of potassium iodide; the method has mild reaction conditions, is environmentally friendly, has high yield, good purity, and is suitable for industrial production.

[0006] The present invention provides a method for electrochemically oxidizing and synthesizing sulfonylated spirocyclic pyrimidine compounds, comprising the following steps: in a non-separation electrolytic cell, using a 1,3-dimethyl-5-(prop-2-yn-1-oxy)pyrimidine-2,4(1H,3H)-dione compound 1 and a sodium sulfinate compound 2 as raw materials, and subjecting them to constant current electrolysis reaction in an organic solvent in the presence of iodide to obtain a spirocyclic pyrimidine derivative 3; the reaction equation is as follows:

[0007]

[0008] Among them, R 1 is selected from phenyl, substituted phenyl, thiophene, benzofuran, ethyl, cyclopropane, and the substituent of the substituted phenyl is selected from one or more of C1-C4 alkyl, C1-C2 alkoxy, phenyl, halogen, ester, cyano, and trifluoromethyl; R 2 The substituent of the substituted phenyl group is selected from phenyl, substituted phenyl, naphthalene, thiophene, pyridine, benzofuran, n-butyl, and cyclopropane. The substituent of the substituted phenyl group is selected from one or more of C1-C4 alkyl, alkoxy, phenyl, halogen, ester, cyano, nitro, trifluoromethyl, and trifluoromethoxy.

[0009] Furthermore, in the above technical solution, the halogen is selected from fluorine, chlorine, bromine or iodine.

[0010] Furthermore, in the above technical solution, the representative structure of compound 1 is as follows:

[0011]

[0012]

[0013] Furthermore, in the above technical solution, the representative structure of compound 2 is as follows:

[0014]

[0015]

[0016] Furthermore, in the above technical solution, the organic solvent is selected from one or more of acetonitrile, water, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, etc. An acetonitrile / water mixed solvent is preferred.

[0017] Furthermore, in the above technical solution, the volume ratio of the acetonitrile / water mixed solvent is 5:1.

[0018] Furthermore, in the above technical solution, the iodide is selected from potassium iodide, tetrabutylammonium iodide or ammonium iodide; preferably potassium iodide.

[0019] Furthermore, in the above technical solution, the constant current means that the output current of the power supply is constant, and the constant current output current is 5-15mA, preferably 10mA.

[0020] Furthermore, in the above technical solution, the molar ratio of the pyrimidine compound 1 and the sodium sulfinate compound 2 to the additive is 1:2:0.1.

[0021] Furthermore, in the above technical solution, the constant current electrolysis reaction temperature is selected from 20-30°C.

[0022] Furthermore, in the above technical solution, during the electrolysis reaction, the electrode anode material is selected from carbon felt, platinum sheet, graphite carbon rod, preferably carbon felt. The cathode material is selected from platinum sheet, stainless steel, preferably platinum sheet.

[0023] Furthermore, in the above technical solution, in the constant current electrolysis reaction, the progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when compound 1 disappears or no longer reacts.

[0024] Furthermore, in the above technical solution, if a crude compound is obtained after the reaction, it can be separated and purified by conventional means such as preparative HPLC, preparative TLC or recrystallization.

[0025] The positive and progressive effect of the present invention is that the preparation method of the present invention can avoid the use of conventional expensive oxidants, and can obtain highly selective products with high yield and good purity, which is more suitable for industrial production. DETAILED DESCRIPTION

[0026] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0027] Example 1

[0028] Condition optimization experiment

[0029]

[0030]

[0031] The optimal conditions were finally determined: compound 1 (0.2 mmol), compound 2 (0.40 mmol), KI (10 mol%), CH3CN / H2O (5 / 1), and 10 mA at 27°C for 3 h.

[0032] Example 2

[0033] Example 2-1

[0034]

[0035] In a non-divided electrolytic cell, substrate 1c (65.2 mg, 0.20 mmol), sodium benzenesulfinate 2a (65.7 mg, 0.4 mmol) and KI (3.3 mg, 0.01 mmol, 10 mol%) were dissolved in a mixed solvent of CH3CN / H2O (5 mL / 1 mL). The electrolysis was carried out at 27 ° C (oil bath temperature) using a constant current of 10.0 mA until the substrate was completely consumed (monitored by TLC). After the reaction, the solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA: 5 / 1) to give a white solid 4b (77.4 mg, yield 80%). 1 H NMR (600MHz, CDCl3): δ7.49(t,J=7.8Hz,1H),7.45(d,J=7.8Hz,2H),7.29(t,J=7.8Hz,2H),7.21(d,J=7.8Hz,2H),6.63(d,J= 8.4Hz,2H),5.36(d,J=13.2Hz,1H),5.27(d,J=13.2Hz,1H),4.75(s,1H),3.52(s,1H),3.05(s,3H),2.60(s,3H),1.27(s,9H). 13 C NMR (150MHz, CDCl3): δ167.1,153.0,151.0,145.7,141.5,139.2,134.0,129.0,128.0,1 26.9,125.3,125.1,92.6,82.1,76.0,34.8,34.1,31.2,28.0.HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 25 H 28 N2NaO6S + 507.1560, found 507.1556.

[0036] Example 2-2

[0037]

[0038] Using the same reaction conditions as above, starting from 1p (55.2 mg, 0.2 mmol), a white solid 4o (75.2 mg, yield 90%) was obtained. 1H NMR (600MHz, DMSO-d6): δ7.73(t,J=7.2Hz,1H),7.65–7.61(m,2H),7.57(t,J=7.8Hz,2H),7.01(t,J=4.2Hz,1H),6 .92–6.72(m,2H),5.16(d,J=13.8Hz,1H),5.12(d,J=13.8Hz,1H),4.94(d,J=5.4Hz,1H),2.93(s,3H),2.57(s,3H). 13 C NMR (150MHz, DMSO-d6): δ167.0,151.0,142.6,140.1,138.8,134.6,129.6,129.5,1 29.3,127.3,126.9,126.8,92.6,80.4,74.9,32.9,27.5.HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 19 H 18 N2NaO5S2 + 441.0549, found 441.0548.

[0039] Example 2-3

[0040]

[0041] Using the same reaction conditions as above, starting from 1s (38.8 mg, 0.2 mmol), a white solid 4r (32.8 mg, yield 43%) was obtained. 1 H NMR (600MHz, CDCl3): δ7.94–7.86(m,2H),7.70(t,J=7.8Hz,1H),7.60(t,J=7.2Hz,2H),4.96(d,J=12.0Hz,1H),4.90( d,J=12.6Hz,1H),4.82(s,1H),3.19(s,3H),3.15(s,3H),2.62–2.55(m,1H),2.52–2.46(m,1H),1.01(t,J=7.2Hz,3H). 13 CNMR (150MHz, CDCl3): δ167.5,152.5,149.6,139.9,137.6,134.6,129.9,127.6,91.4,82.4,75.2,35.2,28.4,18.7,13.6.HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 17 H 20 N2NaO6S+ 403.0934, found 403.0931.

[0042] Using the reaction conditions of Example 2 above, changing the reaction substrate, different compounds 4 were obtained, and the reaction results were as follows:

[0043]

[0044]

[0045] Example 3

[0046] Example 3-1

[0047]

[0048] In a non-divided electrolytic cell, substrate 1a (54.0 mg, 0.20 mmol), substrate 2b (71.3 mg, 0.4 mmol) and KI (3.3 mg, 0.01 mmol, 10 mol%) were dissolved in a mixed solvent of CH3CN / H2O (5 mL / 1 mL). The electrolysis was carried out at 27 ° C (oil bath temperature) using a constant current of 10.0 mA until the substrate was completely consumed (monitored by TLC). After the reaction, the solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA: 5 / 1) to give a white solid 3b (84.9 mg, yield 96%). 1 H NMR (400MHz, CD2Cl2): δ7.46–7.34(m,3H),7.30(t,J=7.6Hz,2H),7.21(d,J=8.0Hz,2H),6.76(d,J=7.2Hz,2H),5 .29(d,J=12.8Hz,1H),5.21(d,J=13.2Hz,1H),4.80(s,1H),3.19(s,1H),3.01(s,3H),2.63(s,3H),2.40(s,3H). 13 CNMR (100MHz, CDCl3): δ167.2,151.3,146.1,145.3,142.0,136.7,130.3,129.8,129. 0,128.6,128.2,127.6,93.1,82.6,76.3,34.4,28.0,21.8.HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 22 H 22 N2NaO6S + 465.1091, found 465.1088.

[0049] Example 3-2

[0050]

[0051] Using the same reaction conditions as above, starting from 2aa (85.7 mg, 0.4 mmol), a white solid 3aa (54.7 mg, yield 57%) was obtained. 1 H NMR (400MHz, CDCl3): δ7.93–7.80(m,3H),7.75–7.50(m,4H),7.25–7.09(m,3H),6.68(d,J=7.6Hz,2H) ,5.44(d,J=12.8Hz,1H),5.35(d,J=13.2Hz,1H),4.79(s,1H),3.23(s,1H),3.02(s,3H),2.65(s,3H). 13 C NMR (150MHz, CDCl3): δ166.9,151.0,145.4,141.9,135.8,135.5,131.9,130.4,129.82,129.80,129.7,1 29.6,128.3,128.2,128.0,127.8,127.1,122.2,92.7,82.3,76.2,34.3,28.0.HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 25 H 22 N2NaO6S + 501.1091, found 501.1085.

[0052] Example 3-3

[0053]

[0054] Using the same reaction conditions as above, starting from 2ah (74.1 mg, 0.4 mmol), a white solid 3ah (87.0 mg, yield 97%) was obtained. 1 H NMR (400MHz, CDCl3): δ7.40–7.27(m,3H),6.75(d,J=7.2Hz,2H),5.45(d,J=12.8Hz,1H),5.34(d ,J=13.2Hz,1H),4.78(s,1H),3.36(s,1H),3.12(s,3H),2.64(s,3H),2.26(s,3H),2.04(s,3H). 13C NMR (100MHz, CDCl3): δ175.4,167.0,157.6,151.0,145.8,142.0,130.3,129.1,128. 0,126.6,115.8,92.7,81.8,76.2,34.0,28.2,12.1,10.4.HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 20 H 21 N3NaO7S + 470.0992, found 470.0988.

[0055] Embodiment 3-4

[0056]

[0057] Using the same reaction conditions as above, starting from 2ap (152.5 mg, 0.4 mmol), a white solid 3ap (97.2 mg, yield 75%) was obtained. 1 H NMR (600MHz, CDCl3): δ7.46–7.42(m,2H),7.37–7.30(m,3H),7.26(t,J=7.2Hz,2H),7.18(d,J=7.8Hz,2H),7.07(d,J=7.8Hz,2H),6 .79–6.69(m,3H),5.35(d,J=13.2Hz,1H),5.25(d,J=13.2Hz,1H),4.79(s,1H),3.65(s,1H),3.07(s,3H),2.65(s,3H),2.38(s,3H). 13 C NMR (100MHz, CDCl3): δ166.9,151.0,146.3,145.4,144.4(q,J C-F =38.0Hz),143.7,141.4,140.0,138.4,130.0,129.9,128.9,128.8,128.6,128.1,127.1,125.6,125.3,121.1(q,J C-F =268.0Hz),106.7,92.8,82.0,75.9,34.2,28.0,21.4. 19 F NMR(565MHz,CDCl3):δ-62.5.HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 32 H 27 F3N4NaO6S +675.1496, found 675.1493.

[0058] Using the reaction conditions of Example 3 above, changing the reaction substrate, different compounds 3 were obtained, and the reaction results were as follows:

[0059]

[0060] Example 4 Activity Test of Representative Compounds

[0061] The anticancer activity of the compounds provided by the present invention is evaluated by studying the antiproliferative activity on cancer cells using the CCK-8 method.

[0062] The specific method is that, first, the cells are inoculated into a 96-well plate with 100 μL of culture medium per well at a density of 5000 cells per well, and incubated overnight at 37°C and 5% CO2. On the second day, 100 μL of the test compound diluted with culture medium (concentration of 0.03nM-30 μM) is added to each well, and then the cells are incubated at 37°C and 5% CO2 for 72 hours. Then, 10 μL of CCK8 is added to each well, and the 96-well plate is incubated at 37°C for 2 hours. The absorbance is measured at 450nm using EnVisionmultilatelbel Reader (Perkinermer) (using 630nm as the reference wavelength), and the IC50 value is calculated using GraphPad Prism 6.0 software. All experiments were administered with two parallel samples and repeated twice. Hela and HCT-116 cancer cells were selected as research objects, and 5-fluorouracil (5-FU) was used as a positive control for the drug.

[0063] The anticancer activity results of some compounds are as follows:

[0064]

[0065]

[0066] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing sulfonylated spirocyclic pyrimidine compounds by electrochemical oxidation, characterized in that: The method comprises the following steps: in a non-separation electrolytic cell, using a 1,3-dimethyl-5-(prop-2-yn-1-oxy)pyrimidine-2,4(1H,3H)-dione compound 1 and a sodium sulfinate compound 2 as raw materials, and in the presence of iodide, performing a constant current electrolytic reaction in an organic solvent to obtain a spirocyclic pyrimidine derivative 3; the reaction equation is as follows: Among them, R 1 is selected from phenyl, substituted phenyl, thiophene, benzofuran, ethyl, cyclopropane, and the substituent of the substituted phenyl is selected from one or more of C1-C4 alkyl, C1-C2 alkoxy, phenyl, halogen, ester, cyano, and trifluoromethyl; R 2 The substituent of the substituted phenyl group is selected from phenyl, substituted phenyl, naphthalene, thiophene, pyridine, benzofuran, n-butyl, and cyclopropane. The substituent of the substituted phenyl group is selected from one or more of C1-C4 alkyl, alkoxy, phenyl, halogen, ester, cyano, nitro, trifluoromethyl, and trifluoromethoxy.

2. The method for electrochemically oxidizing and synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The halogen is selected from fluorine, chlorine, bromine or iodine.

3. The method for synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The organic solvent is selected from an acetonitrile / water mixed solvent.

4. The method for synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 3, characterized in that: The volume ratio of the acetonitrile / water mixed solvent is 5:

1.

5. The method for synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The iodide is selected from potassium iodide, tetrabutylammonium iodide or ammonium iodide.

6. The method for synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The constant current means that the current output by the power supply is constant, and the output current of the constant current is 5-15mA.

7. The method for synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The molar ratio of the compound 1, compound 2 and the additive is 1:2:0.

1.

8. The method for synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The constant current electrolysis reaction temperature is selected from 20-30°C.

9. The method for synthesizing sulfonylated spirocyclic pyrimidine compounds according to claim 1, characterized in that: During the electrolytic reaction, the electrode anode material is selected from carbon felt, platinum sheet, and graphite carbon rod; the cathode material is selected from platinum sheet and stainless steel.

Images