Process for the electrochemical oxidation synthesis of sulfonylated spirocyclic pyrimidines

Abstract

The application discloses a method for synthesizing a sulfonated spirocyclic pyrimidine compound through electrochemical oxidation, and belongs to the field of organic chemistry. In a non-separation electrolytic cell, 1,3-dimethyl-5-(prop-2-yn-1-oxyl) pyrimidine-2,4(1H,3H)-dione compound 1 and sodium sulfinate compound 2 are used as raw materials, and a constant current electrolysis reaction is carried out in an organic solvent in the presence of potassium iodide to obtain a sulfonated spirocyclic pyrimidine compound 3. The method has the advantages of mild reaction conditions, high selectivity and environmental friendliness, and provides a simple and effective synthesis route for sulfonization of a pyrimidine compound.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a sulfonated spiro pyrimidine compound, in particular to a method for electrochemical oxidation synthesis of a sulfonated spiro pyrimidine compound, and belongs to the field of organic chemistry. BACKGROUND

[0002] Spiro pyrimidine is a kind of pyrimidine connected by spiro carbon atom and ring fragment, which has attracted extensive research attention due to its biological importance. Typical examples include spirobarbiturate, which is an important spiro pyrimidine analogue, known for its diverse biological activities and has important biological significance, and has broad application prospects in the field of pharmaceutical and biomedical.

[0003] The synthesis of sulfonated spiro pyrimidine compounds is not sufficient, and only a few reports have disclosed the synthesis of spirofuroxasone. In 2004, Majumdar et al. reported the synthesis of 6-spiro-tetrahydrobenzofuran pyrimidine by amino hydride mediated intramolecular aryl cyclization (Synthesis, 2004, 11, 1864-1868). Subsequently, the research group proved that AgSbF6 and FeCl3 were effective for the construction of dihydrofuran chain spiro pyrimidine by intramolecular 5-external electrophilic cyclization of C5 propyl oxy pyrimidine (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 promoter, and the product lacks structural diversity.

[0004] Therefore, it is necessary to further research and develop more universal and effective synthesis strategies, especially by using a free radical cyclization procedure to expand its structural diversity, and to develop a new green oxidation system. SUMMARY

[0005] In order to overcome the above technical defects, the present application discloses a preparation method for electrochemical oxidation synthesis of sulfonated spiro pyrimidine compounds. The preparation method obtains sulfonated spiro pyrimidine compounds under the conditions of anodic oxidation and in the presence of potassium iodide. The method has mild reaction conditions, is environmentally friendly, has high yield and good purity, and is suitable for industrial production.

[0006] The present application provides a method for electrochemical oxidation synthesis of sulfonated spiro pyrimidine compounds, which comprises the following steps: in a non-separation electrolytic cell, 1,3-dimethyl-5-(prop-2-yn-1-oxyl) pyrimidine-2,4(1H,3H)-dione compound 1 and sodium sulfinic acid compound 2 are used as raw materials, and constant current electrolysis reaction is carried out in the presence of iodide in an organic solvent to obtain spiro pyrimidine derivative 3. The reaction equation is as follows:

[0007]

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

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

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

[0011]

[0012]

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

[0014]

[0015]

[0016] Further, 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. Preferably acetonitrile / water mixed solvent.

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

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

[0019] Further, in the above technical solution, the constant current refers to the constant output current of the power supply, and the constant current output current is 5-15mA. Preferably 10mA.

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

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

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

[0023] Further, 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 generally the reaction endpoint is when compound 1 disappears or no longer reacts.

[0024] Further, in the above technical solution, after the reaction is completed, if a crude compound is obtained, conventional means such as preparative HPLC, preparative TLC or recrystallization can be used for separation and purification.

[0025] The positive progress effect of the present application is that the preparation method of the present application can avoid the use of conventional expensive oxidizing agents, and can obtain a product with high selectivity, high yield and good purity, and is more suitable for industrial production. DETAILED DESCRIPTION

[0026] The present application will be further described by way of examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[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), 10 mA, reaction at 27°C for 3 h.

[0032] Example 2

[0033] Example 2-1

[0034]

[0035] In a non-divided electrolysis 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 mixed solvent 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 complete consumption of the substrate (monitored by TLC). After the reaction, the solvent was removed under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography (PE / EA: 5 / 1) to give white solid 4b (77.4 mg, yield 80%). 1 H NMR (600 MHz, CDC13): δ 7.49 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 5.36 (d, J = 13.2 Hz, 1H), 5.27 (d, J = 13.2 Hz, 1H), 4.75 (s, 1H), 3.52 (s, 1H), 3.05 (s, 3H), 2.60 (s, 3H), 1.27 (s, 9H). 13 C NMR (150 MHz, CDC13): δ 167.1, 153.0, 151.0, 145.7, 141.5, 139.2, 134.0, 129.0, 128.0, 126.9, 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] Following the same reaction conditions as described above, starting from 1p (55.2 mg, 0.2 mmol), white solid 4o (75.2 mg, yield 90%) was obtained. 1H NMR (600 MHz, DMSO-d6): δ 7.73 (t, J = 7.2 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.01 (t, J = 4.2 Hz, 1H), 6.92 - 6.72 (m, 2H), 5.16 (d, J = 13.8 Hz, 1H), 5.12 (d, J = 13.8 Hz, 1H), 4.94 (d, J = 5.4 Hz, 1H), 2.93 (s, 3H), 2.57 (s, 3H). 13 C NMR (150 MHz, DMSO-d6): δ 167.0, 151.0, 142.6, 140.1, 138.8, 134.6, 129.6, 129.5, 129.3, 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] From 1s (38.8 mg, 0.2 mmol) under the same reaction conditions as described above, white solid 4r (32.8 mg, yield 43%) was obtained. 1 H NMR (600 MHz, CDCl3): δ 7.94 - 7.86 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 7.2 Hz, 2H), 4.96 (d, J = 12.0 Hz, 1H), 4.90 (d, J = 12.6 Hz, 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 = 7.2 Hz, 3H). 13 C NMR (150 MHz, CDCl3): δ 167.5, 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 described in Example 2 above, the reaction substrates were changed to obtain different compounds 4, and the results of the reactions were as follows:

[0043]

[0044]

[0045] Example 3

[0046] Example 3-1

[0047]

[0048] In a non-divided electrolytic cell, substrate la (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 mixed solvent 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 complete consumption of the substrates (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 obtain white solid 3b (84.9 mg, yield 96%). 1 H NMR (400 MHz, CD2Cl2): δ 7.46-7.34 (m, 3H), 7.30 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 7.2 Hz, 2H), 5.29 (d, J = 12.8 Hz, 1H), 5.21 (d, J = 13.2 Hz, 1H), 4.80 (s, 1H), 3.19 (s, 1H), 3.01 (s, 3H), 2.63 (s, 3H), 2.40 (s, 3H). 13 CNMR (100 MHz, CDC13): δ 167.2, 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] Following the same reaction conditions described above, starting from 2aa (85.7 mg, 0.4 mmol), white solid 3aa (54.7 mg, yield 57%) was obtained. 1 H NMR (400 MHz, CDC13): δ 7.93 - 7.80 (m, 3H), 7.75 - 7.50 (m, 4H), 7.25 - 7.09 (m, 3H), 6.68 (d, J = 7.6 Hz, 2H), 5.44 (d, J = 12.8 Hz, 1H), 5.35 (d, J = 13.2 Hz, 1H), 4.79 (s, 1H), 3.23 (s, 1H), 3.02 (s, 3H), 2.65 (s, 3H). 13 C NMR (150 MHz, CDC13): δ 166.9, 151.0, 145.4, 141.9, 135.8, 135.5, 131.9, 130.4, 129.82, 129.80, 129.7, 129.6, 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] Following the same reaction conditions described above, starting from 2ah (74.1 mg, 0.4 mmol), white solid 3ah (87.0 mg, yield 97%) was obtained. 1 H NMR (400 MHz, CDC13): δ 7.93 - 7.80 (m, 3H), 7.75 - 7.50 (m, 4H), 7.25 - 7.09 (m, 3H), 6.68 (d, J = 7.6 Hz, 2H), 5.44 (d, J = 12.8 Hz, 1H), 5.35 (d, J = 13.2 Hz, 1H), 4.79 (s, 1H), 3.23 (s, 1H), 3.02 (s, 3H), 2.65 (s, 3H). 13C NMR (100 MHz, CDC13): δ 175.4, 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] Example 3-4

[0056]

[0057] From 2ap (152.5 mg, 0.4 mmol) under the same reaction conditions as described above, white solid 3ap (97.2 mg, yield 75%) was obtained. 1 H NMR (600 MHz, CDC13): δ 7.46 - 7.42 (m, 2H), 7.37 - 7.30 (m, 3H), 7.26 (t, J = 7.2 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.79 - 6.69 (m, 3H), 5.35 (d, J = 13.2 Hz, 1H), 5.25 (d, J = 13.2 Hz, 1H), 4.79 (s, 1H), 3.65 (s, 1H), 3.07 (s, 3H), 2.65 (s, 3H), 2.38 (s, 3H). 13 C NMR (100 MHz, CDC13): δ 166.9, 151.0, 146.3, 145.4, 144.4 (q, J C-F = 38.0 Hz), 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 = 268.0 Hz), 106.7, 92.8, 82.0, 75.9, 34.2, 28.0, 21.4. 19 F NMR (565 MHz, CDC13): 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, the reaction substrates were changed to obtain different compounds 3, and the results of the reaction are as follows:

[0059]

[0060] Activity test of representative compounds of Example 4

[0061] The anti-cancer activity of the compounds is evaluated by studying the anti-proliferative activity on cancer cells using the CCK-8 method.

[0062] Specifically, first, cells were seeded into a 96-well plate at a density of 5000 cells per well in 100 μL of medium per well and incubated at 37°C and 5% CO2 overnight. The next day, 100 μL of the test compound diluted with medium (concentration of 0.03 nM-30 μM) was added to each well, and then the cells were incubated at 37°C and 5% CO2 for 72 hours. Then, 10 μL of CCK8 was added to each well, and the 96-well plate was incubated at 37°C for 2 hours. The absorbance was measured at 450 nm using an EnVision multilabel Reader (Perkinermer) with 630 nm as the reference wavelength, and the IC50 value was calculated using GraphPad Prism 6.0 software. All experiments were performed in duplicate and repeated twice. Hela and HCT-116 cancer cells were selected as the research object, and 5-fluorouracil (5-FU) was used as the positive control of the drug.

[0063] The anti-cancer activity results of some compounds are as follows:

[0064]

[0065]

[0066] The above examples describe the basic principles, main features and advantages of the present application. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the scope of the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. A method for the electrochemical oxidation synthesis of sulfonyl spirocyclic pyrimidine compounds, characterized in that, The process includes the following steps: In a non-separating electrolytic cell, using 1,3-dimethyl-5-(prop-2-ynyl-1-oxy)pyrimidine-2,4(1H,3H)-diketone compound 1 and sodium sulfinate compound 2 as raw materials, a constant current electrolysis reaction is carried out in an organic solvent in the presence of iodide to obtain spirocyclic pyrimidine derivative 3; the reaction equation is as follows: Among them, R 1 The group is selected from phenyl, substituted phenyl, thiophene, benzofuran, ethyl, cyclopropane, and the substituent of the substituted phenyl group is selected from one or more of C1-C4 alkyl, C1-C2 alkoxy, phenyl, halogen, ester, cyano, and trifluoromethyl; R 2 The organic solvent is selected from phenyl, substituted phenyl, naphthalene, thiophene, pyridine, benzofuran, n-butyl, cyclopropane, and the substituent of the substituted phenyl is selected from one or more of C1-C4 alkyl, alkoxy, phenyl, halogen, ester, cyano, nitro, trifluoromethyl, and trifluoromethoxy; the organic solvent is selected from acetonitrile / water mixed solvent; the iodide is selected from potassium iodide, tetrabutylammonium iodide, or ammonium iodide.

2. The method for electrochemical oxidation synthesis of sulfonyl 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 sulfonated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The volume ratio of the acetonitrile / water mixed solvent is 5:

1.

4. The method for synthesizing sulfonated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The constant current refers to the power supply output current being constant, and the output current of the constant current is 5-15mA.

5. The method for synthesizing sulfonated spirocyclic pyrimidine compounds according to claim 1, characterized in that: The reaction also includes an additive, namely HOAc; the molar ratio of compound 1, compound 2 and the additive is 1:2:0.

1.

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

7. The method for synthesizing sulfonated spirocyclic pyrimidine compounds according to claim 1, characterized in that: During the electrolysis reaction, the anode material is selected from carbon felt, platinum sheet, or graphite carbon rod; the cathode material is selected from platinum sheet or stainless steel.

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