A process for the preparation of 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate

Abstract

The application belongs to the field of organic synthesis and particularly relates to a preparation method of 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methyl carbamate. The steps include: S1, adding 3-[1-(dimethylamino)ethyl]phenol and N,N-carbonyl di-(1,2,4-triazole) into an organic solvent to perform an ester exchange reaction at 15 DEG C; S2, cooling the reaction system of S1 to 0-10 DEG C, and adding N-methyl ethylamine; S3, increasing the temperature of the system of S2 to room temperature, adding 5% sodium bicarbonate solution and ethyl acetate to perform extraction, obtaining an ester solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methyl carbamate, and washing the solution with 1% hydrochloric acid solution for 2-3 times; and S4, column chromatography separation to obtain 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methyl carbamate. The synthesis method is mild, reliable and controllable.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. Background Technology

[0002] In US Patent US20080306280 A1, carbonyl diimidazole or a carbonyl diimidazole derivative is used as a raw material to react with methyl ethylamine to generate a monosubstituted compound, which is then reacted with 3-[1-(dimethylamino)ethyl]phenol to generate 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. However, carbonyl diimidazole has low reactivity, long reaction time, and low yield. Summary of the Invention

[0003] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a method for synthesizing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. The method employs transesterification and ammonolysis to obtain 3-[1-(dimethylamino)ethyl]phenol as a raw material. This compound can be used as an intermediate in the synthesis of levamisole. This route has low synthetic difficulty, simple post-processing, few impurities, and a generally mild reaction, making it easier to achieve industrial production.

[0004] This invention provides a method for preparing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate, comprising the following steps:

[0005] S1: Add 3-[1-(dimethylamino)ethyl]phenol and N,N-carbonylbis-(1,2,4-triazole) to an organic solvent to generate (3-[1-(dimethylamino)ethyl]phenyl)carbonyl-1,2,4-triazole;

[0006] S2: Cool the reaction system of S1 to 0-10℃ and add N-methylethylamine to generate 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate;

[0007] S3: Raise the temperature of the S2 system to room temperature, add 5% sodium bicarbonate solution and ethyl acetate to 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate for extraction, and obtain a solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. Wash the solution 2-3 times with 1% hydrochloric acid aqueous solution, dry the organic phase, and remove the organic solvent by rotary evaporation to obtain a concentrated solution.

[0008] S4: The concentrate was separated by column chromatography to obtain 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate.

[0009] Furthermore, in S1, the organic solvent is DMF, THF, DMSO, or NMP.

[0010] Furthermore, in S1, the organic solvent DMF has a water content of 1%-5% and an ester exchange temperature of 15℃.

[0011] Furthermore, in S1, the ratio of 3-[1-(dimethylamino)ethyl]phenol, N,N-carbonylbis-(1,2,4-triazole), and methyl ethylamine is 1:1~1.2:1~1.2.

[0012] The present invention has the following beneficial effects:

[0013] This invention proposes a method for synthesizing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. Using 3-[1-(dimethylamino)ethyl]phenol, N,N-carbonyldi-(1,2,4-triazole), and N-methylethylamine as raw materials, a transesterification reaction is carried out at 15°C, followed by ammonolysis at 0-10°C to obtain a reaction solution containing the product. The target product is obtained after extraction and column chromatography. The synthesis method of this invention features mild conditions, reliable and controllable reaction, few side reactions, and high product yield. Attached Figure Description

[0014] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0015] Figure 1 : The 1H NMR spectrum of 3-acetylphenyl N-ethyl-N-methylcarbamate. Detailed Implementation

[0016] Various exemplary embodiments of the present invention are now described in detail. Unless otherwise specified, the methods used in the embodiments are conventional methods, and the reagents used are commercially available reagents or reagents prepared using conventional methods. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, characteristics, and embodiments of the present invention.

[0017] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0018] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0019] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0020] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0021] As shown in the following chemical equation, this invention provides a method for synthesizing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate, comprising the following steps:

[0022] S1. Add 3-[1-(dimethylamino)ethyl]phenol and N,N-carbonyldi-(1,2,4-triazole) to an organic solvent and carry out an ester exchange reaction at 15°C to generate a monosubstituted compound (3-[1-(dimethylamino)ethyl]phenyl)carbonyl-1,2,4-triazole;

[0023] S2. Cool the reaction system from S1 to 0-10℃, and add N-methylethylamine to generate 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. The reaction process is shown in the figure.

[0024]

[0025] S3. Raise the temperature of the system in S2 to room temperature, add 5% sodium bicarbonate solution and ethyl acetate for extraction, and obtain a solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. Wash the solution 2-3 times with 1% hydrochloric acid aqueous solution, dry the organic phase, remove the organic solvent by rotary evaporation, and obtain a concentrated solution.

[0026] S4, column chromatography separation.

[0027] The following are preferred embodiments of the present invention.

[0028] Example 1

[0029] This embodiment provides a method for synthesizing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate, the steps of which are as follows:

[0030] (1) 0.8232 g of 3-[1-(dimethylamino)ethyl]phenol (5 mmol) was added to a three-necked flask equipped with a thermometer and a magnetic stirrer under nitrogen purging. Vacuum was drawn, 10 mL of LDM was added, and the mixture was stirred to dissolve. 0.9828 g of N,N-carbonyldi-(1,2,4-triazole) (6 mmol) was added, and the mixture was stirred at 15 °C for 8 h. Then the temperature was lowered to 0-10 °C, and N-methylethylamine was added and reacted for 12 h to obtain a reaction solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate.

[0031] (2) Bring the reaction solution to room temperature, add an equal volume of 5% sodium bicarbonate aqueous solution, mix well, add 60 mL of ethyl acetate, extract, repeat three times, combine the ethyl acetate phases, and wash three times with 1% HCl solution.

[0032] (3) The ethyl acetate solution was concentrated by rotary evaporation to obtain an oily mixture, followed by column chromatography. A clean product solution was obtained, evaporated to dryness, and a yellow oily substance was obtained. The yellow oily substance was analyzed by 1H NMR spectroscopy. Figure 1 As shown, the synthesis of 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate was confirmed, with a yield of 49.53%.

[0033] Example 2

[0034] (1) 0.8244 g of 3-[1-(dimethylamino)ethyl]phenol (5 mmol) was added to a three-necked flask equipped with a thermometer and a magnetic stirrer under nitrogen purging. Vacuum was drawn, 10 mL of DMSO was added, and the mixture was stirred to dissolve. 0.9800 g of N,N-carbonyldi-(1,2,4-triazole) (6 mmol) was added, and the mixture was stirred at 15 °C for 8 h. Then the temperature was lowered to 0-10 °C, and N-methylethylamine was added and reacted for 12 h to obtain a reaction solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate.

[0035] (2) Bring the reaction solution to room temperature, add an equal volume of 5% sodium bicarbonate aqueous solution, mix well, add 60 mL of ethyl acetate, extract, repeat three times, combine the ethyl acetate phases, and wash three times with 1% HCl solution.

[0036] (3) The ethyl acetate solution was concentrated by rotary evaporation to obtain an oily mixture, which was then separated by column chromatography. A clean product solution was obtained, which was evaporated to dryness to give a yellow oily substance with a yield of 51.81%.

[0037] Example 3

[0038] (1) 0.8219 g of 3-[1-(dimethylamino)ethyl]phenol (5 mmol) was added to a three-necked flask equipped with a thermometer and a magnetic stirrer under nitrogen purging, vacuum was drawn, 10 mL of NMP was added, and the mixture was stirred to dissolve. 0.9866 g of N,N-carbonyldi-(1,2,4-triazole) (6 mmol) was added, and the mixture was stirred at 15 °C for 8 h. Then the temperature was lowered to 0-10 °C, and N-methylethylamine was added and reacted for 12 h to obtain a reaction solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate.

[0039] (2) Bring the reaction solution to room temperature, add an equal volume of 5% sodium bicarbonate aqueous solution, mix well, add 60 mL of ethyl acetate, extract, repeat three times, combine the ethyl acetate phases, and wash three times with 1% HCl solution.

[0040] (3) The ethyl acetate solution was concentrated by rotary evaporation to obtain an oily mixture, which was then separated by column chromatography. A clean product solution was obtained, which was evaporated to dryness to give a yellow oily substance with a yield of 48.66%.

[0041] Example 4

[0042] (1) 0.8274 g of 3-[1-(dimethylamino)ethyl]phenol (5 mmol) was added to a three-necked flask equipped with a thermometer and a magnetic stirrer under nitrogen purging. Vacuum was drawn, 10 mL of THF was added, and the mixture was stirred to dissolve. 0.9779 g of N,N-carbonyldi-(1,2,4-triazole) (6 mmol) was added, and the mixture was stirred at 15 °C for 8 h. Then the temperature was lowered to 0-10 °C, and N-methylethylamine was added and reacted for 12 h to obtain a reaction solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate.

[0043] (2) Bring the reaction solution to room temperature, add an equal volume of 5% sodium bicarbonate aqueous solution, mix well, add 60 mL of ethyl acetate, extract, repeat three times, combine the ethyl acetate phases, and wash three times with 1% HCl solution.

[0044] (3) The ethyl acetate solution was concentrated by rotary evaporation to obtain an oily mixture, which was then separated by column chromatography. A clean product solution was obtained, which was evaporated to dryness to give a yellow oily substance with a yield of 40.97%.

[0045] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for preparing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate, characterized in that, Includes the following steps: S1: Add 3-[1-(dimethylamino)ethyl]phenol and N,N-carbonylbis-(1,2,4-triazole) to an organic solvent to generate (3-[1-(dimethylamino)ethyl]phenyl)carbonyl-1,2,4-triazole; S2: Cool the reaction system of S1 to 0-10℃ and add N-methylethylamine to generate 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate; S3: Raise the temperature of the S2 system to room temperature, add 5% sodium bicarbonate solution and ethyl acetate to 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate for extraction, and obtain a solution containing 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate. Wash the solution 2-3 times with 1% hydrochloric acid aqueous solution, dry the organic phase, and remove the organic solvent by rotary evaporation to obtain a concentrated solution. S4: The concentrate was separated by column chromatography to obtain 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate.

2. The preparation method according to claim 1, characterized in that, In S1, the organic solvent is DMF, THF, DMSO, or NMP.

3. The preparation method according to claim 1, characterized in that, In S1, the organic solvent DMF has a water content of 1%-5% and an ester exchange temperature of 15℃.

4. The preparation method according to claim 1, characterized in that, In S1, the ratio of 3-[1-(dimethylamino)ethyl]phenol, N,N-carbonylbis-(1,2,4-triazole), and methyl ethylamine is 1:1~1.2:1~1.

2.

5. An intermediate product for the synthesis of 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate, characterized in that, The molecular formula is (3-[1-(dimethylamino)ethyl]phenyl)carbonyl-1,2,4-triazole.

6. An intermediate product for the synthesis of 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate, characterized in that, The molecular formula is 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate.

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