Preparation method of phenazine compound

Abstract

The invention discloses a preparation method of a phenazine compound, and belongs to the technical field of synthesis of phenazine derivatives. According to the key point of the technical scheme, a catechol compound 1, an o-phenylenediamine compound 2 and PhI (OAc) 2 are subjected to cascade reaction in a cyclic ether solvent to prepare the target product phenazine compound 3. The catechol compound 1, o-phenylenediamine 2 and PhI (OAc) 2 are subjected to domino reaction to construct a phenazine structural framework to synthesize a series of phenazine derivatives, the synthesis process is simple and easy to control, the structures of target products are diversified, and a foundation is laid for synthesis of drug molecules containing phenazine structures.

Description

Technical Field

[0001] The present invention belongs to the technical field of synthesis of phenazine derivatives, and specifically relates to a method for preparing phenazine compounds. Background Art

[0002] Phenazines are a class of secondary metabolites with redox activity produced by Gram-positive bacteria, Gram-negative bacteria and archaea. Compounds containing phenazine nuclei have a variety of biological activities such as antibacterial, antitumor and antiviral. In addition, phenazines are also widely used in dyes, biosensors, pesticides and organic batteries. Since phenazines are widely present in nature and have important application value, their synthesis has always received close attention. The reported synthesis methods mainly include: high temperature and low efficiency Wohl-Aue phenazine synthesis; oxidation of catechol with cerium sulfate, o-tetrachlorobenzoquinone or silver oxide to generate o-benzoquinone derivatives, and then condensation with o-phenylenediamine derivatives under acidic conditions; high temperature reaction of o-phenylenediamine and catechol, palladium-catalyzed cross-coupling-oxidation reaction, metal old catalyzed tandem cyclization reaction of azobenzene with azide and nitroso compounds, dipole flip strategy of 2-aryldiazaborane, oxidation or electro-oxidative demethylation of dibenzodiazepines, etc.

[0003] Although a variety of synthetic methods for phenazines have been reported, these synthetic methods all have certain shortcomings to a greater or lesser extent, such as limited substrate availability, lengthy pre-preparation steps required to obtain key intermediates, difficult and unstable intermediate preparation, limitations on phenazine substitution positions, low step effectiveness and atom efficiency, use of toxic reagents, and extremely low or high temperatures, etc. Therefore, the direct synthesis of phenazines from simple and commercially available starting materials, especially the research on functional products, continues to attract the attention of the scientific community. The present invention designs a new method for constructing a phenazine ring and synthesizes a series of phenazine compounds with diverse structures, laying a foundation for further preparation of phenazine drug molecules. Summary of the invention

[0004] The technical problem solved by the present invention is to provide a method for preparing phenazine compounds with a simple and easy-to-control synthesis process. The method comprises the steps of: reacting a catechol compound with an o-phenylenediamine compound and PhI(OAc) 2 A series of phenazine derivatives synthesized by constructing the phenazine structural skeleton through domino reaction.

[0005] The present invention adopts the following technical solution to solve the above technical problems: a method for preparing phenazine compounds, characterized in that the specific steps are: reacting a catechol compound 1 with an o-phenylenediamine compound 2 and PhI(OAc) 2 The target product phenazine compound 3 was prepared by tandem reaction in a cyclic ether solvent. The reaction equation of the preparation process is:

[0006]

[0007] Where R 1 is hydrogen, alkyl, halogen, alkoxy, carboxyethyl or benzoyl, R 2 is hydrogen, alkyl, halogen, trifluoromethyl, nitrile, nitro, benzoyl, carboxyl, carbamoyl or alkoxycarbonyl, R 2 It is a mono- or di-substituted.

[0008] It is further defined that the phenazine compound 3 is one of the following compounds:

[0009]

[0010] It is further defined that the catechol compound 1, o-phenylenediamine 2 and PhI(OAc) 2 The feeding molar ratio is 1:1:1~2.

[0011] It is further specified that the cyclic ether solvent is one or more of tetrahydrofuran or dioxane.

[0012] It is further defined that the reaction temperature during the preparation process is -20°C to room temperature.

[0013] Further defined, catechol and PhI(OAc) 2 The mixture was dissolved in a mixed solvent of tetrahydrofuran and dioxane in a volume ratio of 1:1, stirred and reacted at -15°C for 10 to 30 minutes, and then o-phenylenediamine was added to continue the reaction for 3 to 5 minutes. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the target product phenazine compound 3 was obtained by column chromatography separation.

[0014] Compared with the prior art, the present invention has the following advantages and beneficial effects: the present invention combines a catechol compound 1 with o-phenylenediamine 2 and PhI(OAc) 2 A series of phenazine derivatives were synthesized by constructing a phenazine structural skeleton through domino reaction. The synthesis process is simple and easy to control, and the target product structures are diverse, laying the foundation for the synthesis of drug molecules containing phenazine structures. DETAILED DESCRIPTION

[0015] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0016] Analytical instruments and reagents: Nuclear magnetic resonance hydrogen spectrum was recorded by Bruker ASCEND 400 nuclear magnetic resonance instrument, and the unit of chemical shift δ was ppm. All reaction solvents were purified according to conventional methods. Silica gel (200-300 mesh) for column chromatography was produced by Qingdao Ocean Chemical Branch. GF254 high-efficiency plate was used for thin layer chromatography, which was produced by Yantai Chemical Research Institute. All solvents were analytically pure reagents, and all reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd. Iodine, ultraviolet fluorescence and other methods were used for color development. The organic solvent was removed by reduced pressure evaporation in a rotary evaporator.

[0017] Example 1

[0018] 0.5mmol of catechol and 0.75mmol of PhI(OAc) 2 The mixture was dissolved in 2 mL of a mixed solvent of tetrahydrofuran and dioxane (volume ratio 1:1), stirred in an ice-salt bath (-15°C) for 10 minutes, and then 0.5 mmol of o-phenylenediamine was added and stirred for 3 to 5 minutes. After the reaction was completed, the solvent was removed by rotary evaporation. 74.3 mg of compound 3-1 was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1, v / v), with a yield of 83%.

[0019]

[0020] 1 H NMR (400 MHz, CDCl 3 )δ8.26–8.20(m,4H),7.87–7.80(m,4H).

[0021] Example 2

[0022]

[0023] Compound 3-2 was prepared in the same manner as compound 3-1, except that 3-fluorocatechol was used instead of catechol, with a yield of 79%.

[0024] 1 H NMR (400 MHz, CDCl 3 )δ8.37–8.32(m,1H),8.27–8.20(m,1H),8.06(d,J=8.9Hz,1H),7.91–7.85(m,2H),7.77(ddd,J=8.8,7.6,5.5Hz,1H),7.54–7.47(m,1H).

[0025] Example 3

[0026]

[0027] Compound 3-3 was prepared in the same manner as compound 3-1, except that 3-chloro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 60%.

[0028] 1 H NMR (400 MHz, CDCl 3 )δ8.39–8.33(m,1H),8.25–8.20(m,1H),8.16(dd,J=8.8,1.2Hz,1H),7.94(dd,J=7.3,1.2Hz,1H),7.89–7.84(m,2H),7.73(dd,J=8.8,7.3Hz,1H).

[0029] Example 4

[0030]

[0031] Method 1: Compound 3-4 was prepared in the same manner as compound 3-1, except that 3-methylcatechol was used instead of catechol, with a yield of 67%.

[0032] Method 2: Compound 3-4 was prepared in the same manner as compound 3-1, except that 3-methyl-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 60%.

[0033] 1 H NMR (400 MHz, CDCl 3 )δ8.30–8.24(m,1H),8.24–8.19(m,1H),8.06(d,J=8.7Hz,1H),7.85–7.75(m ,2H),7.70(dd,J=8.7,6.8Hz,1H),7.62(dd,J=5.7,1.1Hz,1H),2.91(s,3H).

[0034] Example 5

[0035]

[0036] Compound 3-5 was prepared in the same manner as compound 3-1, except that 3-methoxycatechol was used instead of catechol, with a yield of 99%.

[0037] 1 H NMR (400 MHz, DMSO-D 6)δ8.30–8.25(m,1H),8.24–8.19(m,1H),7.98–7.90(m,2H),7.84(dd,J=8.8,7. 6Hz, 1H), 7.76 (dd, J=8.8, 1.1Hz, 1H), 7.25 (dd, J=7.5, 0.8Hz, 1H), 4.07 (s, 3H).

[0038] Example 6

[0039]

[0040] Compound 3-6 was prepared in the same manner as compound 3-1, except that 2,3-diaminobenzoic acid was used instead of o-phenylenediamine, with a yield of 73%.

[0041] 1 H NMR (400 MHz, CDCl 3 )δ15.54(s,1H),8.94(d,J=7.1Hz,1H),8.49(d,J=8.8Hz,1H),8.30(d,J=7.6Hz,1H),8.24(d,J=7.7Hz,1H),8.07–7.88(m,3H).

[0042] Example 7

[0043]

[0044] Compound 3-7 was prepared in the same manner as compound 3-1, except that methyl 2,3-diaminobenzoate was used instead of o-phenylenediamine, with a yield of 68%.

[0045] 1 H NMR (400 MHz, CDCl 3 )δ8.40–8.34(m,1H),8.34–8.29(m,1H),8.25–8.17(m,2H),7.88–7.81(m,3H),4.10(s,3H).

[0046] Example 8

[0047]

[0048] Compound 3-8 was prepared in the same manner as compound 3-1, except that 2,3-diaminobenzamide was used instead of o-phenylenediamine, with a yield of 90%.

[0049] 1 H NMR (400 MHz, DMSO-D 6)δ9.73(s,1H),8.67(d,J=6.8Hz,1H),8.41–8.30(m,2H),8.23(d,J=8.9Hz,1H),8.12(s,1H),8.06–7.95(m,3H).

[0050] Example 9

[0051]

[0052] Compound 3-9 was prepared in the same manner as compound 3-1, except that 4-fluoro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 90%.

[0053] 1 H NMR (400 MHz, DMSO-D 6 )δ8.36(dd,J=9.5,6.1Hz,1H),8.29–8.20(m,2H),8.04–7.92(m,4H).

[0054] Example 10

[0055]

[0056] Method 1: Compound 3-10 was prepared in the same manner as compound 3-1, except that 4-chlorocatechol was used instead of catechol, with a yield of 64%.

[0057] Method 2: Compound 3-10 was prepared in the same manner as compound 3-1, except that 4-chloro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 84%.

[0058] 1 H NMR (400 MHz, CDCl 3 )δ8.23–8.14(m,4H),7.88–7.81(m,2H),7.75(dd,J=9.3,2.3Hz,1H).

[0059] Embodiment 11

[0060]

[0061] Compound 3-11 was prepared in the same manner as compound 3-1, except that 4-bromo-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 66%.

[0062] 1 H NMR (400 MHz, DMSO-D 6)δ8.47(d,J=2.1Hz,1H),8.25–8.20(m,2H),8.17(d,J=9.2Hz,1H),8.03(dd,J=9.2,2.2Hz,1H),7.98(dd,J=6.8,3.4Hz,2H).

[0063] Example 12

[0064]

[0065] Compound 3-12 was prepared in the same manner as compound 3-1, except that 4-iodo-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 71%.

[0066] 1 H NMR (400 MHz, CDCl 3 )δ8.68(d,J=1.8Hz,1H),8.22–8.16(m,2H),8.01(dd,J=9.1,1.9Hz,1H),7.91(d,J=9.1Hz,1H),7.86–7.81(m,2H).

[0067] Embodiment 13

[0068]

[0069] Method 1: Compound 3-13 was prepared in the same manner as compound 3-1, except that 4-methylcatechol was used instead of catechol, with a yield of 84%.

[0070] Method 2: Compound 3-13 was prepared in the same manner as compound 3-1, except that 4-methyl-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 51%.

[0071] 1 H NMR (400 MHz, CDCl 3 )δ8.20(ddd,J=6.1,4.1,1.4Hz,2H),8.11(d,J=8.9Hz,1H),7.97(s,1H),7.82–7.76(m,2H),7.65(dd,J=8.9,1.9Hz,1H),2.63(d,J=0.9Hz,3H).

[0072] Embodiment 14

[0073]

[0074] Method 1: Compound 3-14 was prepared in the same manner as compound 3-1, except that 4-tert-butylcatechol was used instead of catechol, with a yield of 92%.

[0075] Method 2: Compound 3-14 was prepared in the same manner as compound 3-1, except that 4-tert-butyl o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 76%.

[0076] 1 H NMR (400 MHz, CDCl 3 )δ8.21(ddd,J=5.4,3.0,1.6Hz,2H),8.18–8.12(m,2H),7.93(dd,J=9.2,2.1Hz,1H),7.82–7.78(m,2H),1.47(s,9H).

[0077] Embodiment 15

[0078]

[0079] Compound 3-15 was prepared in the same manner as compound 3-1, except that 4-trifluoromethyl-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 87%.

[0080] 1 H NMR (400 MHz, CDCl 3 )δ8.56(s,1H),8.34(d,J=9.1Hz,1H),8.27–8.22(m,2H),7.95(dd,J=9.1,1.9Hz,1H),7.92–7.85(m,2H).

[0081] Example 16

[0082]

[0083] Compound 3-16 was prepared in the same manner as compound 3-1, except that 4-nitrile o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 77%.

[0084] 1 H NMR (400 MHz, CDCl 3 )δ8.66–8.58(m,1H),8.30(d,J=9.0Hz,1H),8.26–8.21(m,2H),7.95–7.87(m,3H).

[0085] Embodiment 17

[0086]

[0087] Compound 3-17 was prepared in the same manner as compound 3-1, except that 4-nitro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 60%.

[0088] 1 H NMR (400MHz, F 3 CCO 2 D) δ9.40 (d, J = 2.30Hz, 1H), 8.86 (dd, J = 9.54, 2.35Hz, 1H), 8.42 (d, J = 8.84Hz, 1H), 8.35 (t, J = 8.60Hz, 1H), 8.24 (t, J = 7.48Hz, 1H).

[0089] Embodiment 18

[0090]

[0091] Method 1: Compound 3-18 was prepared in the same manner as compound 3-1, except that 4-benzoylcatechol was used instead of catechol, with a yield of 23%.

[0092] Method 2: Compound 3-18 was prepared in the same manner as compound 3-1, except that 4-benzoyl-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 70%.

[0093] 1 H NMR (400 MHz, CDCl 3 )δ8.59(d,J=3.5Hz,1H),8.37–8.20(m,4H),7.95–7.85(m,4H),7.65(ddd,J=8.1,3.0,1.9Hz,1H),7.57–7.50(m,2H).

[0094] Embodiment 19

[0095]

[0096] Compound 3-19 was prepared in the same manner as compound 3-1, except that 3,4-dihydroxyphenylpropionic acid was used instead of catechol, with a yield of 98%.

[0097] 1 H NMR (400 MHz, DMSO-D 6 )δ12.28(s,1H),8.22–8.16(m,2H),8.13(d,J=8.9Hz,1H),7.99(s,1H),7.93–7.87 (m, 2H), 7.85 (dd, J = 9.0, 1.8Hz, 1H), 3.14 (t, J = 7.4Hz, 2H), 2.76 (t, J = 7.5Hz, 2H).

[0098] Embodiment 20

[0099]

[0100] Compound 3-20 was prepared in the same manner as compound 3-1, except that 3,4-difluoro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 50%.

[0101] 1 H NMR (400MHz, F 3 CCO 2 D) δ8.45(dd,J=6.8,3.4Hz,1H),8.37(m,1H),8.26(ddd,J=9.9,4.3,2.0Hz,1H),8.19(m,2H),8.02(td,J=9.6,7.1Hz,1H).

[0102] Embodiment 21

[0103]

[0104] Compound 3-21 was prepared in the same manner as compound 3-1, except that 3,5-difluoro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 56%.

[0105] 1 H NMR (400MHz, F 3 CCO 2 D) δ8.53(d,J=8.8Hz,1H),8.27(m,1H),8.13(m,1H),7.76(dt,J=7.7,2.1Hz,1H),7.55(td,J=8.7,2.4Hz,1H).

[0106] Embodiment 22

[0107]

[0108] Compound 3-22 was prepared in the same manner as compound 3-1, except that 3-chloro-5-bromo-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 77%.

[0109] 1 H NMR (400 MHz, CDCl 3 )δ8.36–8.28(m,2H),8.23–8.17(m,1H),8.01(d,J=2.0Hz,1H),7.91–7.86(m,2H).

[0110] Embodiment 23

[0111]

[0112] Compound 3-23 was prepared in the same manner as compound 3-1, except that 3-bromo-5-trifluoromethyl-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 60%.

[0113] 1 H NMR (400 MHz, CDCl 3 )δ8.54(dd,J=1.8,1.0Hz,1H),8.41–8.36(m,1H),8.27(ddd,J=10.4,6.9,2.9Hz,2H),7.98–7.91(m,2H).

[0114] Embodiment 24

[0115]

[0116] Compound 3-24 was prepared in the same manner as compound 3-1 except that 3,6-dibromo-o-phenylenediamine was used instead of o-phenylenediamine. The yield was 50%.

[0117] 1 H NMR (400 MHz, CDCl 3 )δ8.41–8.35(m,2H),8.02(s,2H),7.95–7.90(m,2H).

[0118] Embodiment 25

[0119]

[0120] Compound 3-25 was prepared in the same manner as compound 3-1, except that 3-methyl-5-bromo-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 76%.

[0121] 1 H NMR (400 MHz, CDCl 3 )δ8.24–8.19(m,2H),8.19–8.15(m,1H),7.85–7.79(m,2H),7.68(s,1H),2.87(s,3H).

[0122] Embodiment 26

[0123]

[0124] Compound 3-26 was prepared in the same manner as compound 3-1, except that 4,5-difluoro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 67%.

[0125] 1 H NMR (400MHz, F 3 CCO2 D) δ8.35(dd,J=6.8,3.3Hz,2H),8.19–8.10(m,4H).

[0126] Embodiment 27

[0127]

[0128] Compound 3-27 was prepared in the same manner as compound 3-1, except that 4,5-dichloro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 86%.

[0129] 1 H NMR (400MHz, F 3 CCO 2 D) δ8.51(s,1H),8.29–8.35(m,1H),8.11–8.15(m,1H).

[0130] Embodiment 28

[0131]

[0132] Compound 3-28 was prepared in the same manner as compound 3-1, except that 4,5-dibromo-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 71%.

[0133] 1 H NMR (400 MHz, CDCl 3 )δ8.58(s,2H),8.22–8.16(m,2H),7.89–7.85(m,2H).

[0134] Embodiment 29

[0135]

[0136] Compound 3-29 was prepared in the same manner as compound 3-1, except that 4-chloro-5-fluoro-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 68%.

[0137] 1 H NMR (400MHz, F 3 CCO 2 D) δ8.58(d,J=6.9Hz,2H),8.45–8.38(m,1H),8.37–8.31(m,2H),8.23–8.13(m,3H),8.10(dd,J=8.2,4.1Hz,1H).

[0138] Embodiment 30

[0139]

[0140] Compound 3-30 was prepared in the same manner as compound 3-1, except that 4-methyl-5-bromo-o-phenylenediamine was used instead of o-phenylenediamine, with a yield of 81%.

[0141] 1 H NMR (400 MHz, CDCl 3 )δ8.25–8.14(m,3H),7.85–7.78(m,2H),7.68(dd,J=2.1,1.1Hz,1H),2.87(s,3H).

[0142] The above has been described in detail with general descriptions and specific embodiments of the present invention, but on the basis of the present invention, some modifications or improvements can be made, which are easy to operate for those skilled in the art. Therefore, these modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

Claims

1. A method for preparing a phenazine compound, characterized in that The specific process is: catechol compound 1, o-phenylenediamine compound 2 and PhI(OAc)2 are reacted in series in a cyclic ether solvent to obtain the target product phenazine compound 3. The reaction equation of the preparation process is: Where R 1 is hydrogen, alkyl, halogen, alkoxy, carboxyethyl or benzoyl, R 2 is hydrogen, alkyl, halogen, trifluoromethyl, nitrile, nitro, benzoyl, carboxyl, carbamoyl or alkoxycarbonyl, R 2 It is a mono- or di-substituted.

2. The method for preparing phenazine compounds according to claim 1, characterized in that The phenazine compound 3 is one of the following compounds:

3. The method for preparing phenazine compounds according to claim 1, characterized in that: The molar ratio of the catechol compound 1, o-phenylenediamine 2 and PhI(OAc)2 is 1:1:1-2.

4. The method for preparing phenazine compounds according to claim 1, characterized in that: The cyclic ether solvent is one or more of tetrahydrofuran and dioxane.

5. The method for preparing phenazine compounds according to claim 1, characterized in that: The reaction temperature during the preparation process is -20°C to room temperature.

6. The method for preparing phenazine compounds according to claim 1, characterized in that The specific steps are as follows: dissolve catechol and PhI(OAc)2 in a mixed solvent of tetrahydrofuran and dioxane in a volume ratio of 1:1, stir and react at -15°C for 10 to 30 minutes, then add o-phenylenediamine and continue to stir and react for 3 to 5 minutes. After the reaction is complete, remove the reaction solvent by rotary evaporation, and separate by column chromatography to obtain phenazine compound 3.

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