Method for synthesizing 3-amino azetidine-1-tert-butyl formate
By reacting 3-oxoazetidane-1-carboxylic acid tert-butyl ester with trisubstituted silamine and tetrahydroxydibor under palladium carbon catalysis, the safety hazards and low yields of the existing 3-aminoazetidane-1-carboxylic acid tert-butyl ester synthesis method are solved, and an efficient and safe synthesis process is achieved.
Patent Information
- Application Number
- CN202411902156.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-23
- Publication Date
- 2025-03-28
AI Technical Summary
The existing 3-aminoazetidane-1-formate synthesis method has safety hazards, complicated steps and low yields, and it is difficult to adapt to the requirements of industrial production.
The tert-butyl 3-oxoazetidane-1-carboxylic acid is used to react with trisubstituted silamine and tetrahydroxydibor under palladium carbon catalysis, and tert-butyl 3-aminoazetidane-1-carboxylic acid is prepared through the deprotection step.
This method is original, has short steps and high yield, with a maximum reaction yield of up to 90%, and is safe and easy to operate, avoiding the use of unstable azide compounds and highly drug methanesulfonyl chloride.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate, and belongs to the field of drug intermediate synthesis. Background Art
[0002] 3-Aminoazetidine-1-carboxylic acid tert-butyl ester is a heterocyclic amine compound. Amines are widely present in the biological world and have extremely important physiological and biological activities. For example, proteins, nucleic acids, many hormones, antibiotics and alkaloids are all derivatives of amines. Most drugs used clinically are also amines or amine derivatives. Understanding the properties and synthesis methods of amines is a prerequisite for studying these complex natural products and better maintaining human health.
[0003] Therefore, the development of a synthesis of heterocyclic amine compounds has important application value. At present, the synthesis method of 3-aminoazetidine-1-tert-butyl formate has various shortcomings. The literature synthesis method of 3-aminoazetidine-1-tert-butyl formate usually uses 1-Boc-3-azidoazetidine as a raw material and is prepared by palladium carbon hydrogenation reduction, but the azide compound is unstable and easily causes explosion, which has a great safety hazard. Other routes require the use of highly toxic methanesulfonyl chloride, some have long steps and low yields. The above shortcomings make the existing synthesis method not in line with the concept of safe production and difficult to adapt to the requirements of industrial production.
[0004] Therefore, it is urgent to find a new method for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate. Summary of the invention
[0005] In order to overcome the above technical defects, the present invention uses tert-butyl 3-oxoazetidine-1-carboxylate as a raw material, reacts with trisubstituted silylamine and tetrahydroxydiboron under palladium carbon catalysis, and then deprotects to obtain tert-butyl 3-aminoazetidine-1-carboxylate. The method has the advantages of originality, short steps and high yield.
[0006] The method for synthesizing tert-butyl 3-oxoazetidine-1-carboxylate of the present invention comprises the following steps:
[0007]
[0008] 3-Oxoazetidine-1-carboxylic acid tert-butyl ester, anhydrous magnesium sulfate and trisubstituted silylamine are mixed in an organic solvent for reaction, and then tetrahydroxydiboron and palladium on carbon are added, the temperature is raised to 45-50° C. for reduction reaction, and tetra-n-butylammonium fluoride is added for deprotection to obtain 3-aminoazetidine-1-carboxylic acid tert-butyl ester.
[0009] Furthermore, in a preferred technical solution, the trisubstituted silylamine is selected from trimethylsilylamine, triethylsilylamine, triphenylsilylamine or tert-butyldimethylsilylamine.
[0010] Furthermore, in a preferred technical solution, the organic solvent is selected from methanol, ethanol or isopropanol.
[0011] Furthermore, in a preferred technical solution, the palladium-carbon is selected from 5% palladium-carbon or 10% palladium-carbon.
[0012] Furthermore, in the preferred technical solution, the weight ratio of tert-butyl 3-oxoazetidine-1-carboxylate to palladium on carbon is 1:0.003-0.05.
[0013] Furthermore, in the preferred technical solution, the weight ratio of tert-butyl 3-oxoazetidine-1-carboxylate, anhydrous magnesium sulfate, trisubstituted silylamine, tetrahydroxydiboron and tetra-n-butylammonium fluoride is 1:0.15-0.3:1-1.5:2-5:0.01-0.05.
[0014] Furthermore, in the preferred technical scheme, the typical operating steps are: add tert-butyl 3-oxoazetidine-1-carboxylate, anhydrous magnesium sulfate, trisubstituted silicon-based amine and an organic solvent into a reaction bottle, dehydrate and react for 2 hours under stirring at room temperature, then add tetrahydroxydiboron and palladium carbon, heat to 45-50°C for reduction reaction for 18-24 hours, add tetra-n-butylammonium fluoride, stir for 1 hour, terminate the reaction, filter, add water and extraction solvent to the filtrate, separate the layers, and distill the organic layer under reduced pressure to obtain the product tert-butyl 3-aminoazetidine-1-carboxylate.
[0015] Advantageous Effects of the Invention
[0016] 1. This method uses tert-butyl 3-oxoazetidine-1-carboxylate as a raw material, reacts with trisubstituted silicon-based amine and tetrahydroxydiboron under palladium-carbon catalysis to prepare tert-butyl 3-aminoazetidine-1-carboxylate. This method is original and the process is safe and easy to operate. It has the advantages of short steps and high yield, and the maximum yield of the reaction can reach 90%.
[0017] 2. The raw material used in this method, tert-butyl 3-oxoazetidine-1-carboxylate, is cheap, with a market price of 1,000 yuan / kg, and is relatively cheap and easy to obtain.
[0018] 3. The method of the present invention has potential technical advantages, short steps, high yield and safe operation, and provides a good method for the synthesis of tert-butyl 3-aminoazetidine-1-carboxylate. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 It is the HNMR spectrum of tert-butyl 3-aminoazetidine-1-carboxylate in Example 1. Specific embodiments
[0020] Example 1
[0021] 17.12 g (100 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate, 2.41 g (20 mmol) of anhydrous magnesium sulfate, 10.71 g (120 mmol) of trimethylsilylamine and 100 g of methanol were added into a glass bottle, and the mixture was stirred at room temperature for 2 hours for dehydration reaction. Then, 26.90 g (300 mmol) of tetrahydroxydiboron and 0.09 g of 10% palladium carbon were added, and the temperature was raised to 50° C. for reaction for 24 hours. After sampling, the reduction reaction was completed, 0.78 g (3 mmol) of tetra-n-butylammonium fluoride was added, and the mixture was stirred for 1 hour. After sampling, the deprotection reaction was completed by GC detection, and the mixture was filtered. 200 g of water and 170 g of ethyl acetate were added to the filtrate, and the layers were separated. The water layer was extracted once with 170 g of ethyl acetate. The ethyl acetate layers were combined and distilled under reduced pressure to concentrate the ethyl acetate. The oil pump was used for distillation under reduced pressure to collect the 70-90° C. fraction to obtain 15.50 g of the product. tert-Butyl 3-aminoazetidine-1-carboxylate, light yellow liquid, GC≥98.9%, yield 90%.
[0022] Example 2
[0023] 17.12 g (100 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate, 2.41 g (20 mmol) of anhydrous magnesium sulfate, 15.75 g (120 mmol) of triethylsilylamine and 100 g of methanol were added into a glass bottle, and the mixture was stirred at room temperature for dehydration reaction for 2 hours. Then, 26.90 g (300 mmol) of tetrahydroxydiboron and 0.09 g of 10% palladium on carbon were added, and the temperature was raised to 50°C for reaction for 24 hours. After sampling, 0.78 g ( 3mmol) tetra-n-butylammonium fluoride, stirred for 1 hour, sampled, GC detected the end of the deprotection reaction, filtered, 200g of water and 170g of ethyl acetate were added to the filtrate, the layers were separated, the water layer was extracted once with 170g of ethyl acetate, the ethyl acetate layers were combined, and vacuum distillation was performed to concentrate the ethyl acetate, and vacuum distillation was performed using an oil pump, and the 70-90°C fraction was collected to obtain 14.47g of tert-butyl 3-aminoazetidine-1-carboxylate, a light yellow liquid, GC≥98.5%, and a yield of 84%.
[0024] Example 3
[0025] 17.12 g (100 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate, 2.41 g (20 mmol) of anhydrous magnesium sulfate, 33.05 g (120 mmol) of triphenylsilylamine, and 100 g of methanol were added into a glass bottle, and the mixture was stirred at room temperature for dehydration reaction for 2 hours. Then, 26.90 g (300 mmol) of tetrahydroxydiboron and 0.09 g of 10% palladium on carbon were added, and the temperature was raised to 50°C for reaction for 24 hours. After sampling, 0.78 g ( 3mmol) tetra-n-butylammonium fluoride, stirred for 1 hour, sampled, GC detected the end of the deprotection reaction, filtered, 200g of water and 170g of ethyl acetate were added to the filtrate, the layers were separated, the water layer was extracted once with 170g of ethyl acetate, the ethyl acetate layers were combined, and vacuum distillation was performed to concentrate the ethyl acetate, and vacuum distillation was performed using an oil pump, and the 70-90°C fraction was collected to obtain 12.92g of tert-butyl 3-aminoazetidine-1-carboxylate, a light yellow liquid, GC≥98.1%, and a yield of 75%.
[0026] Example 4
[0027] 17.12 g (100 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate, 3.61 g (30 mmol) of anhydrous magnesium sulfate, 13.38 g (150 mmol) of trimethylsilylamine and 150 g of methanol were added into a glass bottle, and the mixture was stirred at room temperature for dehydration reaction for 2 hours. Then, 17.93 g (200 mmol) of tetrahydroxydiboron and 0.51 g of 10% palladium on carbon were added, and the mixture was heated to 50°C for reaction for 18 hours. After sampling, 1.31 g ( 5mmol) tetra-n-butylammonium fluoride, stirred for 1 hour, sampled, GC detected the end of the deprotection reaction, filtered, 300g of water and 200g of ethyl acetate were added to the filtrate, the layers were separated, the water layer was extracted once with 200g of ethyl acetate, the ethyl acetate layers were combined, and vacuum distillation was performed to concentrate the ethyl acetate, and vacuum distillation was performed using an oil pump, and the 70-90°C fraction was collected to obtain 14.12g of tert-butyl 3-aminoazetidine-1-carboxylate, a light yellow liquid, GC≥98.8%, and a yield of 82%.
[0028] Comparative Example 1: Liquid ammonia replaces trisubstituted silicon-based amine
[0029] 17.12 g (100 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate, 12.04 g (100 mmol) of anhydrous magnesium sulfate and 170 g of methanol were added into a glass bottle, cooled to -15 °C, 17.00 g (1 mol) of liquid ammonia was introduced into the bottle, and the temperature was slowly raised to room temperature under stirring, and the dehydration reaction was carried out for 4 hours. Then 26.90 g (300 mmol) of tetrahydroxydiboron and 0.51 g of 10% palladium on carbon were added, the temperature was raised to 50 °C and the reaction was carried out for 24 hours. Sampling was performed, and the reduction reaction was completed. 1.31 g (5 mmol) of tetra-n-butylammonium fluoride was added, stirred for 1 hour, sampled, and the deprotection reaction was completed by GC detection. The mixture was filtered, and 200 g of water and 170 g of ethyl acetate were added to the filtrate. The layers were separated, and the water layer was extracted once with 170 g of ethyl acetate. The ethyl acetate layers were combined and distilled under reduced pressure to concentrate the ethyl acetate. The distillation under reduced pressure was performed using an oil pump, and the fractions at 70-90 ° C were collected to obtain 10.68 g of tert-butyl 3-aminoazetidine-1-carboxylate as a light yellow liquid product with a GC value of ≥98.2% and a yield of 62%.
[0030] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.
Claims
1. A method for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate, characterized in that: The following steps are involved: 3-Oxoazetidine-1-carboxylic acid tert-butyl ester, anhydrous magnesium sulfate and trisubstituted silylamine are mixed in an organic solvent for reaction, and then tetrahydroxydiboron and palladium on carbon are added, the temperature is raised to 45-50° C. for reduction reaction, and tetra-n-butylammonium fluoride is added for deprotection to obtain 3-aminoazetidine-1-carboxylic acid tert-butyl ester.
2. The process for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate according to claim 1, characterized in that: The trisubstituted silylamine is selected from trimethylsilylamine, triethylsilylamine, triphenylsilylamine or tert-butyldimethylsilylamine.
3. The process for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate according to claim 1, characterized in that: The organic solvent is selected from methanol, ethanol or isopropanol.
4. The process for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate according to claim 1, characterized in that: The palladium carbon is selected from 5% palladium carbon or 10% palladium carbon.
5. The process for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate according to claim 1, characterized in that: The weight ratio of the tert-butyl 3-oxoazetidine-1-carboxylate to palladium on carbon is 1:0.003-0.
05.
6. The process for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate according to claim 1, characterized in that: The weight ratio of the tert-butyl 3-oxoazetidine-1-carboxylate, anhydrous magnesium sulfate, trisubstituted silicon-based amine, tetrahydroxydiboron and tetra-n-butylammonium fluoride is 1:0.15-0.3:1-1.5:2-5:0.01-0.
05.
7. The process for synthesizing tert-butyl 3-aminoazetidine-1-carboxylate according to claim 1, characterized in that: The typical operation steps are: add tert-butyl 3-oxoazetidine-1-carboxylate, anhydrous magnesium sulfate, trisubstituted silylamine and organic solvent into a reaction bottle, dehydrate and react for 2 hours under stirring at room temperature, then add tetrahydroxydiboron and palladium carbon, heat to 45-50°C for reduction reaction for 18-24 hours, add tetra-n-butylammonium fluoride, stir for 1 hour, terminate the reaction, filter, add water and extraction solvent to the filtrate, separate the layers, and distill the organic layer under reduced pressure to obtain tert-butyl 3-aminoazetidine-1-carboxylate.