A method for synthesizing 2,3-diaminoindole compounds

Abstract

The invention discloses a method for synthesizing 2,3-diaminoindole compounds, and belongs to the technical field of chemical synthesis. The method comprises the following steps: adding o-ethynylaniline, arylamine, lithium perchlorate, tetrabutylammonium iodide and tetramethylpiperidinoxide into a three-necked flask, and finally adding a solvent; under the condition of power on, using a platinum electrode as an anode and a carbon electrode as a cathode, stirring and reacting for 8-12 hours under the condition of constant current; after the reaction is completed, extracting the reaction liquid, rotary evaporating the extracted reaction liquid, and separating the target product through silica gel column chromatography; the method does not require metal catalysis, and the reaction can be carried out at room temperature; the method can react mildly in a solvent system of water and acetonitrile, is particularly suitable for the synthesis of some drugs, fundamentally eliminates the problem of metal residue and the like, and has high economic applicability; and solves the problem that expensive transition metals are basically used in the existing method and a high reaction temperature is required.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing 2,3-diaminoindole compounds. Background Art

[0002] Aminoindole is an important component of many plants, mainly from the biosynthesis of plants themselves and microorganisms such as bacteria using tryptophan as a precursor. Some natural aminoindole alkaloids have been approved by the FDA for use as drugs. For the specific synthesis methods of organic synthetic aminoindole compounds. At present, the main methods for synthesizing aminoindole compounds are: using copper (II) to catalyze the hydroxylation reaction of indole to obtain aminoindole compounds, using metal catalysts to construct CN bonds at the C2 or C3 position of indole, and then subsequent conversion can obtain aminoindole compounds, and using rhodium metal to catalyze intermolecular oxidative amidation reactions to obtain aminoindole compounds. Although these methods can indeed obtain some aminoindole compounds and are quite effective, these methods basically all require the use of expensive transition metals and require high reaction temperatures. This is not conducive to large-scale industrial synthesis.

[0003] Therefore, it is necessary to develop a method for rapidly synthesizing aminoindole compounds under mild and metal-free conditions. Therefore, the present invention develops a method for synthesizing 2,3-diaminoindole compounds, which can synthesize 2,3-diaminoindole compounds under mild and metal-free conditions. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing 2,3-diaminoindole compounds to solve the problems raised in the above background technology.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A method for synthesizing 2,3-diaminoindole compounds comprises the following steps:

[0007] Add o-ethynylaniline, arylamine, lithium perchlorate, tetrabutylammonium iodide, tetramethylpiperidinoxide into a three-necked flask, and finally add water and acetonitrile as solvents. Under the condition of power supply, use a platinum electrode as an anode and a carbon electrode as a cathode, and stir the reaction for 8-12 hours under constant current conditions. After the reaction is completed, extract the reaction solution with ethyl acetate, then use a rotary evaporator to rotary evaporate the extracted reaction solution, and then separate it through silica gel column chromatography to obtain the target product. The structure of the 2,3-diaminoindole compound in the present invention is shown in Formula I:

[0008] Formula I:

[0009] As a further solution of the present invention: the molar ratio of the o-ethynylaniline to the arylamine is 1:3-4.

[0010] As a further solution of the present invention: the molar ratio of the o-ethynylaniline to the lithium perchlorate is 1:2-3.

[0011] As a further solution of the present invention: the molar ratio of the o-ethynylaniline to the tetrabutylammonium iodide is 1:0.1-0.3.

[0012] As a further embodiment of the present invention: the tetramethylpiperidinyl oxide is 5-10 mol%.

[0013] As a further solution of the present invention: the volume ratio of water to acetonitrile in the solvent is 1:3-6.

[0014] As a further solution of the present invention: the rotation speed of the rotary evaporation is 100-200 rpm, the temperature is 25-30° C., the vacuum is 0.08-0.12 Mpa, and the processing time is 3-5 min.

[0015] As a further solution of the present invention: the chromatography uses 200 mesh column chromatography silica gel, the developing agent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 20:1-4.

[0016] As a further solution of the present invention: the structure of the o-ethynylaniline is shown in Formula II:

[0017] Formula II:

[0018]

[0019] The R group in formula II includes methyl, methoxy, halogen, etc.

[0020] As a further embodiment of the present invention: the structure of the arylamine is shown in Formula III:

[0021] Formula III

[0022] The R1 group in formula III includes a monosubstituted group and a polysubstituted group, and the substituents include methyl, methoxy, ester group and the like.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The synthesis method of 2,3-diaminoindole compounds provided by the present invention, thereby obtaining a new preparation method of 2,3-diaminoindole compounds and their derivatives;

[0025] (2) The entire reaction does not require metal catalysis and can be carried out at room temperature. It can react mildly in a solvent system of water and acetonitrile, and is particularly suitable for the synthesis of some drugs. It fundamentally eliminates problems such as metal residues and has high economic applicability.

[0026] (3) Simple operation, mild reaction conditions and high yield;

[0027] (4) The range of applicable substrates is relatively wide. Not only some simple substrates but also some complex natural products can be modified by this method. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the H NMR spectrum of the compound in Example 1.

[0029] Figure 2 This is the NMR spectrum C of the compound in Example 1.

[0030] Figure 3 This is the H spectrum of the NMR spectrum of the compound in Example 2.

[0031] Figure 4 This is the NMR spectrum C of the compound in Example 2.

[0032] Figure 5 This is the H spectrum of the NMR spectrum of the compound in Example 3.

[0033] Figure 6 This is the NMR spectrum C of the compound in Example 3. DETAILED DESCRIPTION

[0034] The technical solution of this patent is further described in detail below in conjunction with specific implementation methods.

[0035] Example 1

[0036] A method for synthesizing 2,3-diaminoindole compounds comprises the following steps: a stirring bar is placed in a dry 10 mL three-necked flask, and N-(2-ethynylphenyl)-4-toluenesulfonamide (83 mg, 0.3 mmol), isopropyl 4-aminobenzoate (219.4 mg, 1.2 mmol), tetrabutylammonium iodide (23 mg, 0.06 mmol), lithium perchlorate (83 mg, 0.75 mmol), tetramethylpiperidinoxide (2.2 mg, 5 mol%), potassium carbonate (2 equivalents), water (1.0 ml) and acetonitrile (5.0 ml) are added in sequence at room temperature. At room temperature, a platinum electrode was used as the anode and a carbon electrode as the cathode, and the reaction was carried out at a constant current of 5 mA for 10 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the extracted reaction solution was transferred to a 50 ml eggplant-shaped bottle. A Heidolph rotary evaporator was used with a speed of 80-100 rpm, a temperature of 38°C, a vacuum degree of 0.1 MPa, and the treatment was carried out for 3 minutes. The residue was then subjected to column chromatography using 200 mesh column chromatography silica gel, and the developing solvent was petroleum ether: ethyl acetate = 4:1, and the target compound (137.1 mg, a yield of 73%) was separated.

[0037] The structure of the 2,3-diaminoindole compound obtained in this example is shown below:

[0038]

[0039] The structural characterization data of the product are:

[0040] 1 HNMR(600MHz, CDCl3)δ8.25(d,J=8.4Hz,1H),7.53(d,J=8.3Hz,2H),7.36–7.31(m,1H),7.24–7.21(m,2H),7.13–7.05(m,4H),7. 02(d,J=8.2Hz,2H),6.84(t,J=7.3Hz,1H),6.78(t,J=7.3Hz,1H),6.53(d,J=7.5Hz,4H),6.49(s,1H),4.84(s,1H),2.31(s,3H).

[0041] 13 C NMR (150MHz, CDCl3) δ144.8,144.4,142.2,134.9,132.7,129.6,129.2,129.0,128.2, 126.9,126.9,124.1,123.7,120.5,119.2,119.1,115.3,115.02,114.97,114.0,21.5.

[0042] HRMS-ESI(m / z)[M+Na] + calculated for C 27 H 23 N3NaO2S 476.1403,found476.1406.

[0043] Example 2

[0044] Place a stirring bar in a dry 10 mL three-necked flask, and add N-(2-ethynylphenyl)-4-toluenesulfonamide (83 mg, 0.3 mmol), isopropyl 4-aminobenzoate (219.4 mg, 1.2 mmol), tetrabutylammonium iodide (23 mg, 0.06 mmol), lithium perchlorate (83 mg, 0.75 mmol), tetramethylpiperidinoxide (2.2 mg, 5 mol%), potassium carbonate (2 equivalents), water (1.0 ml) and acetonitrile (5.0 ml) in sequence at room temperature. At room temperature, a platinum electrode was used as the anode and a carbon electrode as the cathode, and the reaction was carried out at a constant current of 5 mA for 10 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the extracted reaction solution was transferred to a 50 ml eggplant-shaped bottle. A Heidolph rotary evaporator was used with a speed of 80-100 rpm, a temperature of 38°C, a vacuum degree of 0.1 MPa, and the treatment was carried out for 3 minutes. The residue was then subjected to column chromatography using 200 mesh column chromatography silica gel, and the developing solvent was petroleum ether: ethyl acetate = 4:1, and the target compound (137.1 mg, a yield of 73%) was separated.

[0045] The structure of the 2,3-diaminoindole compound obtained in this example is shown below:

[0046]

[0047] The structural characterization data of the product are:

[0048] 1 HNMR (600MHz, CDCl 3) δ8.24(d,J=8.4Hz,1H),7.77(d,J=8.8Hz,2H),7.69(d,J=8.7Hz,2H),7.47(d,J=8.4Hz,2H),7.37–7.31(m,1H),7.24–7.17(m,2H),6.97(d, J=8.2Hz,2H),6.73(s,1H),6.49(d,J=8.8Hz,2H),6.43(d,J=8.7Hz,2H),5.35(s,1H),5.25–5.11(m,2H),2.25(s,3H),1.36–1.29(m,12H).

[0049] 13 C NMR (150MHz, CDCl3) δ166.1,165.8,148.0,145.9,145.3,134.7,132.8,131.2,129.8,127.5,126.8, 126.0,124.9,124.0,122.7,121.3,119.1,115.1,114.0,113.7,113.6,67.9,67.7,22.0,22.0,21.5.

[0050] HRMS-ESI(m / z)[M+Na] + calculated for C 35 H 35 N3NaO6S 648.2139,found648.2136.

[0051] Example 3

[0052] Place a stirring bar in a dry 10 mL three-necked flask, and add N-(2-ethynylphenyl)-4-toluenesulfonamide (83 mg, 0.3 mmol), methyl 4-aminobenzoate (185.3 mg, 1.2 mmol), tetrabutylammonium iodide (23 mg, 0.06 mmol), lithium perchlorate (83 mg, 0.75 mmol), tetramethylpiperidinoxide (2.2 mg, 5 mol%), potassium carbonate (2 equivalents), water (1.0 ml) and acetonitrile (5.0 ml) in sequence at room temperature. At room temperature, a platinum electrode was used as the anode and a carbon electrode as the cathode, and the reaction was carried out at a constant current of 5 mA for 10 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the extracted reaction solution was transferred to a 50 ml eggplant-shaped bottle. A Heidolph rotary evaporator was used with a speed of 80-100 rpm, a temperature of 38°C, a vacuum degree of 0.1 MPa, and the treatment was carried out for 3 minutes. The residue was then subjected to column chromatography using 200 mesh column chromatography silica gel, and the developing solvent was petroleum ether: ethyl acetate = 4:1, and the target compound (82.3 mg, yield 47%) was separated.

[0053] The structure of the 2,3-diaminoindole compound obtained in this example is shown below:

[0054]

[0055] The structural characterization data of the product are:

[0056] 1H NMR (600MHz, CDCl3) δ8.11(d,J=8.5Hz,1H),7.77(d,J=8.8Hz,2H),7.69(d,J=8.7Hz,2H),7.46(d,J=8.4Hz,2H),7.17(dd,J=8.5,1.2Hz,1H),7.00(s,1 H),6.98(d,J=8.2Hz,2H),6.73(s,1H),6.47(d,J=8.8Hz,2H),6.42(d,J=8. 7Hz,2H),5.23(s,1H),3.84(s,3H),3.84(s,3H),2.36(s,3H),2.26(s,3H).

[0057] 13 C NMR (150MHz, CDCl3) δ167.1,166.8,148.1,145.9,145.3,134.7,134.0,131.3,131.2,130.9,129.7, 127.6,126.8,126.3,126.2,121.9,120.5,118.7,114.9,114.2113.5,113.1,51.8,51.7,21.5,21.4.

[0058] HRMS-ESI(m / z)[M+Na] + calculated for C 32 H 29 N3NaO6S 606.1669,found606.1662.

[0059] Working principle: The present invention provides a method for synthesizing 2,3-diaminoindole compounds, which uses o-ethynylaniline and aromatic amine as raw materials to react to generate 2,3-diaminoindole compounds. The entire reaction does not require metal catalysis and reacts mildly in a solvent system of water and acetonitrile. It is particularly suitable for the synthesis of some drugs, and fundamentally eliminates problems such as metal residues. It has high economic applicability, simple operation, high yield, mild conditions, and a wide range of substrates. Not only simple substrates can be applied, but complex natural products can also be modified by this method. The compounds developed and prepared are not only popular intermediates, but can also be subsequently derived into the basic skeletons of various natural products such as drugs.

[0060] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing 2,3-diaminoindole compounds, characterized in that: Select from the following steps: Add o-ethynylaniline compounds, aromatic amines, lithium perchlorate, tetrabutylammonium iodide, tetramethylpiperidinoxide, and finally add water and acetonitrile as solvents into a three-necked flask. Under the condition of power supply, use a platinum electrode as an anode and a carbon electrode as a cathode, and stir the reaction under constant current conditions for 8-12 hours. After the reaction is completed, extract the reaction solution with ethyl acetate, then use a rotary evaporator to rotary evaporate the extracted reaction solution, and then separate it by silica gel column chromatography to obtain the target product. The structure of the 2,3-diaminoindole compound is shown in Formula I: ; The structure of the o-ethynylaniline compound is shown in Formula II: Wherein the R group in formula I and formula II is selected from methyl, methoxy and halogen; The structure of the arylamine is shown in Formula III: In formula I and formula III, the R1 group is selected from a monosubstituted group or a polysubstituted group, and the substituent is selected from a methyl group and a methoxy group.

2. The method for synthesizing 2,3-diaminoindole compounds according to claim 1, characterized in that: The molar ratio of the o-ethynylaniline compound to the arylamine is 1:3-4.

3. The method for synthesizing 2,3-diaminoindole compounds according to claim 1, characterized in that: The molar ratio of the o-ethynylaniline compound to the lithium perchlorate is 1:2-3.

4. The method for synthesizing 2,3-diaminoindole compounds according to claim 1, characterized in that: The molar ratio of the o-ethynylaniline compound to the tetrabutylammonium iodide is 1:0.1-0.

3.

5. The method for synthesizing 2,3-diaminoindole compounds according to claim 1, characterized in that: The volume ratio of water to acetonitrile in the solvent is 1:3-6.

6. The method for synthesizing 2,3-diaminoindole compounds according to claim 1, characterized in that: The rotation speed of the rotary evaporation is 100-200 rpm, the temperature is 25-30° C., the vacuum is 0.08-0.12 Mpa, and the processing time is 3-5 min.

7. The method for synthesizing 2,3-diaminoindole compounds according to claim 1, characterized in that: The column chromatography uses 200 mesh column chromatography silica gel, and the developing agent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 20:1-4.

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