Method for synthesizing 2, 3, 3-trimethylindole quaternary ammonium salt by one-pot process

Abstract

The invention relates to the field of quaternary ammonium salt synthesis, and particularly discloses a method for synthesizing 2, 3, 3-trimethylindole quaternary ammonium salts by a one-pot process, which comprises the following steps: reacting 4-substituent phenylhydrazine hydrochloride with methyl isopropyl ketone in a first solvent to obtain a first mixture containing a 2, 3, 3-trimethylindole intermediate; mixing the first mixture with a compound shown in a formula III, and reacting to obtain a second mixture containing 2, 3, 3-trimethylindole quaternary ammonium salt; and separating the 2, 3, 3-trimethylindole quaternary ammonium salt from the second mixture. The whole technological process is easy and convenient to operate, the labor and environmental protection pressure is greatly relieved, and the preparation efficiency of the quaternary ammonium salt is improved.

Description

Technical Field

[0001] The present application relates to the field of quaternary ammonium salt synthesis, and specifically to a method for synthesizing 2,3,3-trimethylindole quaternary ammonium salts by a one-pot process. Background Art

[0002] Indole derivatives were first used in the dye industry. Among them, 2,3,3-trimethylindole quaternary ammonium salt is an important intermediate for the synthesis of photosensitizers and conjugated cyanine dyes. It can be used to synthesize various indole cyanine dyes with high fluorescence efficiency and controllable properties. Such cyanine dyes can be widely used in the printing field and have significant characteristics such as good safety, high stability and environmental friendliness.

[0003] At present, there are many reports on the synthesis of 2,3,3-trimethylindole quaternary ammonium salts, all of which are synthesized by a two-step method. The first step reaction is the reaction of phenylhydrazine hydrochloride and methyl isopropyl ketone. This reaction generally requires a high temperature and a long reaction time. At the same time, the purification of the crude product requires high-temperature vacuum distillation at about 240°C to 270°C, and the purification process is harsh. The second step reaction is the reaction of the first step product 2,3,3-trimethylindole and p-toluenesulfonate. A large amount of solvent is added during the post-treatment process to precipitate and filter to obtain a quaternary ammonium salt product. The entire process needs to take into account the reaction effect and the requirements of environmental protection policies before industrial production can be carried out. The first step reaction in this route requires complex post-treatment operations, and the high temperature and vacuum conditions required during the crude product purification process greatly increase the discharge of three wastes and the complexity of the process, which in disguise increases the environmental protection cost and labor cost. Therefore, the existing synthesis method of 2,3,3-trimethylindole quaternary ammonium salts needs to be improved. Summary of the invention

[0004] This application is based on the inventor's discovery and understanding of the following facts and problems:

[0005] In the related art, there are many methods for synthesizing 2,3,3-trimethylindole quaternary ammonium salts, most of which are synthesized by a two-step method. The two-step synthesis usually requires controlling a higher reaction temperature and a longer reaction time. In addition, the purification process of the crude product is harsh and requires complex post-processing operations. The entire process greatly increases the discharge of three wastes and increases the complexity of the process, thereby increasing environmental protection costs and labor costs in disguise. Therefore, the inventors proposed a method for synthesizing 2,3,3-trimethylindole quaternary ammonium salts by a one-pot process. The synthesis process is simple, and no intermediate post-processing operation and intermediate purification are required. The preparation efficiency of such quaternary ammonium salts can be greatly improved, the discharge of three wastes can be reduced, and low-cost production can be achieved.

[0006] The present application aims to solve at least one of the technical problems in the related art to a certain extent. To this end, the present application proposes a one-pot process for synthesizing 2,3,3-trimethylindole quaternary ammonium salts with simple operation, energy saving and environmental protection or high preparation efficiency.

[0007] The present application proposes a method for synthesizing 2,3,3-trimethylindole quaternary ammonium salts by a one-pot process, comprising: reacting 4-substituted phenylhydrazine hydrochloride shown in formula I and methyl isopropyl ketone in a first solvent to obtain a first mixture containing a 2,3,3-trimethylindole intermediate shown in formula II; mixing the first mixture with a compound shown in formula III and reacting them to obtain a second mixture containing a 2,3,3-trimethylindole quaternary ammonium salt shown in formula IV; and separating the 2,3,3-trimethylindole quaternary ammonium salt shown in formula IV from the second mixture;

[0008]

[0009] wherein R is selected from halogen, nitro and sulfonic acid;

[0010] R1 is selected from C 1-12 Alkyl, C 1-12 Alkoxyalkyl, C 1-12 Saturated fatty acid methyl ester and C 1-12 Saturated fatty acid ethyl ester;

[0011] W is selected from p-toluenesulfonic acid group and halogen. Therefore, the synthesis method is simple to operate, does not require intermediate post-processing operation and intermediate purification, improves the preparation efficiency of such quaternary ammonium salt, and thus reduces labor and environmental pressure.

[0012] In some embodiments, R is selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group and a sulfonic acid group; R1 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a methoxymethyl group, a methoxyethyl group and a methyl acetate group; W is selected from a p-toluenesulfonic acid group, a chlorine atom, a bromine atom and an iodine atom.

[0013] In some embodiments, the first solvent includes at least one of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclopentane and o-xylene; in other embodiments, the first solvent includes at least one of dimethylformamide, dimethyl sulfoxide and cyclopentane; in some specific examples, the first solvent is dimethyl sulfoxide. Thus, a higher reaction temperature can be supported.

[0014] In some embodiments, the temperature of the reaction of 4-substituted phenylhydrazine hydrochloride and methyl isopropyl ketone is 80°C to 140°C, and the reaction time is 12h to 36h; in other embodiments, the temperature of the reaction of 4-substituted phenylhydrazine hydrochloride and methyl isopropyl ketone is 100°C to 140°C, and the reaction time is 12h to 24h; in some specific examples, the temperature of the reaction of 4-substituted phenylhydrazine hydrochloride and methyl isopropyl ketone is 120°C, and the reaction time is 20h. This can promote the first step of the reaction to be sufficient, reduce side reactions, and improve the reaction efficiency.

[0015] In some embodiments, the molar ratio of the 4-substituted phenylhydrazine hydrochloride to methyl isopropyl ketone is 1: (1-5); in other embodiments, the molar ratio of the 4-substituted phenylhydrazine hydrochloride to methyl isopropyl ketone is 1: (1-3); in some specific examples, the molar ratio of the 4-substituted phenylhydrazine hydrochloride to methyl isopropyl ketone is 1: (1-2). This can make the reaction more complete, without causing waste of raw materials, and the intermediate obtained does not need to undergo complex and harsh post-treatment and purification processes.

[0016] In some embodiments, the compound represented by formula III includes at least one of the following compounds:

[0017]

[0018] In some embodiments, the temperature of the reaction between the first mixture and the compound of formula III is 100°C to 140°C, and the reaction time is 1h to 8h; in other embodiments, the temperature of the reaction between the first mixture and the compound of formula III is 110°C to 140°C, and the reaction time is 2h to 6h; in some specific examples, the temperature of the reaction between the first mixture and the compound of formula III is 130°C, and the reaction time is 4h. In this way, the first mixture and the compound of formula III can react fully, thereby improving the reaction efficiency.

[0019] In some embodiments, the molar ratio of the 2,3,3-trimethylindole intermediate to the compound of formula III is 1:(0.8-1.5); in other embodiments, the molar ratio of the 2,3,3-trimethylindole intermediate to the compound of formula III is 1:(0.9-1.2); in some specific examples, the molar ratio of the 2,3,3-trimethylindole intermediate to the compound of formula III is 1:1. In this way, the intermediate and the compound of formula III can react fully to avoid the waste of raw materials.

[0020] In some embodiments, the compound represented by formula IV includes at least one of the following compounds:

[0021]

[0022] In some embodiments, separating the 2,3,3-trimethylindole quaternary ammonium salt of formula IV from the second mixture comprises: cooling the second mixture to 50° C. to 90° C., adding a second solvent to precipitate solids, cooling to room temperature, and filtering to obtain the 2,3,3-trimethylindole quaternary ammonium salt;

[0023] Wherein, the second solvent includes at least one of petroleum ether, n-hexane, ether and methyl tert-butyl ether; in some other embodiments, the second solvent includes at least one of petroleum ether, n-hexane and methyl tert-butyl ether; in some specific examples, the second solvent is n-hexane. This step is simple to operate, and the product yield is high and the purity is high.

[0024] The one-pot process for synthesizing 2,3,3-trimethylindole quaternary ammonium salts in the present application has at least the following beneficial effects:

[0025] 1. The one-pot method replaces the two-step method to synthesize 2,3,3-trimethylindole quaternary ammonium salts. No post-processing operation is required between the two steps, which can effectively reduce manual operation; 2. The intermediate decompression and high-temperature purification step is omitted, the operation is simple, and the synthesis process is more in line with industrial production requirements; 3. The waste liquid discharge generated during the intermediate discharge process is effectively reduced, which can greatly reduce the environmental protection pressure. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the NMR spectrum of the product obtained in Example 1;

[0027] Figure 2 is the NMR spectrum of the product obtained in Example 2;

[0028] Figure 3 is the NMR spectrum of the product obtained in Example 3;

[0029] Figure 4 is the NMR spectrum of the product obtained in Example 4;

[0030] Figure 5 is the NMR spectrum of the product obtained in Example 5;

[0031] Figure 6 is the NMR spectrum of the product obtained in Example 6;

[0032] Figure 7 is the NMR spectrum of the product obtained in Example 7;

[0033] Figure 8 It is the NMR spectrum of the product obtained in Example 8. DETAILED DESCRIPTION

[0034] The embodiments of the present application are described in detail below, and examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and are intended to be used to explain the present application, but cannot be understood as limiting the present application.

[0035] This application is completed by the inventor based on the following findings and understandings: In the early stage of the experiment, the inventor synthesized by a two-step method. The first step was subjected to a complicated post-treatment process to obtain a crude 2,3,3-trimethylindole intermediate with a liquid content of 80%-88%. The crude product was then subjected to high-temperature reduced pressure distillation to obtain a fine intermediate with a content greater than 95%. The conditions of the entire experimental process were relatively harsh, and the yield was low, making it difficult to achieve industrial production. Therefore, by first trying to directly use the crude product for the next step of feeding reaction, it was found that the reaction was good and the target product could be obtained. Further, it was thought that the same solvent was used in the two steps, and the first step of the reaction was completed without post-treatment and the material was directly added to the raw materials required for the second step, thereby realizing a one-pot preparation. In the later stage, by trying and optimizing various solvents, a variety of high-boiling point solvents were selected, which had good stability and strong solubility. They could not only provide the reaction temperature required for the two-step reaction, but also maintain good stability for a long time at a higher temperature. After a large number of experimental explorations, the one-pot process synthesis of 2,3,3-trimethylindole quaternary ammonium salts was finally achieved.

[0036] The present application proposes a method for synthesizing a 2,3,3-trimethylindole quaternary ammonium salt by a one-pot process, the method comprising: reacting a 4-substituted phenylhydrazine hydrochloride shown in formula I and methyl isopropyl ketone in a first solvent to obtain a first mixture containing a 2,3,3-trimethylindole intermediate shown in formula II; mixing the first mixture with a compound shown in formula III and reacting them to obtain a second mixture containing a 2,3,3-trimethylindole quaternary ammonium salt shown in formula IV; and separating the 2,3,3-trimethylindole quaternary ammonium salt shown in formula IV from the second mixture;

[0037]

[0038]

[0039] wherein R is selected from halogen, nitro and sulfonic acid;

[0040] R1 is selected from C 1-12 Alkyl, C 1-12 Alkoxyalkyl, C 1-12 Saturated fatty acid methyl ester and C 1-12 Saturated fatty acid ethyl ester;

[0041] W is selected from p-toluenesulfonic acid and halogen. The 2,3,3-trimethylindole quaternary ammonium salt is synthesized by a one-pot method, the reaction solvents in steps one and two are unified, and no intermediate post-processing operation and intermediate purification are required, which greatly improves the preparation efficiency and reduces the three wastes, thereby achieving low-cost production.

[0042] In some embodiments, in the 4-substituted phenylhydrazine hydrochloride shown in Formula I, R is selected from any one of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group and a sulfonic acid group. As a specific example, R can be a fluorine atom, that is, Formula I is p-fluorophenylhydrazine hydrochloride. That is, the 4-substituted phenylhydrazine hydrochloride shown in Formula I is at least one of the following compounds:

[0043]

[0044] In the compound represented by formula III, R1 is selected from any one of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxymethyl, methoxyethyl and methyl acetate, that is, the compound represented by formula III is at least one of the following compounds:

[0045]

[0046] W is selected from any one of p-toluenesulfonic acid group, chlorine atom, bromine atom and iodine atom. As a specific example, R1 can be ethyl group, and W can be p-toluenesulfonic acid group, that is, the compound shown in Formula III is ethyl p-toluenesulfonate.

[0047] In some embodiments, the first solvent includes at least one of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, cyclopentane and o-xylene. Thus, the material source is wide and the cost is low. Selecting such a solvent or mixed solvent has good solubility for the reaction raw materials and a high boiling point, which can not only provide a higher temperature to promote the reaction, but also has good thermal stability, providing a basic condition for realizing a one-pot reaction.

[0048] In some embodiments, reacting the 4-substituted phenylhydrazine hydrochloride and methyl isopropyl ketone shown in Formula I in a first solvent includes: stirring dimethyl sulfoxide and 4-substituted phenylhydrazine hydrochloride evenly, adding methyl isopropyl ketone dropwise at 90°C, reacting at 80°C to 140°C (such as 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, etc.) for 12h to 36h (such as 12h, 14h, 16h, 18h, 20h, 22h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, etc.) to obtain 2,3,3-trimethylindole compounds.

[0049] In some embodiments, the molar ratio of 4-substituted phenylhydrazine hydrochloride to methyl isopropyl ketone can be 1:(1-5), for example, 1:1, 1:2, 1:3, 1:4 or 1:5, etc. The above ratio is conducive to obtaining 2,3,3-trimethylindole intermediates.

[0050] In some embodiments, p-toluenesulfonate is added to the reaction solution (i.e., the first mixture) of the obtained 2,3,3-trimethylindole intermediate, and the mixture is kept warm for 1 h to 8 h (e.g., 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, etc.) at 100° C. to 140° C. (e.g., 100° C., 110° C., 120° C., 130° C., etc.), and after the reaction is completed, the mixture is cooled to 70° C., a second solvent is added dropwise to precipitate a solid, the mixture is cooled to room temperature, and the mixture is filtered to obtain a quaternary ammonium salt of 2,3,3-trimethylindole. The second solvent includes at least one of petroleum ether, n-hexane, ether, and methyl tert-butyl ether.

[0051] In some embodiments, the molar ratio of the 2,3,3-trimethylindole intermediate to the compound represented by formula III can be 1:(0.8-1.5), for example, it can be 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, etc.

[0052] In some embodiments, the compound of formula IV includes at least one of the following compounds:

[0053] When R is a fluorine atom and R1 is an ethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-1;

[0054] When R is a fluorine atom and R1 is a methoxymethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-2;

[0055] When R is a chlorine atom and R1 is an ethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-3;

[0056] When R is a chlorine atom and R1 is a methoxyethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-4;

[0057] When R is a chlorine atom and R1 is a propyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-5;

[0058] When R is a chlorine atom and R1 is a tert-butyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-6;

[0059] When R is a chlorine atom and R1 is a methoxymethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-7;

[0060] When R is a chlorine atom and R1 is a methyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-8;

[0061] When R is a bromine atom and R1 is an ethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-9;

[0062] When R is a bromine atom and R1 is a methoxyethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-10;

[0063] When R is a bromine atom and R1 is a methyl acetate group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-11;

[0064] When R is a bromine atom and R1 is a propyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-12;

[0065] When R is an iodine atom and R1 is an ethyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-13;

[0066] When R is an iodine atom and R1 is a butyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-14;

[0067] When R is nitro and R1 is ethyl, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-15;

[0068] When R is a sulfonic acid group and R1 is an isopropyl group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-16;

[0069] When R is a chlorine atom and R1 is an ethyl acetate group, the 2,3,3-trimethylindole quaternary ammonium salt is a compound having structure IV-17;

[0070]

[0071] The one-pot process for synthesizing 2,3,3-trimethylindole quaternary ammonium salts in the present application has at least the following beneficial effects:

[0072] 1. The one-pot method replaces the two-step method to synthesize 2,3,3-trimethylindole quaternary ammonium salts. No post-processing operation is required between the two steps, which can effectively reduce manual operation; 2. The intermediate decompression and high-temperature purification step is omitted, the operation is simple, and the synthesis process is more in line with industrial production requirements; 3. The waste liquid discharge generated during the intermediate discharge process is effectively reduced, which can greatly reduce the environmental protection pressure.

[0073] The embodiments of the present application are described in detail below.

[0074] Example 1: Synthesis of Compound IV-1

[0075] Compound IV-1 was synthesized according to the following synthetic route:

[0076]

[0077] In a dry three-necked flask, add 25.0g (0.15mol, 1eq) of p-fluorophenylhydrazine hydrochloride and 50ml of dimethyl sulfoxide, stir evenly at 90°C, slowly drop 38.8g (0.45mol, 3eq) of methyl isopropyl ketone, after the dropwise addition is complete, heat to 130°C for reaction for 30h, add 30.0g (0.15mol, 1eq) of ethyl p-toluenesulfonate, stir at 120°C for 6h, after the reaction is complete, cool to 70°C, slowly drop 150ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 31.6g of light pink product with a yield of 55.8%; MS (ESI) m / z=206, consistent with the theoretical value data;

[0078] H-NMR {DMSO, (1.41ppm, 3H), (1.51ppm, 6H), (2.29ppm, 3H), (2.82ppm, 3H), (4.49ppm, 2H), (7.11ppm, 2H), (7.48ppm, 2H), (7.72ppm, 1H), (8.03ppm, 2H)}.

[0079] Example 2: Synthesis of Compound IV-2

[0080] Compound IV-2 was synthesized according to the following synthetic route:

[0081]

[0082] In a dry three-necked flask, add 25.0g (0.15mol, 1eq) of p-fluorophenylhydrazine hydrochloride and 50ml of dimethyl sulfoxide, stir evenly at 90°C, slowly drop 38.8g (0.45mol, 3eq) of methyl isopropyl ketone, after the dropwise addition is complete, heat to 130°C for reaction for 30h, add 35.7g (0.16mol, 1.1eq) of methoxymethyl p-toluenesulfonate and stir at 120°C for 6h, after the reaction is complete, cool to 70°C, slowly drop 150ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 36.0g of light pink product with a yield of 61.2%; MS (ESI) m / z=235, consistent with the theoretical value data;

[0083] H-NMR{DMSO, (1.40ppm, 3H),, (1.54ppm, 6H), (2.29ppm, 3H), (2.83ppm, 3H), (4.46pp m, 2H), (7.10ppm, 2H), (7.46ppm, 2H), (7.70ppm, 1H), (8.00ppm, 1H), (8.05ppm, 1H)}.

[0084] Example 3: Synthesis of Compound IV-3

[0085] Compound IV-3 was synthesized according to the following synthetic route:

[0086]

[0087] In a dry three-necked flask, add 35.5g (0.20mol, 1eq) p-chlorophenylhydrazine hydrochloride and 70ml dimethyl sulfoxide, stir evenly at 90°C, slowly drop 51.7g (0.60mol, 3eq) of methyl isopropyl ketone, after the addition is complete, heat to 120°C for reaction for 24h, add 40.0g (0.20mol, 1eq) of ethyl p-toluenesulfonate, stir at 120°C for 6h, after the reaction is complete, cool to 70°C, slowly drop 210ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 47.5g of pale white product with a yield of 60.3%; MS (ESI) m / z = 222, consistent with the theoretical value data;

[0088] H-NMR {DMSO, (1.41ppm, 3H), (1.52ppm, 6H), (2.28ppm, 3H), (2.83ppm, 3H), (4.48ppm , 2H), (7.10ppm, 2H), (7.47ppm, 2H), (7.73ppm, 1H), (8.01ppm, 1H), (8.06ppm, 1H)}.

[0089] Example 4: Synthesis of Compound IV-4

[0090] Compound IV-4 was synthesized according to the following synthetic route:

[0091]

[0092] In a dry three-necked flask, add 35.5g (0.20mol, 1eq) p-chlorophenylhydrazine hydrochloride and 70ml dimethyl sulfoxide, stir evenly at 90°C, slowly drop 43.1g (0.5mol, 2.5eq) of methyl isopropyl ketone, after the addition is complete, heat to 120°C for reaction for 24h, add 46.1g (0.20mol, 1eq) of 2-methoxyethyl p-toluenesulfonate, stir at 120°C for 5h, after the reaction is complete, cool to 70°C, slowly drop 210ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 49.1g of pink product with a yield of 57.9%; MS (ESI) m / z = 252, consistent with the theoretical value data;

[0093] H-NMR{DMSO, (1.54ppm, 6H), (2.28ppm, 3H), (2.82ppm, 3H), (3.58ppm, 3H), (3.78ppm, 2H), ( 4.73ppm, 2H), (7.11ppm, 2H), (7.50ppm, 2H), (7.67ppm, 1H), (8.00ppm, 1H), (8.05ppm, 1H)}.

[0094] Example 5: Synthesis of Compound IV-5

[0095] Compound IV-5 was synthesized according to the following synthetic route:

[0096]

[0097] In a dry three-necked flask, add 35.5g (0.20mol, 1eq) p-chlorophenylhydrazine hydrochloride and 70ml dimethyl sulfoxide, stir evenly at 90°C, slowly drop 43.1g (0.50mol, 2.5eq) of methyl isopropyl ketone, after the addition is complete, heat to 120°C for reaction for 24h, add 51.4g (0.24mol, 1.2eq) of propyl p-toluenesulfonate, stir at 120°C for 4h, after the reaction is complete, cool to 70°C, slowly drop 210ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 42.6g of light pink product with a yield of 52.2%; MS (ESI) m / z = 236, consistent with the theoretical value data;

[0098] H-NMR{DMSO, (1.55ppm, 6H), (2.29ppm, 3H), (2.85ppm, 3H), (3.21ppm, 3H), (3.76ppm, 2H), ( 4.75ppm, 2H), (7.12ppm, 2H), (7.53ppm, 2H), (7.66ppm, 1H), (7.98ppm, 1H), (8.06ppm, 1H)}.

[0099] Example 6: Synthesis of Compound IV-10

[0100] Compound IV-10 was synthesized according to the following synthetic route:

[0101]

[0102] In a dry three-necked flask, add 22.5g (0.10mol, 1eq) p-bromophenylhydrazine hydrochloride and 45ml dimethyl sulfoxide, stir evenly at 90°C, slowly drop 25.9g (0.3mol, 3eq) of methyl isopropyl ketone, after the dropwise addition is complete, heat to 120°C and keep warm for 20h, add 23.0g (0.10mol, 1eq) of 2-methoxyethyl p-toluenesulfonate, stir at 130°C for 5h, after the reaction is complete, cool to 70°C, slowly drop 135ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 21.4g of light gray product with a yield of 45.8%; MS (ESI) m / z = 297, consistent with the theoretical value data;

[0103] H-NMR{DMSO, (1.52ppm, 6H), (2.26ppm, 3H), (2.83ppm, 3H), (3.25ppm, 3H), (3.77ppm, 2H), ( 4.72ppm, 2H), (7.10ppm, 2H), (7.51ppm, 2H), (7.66ppm, 1H), (8.01ppm, 1H), (8.06ppm, 1H)}.

[0104] Example 7: Synthesis of Compound IV-13

[0105] Compound IV-13 was synthesized according to the following synthetic route:

[0106]

[0107] In a dry three-necked flask, add 27.0g (0.10mol, 1eq) of p-iodophenylhydrazine hydrochloride and 54ml of dimethyl sulfoxide, stir evenly at 90°C, slowly drop 25.9g (0.30mol, 3eq) of methyl isopropyl ketone, after the dropwise addition is complete, heat to 120°C for reaction for 20h, add 20.0g (0.1mol, 1eq) of ethyl p-toluenesulfonate, stir at 120°C for 6h, after the reaction is complete, cool to 70°C, slowly drop 162ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 17.5g of light brown product with a yield of 35.9%; MS (ESI) m / z=314, consistent with the theoretical value data;

[0108] H-NMR {DMSO, (1.41ppm, 3H), (1.53ppm, 6H), (2.28ppm, 3H), (2.81ppm, 3H), (4.49ppm , 2H), (7.12ppm, 2H), (7.47ppm, 2H), (7.72ppm, 1H), (8.02ppm, 1H), (8.07ppm, 1H)}.

[0109] Example 8: Synthesis of Compound IV-16

[0110] Compound IV-16 was synthesized according to the following synthetic route:

[0111]

[0112] In a dry three-necked flask, add 22.5g (0.10mol, 1eq) p-sulfonic acid phenylhydrazine hydrochloride and 45ml dimethyl sulfoxide, stir evenly at 90°C, slowly drop 34.4g (0.4mol, 4eq) of methyl isopropyl ketone, after the dropwise addition is complete, heat to 130°C for reaction for 24h, add 21.5g (0.1mol, 1eq) of isopropyl p-toluenesulfonate, stir at 140°C for 6h, after the reaction is complete, cool to 70°C, slowly drop 135ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 19.7g of pale white product with a yield of 43.6%; MS (ESI) m / z = 282, consistent with the theoretical value data;

[0113] H-NMR {DMSO, (1.51ppm, 6H), (2.27ppm, 3H), (2.82ppm, 3H), (3.21ppm, 3H), (3.58ppm, 3H), (3.78ppm , 1H), (4.73ppm, 1H), (7.11ppm, 2H), (7.52ppm, 2H), (7.67ppm, 1H), (8.00ppm, 1H), (8.06ppm, 1H)}.

[0114] Example 9: Synthesis of Compound IV-6

[0115] The preparation method of Example 3 was repeated, except that tert-butyl p-toluenesulfonate was used instead of ethyl p-toluenesulfonate to obtain compound IV-6.

[0116] Example 10: Synthesis of Compound IV-7

[0117] The preparation method of Example 3 was repeated, except that methoxymethyl p-toluenesulfonate was used instead of ethyl p-toluenesulfonate to obtain compound IV-7.

[0118] Example 11: Synthesis of Compound IV-8

[0119] The preparation method of Example 3 was repeated, except that methyl p-toluenesulfonate was used instead of ethyl p-toluenesulfonate, to obtain compound IV-8.

[0120] Example 12: Synthesis of Compound IV-9

[0121] The preparation method of Example 3 was repeated, except that p-bromophenylhydrazine hydrochloride was used instead of p-chlorophenylhydrazine hydrochloride to obtain compound IV-9.

[0122] Example 13: Synthesis of Compound IV-11

[0123] The preparation method of Example 3 was repeated, except that p-bromophenylhydrazine hydrochloride was used instead of p-chlorophenylhydrazine hydrochloride, and methyl p-toluenesulfonate was used instead of ethyl p-toluenesulfonate, to obtain compound IV-11.

[0124] Example 14: Synthesis of Compound IV-12

[0125] The preparation method of Example 3 was repeated, except that p-bromophenylhydrazine hydrochloride was used instead of p-chlorophenylhydrazine hydrochloride, and p-toluenesulfonate was used instead of ethyl p-toluenesulfonate to obtain compound IV-12.

[0126] Example 15: Synthesis of Compound IV-14

[0127] The preparation method of Example 3 was repeated, except that p-iodophenylhydrazine hydrochloride was used instead of p-chlorophenylhydrazine hydrochloride, and butyl p-toluenesulfonate was used instead of ethyl p-toluenesulfonate, to obtain compound IV-14.

[0128] Example 16: Synthesis of Compound IV-15

[0129] The preparation method of Example 3 was repeated, except that p-nitrophenylhydrazine hydrochloride was used instead of p-chlorophenylhydrazine hydrochloride to obtain compound IV-15.

[0130] Embodiment 17:

[0131] The preparation method of Example 3 was repeated, except that 2-bromoethyl acetate was used instead of ethyl p-toluenesulfonate to obtain compound IV-17.

[0132] Comparative Example: Synthesis of Compound IV-1

[0133] Compound IV-1 was synthesized according to the following synthetic route:

[0134]

[0135] The first step of reaction: add 25.0g (0.15mol, 1eq) of p-fluorophenylhydrazine hydrochloride and 100ml of glacial acetic acid to a dry three-necked flask, stir evenly at 90°C, slowly drop 38.8g (0.45mol, 3eq) of methyl isopropyl ketone, and react at 130°C for 24h. After the reaction is completed, most of the solvent is evaporated at 90°C under reduced pressure, and the residue is stirred with water and dichloromethane. The PH value is adjusted to about 8-9 with saturated sodium bicarbonate solution. The organic phase is washed with saturated brine 3 times, and the solvent is evaporated under reduced pressure to obtain a crude product. The crude product is heated with an electric heating mantle and distilled under reduced pressure. The distillate at 240°C-270°C is collected to obtain about 9.4g of a purified product with a yield of 35%.

[0136] The second step reaction: In a dry three-necked flask, add 9.0g (0.05mol, 1.0eq) of the purified product of the first step, 15.0g (0.075mol, 1.5eq) of ethyl p-toluenesulfonate, and 20ml of dimethylacetamide (DMAc), and stir at a constant temperature of 120°C for 6h. After the reaction is completed, cool to 70°C, slowly drop 50ml of n-hexane, cool to room temperature, filter, and dry to constant weight to obtain 13.2g of light pink product with a yield of 70.1%; MS (ESI) m / z=206, which is consistent with the theoretical value data.

[0137] It can be seen from the above test data that compared with the comparative example, the product yield of the embodiment of the present application is higher, which shows that the preparation method of the present application is simple to operate, has high preparation efficiency, and greatly reduces labor and environmental pressure.

[0138] In the description of the present application, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of the features. In the description of the present application, "plurality" means at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0139] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0140] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in the field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A method for synthesizing 2,3,3-trimethylindole quaternary ammonium salts by a one-pot process, characterized in that: include: Reacting 4-substituted phenylhydrazine hydrochloride of formula I and methyl isopropyl ketone in a first solvent to obtain a first mixture containing a 2,3,3-trimethylindole intermediate of formula II; The first mixture and the compound represented by formula III are mixed and reacted to obtain a second mixture containing the 2,3,3-trimethylindole quaternary ammonium salt represented by formula IV; Separating the 2,3,3-trimethylindole quaternary ammonium salt represented by formula IV from the second mixture; wherein R is selected from halogen, nitro and sulfonic acid; R1 is selected from C 1-12 Alkyl, C 1-12 Alkoxyalkyl, C 1-12 Saturated fatty acid methyl ester and C 1-12 Saturated fatty acid ethyl ester; W is selected from p-toluenesulfonate and halogen.

2. The method according to claim 1, characterized in that R is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group and a sulfonic acid group; R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxymethyl, methoxyethyl and methyl acetate; W is selected from a p-toluenesulfonic acid group, a chlorine atom, a bromine atom and an iodine atom.

3. The method according to claim 1, characterized in that The first solvent comprises at least one of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane and o-xylene; Preferably, the first solvent comprises at least one of dimethylformamide, dimethyl sulfoxide and sulfolane; More preferably, the first solvent comprises dimethyl sulfoxide.

4. The method according to claim 1, characterized in that The reaction temperature of the 4-substituted phenylhydrazine hydrochloride and the methyl isopropyl ketone is 80° C. to 140° C., and the reaction time is 12 h to 36 h; Preferably, the reaction temperature of the 4-substituted phenylhydrazine hydrochloride and the methyl isopropyl ketone is 100° C. to 140° C., and the reaction time is 12 h to 24 h; More preferably, the reaction temperature of the 4-substituted phenylhydrazine hydrochloride and the methyl isopropyl ketone is 120° C. and the reaction time is 20 h.

5. The method according to claim 1, characterized in that The molar ratio of the 4-substituted phenylhydrazine hydrochloride to the methyl isopropyl ketone is 1:(1-5); Preferably, the molar ratio of the 4-substituted phenylhydrazine hydrochloride to the methyl isopropyl ketone is 1:(1-3); More preferably, the molar ratio of the 4-substituted phenylhydrazine hydrochloride to the methyl isopropyl ketone is 1:(1-2).

6. The method according to claim 1, characterized in that The compound represented by formula III includes at least one of the following compounds:

7. The method according to claim 1, characterized in that The temperature for reacting the first mixture with the compound represented by formula III is 100° C. to 140° C., and the reaction time is 1 h to 8 h; Preferably, the temperature for reacting the first mixture with the compound represented by formula III is 110° C. to 140° C., and the reaction time is 2 h to 6 h; More preferably, the temperature for reacting the first mixture with the compound represented by formula III is 130° C., and the reaction time is 4 hours.

8. The method according to claim 1, characterized in that The molar ratio of the 2,3,3-trimethylindole intermediate to the compound represented by formula III is 1:(0.8-1.5); Preferably, the molar ratio of the 2,3,3-trimethylindole intermediate to the compound represented by formula III is 1:(0.9-1.2); More preferably, the molar ratio of the 2,3,3-trimethylindole intermediate to the compound represented by formula III is 1:

1.

9. The method according to claim 1, characterized in that: The 2,3,3-trimethylindole quaternary ammonium salt shown in formula IV includes at least one of the following compounds:

10. The method according to claim 1, characterized in that Separating the 2,3,3-trimethylindole quaternary ammonium salt of formula IV from the second mixture comprises: The second mixture is cooled to 50° C. to 90° C., a second solvent is added to precipitate a solid, and the mixture is cooled to room temperature and filtered to obtain the 2,3,3-trimethylindole quaternary ammonium salt represented by formula IV; Wherein, the second solvent comprises at least one of petroleum ether, n-hexane, diethyl ether and methyl tert-butyl ether; Preferably, the second solvent comprises at least one of petroleum ether, n-hexane and methyl tert-butyl ether; More preferably, the second solvent comprises n-hexane.

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