A method for synthesizing 1-amino-2-methyl-2-propanol
By combining glycine ethyl ester hydrochloride with Grignard reagents, the safety hazards in the existing technology have been solved, and the efficient synthesis of 1-amino-2-methyl-2-propanol has been achieved, which is suitable for large-scale production.
Patent Information
- Application Number
- CN202310940677.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-28
- Publication Date
- 2025-10-28
- Estimated Expiration
- 2043-07-28
AI Technical Summary
In the existing technology, when 1-amino-2-methyl-2-propanol is synthesized from β-hydroxyisovaleric acid via the Curtius reaction, diphenyl azidophosphate (DPPA) is used, which generates a large amount of nitrogen gas, posing a safety hazard and making it unsuitable for large-scale production.
Using inexpensive glycine ethyl ester hydrochloride as a raw material, the amino group is first protected by Boc, and then the ester is reacted with Grignard reagent to generate a tertiary hydroxyl group. The process is optimized by controlling the temperature and solvent selection to avoid the generation of hazardous substances.
It achieves simple operation, high yield, and is suitable for large-scale production of 1-amino-2-methyl-2-propanol, while improving safety and economy.
Smart Images
Figure CN116947658B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing 1-amino-2-methyl-2-propanol. Background Technology
[0002] There are reports of using β-hydroxyisovaleric acid as a starting material to rearrange amino compounds via the Curtius reaction (CN106496085). However, this method uses diphenyl azide phosphate (DPPA), which generates a large amount of nitrogen gas during the rearrangement reaction, making it relatively dangerous and unsuitable for large-scale synthesis. Summary of the Invention
[0003] A method for synthesizing 1-amino-2-methyl-2-propanol, comprising:
[0004]
[0005] Furthermore, the alkali is one or more of triethylamine, sodium hydroxide, potassium hydroxide, or sodium bicarbonate.
[0006] Furthermore, in the step of preparing compound III from compound II, the molar ratio of glycine ethyl ester hydrochloride, ditert-butyl dicarbonate, and base is 1:1 to 1.1:1 to 2.0.
[0007] Furthermore, in the step of preparing compound III from compound II, glycine ethyl ester hydrochloride and triethylamine are added in organic solvent 1 under ice bath conditions, followed by the dropwise addition of di-tert-butyl dicarbonate, with the dropwise addition rate controlled to keep the temperature of the reaction solution below 20°C, and the reaction is stirred.
[0008] Wherein, the organic solvent 1 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl ether, and toluene.
[0009] Furthermore, in the step of preparing compound IV from compound III, compound III is added to organic solvent 2 under ice bath conditions, the reaction system is replaced with nitrogen gas, Grignard reagent is added dropwise to the reaction solution, the reaction temperature is kept below room temperature, and the reaction is stirred.
[0010] The organic solvent 2 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl ether, and toluene.
[0011] Furthermore, the Grignard reagent is methyl magnesium bromide, methyl magnesium iodide, or CH3X reacting with metallic magnesium to form CH3XMg, wherein X is Cl, Br, or I.
[0012] Furthermore, the molar ratio of compound III to Grignard reagent is 1:2.2.
[0013] Furthermore, in the step of preparing compound I from compound IV, compound IV is added to organic solvent 3 under ice bath conditions, and trimethylchlorosilane is added dropwise to keep the reaction temperature below room temperature while stirring the reaction.
[0014] The organic solvent 3 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl ether, and toluene.
[0015] Furthermore, the molar ratio of compound IV to trimethylchlorosilane is 1:1.1 to 2.
[0016] Furthermore, the solvent used in the entire reaction process is one or more of the following: dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl ether, and toluene.
[0017] The advantages of this application are as follows: This method uses inexpensive glycine ethyl ester hydrochloride as a raw material, first protecting the amino group with Boc, and then reacting it with Grignard reagent to generate a tertiary hydroxyl group. This method is simple to operate, has a high yield, and is suitable for large-scale production. Attached Figure Description
[0018] Figure 1 This is a gas phase spectrum of the product prepared in Example 1 of the synthesis method of 1-amino-2-methyl-2-propanol according to the present invention.
[0019] Figure 2 This is the hydrogen spectrum of the product prepared in Example 1 of the synthesis method of 1-amino-2-methyl-2-propanol according to the present invention. Detailed Implementation
[0020] To facilitate understanding of the technical solution applied for, the technical solution will now be further explained and illustrated through embodiments.
[0021] Example 1
[0022] The specific steps for preparing compound III from compound II are as follows:
[0023] Add 3.5 L of dichloromethane to a 5 L four-necked flask, then add 837 g (6 mol, 1 eq) of glycine ethyl ester hydrochloride and 667 g (6.6 mol, 1.1 eq) of triethylamine. Cool the reaction mixture in an ice-water bath to maintain the internal temperature at approximately 10 °C. Transfer 1439 g (6.6 mol, 1.1 eq) of di-tert-butyl dicarbonate to a constant-pressure dropping funnel and slowly add it dropwise to the reaction mixture, controlling the dropping rate to keep the temperature of the reaction mixture below 20 °C. The addition should be completed in approximately 1 hour. Continue stirring the reaction mixture for 4 hours. Wash the reaction mixture twice with 2 L of saturated sodium bicarbonate solution, then once with 1 L of saturated brine. Dry the dichloromethane phase with anhydrous sodium sulfate, filter, and rotary evaporate the filtrate under reduced pressure to obtain 1195 g of N-Boc glycine ethyl ester (compound III), with a yield of 98%. The gas phase showed a purity of 99.5%. This was used directly for the next step.
[0024] The steps for preparing compound IV from compound III are as follows:
[0025] 1.5 L of anhydrous tetrahydrofuran was added to a 5 L four-necked flask, followed by 609 g (3 mol, 1 eq) of compound III obtained in the previous step. The reaction mixture was then placed in an ice-water bath to maintain an internal temperature of approximately 5 °C. The reaction system was purged with nitrogen gas. 2.2 L (6.6 mol, 2.2 eq) of 3M methyl magnesium bromide was slowly added dropwise to the reaction mixture, keeping the temperature below 10 °C, over approximately 3 hours. After the addition was complete, the reaction mixture was allowed to gradually rise to room temperature, and the reaction was stirred for another 10 hours. TLC showed that the reaction was complete. 1 L of 4N HCl was prepared and added dropwise to the reaction mixture. The reaction mixture was then rotary evaporated under reduced pressure to distill off most of the tetrahydrofuran. 1 L of dichloromethane was added, and the mixture was stirred for 10 minutes. After standing and separating the phases, the aqueous phase was extracted with 1 L of dichloromethane. The dichloromethane phases were combined and washed with 1 L of saturated sodium bicarbonate solution and 1 L of water, respectively. The dichloromethane phase was then subjected to vacuum distillation. First, the dichloromethane was distilled off at low temperature, and then product compound IV was distilled off using an oil pump, yielding 467.7 g, with a yield of 82.5%.
[0026] Results of Step 2 Reaction Condition Optimization
[0027] Serial Number Equivalent (methylmagnesium bromide) solvent Reaction time Yield % 1 2 Tetrahydrofuran 10 63 2 2.1 Tetrahydrofuran 10 74 3 2.15 Tetrahydrofuran 10 78 4 2.2 Tetrahydrofuran 10 82.5 5 2.25 Tetrahydrofuran 10 83.1 6 2.3 Tetrahydrofuran 10 82.7 7 2.2 Tetrahydrofuran 8 77 8 2.2 Tetrahydrofuran 12 81.8 9 2.2 Toluene 10 68 10 2.2 Isopropyl ether 10 47
[0028] The steps for preparing compound I from compound IV are as follows:
[0029] 5 L of dichloromethane was added to a 10 L four-necked flask, followed by 1 L of methanol, and then 756 g (4 mol, 1 eq) of compound IV. The reaction mixture was placed in an ice-water bath at 0-5 °C. 653 g (6 mol, 1.5 eq) of trimethylchlorosilane was added dropwise, ensuring the reaction temperature did not exceed 5 °C, and the addition was completed over approximately 2 hours. The reaction mixture was then heated in an oil bath at 35 °C for 4 hours. 2 L of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred for 30 minutes. After standing and separating the phases, the dichloromethane phase was washed twice with 1 L of water. The mixture was then distilled under reduced pressure using a water pump. Since product A4 has a low boiling point, a 30 cm distillation column (glass packed) was used to completely separate the product from the dichloromethane. 342.5 g of product compound I was obtained, with a yield of 96%. GC analysis showed a purity of 99.75%. Figure 1 As shown. ¹H NMR (400MHz, Chloroform-d) δ: 2.54 (s, 2H), 2.03 (s, 2H), 1.12 (s, 6H) ppm, as... Figure 2 As shown.
[0030]
[0031] Example 2
[0032] The specific steps for preparing compound III from compound II are as follows:
[0033] 3.5 L of dichloromethane was added to a 5 L four-necked flask, followed by 837 g (6 mol, 1 eq) of glycine ethyl ester hydrochloride, and then 852.7 g (6.6 mol, 1.1 eq) of N,N-diisopropylethylamine. The reaction mixture was cooled in an ice-water bath to maintain an internal temperature of approximately 10 °C. 1439 g (6.6 mol, 1.1 eq) of di-tert-butyl dicarbonate was transferred to a constant-pressure dropping funnel and slowly added dropwise to the reaction mixture, controlling the dropping rate to ensure the temperature of the reaction mixture did not exceed 20 °C. The addition was completed in approximately 1 hour. The reaction mixture was then stirred for another 4 hours. The reaction mixture was washed twice with 2 L of saturated sodium bicarbonate solution, and then once with 1 L of saturated saline solution. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure to obtain 1108 g of the product N-Boc glycine ethyl ester (compound III), with a yield of 91%. The gas chromatography showed a purity of 99%.
[0034] The steps for preparing compound IV from compound III are as follows:
[0035] 1.5 L of anhydrous tetrahydrofuran was added to a 5 L four-necked flask, followed by 609 g (3 mol, 1 eq) of compound III obtained in the previous step. The reaction mixture was then placed in an ice-water bath to maintain an internal temperature of approximately 5 °C. The reaction system was purged with nitrogen. 2.2 L (6.6 mol, 2.2 eq) of 3M methyl magnesium bromide was slowly added dropwise to the reaction mixture, keeping the temperature below 10 °C, over approximately 3 hours. After the addition was complete, the reaction mixture was allowed to gradually rise to room temperature, and the reaction was stirred for another 10 hours. TLC showed that the reaction was complete. The reaction mixture was transferred to a 10 L four-necked flask, and 1 L of 4N HCl was prepared and added dropwise to the reaction mixture. The reaction mixture was then subjected to rotary evaporation under reduced pressure to distill off most of the tetrahydrofuran. 1 L of dichloromethane was added, and the mixture was stirred for 10 minutes. After standing and separating the phases, the aqueous phase was extracted with 1 L of dichloromethane. The dichloromethane phases were combined and washed with 1 L of saturated sodium bicarbonate solution and 1 L of water, respectively. The dichloromethane phase was then subjected to vacuum distillation. First, the dichloromethane was distilled off at low temperature, and then product compound IV was distilled off using an oil pump, yielding 476.8 g, with a yield of 84.1%.
[0036] The steps for preparing compound I from compound IV are as follows:
[0037] 5 L of methanol was added to a 10 L four-necked flask, followed by 756 g (4 mol, 1 eq) of compound IV. The reaction mixture was placed in an ice-water bath at 0-5 °C, and 518.5 g (4.8 mol, 1.2 eq) of trimethylchlorosilane was added dropwise, ensuring the reaction temperature did not exceed 5 °C, over approximately 2 hours. The reaction mixture was then heated in an oil bath at 35 °C for 4 hours. The reaction mixture was then evaporated to dryness, and 5 L of dichloromethane and 2 L of saturated sodium bicarbonate solution were added to the reaction system, followed by stirring for 30 minutes. After standing and separating the phases, the dichloromethane phase was washed twice with 1 L of water. The mixture was then distilled under reduced pressure using a water pump. Due to the low boiling point of product compound I, a 30 cm distillation column (glass packing) was used to completely separate the product from the dichloromethane. 217.2 g of product compound I was obtained, with a yield of 61%. GC analysis showed a purity of 99%.
[0038] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.
Claims
1. A method for synthesizing 1-amino-2-methyl-2-propanol, characterized in that, include: ； The base is triethylamine; in the step of preparing compound III from compound II, the molar ratio of glycine ethyl ester hydrochloride, ditert-butyl dicarbonate, and base is 1:1 to 1.1:1 to 2.0; In the step of preparing compound III from compound II, glycine ethyl ester hydrochloride and triethylamine are added in organic solvent 1 under ice bath conditions, followed by the dropwise addition of di-tert-butyl dicarbonate. The dropping rate is controlled so that the temperature of the reaction solution does not exceed 20°C, and the reaction is stirred. Wherein, the organic solvent 1 is one or more of dichloromethane, tetrahydrofuran, methanol, methyl ether, and toluene; In the step of preparing compound IV from compound III, compound III is added to organic solvent 2 under ice bath conditions, the reaction system is replaced with nitrogen gas, Grignard reagent is added dropwise to the reaction solution, the reaction temperature is kept below room temperature, and the reaction is stirred. Wherein, the organic solvent 2 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl tert-methyl ether, and toluene; the Grignard reagent is: methyl magnesium bromide or methyl magnesium iodide. In the step of preparing compound I from compound IV, compound IV is added to organic solvent 3 under ice bath conditions, trimethylchlorosilane is added dropwise, the reaction temperature is kept below room temperature, and the reaction is stirred. Wherein, the organic solvent 3 is a mixed solution of dichloromethane and methanol; the molar ratio of compound IV to trimethylchlorosilane is 1:1.
5.
2. The method for synthesizing 1-amino-2-methyl-2-propanol according to claim 1, characterized in that, The molar ratio of compound III to Grignard reagent is 1:2.2.
Citation Information
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