Preparation method of N-alkylamino substituted cyanobenzene compound

Abstract

The invention provides a preparation method of an N-alkylamino substituted cyanobenzene compound, which comprises the following step: in an organic solvent, under the action of alkali, a fluorinating agent and a catalyst, reacting a compound as shown in a formula (II) with a compound as shown in a formula (III) to obtain a compound as shown in a formula (I). The preparation method provided by the invention adopts one-step reaction to directly obtain the target compound, and has the advantages of low raw material cost, high yield, convenience in operation and the like. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing an N-alkylamino-substituted benzonitrile compound. Background Art

[0002] N-Alkylamino substituted benzonitrile compounds are an important class of organic synthesis intermediates, widely used in pesticides, medicines, dyes, materials and other fields. The current preparation methods mainly include the following:

[0003] The first method uses amino-substituted benzonitrile and different alkylating agents as raw materials, and obtains the target product through a two-step substitution reaction in the presence of a base:

[0004]

[0005] The second method uses fluorobenzonitrile and alkyl-substituted primary amine as raw materials, obtains an intermediate through a substitution reaction in the presence of a base, and then reacts with an alkylating agent to obtain the target product:

[0006]

[0007] The third method uses chlorobenzonitrile and alkyl-substituted secondary amine as raw materials to directly obtain the target product under the catalysis of a metal catalyst:

[0008]

[0009] Analysis of the above three preparation methods shows that the first method has high raw material costs, and the first step reaction selectivity is not high, the yield is below 50%, and there are problems such as low yield and difficult purification; the second method also has the problem of high raw material costs; the third method requires the use of expensive metal catalysts, and the reaction conditions are harsh, usually requiring high temperature, anhydrous conditions, etc. Therefore, it is necessary to develop a new process route suitable for industrial production. Summary of the invention

[0010] Purpose of the invention: In view of the shortcomings of the prior art, the present invention provides a method for preparing N-alkylamino-substituted benzonitrile compounds, which directly obtains the target compound by a one-step reaction, and has the advantages of low raw material cost, high yield, and convenient operation.

[0011] Technical solution: In order to achieve the above-mentioned purpose, the preparation method of N-alkylamino substituted benzonitrile compounds described in the present invention comprises the following steps:

[0012] In an organic solvent, the compound represented by formula (II) reacts with the compound represented by formula (III) under the action of a fluoride to obtain a compound represented by formula (I):

[0013]

[0014] In the compound represented by the above structural formula, each substituent is as follows:

[0015] R 1 , R 2 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or The structure is in the form of a ring;

[0016] X is selected from chlorine, bromine or iodine;

[0017] R 3 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, cyano, hydroxyl, amino or nitro;

[0018] n is an integer from 0 to 3.

[0019] The organic solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

[0020] Preferably, the organic solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

[0021] Wherein, the fluoride is selected from an inorganic fluorinating agent or an organic fluorinating agent, the inorganic fluorinating agent is selected from fluoride salts of alkali metals and alkaline earth metals, and the organic fluorinating agent is selected from fluoride salts of tetraalkylammonium.

[0022] Preferably, the inorganic fluorinating agent is selected from at least one of sodium fluoride, potassium fluoride, cesium fluoride and calcium fluoride; and the organic base is selected from at least one of triethylamine, diisopropylethylamine, pyridine and N,N-dimethylaminopyridine.

[0023] The reaction system further includes a base and a catalyst, wherein the base is selected from an inorganic base or an organic base, the inorganic base is selected from carbonates, bicarbonates or hydroxides of alkali metals and alkaline earth metals, the organic base is selected from one of C1-C4 sodium alcoholate, C1-C4 potassium alcoholate, triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine and methylpyridine; and the catalyst is selected from crown ethers, polyethers, tertiary amines, quaternary ammonium salts or quaternary phosphonium salts.

[0024] Preferably, the inorganic fluorinating agent is selected from at least one of sodium fluoride, potassium fluoride, cesium fluoride and calcium fluoride; the organic fluorinating agent is selected from at least one of tetramethylammonium fluoride and tetrabutylammonium fluoride; the catalyst is selected from at least one of trimethylamine hydrochloride, tetrabutylammonium bromide, tetraphenylphosphonium bromide and methyltriphenylphosphonium bromide.

[0025] Among them, the The structure is selected from any of the following:

[0026] Where R 4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; m is an integer from 0 to 3.

[0027] Wherein, when using a base and a catalyst, the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the base, the fluoride and the catalyst is (1-10):1:(0-5):(0-5):(0-1), the reaction temperature is 0-250°C, and the reaction time is 1-24h.

[0028] Preferably, when using a base and a catalyst, the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the base, the fluoride and the catalyst is (2-5):1:(0-2):(0-1):(0-0.2), the reaction temperature is 60-180°C, and the reaction time is 4-12h.

[0029] Preferably, during the preparation process of the present invention:

[0030] Preferably, R 1 , R 2 Independently selected from C1-C3 alkyl, C3-C6 cycloalkyl, or The structure is a ring-closed form:

[0031] Preferably, R 4 Independently selected from hydrogen, C1-C3 alkyl;

[0032] Preferably, m is an integer of 0-2.

[0033] Preferably, the substituents X are independently selected from chlorine.

[0034] Preferably, R 3 Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C3 alkanoyloxy.

[0035] Preferably, n is an integer of 0-2.

[0036] The present invention uses cheap and readily available chlorobenzonitrile instead of fluorobenzonitrile as a raw material, adopts a one-step reaction to directly synthesize the target compound, and solves the problem that the chlorobenzonitrile has low reaction activity and cannot directly react with alkylamine for amination. The conventional method first uses chlorobenzonitrile to prepare fluorobenzonitrile with high reaction activity, and then reacts fluorobenzonitrile with alkylamine to prepare N-alkylamino-substituted benzonitrile. The disadvantages are: the two-step reaction requires two post-treatments, the operation is complicated, and more three wastes are generated; the first step reaction requires an excessive amount of fluorination reagent (usually 1-2 equivalents of potassium fluoride); the second step reaction requires the addition of alkali and solvent. The present invention only requires the addition of a small amount of fluorination reagent (about 0.4 equivalents of potassium fluoride, and potassium fluoride can be recycled during the reaction), and the alkali and solvent only need to be added once, which has the advantages of low raw material cost, high yield, and convenient operation.

[0037] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0038] The invention provides a novel method for preparing N-alkylamino-substituted benzonitrile compounds, which directly obtains the target compound by a one-step reaction and has the advantages of low raw material cost, high yield, convenient operation, and the like. DETAILED DESCRIPTION

[0039] The present invention is further described below in conjunction with specific embodiments, but the present invention is not limited to these specific embodiments. Those skilled in the art should recognize that the present invention covers all possible alternatives, improvements and equivalents within the scope of the claims.

[0040] The experimental methods described in the examples are conventional methods unless otherwise specified; the materials, reagents, etc. used in the examples are all commercially available unless otherwise specified.

[0041] Example 1

[0042] Synthesis of 4-(N-ethyl-N-methylamino)benzonitrile (CAS:154667-33-1)

[0043]

[0044] 4-Chlorobenzonitrile (5g, 36.3mmol), N-methylethylamine (8.59g, 145.4mmol), spray-dried potassium fluoride (0.85g, 14.5mmol), tetraphenylphosphonium bromide (0.76g, 1.82mmol), anhydrous potassium carbonate (5.01g, 36.3mmol) and 40ml N,N-dimethylacetamide were added to the reaction kettle, the reaction kettle was sealed, and the reaction was heated to 150℃ for 14h. After the reaction was completed, it was cooled, filtered under reduced pressure, and the filtrate was added with 100ml of deionized water, extracted with ethyl acetate (100ml*2), and the organic phase was washed with saturated brine (50ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and distilled under reduced pressure. The 120-130℃ / 0.7mbar fraction was collected to obtain 5.5g of pure 4-(N-ethyl-N-methylamino)benzonitrile, with a yield of 95%. 1 HNMR (CDCl3, 400MHz) δ: 7.44 (d, J = 9.2Hz, 2H, Ph-H), 6.62 (d, J = 9.2Hz, 2H, Ph-H), 3.44 (q, J = 7.2Hz, 2H, -CH2), 2.98 (s, 3H, -CH3), 1.15 (t, J = 7.2Hz, 3H, -CH3).

[0045] Example 2

[0046] Synthesis of 4-(N-propyl-N-methylamino)benzonitrile (CAS: 1094931-44-8)

[0047]

[0048] N-methyl-n-propylamine (7.96 g, 108.9 mmol) was used to replace the N-methylethylamine in Example 1. The remaining operations were the same as in Example 1. The final yield was 92%. 1 H NMR (CDCl3, 400MHz) δ: 7.44 (d, J=9.2Hz, 2H, Ph-H), 6.61 (d, J=8.8Hz, 2H, Ph-H), 3.33 (t, J= 7.6Hz,2H,-CH2),3.00(s,3H,-CH3),1.66-1.57(m,2H,-CH2),0.94(t,J=7.6Hz,3H,-CH3).

[0049] Example 3

[0050] Synthesis of 4-(N,N-diethylamino)benzonitrile (CAS: 2873-90-7)

[0051]

[0052] Diethylamine (7.96 g, 108.9 mmol) was used to replace the N-methylethylamine in Example 1. The remaining operations were the same as in Example 1. The final yield was 93%. 1 HNMR (CDCl3, 400MHz) δ: 7.42 (d, J = 9.2Hz, 2H, Ph-H), 6.59 (d, J = 8.8Hz, 2H, Ph-H), 3.38 (q, J = 7.2Hz, 4H, -CH2), 1.17 (t, J = 7.2Hz, 6H, -CH3).

[0053] Example 4

[0054] Synthesis of 4-(tetrahydropyrrol-1-yl)benzonitrile (CAS:10282-30-1)

[0055]

[0056] Tetrahydropyrrole (7.74 g, 108.9 mmol) was used to replace the N-methylethylamine in Example 1. The remaining operations were the same as in Example 1. The final yield was 92%. 1 H NMR (CDCl3, 400MHz) δ: 7.38 (d, J = 8.8Hz, 2H, Ph-H), 6.45 (d, J = 8.8Hz, 2H, Ph-H), 3.27 (t, J = 6.4Hz, 4H, -CH2), 2.02-1.99 (m, 4H, -CH2).

[0057] Example 5-15

[0058] Referring to the method of Example 1, the N-alkylamino substituted benzonitrile compounds shown in Examples 5-15 in Table 1 below can be prepared. The substituents R1-R3 in Table 1 are substituents of the compound shown in formula (I),

[0059]

[0060] Table 1

[0061]

[0062]

Claims

1. A method for preparing an N-alkylamino-substituted benzonitrile compound, characterized in that: The steps include: In an organic solvent, the compound represented by formula (II) reacts with the compound represented by formula (III) under the action of a fluoride to obtain a compound represented by formula (I): In the compound represented by the above structural formula, each substituent is as follows: R 1 , R 2 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or The structure is in the form of a ring; X is selected from chlorine, bromine or iodine; R 3 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, cyano, hydroxyl, amino or nitro; n is an integer from 0 to 3.

2. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 1, characterized in that: The organic solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

3. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 2, characterized in that: The organic solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

4. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 1, characterized in that: The fluoride is selected from an inorganic fluorinating agent or an organic fluorinating agent. The inorganic fluorinating agent is selected from fluoride salts of alkali metals and alkaline earth metals. The organic fluorinating agent is selected from fluoride salts of tetraalkylammonium.

5. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 4, characterized in that: The inorganic fluorinating agent is selected from at least one of sodium fluoride, potassium fluoride, cesium fluoride and calcium fluoride; the organic base is selected from at least one of triethylamine, diisopropylethylamine, pyridine and N,N-dimethylaminopyridine.

6. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 1, characterized in that: The reaction system preferably also includes a base and a catalyst, wherein the base is selected from an inorganic base or an organic base, the inorganic base is selected from carbonates, bicarbonates or hydroxides of alkali metals and alkaline earth metals, and the organic base is selected from one of C1-C4 sodium alcoholate, C1-C4 potassium alcoholate, triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine and picoline; and the catalyst is selected from crown ethers, polyethers, tertiary amines, quaternary ammonium salts or quaternary phosphonium salts.

7. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 6, characterized in that: The inorganic fluorinating agent is selected from at least one of sodium fluoride, potassium fluoride, cesium fluoride and calcium fluoride; the organic fluorinating agent is selected from at least one of tetramethylammonium fluoride and tetrabutylammonium fluoride; the catalyst is selected from at least one of trimethylamine hydrochloride, tetrabutylammonium bromide, tetraphenylphosphonium bromide and methyltriphenylphosphonium bromide.

8. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 1, characterized in that: Said The structure is selected from any of the following: Where R 4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; m is an integer from 0 to 3.

9. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 1, characterized in that: When using a base and a catalyst, the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the base, the fluoride and the catalyst is (1-10):1:(0-5):(0-5):(0-1), the reaction temperature is 0-250°C, and the reaction time is 1-24h.

10. The method for preparing N-alkylamino-substituted benzonitrile compounds according to claim 1, characterized in that: When using a base and a catalyst, the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the base, the fluoride and the catalyst is (2-5):1:(0-2):(0-1):(0-0.2), the reaction temperature is 60-180°C, and the reaction time is 4-12h.

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