Synthesis method of (S)-2-((tert-butoxycarbonyl) amino) propyl methanesulfonate

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of (S)-2-((tert-butoxycarbonyl) amino) propyl methanesulfonate, which specifically comprises the following steps: step 1, L-aminopropanol and BOC anhydride react to protect amino, and an intermediate N-Boc-L-alaninol is obtained; and 2, carrying out an acylation reaction on the intermediate N-Boc-L-alaninol and methylsulfonyl chloride to obtain the (S)-2-((tert-butoxycarbonyl) amino) propyl methanesulfonate. The synthetic method of the (S)-2-((t-butoxycarbonyl) amino) propyl methanesulfonate has the beneficial effects that the reaction yield, the product purity and the safety are high, expensive dioxane is not needed to serve as a solvent, and dichloromethane serving as a solvent can be recycled, so that the raw material cost is reduced, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate. Background Art

[0002] (S)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate is used as an organic synthesis intermediate for the synthesis of a variety of organic compounds. It can be used as an important drug intermediate in the pharmaceutical field. In the pesticide and dye fields, it can be used as a raw material for the synthesis of high-efficiency and low-toxic pesticides to improve the insecticidal and bactericidal effects of pesticides. It can also be used as a catalyst or reagent for chemical reactions and plays an important role in chemical analysis.

[0003] The existing synthesis method of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate has the problem of low reaction yield. At the same time, the purity of the prepared (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate is low. When L-aminopropanol and BOC anhydride react, dioxane, which is expensive and difficult to recover, is used as a solvent. When N-Boc-L-alaninol and methanesulfonyl chloride react, nitrogen methyl morpholine, which is highly toxic, is used as an acid-binding agent, and the reaction conditions are harsh. Therefore, how to improve the reaction yield, product purity and safety of the synthesis of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, while reducing the cost of raw materials, has become an urgent problem to be solved. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate.

[0005] The present invention relates to a method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, which specifically comprises the following steps: Step 1: Add dichloromethane, L-aminopropanol and sodium bicarbonate to a reaction bottle, then add BOC anhydride, stir evenly, heat to reflux, and carry out heat preservation reaction. The reaction is monitored by TLC. After the reaction is complete, the solvent is removed by vacuum concentration to obtain an oily substance, the solvent is collected, and water is added to the oily substance for crystallization to obtain a white solid, which is filtered, the filter cake is washed with water, and the filter cake is dried to obtain the intermediate N-Boc-L-alaninol; Step 2: Add dichloromethane, intermediate N-Boc-L-alaninol and sodium bicarbonate to the reaction bottle, then add methanesulfonyl chloride dropwise, and after the addition is completed, keep warm for reaction. Monitor the reaction by TLC. After the reaction is complete, add water to dissolve the solid, separate the aqueous phase, and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid. Recrystallize with ethanol and filter. Dry the filter cake to obtain (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate.

[0006] Preferably, the synthetic route is as follows: .

[0007] Preferably, in step 1, the molar ratio of L-aminopropanol, Boc anhydride and sodium bicarbonate is 1:1-3:1-3.

[0008] Preferably, in the step 1, the weight ratio of the L-aminopropanol to dichloromethane is 1:5-20, and the weight ratio of the L-aminopropanol to water is 1:5-20.

[0009] Preferably, in step 1, the temperature is raised to 40-50° C. and the reaction is kept warm for 3-8 hours.

[0010] Preferably, in the step 2, the molar ratio of N-Boc-L-alaninol, methanesulfonyl chloride and sodium bicarbonate is 1:1-3:1-3.

[0011] Preferably, in the step 2, the weight ratio of the N-Boc-L-alaninol to dichloromethane is 1:5-20, and the weight ratio of the N-Boc-L-alaninol to water is 1:5-20.

[0012] Preferably, in the step 2, the temperature is controlled at 20-25° C. when the methanesulfonyl chloride is added dropwise, and the reaction is carried out at 20-30° C. for 1-3 hours after the addition of methanesulfonyl chloride is completed.

[0013] Preferably, in the step 2, the weight ratio of N-Boc-L-alaninol to ethanol is 1:0.5-10.

[0014] Preferably, in the step 2, the recrystallization temperature is -5 to 10°C and the time is 0.5 to 3 hours.

[0015] Compared with the prior art, the advantages and positive effects of the present invention are: (1) The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate has a high total reaction yield, reduces production costs, improves the utilization efficiency of raw materials, and thus improves economic benefits. The obtained (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate has high purity, which improves market competitiveness. No complicated subsequent purification process is required, thereby reducing costs and time consumption. (2) The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate does not require expensive dioxane as a solvent, and dichloromethane as a solvent can be recycled, thereby reducing the cost of raw materials; (3) The synthesis method of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate has mild reaction conditions, so that the reaction process is more stable, making the production process safer and easier to control, and the reaction performance will not be affected when it is scaled up to industrial production scale; (4) The synthesis method of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate is simple to operate, reduces labor costs, and improves the stability and reliability of large-scale production. DETAILED DESCRIPTION

[0016] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments.

[0017] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0018] Example 1 A method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, comprising the following steps: Step 1: Add 75 kg of dichloromethane, 5 kg of L-aminopropanol and 10 kg of sodium bicarbonate to a 100 L reactor, then add 29 kg of Boc anhydride, heat to 45 ° C, keep warm for 8 hours, monitor the reaction by TLC, and after the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain an oily substance, collect the solvent, and add 80 kg of water to the oily substance for crystallization to obtain a white solid, filter, wash the filter cake with water, and dry the filter cake to obtain 11.2 kg of the intermediate N-Boc-L-alaninol. The reaction yield is 96.1%, and the purity of N-Boc-L-alaninol is 99.7%.

[0019] Step 2: Add 150 kg of dichloromethane, 10 kg of intermediate N-Boc-L-alaninol and 7.2 kg of sodium bicarbonate to a 100 L reactor, add 9.8 kg of methanesulfonyl chloride dropwise, and control the temperature during the addition to be 20 ° C. After the addition is completed, react at 25 ° C for 3 hours, monitor the reaction by TLC, and after the reaction is complete, add water to dissolve the solid, separate the aqueous phase, and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, which is recrystallized with 10 kg of ethanol at -5 ° C for 2 hours, filtered, and the filter cake is dried to obtain 13.3 kg of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, the reaction yield is 92.0%, and the purity of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate is 99.4%.

[0020] Example 2 A method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, comprising the following steps: Step 1: Add 1.5 kg of dichloromethane, 250 g of L-aminopropanol and 800 g of sodium bicarbonate to a 5L reaction bottle, then add 1 kg of Boc anhydride, heat to 50°C, keep warm for 3 hours, monitor the reaction by TLC, and after the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain an oily substance, collect the solvent, and add 2 kg of water to the oily substance for crystallization to obtain a white solid, filter, wash the filter cake with water, and dry the filter cake to obtain 540 g of the intermediate N-Boc-L-alaninol, the reaction yield is 92.5%, and the purity of N-Boc-L-alaninol is 99.1%.

[0021] Step 2: Add 5 kg of dichloromethane, 500 g of intermediate N-Boc-L-alaninol and 360 g of sodium bicarbonate to a 5L reaction bottle, add 653 g of methanesulfonyl chloride dropwise, and control the temperature during the addition to be 25°C. After the addition is completed, react at 30°C for 1 hour, monitor the reaction by TLC, and after the reaction is complete, add water to dissolve the solid, separate the aqueous phase, and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, which is recrystallized with 300 g of ethanol at 10°C for 3 hours, filtered, and the filter cake is dried to obtain 677.3 g of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, with a reaction yield of 93.7% and a purity of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate of 99.3%.

[0022] Example 3 A method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, comprising the following steps: Step 1: Add 500 g of the solvent collected in Example 1, 50 g of L-aminopropanol and 85 g of sodium bicarbonate to a 1 L reaction bottle, then add 150 g of Boc anhydride, heat to 40 ° C, keep warm for 4 hours, monitor the reaction by TLC, and after the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain an oily substance, collect the solvent, and add 500 g of water to the oily substance for crystallization to obtain a white solid, filter, wash the filter cake with water, and dry the filter cake to obtain 110 g of the intermediate N-Boc-L-alaninol. The reaction yield is 94.8%, and the purity of N-Boc-L-alaninol is 99.5%.

[0023] Step 2: Add 500g of dichloromethane, 100g of intermediate N-Boc-L-alaninol and 80g of sodium bicarbonate to a 1L reaction bottle, add 78.4g of methanesulfonyl chloride dropwise, and control the temperature during the addition to be 25°C. After the addition is completed, react at 30°C for 2h, monitor the reaction by TLC, and after the reaction is complete, add water to dissolve the solid, separate the aqueous phase, and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid, which is recrystallized with 500g of ethanol at 0°C for 1h, filtered, and the filter cake is dried to obtain 134g of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, with a reaction yield of 93.0%, and a purity of (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate of 99.2%.

[0024] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate, characterized in that: The specific steps include: Step 1: Add dichloromethane, L-aminopropanol and sodium bicarbonate to a reaction bottle, then add Boc anhydride, stir evenly, heat to reflux, and carry out heat preservation reaction. Monitor the reaction by TLC. After the reaction is complete, concentrate under reduced pressure to remove the solvent to obtain an oily substance, collect the solvent, and add water to the oily substance to crystallize to obtain a white solid, filter, wash the filter cake with water, and dry the filter cake to obtain the intermediate N-Boc-L-alaninol; Step 2: Add dichloromethane, intermediate N-Boc-L-alaninol and sodium bicarbonate to the reaction bottle, then add methanesulfonyl chloride dropwise, and after the addition is completed, keep warm for reaction. Monitor the reaction by TLC. After the reaction is complete, add water to dissolve the solid, separate the aqueous phase, and concentrate the organic phase under reduced pressure to remove the solvent to obtain a white solid. Recrystallize with ethanol and filter. Dry the filter cake to obtain (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate.

2. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 1, characterized in that: The synthetic route is as follows: 。 3. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 2, characterized in that: In the step 1, the molar ratio of the L-aminopropanol, Boc anhydride and sodium bicarbonate is 1:1-3:1-3.

4. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 3, characterized in that: In the step 1, the weight ratio of the L-aminopropanol to dichloromethane is 1:5-20, and the weight ratio of the L-aminopropanol to water is 1:5-20.

5. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 4, characterized in that: In the step 1, the temperature is raised to 40-50° C. and the reaction is kept at this temperature for 3-8 hours.

6. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 5, characterized in that: In the step 2, the molar ratio of the N-Boc-L-alaninol, methanesulfonyl chloride and sodium bicarbonate is 1:1-3:1-3.

7. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 6, characterized in that: In the step 2, the weight ratio of the N-Boc-L-alaninol to dichloromethane is 1:5-20, and the weight ratio of the N-Boc-L-alaninol to water is 1:5-20.

8. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 7, characterized in that: In the step 2, the temperature is controlled at 20-25° C. when the methanesulfonyl chloride is added dropwise, and the reaction is carried out at 20-30° C. for 1-3 hours after the addition of the methanesulfonyl chloride is completed.

9. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 8, characterized in that: In the step 2, the weight ratio of the N-Boc-L-alaninol to ethanol is 1:0.5-10.

10. The method for synthesizing (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate according to claim 9, characterized in that: In the step 2, the recrystallization temperature is -5 to 10°C and the time is 0.5 to 3 hours.

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