A kind of synthetic method of tetracaine

Abstract

The present invention relates to a method for synthesizing tetracaine, comprising the steps of: using N-Boc-4-aminobenzoic acid (A) as a raw material, and reacting with n-butyl bromide to obtain N-Boc-N-butyl-4-aminobenzoic acid butyl ester (B); removing Boc from N-Boc-N-butyl-4-aminobenzoic acid butyl ester (B) under weak acid to obtain N-butyl-4-aminobenzoic acid butyl ester (C); and reacting N-butyl-4-aminobenzoic acid butyl ester (C) with N,N-dimethylethanolamine to obtain tetracaine (I). This method effectively reduces the risk of generating N-disubstituted butyl impurities, does not require palladium-carbon hydrogenation, and the purity and yield of the prepared tetracaine are both high, the product purity is greater than 99.8%, and the single impurity is less than 0.05%, which meets the requirements of medicinal raw materials.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis technology, and particularly relates to a method for synthesizing tetracaine. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Tetracaine, chemically known as 4-(butylamino)-benzoic acid-2-(dimethylamino)ethyl ester, is a long-acting ester local anesthetic with good lipid solubility and permeability. It is suitable for mucosal surface anesthesia, nerve block anesthesia, epidural anesthesia and subarachnoid anesthesia. It is commonly used for various ophthalmic tests and diagnoses or local anesthesia of the nose and throat. It can also be used for endoscopic examinations or spinal and epidural block anesthesia.

[0004] Patent CN201210242596.7 provides a method for preparing tetracaine, which uses aminobenzoic acid and n-butyraldehyde to produce 4-(n-butylamino)benzoic acid. Palladium on carbon (10%) is then added and reduced with hydrogen to yield 4-(n-butylamino)benzoic acid. This method involves the addition of hydrogen, significantly increasing the risk to production personnel. Furthermore, the palladium on carbon catalyst is expensive, leading to high production costs.

[0005] In view of the above situation, the present invention believes that it is of great significance to provide a tetracaine production process with simple process, low cost and high safety factor. Summary of the Invention

[0006] Based on the above technical background, the present invention aims to provide a method for preparing tetracaine with mild reaction conditions and high product yield. In order to achieve this technical purpose, the present invention provides the following scheme:

[0007] The first aspect of the present invention provides a method for synthesizing tetracaine, and the synthetic route is as follows:

[0008]

[0009]

[0010] The above-mentioned synthesis method has the following specific steps:

[0011] (1) The raw material N-Boc-4-aminobenzoic acid (A) reacts with n-butyl bromide in an alkaline solvent to obtain compound B;

[0012] (2) Compound B is subjected to removal of the Boc protecting group in a weak acid to prepare compound C;

[0013] (3) Compound C reacts with N,N-dimethylethanolamine to obtain tetracaine (I).

[0014] In step (1):

[0015] The molar ratio of N-Boc-4-aminobenzoic acid to n-butane bromide is 1:2 to 1:8, more preferably 1:3 to 1:5.

[0016] The alkaline solvent is a mixed solution of an alkaline reagent and an organic reagent, wherein the alkaline reagent is selected from one or a combination of triethylamine, N,N-diisopropylethylamine, sodium carbonate, and potassium carbonate, preferably triethylamine or potassium carbonate; and the organic reagent is selected from one or more of acetonitrile, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, preferably acetonitrile or toluene.

[0017] Furthermore, the dosage ratio of the alkaline reagent to the organic reagent is 55-65 g: 90-110 ml.

[0018] In one embodiment, the specific synthesis method of the above step (1) is as follows:

[0019] An alkaline solvent and N-Boc-4-aminobenzoic acid were added to a reaction vessel and the temperature was raised to 55-65° C., and n-butane bromide was slowly added dropwise. After the addition was complete, the temperature was kept at 65-75° C. for 5-7 hours. After the reaction was completed, a 45-55% ethyl acetate solution was added to the reaction system for separation. The organic phase was retained, dried and filtered, and n-hexane was added to heat and reflux for 0.4-0.6 hours. The mixture was then stirred and crystallized at 10-20° C. for 2 hours, and vacuum dried at 40-45° C. for 4-6 hours to obtain compound B.

[0020] In step (2):

[0021] The weak acid is an acidic reagent with a low concentration. Available acidic reagents include formic acid, glacial acetic acid, and trifluoroacetic acid, preferably formic acid and glacial acetic acid. Available concentrations include 8 to 12 g / L.

[0022] The reaction temperature is 40-50°C and stirred for 5-7 hours to remove the Boc protecting group.

[0023] In a specific embodiment, the reaction steps are as follows:

[0024] Compound B was added to the above-mentioned low concentration acidic reagent and stirred at 35-45°C for 5-7 hours; 45-55% ethyl acetate solution was added to the reaction system for liquid separation, the organic phase was retained and dried and concentrated, n-hexane was added and heated to reflux, stirred at 0-10°C for crystallization for 2-4 hours, and vacuum dried at 40-45°C for 4-6 hours to obtain compound C.

[0025] In step (3):

[0026] The molar ratio of compound C to N,N-dimethylethanolamine is 1:2 to 1:6, preferably 1:3 to 1:5. In a specific embodiment, compound C and sodium methoxide are put into a solvent, heated to 55 to 65°C and stirred for 0.4 to 0.6 hours, N,N-dimethylethanolamine is slowly added, and the temperature is continued to be raised to 80 to 90°C for reaction for 4 to 6 hours; after the reaction is completed, dichloromethane and water are added for extraction, the organic phase is obtained, water is added and the pH is adjusted to 5 to 6 for phase separation, dichloromethane is added to the aqueous phase and the pH is adjusted to 8 to 9, the dichlorohexane portion is retained, dried and concentrated, n-hexane is added, heated under reflux, stirred and crystallized at 30 to 40°C for 0.4 to 0.6 hours, and then kept at 10 to 15°C with stirring for 1 to 3 hours, filtered, and dried at 30 to 40°C for 5 to 7 hours to obtain the product.

[0027] Furthermore, the above solvent is selected from toluene, N,N-dimethylformamide or N,N-dimethylacetamide; more preferably N,N-dimethylformamide or N,N-dimethylacetamide.

[0028] The beneficial effects of one or more of the above technical solutions are:

[0029] 1. The present invention discovered that, during the substitution reaction between 4-aminobenzoic acid and n-butyl bromide, exposure of the amino group can lead to the formation of dibutyl substitution impurities. To address this issue, the present invention provides a novel process route in which the amino group of the raw material is protected by BOC and reacts with n-butyl bromide, thereby avoiding the occurrence of dibutyl substitution reaction on the N-side and effectively reducing the formation of impurities.

[0030] 2. The synthesis method provided by the present invention does not require the use of a high-pressure reactor, high-temperature operation, expensive raw materials such as palladium-carbon metal catalysts, and no reaction raw materials with high risk factors such as hydrogen. The reaction conditions are mild; and thanks to the reasonable temperature range of the synthesis process of the present invention, the obtained product has the appearance of a white crystalline powder without darkening or yellowing.

[0031] 3. The tetracaine product synthesized by the present invention has high purity. The purity of the prepared product is greater than 99.8%, the content of a single impurity is less than 0.05%, and the product yield is above 60%. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0033] Figure 1 The chromatogram (A) and the partial enlarged view (B) of the tetracaine product in the comparative example;

[0034] Figure 2 The chromatogram (A) and the partial enlarged view (B) of the tetracaine product in Example 1;

[0035] Figure 3 The chromatogram (A) and the partial enlarged view (B) of the tetracaine product in Example 2. DETAILED DESCRIPTION

[0036] It should be noted that the following detailed descriptions are exemplary and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0037] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0038] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0039] Comparative Example

[0040] Comparative Example: CN102731333B

[0041] 1. Add 100 ml of anhydrous methanol to the reaction flask, add 13.7 g of p-aminobenzoic acid and 8 g of n-butyraldehyde to the anhydrous methanol, heat to 50°C and stir for 4 hours, and concentrate the methanol under reduced pressure to obtain 4-(n-butenylamino)benzoic acid.

[0042] 2. 4-(n-Butenylamino)benzoic acid, 100 ml of water, and 6 g of sodium hydroxide were added to an autoclave, followed by 1.0 g of 10% palladium on carbon. The mixture was reacted at 90°C under a hydrogen pressure of 1.5 MPa for 4 h. The filtrate was filtered, the pH of the filtrate was adjusted to 2 with 10% hydrochloric acid, and the resulting solid was dried under vacuum at 50°C for 4 h to yield 4-(n-butylamino)benzoic acid.

[0043] 3. Add 4-(n-butylamino)benzoic acid to a reaction flask, add 100 ml of toluene, 10 g of N,N-dimethylethanolamine, and 5 g of concentrated sulfuric acid, and reflux to remove the water. After the reaction, add 10% hydrochloric acid to adjust the pH to 2. Separate the aqueous layer, add 50 ml of dichloromethane to the aqueous layer, and add 20% sodium hydroxide to adjust the pH to 13. Separate the organic layer, concentrate the dichloromethane to dryness, and dry the resulting solid to obtain crude tetracaine.

[0044] 4. The crude tetracaine was dissolved in 100 ml of 5% hydrochloric acid, 50 ml of dichloromethane was added, and 20% sodium hydroxide was added to adjust the pH to 12. The organic layer was separated and the dichloromethane was concentrated to dryness under reduced pressure. The resulting solid was dried in vacuo at 35°C for 5 h to obtain 10.0 g of off-white tetracaine.

[0045] The total yield is 37.9%. The purity of the finished product is 99.573%. Its liquid phase spectrum is as follows: Figure 1 shown.

[0046] Example 1

[0047] 1. Preparation of N-Boc-N-butyl-4-aminobenzoic acid butyl ester:

[0048] To a 1L four-necked reaction flask, add 100ml of acetonitrile, 50g of N-Boc-4-aminobenzoic acid, and 61g of potassium carbonate. Raise the temperature to 60°C and slowly add 60g of n-butyl bromide dropwise. After the addition is complete, incubate at 70°C for 6h. Cool to room temperature, add 250ml each of ethyl acetate and water, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Add 200ml of n-hexane, heat under reflux with stirring for 0.5h, stir at 10-20°C to crystallize for 2h, filter, and dry the filter cake in a vacuum at 40-45°C for 5h to obtain 59.8g of butyl N-Boc-N-butyl-4-aminobenzoate (yield: 81.2%).

[0049] 2. Preparation of N-butyl-4-aminobenzoic acid butyl ester:

[0050] To a 1L four-necked reaction flask, add 50g of butyl N-Boc-N-butyl-4-aminobenzoate, 200ml of acetonitrile, and 17g of formic acid. Stir and react at 40°C for 6h. Add 250ml of ethyl acetate and 250ml of water, extract and separate, and wash the organic phase with 200ml of water. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Add 200ml of n-hexane, heat under reflux with stirring for 0.5h, stir and crystallize at 0-10°C for 3h, filter, and dry the filter cake under vacuum at 40-45°C for 5h to obtain 31.7g of butyl N-butyl-4-aminobenzoate (yield: 88.9%).

[0051] 3. Preparation of Tetracaine:

[0052] In a 1L four-necked reaction flask, add 30g of butyl N-butyl-4-aminobenzoate, 100ml of N,N-dimethylformamide, and 1.2g of sodium methoxide. Heat to 60°C and stir for 0.5h. Slowly add 21g of N,N-dimethylethanolamine and continue heating to 85°C with stirring for 5h. After the reaction is complete, cool the system to room temperature and add 200ml each of dichloromethane and water. Extract and separate the liquids. Wash the organic phase again with 100ml of water. Add 150ml of water to the organic phase and adjust the pH to 5-6 with 2N hydrochloric acid. The solution was stirred for 30 minutes, the phases were separated, 150 ml of dichloromethane was added to the aqueous phase, the pH was adjusted to 8-9 with 10% sodium hydroxide, the liquids were extracted, the dichloromethane layer was washed with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 50 ml of n-hexane was added to the concentrate, stirred at 30-40°C for 0.5 h, then kept stirring at 10-15°C for 2 h, filtered, and the filter cake was vacuum dried at 35°C for 6 h to obtain 27.1 g of white crystalline powder with a yield of 85.2%.

[0053] The total yield of the three steps is 61.5%, and the purity of the finished product is 99.881%. The liquid phase spectrum is as follows: Figure 2 shown.

[0054] Example 2

[0055] 1. Preparation of N-Boc-N-butyl-4-aminobenzoic acid butyl ester:

[0056] To a 1L four-necked reaction flask, add 100ml of toluene, 50g of N-Boc-4-aminobenzoic acid, and 61g of triethylamine. Raise the temperature to 60°C and slowly add 85g of n-butane bromide dropwise. After the addition is complete, incubate at 65°C for 6 hours. Cool to room temperature, add 250ml each of ethyl acetate and water, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Add 200ml of n-hexane, heat under reflux with stirring for 0.5h, stir at 10-20°C to crystallize for 2h, filter, and dry the filter cake in a vacuum at 40-45°C for 5h to obtain 61.1g of butyl N-Boc-N-butyl-4-aminobenzoate (yield: 83.0%).

[0057] 2. Preparation of N-butyl-4-aminobenzoic acid butyl ester:

[0058] To a 1L four-necked reaction flask, add 50g of butyl N-Boc-N-butyl-4-aminobenzoate, 200ml of n-hexane, and 20g of glacial acetic acid. Stir and react at 45°C for 6h. Add 250ml of ethyl acetate and 250ml of water, extract and separate, and wash the organic phase with 200ml of water. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Add 200ml of n-hexane, heat under reflux with stirring for 0.5h, stir and crystallize at 0-10°C for 3h, filter, and dry the filter cake under vacuum at 40-45°C for 5h to obtain 30.9g of butyl N-butyl-4-aminobenzoate (yield: 86.6%).

[0059] 3. Preparation of Tetracaine:

[0060] In a 1L four-necked reaction flask, add 30g of butyl N-butyl-4-aminobenzoate, 100ml of N,N-dimethylacetamide, and 1.5g of sodium methoxide. Heat to 70°C and stir for 0.5h. Slowly add 23g of N,N-dimethylethanolamine and continue heating to 80°C with stirring for 5h. After the reaction is complete, cool the system to room temperature and add 200ml each of dichloromethane and water. Extract and separate the liquids. Wash the organic phase again with 100ml of water. Add 150ml of water to the organic phase and adjust the pH to 5-6 with 2N hydrochloric acid. The solution was stirred for 30 minutes, the phases were separated, 150 ml of dichloromethane was added to the aqueous phase, the pH value was adjusted to 8-9 with 10% sodium hydroxide, the liquids were extracted, the dichloromethane layer was washed with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 50 ml of n-hexane was added to the concentrate, stirred at 30-40°C for 0.5 h, then kept stirring at 10-15°C for 2 h, filtered, and the filter cake was vacuum dried at 35°C for 6 h to obtain 28.3 g of white crystalline powder, yield: 89.0%.

[0061] The total yield of the three steps is 64.0%, the purity of the finished product is 99.858%, and its liquid phase spectrum is as follows: Figure 3 shown.

[0062] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A method for synthesizing tetracaine, characterized in that: The synthetic route is as follows: ； The specific steps are as follows: (1) The raw material N-Boc-4-aminobenzoic acid (A) reacts with n-butyl bromide in an alkaline solvent to obtain compound B; The alkaline solvent is a mixed solution of an alkaline reagent and an organic reagent, wherein the alkaline reagent is triethylamine or potassium carbonate, and the organic reagent is selected from acetonitrile or toluene, and the dosage ratio of the alkaline reagent to the organic reagent is 55-65 g:90-110 ml; The specific synthesis method of step (1) is as follows: A basic solvent and N-Boc-4-aminobenzoic acid were added to a reaction vessel, and the temperature was raised to 55-65°C. n-Butane bromide was slowly added dropwise. After the addition was complete, the temperature was kept at 65-75°C for 5-7 hours. After the reaction was completed, a 45-55% ethyl acetate solution was added to the reaction system for separation. The organic phase was retained, dried and filtered, and n-hexane was added to heat and reflux for 0.4-0.6 hours. The mixture was then stirred and crystallized at 10-20°C for 2 hours, and vacuum dried at 40-45°C for 4-6 hours to obtain compound B. (2) Compound B is subjected to removal of the Boc protecting group in a weak acid to prepare compound C; In step (2), the weak acid is a low-concentration acidic reagent selected from formic acid, glacial acetic acid, and trifluoroacetic acid, with a concentration of 8 to 12 g / L; The specific implementation of step (2) is as follows: Compound B was added to a low concentration of an acidic reagent and stirred at 35-45°C for 5-7 hours; 45-55% ethyl acetate solution was added to the reaction system for separation, the organic phase was retained and dried and concentrated, n-hexane was added and heated to reflux, stirred at 0-10°C for crystallization for 2-4 hours, and vacuum dried at 40-45°C for 4-6 hours to obtain compound C; (3) Compound C reacts with N,N-dimethylethanolamine to obtain tetracaine (Ⅰ); In a specific embodiment of step (3), compound C and sodium methoxide are put into a solvent, heated to 55-65°C and stirred for 0.4-0.6h, N,N-dimethylethanolamine is slowly added, and the temperature is continued to be raised to 80-90°C for reaction for 4-6h; after the reaction is completed, dichloromethane and water are added for extraction, the organic phase is obtained, water is added and the pH is adjusted to 5-6 for phase separation, dichloromethane is added to the aqueous phase and the pH is adjusted to 8-9, the dichloromethane portion is retained, dried and concentrated, n-hexane is added, heated under reflux, stirred and crystallized at 30-40°C for 0.4-0.6h, and then kept at 10-15°C with stirring for 1-3h, filtered, and dried at 30-40°C for 5-7h to obtain the product.

2. The synthesis method according to claim 1, wherein In step (1), the molar ratio of N-Boc-4-aminobenzoic acid to n-butyl bromide is 1:2 to 1:

8.

3. The synthesis method according to claim 1, wherein The reaction temperature is 40-45°C and stirred for 5-7 hours to remove the Boc protecting group.

4. The synthesis method according to claim 1, wherein In step (3): the molar ratio of compound C to N,N-dimethylethanolamine is 1:2 to 1:

6.

5. The synthesis method according to claim 1, wherein The solvent is selected from toluene, N,N-dimethylformamide or N,N-dimethylacetamide.

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