CN116947658A - A kind of synthesis method of 1-amino-2-methyl-2-propanol - Google Patents

Abstract

The application relates to the technical field of organic synthesis, in particular to a synthesis method of 1-amino-2-methyl-2-propanol, which comprises the following steps: adding glycine ethyl ester hydrochloride into an organic solvent, and reacting with di-tert-butyl dicarbonate under an alkaline condition to prepare a compound III; reacting the compound III with a Grignard reagent to prepare a compound IV; the compound IV reacts with trimethylchlorosilane to prepare the 1-amino-2-methyl-2-propanol. The application adopts cheap glycine ethyl ester hydrochloride as a raw material, uses Boc to protect amino, and then adopts Grignard reagent to react with ester to generate tertiary hydroxyl. The method is simple to operate, has higher yield and is suitable for large-scale production.

Description

A kind of synthesis method of 1-amino-2-methyl-2-propanol

Technical field

The invention relates to the technical field of organic synthesis, and specifically relates to a synthesis method of 1-amino-2-methyl-2-propanol.

Background technique

It has been reported that β-hydroxyisovaleric acid is used as raw material and rearranged to generate amino compounds through Curtius reaction (CN106496085). However, this method uses diphenylphosphoryl azide (DPPA). During the rearrangement reaction, a large amount of nitrogen will be generated, which is relatively dangerous and is not suitable for large-scale synthesis.

Contents of the invention

A synthetic method of 1-amino-2-methyl-2-propanol, including:

Further, the base is one or more of triethylamine, sodium hydroxide, potassium hydroxide or sodium bicarbonate.

Further, in the step of preparing compound III from compound II, the molar ratio of glycine ethyl ester hydrochloride, di-tert-butyl dicarbonate, and base is 1:1 to 1.1: 1 to 2.0.

Further, in the step of preparing compound III from compound II, add glycine ethyl ester hydrochloride and triethylamine to organic solvent 1 under an ice bath, and then add di-tert-butyl dicarbonate dropwise, and control the dropping speed to make 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, n-hexane, n-heptane, methyl tertiary ether, and toluene.

Further, in the step of preparing compound IV from compound III, add compound III to organic solvent 2 under an ice bath, replace the reaction system with nitrogen, add Grignard reagent dropwise to the reaction solution, so that the reaction temperature does not exceed room temperature, Stir the reaction;

Wherein, the organic solvent 2 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl tertiary ether, and toluene.

Further, the Grignard reagent is methylmagnesium bromide, methylmagnesium iodide or CH ₃ X reacts with metal magnesium to generate CH ₃ XMg, where X is Cl, Br or I.

Further, the molar ratio of compound III to Grignard reagent is: 1:2.2.

Further, in the step of preparing compound I from compound IV, compound IV is added to organic solvent 3 under an ice bath, trimethylsilyl chloride is added dropwise, so that the reaction temperature does not exceed room temperature, and the reaction is stirred;

Wherein, the organic solvent 3 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl tertiary ether, and toluene.

Further, the molar ratio of compound IV to trimethylchlorosilane is 1:1.1-2.

Further, the solvent of the entire reaction process is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl tertiary ether, and toluene.

The beneficial effects of this application are as follows: This method uses cheap glycine ethyl ester hydrochloride as raw material, first uses Boc to protect the amino group, and then uses Grignard reagent and ester reaction to generate tertiary hydroxyl groups. This method is simple to operate, has a high yield, and is suitable for large-scale production.

Description of the drawings

Figure 1 is a gas phase spectrum of the product prepared in Example 1 of a synthesis method of 1-amino-2-methyl-2-propanol of the present invention.

Figure 2 is a hydrogen spectrum of the product prepared in Example 1 of the synthesis method of 1-amino-2-methyl-2-propanol of the present invention.

Detailed ways

In order to facilitate understanding of the technical solution of the application, the technical solution is now further explained through examples.

Example 1

The specific steps for preparing compound III from compound II are as follows:

Add 3.5L methylene chloride to a 5L four-neck flask, add 837g glycine ethyl ester hydrochloride (6mol, 1eq), then add 667g triethylamine (6.6mol, 1.1eq), and cool the reaction solution in an ice water bath. Keep the internal temperature of the reaction solution at about 10°C. Transfer 1439g of di-tert-butyl dicarbonate (6.6mol, 1.1eq) into a constant pressure dropping funnel, slowly add it dropwise to the reaction solution, control the dropping speed so that the temperature of the reaction solution does not exceed 20°C, and complete the dropwise addition in about 1 hour. . Then continue to stir the reaction for 4 hours. The reaction solution was washed twice with 2 L of saturated sodium bicarbonate solution and once with 1 L of saturated brine. The dichloromethane phase was dried over anhydrous sodium sulfate, then filtered, and the filtrate was evaporated 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%. Use it directly for the next step.

The steps for preparing compound IV from compound III are as follows:

Add 1.5L anhydrous tetrahydrofuran to a 5L four-neck flask, then add 609g (3mol, 1eq) of compound III obtained in the previous step, and then place the reaction solution in an ice-water bath to keep the internal temperature of the reaction solution at about 5°C. The reaction system was replaced with nitrogen. Slowly add 2.2L of 3M methylmagnesium bromide (6.6 mol, 2.2eq) dropwise into the reaction solution so that the temperature of the reaction solution does not exceed 10°C. The addition will be completed in about 3 hours. After the dropwise addition was completed, the reaction solution was allowed to gradually rise to room temperature, and the reaction was continued to stir for 10 h. TLC showed the reaction was complete. Prepare 1L of 4NHCl and add dropwise to the reaction solution. Then, the reaction solution was rotary evaporated under reduced pressure to distill out most of the tetrahydrofuran. Add 1 L of methylene chloride and stir for 10 minutes. After standing for separation, the aqueous phase was extracted with 1L methylene chloride. Combine the dichloromethane phases and wash with 1L saturated sodium bicarbonate solution and 1L water respectively. Afterwards, the methylene chloride phase was distilled under reduced pressure. The methylene chloride was first evaporated at low temperature, and then the product compound IV was evaporated using an oil pump to obtain 467.7g, with a yield of 82.5%.

Optimization results of reaction conditions in step 2

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

The steps for preparing compound I from compound IV are as follows:

Add 5L methylene chloride into a 10L four-neck bottle, then add 1L methanol, then add 756g of compound IV (4mol, 1eq), place the reaction solution in an ice water bath, the temperature of the reaction solution is 0-5°C, and add trimethyltrimethyl dropwise 653g of chlorosilane (6mol, 1.5eq) should be added dropwise so that the temperature of the reaction solution does not exceed 5°C, and the drops should be completed in about 2 hours. Finally, the reaction solution was placed in an oil bath and heated to an internal temperature of 35°C for 4 hours. Add 2L of saturated sodium bicarbonate solution to the reaction solution and stir for 30 minutes. After standing for separation, the dichloromethane phase was washed twice with 1 L of water. Then use a water pump to distill under reduced pressure. Since the boiling point of product A4 is low, adding a 30cm distillation column (glass packing) can completely separate the product and methylene chloride. 342.5 g of product compound I was obtained with a yield of 96%. GC showed a purity of 99.75% as shown in Figure 1. HNMR (400MHz, Chloroform-d) δ: 2.54 (s, 2H), 2.03 (s, 2H), 1.12 (s, 6H) ppm, as shown in Figure 2.

Example 2

The specific steps for preparing compound III from compound II are as follows:

Add 3.5L methylene chloride into a 5L four-neck bottle, then add 837g glycine ethyl ester hydrochloride (6mol, 1eq) in one go, and then add 852.7g N,N-diisopropylethylamine (6.6mol, 1.1 eq), cool the reaction solution in an ice-water bath to keep the internal temperature of the reaction solution at about 10°C. Transfer 1439g of di-tert-butyl dicarbonate (6.6mol, 1.1eq) into a constant pressure dropping funnel and slowly add it dropwise to the reaction solution. Control the dropping speed so that the temperature of the reaction solution does not exceed 20°C. The addition will be completed in about 1 hour. . Then continue to stir the reaction for 4 hours. The reaction solution was washed twice with 2 L of saturated sodium bicarbonate solution and once with 1 L of saturated brine. The dichloromethane phase was dried over anhydrous sodium sulfate, then filtered, and the filtrate was evaporated under reduced pressure to obtain 1108 g of product N-Boc glycine ethyl ester (compound III) with a yield of 91%. The gas phase showed a purity of 99%.

The steps for preparing compound IV from compound III are as follows:

Add 1.5L anhydrous tetrahydrofuran to a 5L four-neck flask, then add 609g (3mol, 1eq) of compound III obtained in the previous step, and then place the reaction solution in an ice-water bath to keep the internal temperature of the reaction solution at about 5°C. The reaction system was replaced with nitrogen. Slowly add 2.2L of 3M methylmagnesium bromide (6.6 mol, 2.2eq) dropwise into the reaction solution so that the temperature of the reaction solution does not exceed 10°C. The addition will be completed in about 3 hours. After the dropwise addition was completed, the reaction solution was allowed to gradually rise to room temperature, and the reaction was continued to stir for 10 h. TLC showed the reaction was complete. Transfer the reaction solution to a 10L four-neck bottle, prepare 1L of 4NHCl, and add it dropwise to the reaction solution. Then, the reaction solution was rotary evaporated under reduced pressure to distill out most of the tetrahydrofuran. Add 1 L of methylene chloride and stir for 10 minutes. After standing for separation, the aqueous phase was extracted with 1L methylene chloride. Combine the dichloromethane phases and wash with 1L saturated sodium bicarbonate solution and 1L water respectively. The methylene chloride phase was then distilled under reduced pressure. The methylene chloride was first evaporated at low temperature, and then the product compound IV was evaporated using an oil pump to obtain 476.8 g, with a yield of 84.1%.

The steps for preparing compound I from compound IV are as follows:

Add 5L methanol into a 10L four-neck flask, and then add 756g (4mol, 1eq) of compound IV. Place the reaction solution in an ice water bath. The temperature of the reaction solution is 0-5°C. Add 518.5g (4.8mol) of trimethylchlorosilane dropwise. ,1.2eq), when adding dropwise, the temperature of the reaction solution should not exceed 5°C, and the dripping should be completed in about 2 hours. Finally, the reaction solution was placed in an oil bath and heated to an internal temperature of 35°C for 4 hours. Then spin the reaction liquid to dryness, add 5L of methylene chloride to the reaction system, then add 2L of saturated sodium bicarbonate solution, and stir for 30 minutes. After standing for separation, the dichloromethane phase was washed twice with 1 L of water. Then use a water pump to distill under reduced pressure. Since the boiling point of the product compound I is low, adding a 30cm distillation column (glass packing) can completely separate the product and methylene chloride. 217.2 g of product compound I was obtained with a yield of 61%. GC showed 99% purity.

The above are only a few embodiments of the present application, and are not intended to limit the present application in any way. Although the present application is disclosed as above with preferred embodiments, they are not intended to limit the present application. Any skilled person familiar with this field, Without departing from the scope of the technical solution of this application, slight changes or modifications made using the technical content disclosed above are equivalent to equivalent implementation examples and fall within the scope of the technical solution.

Claims (9)

1. A synthetic method of 1-amino-2-methyl-2-propanol, which is characterized in that it includes: 2. the synthetic method of a kind of 1-amino-2-methyl-2-propanol according to claim 1, is characterized in that, described alkali is triethylamine, sodium hydroxide, potassium hydroxide or carbonic acid One or more types of sodium hydrogen. 3. A kind of synthetic method of 1-amino-2-methyl-2-propanol according to claim 1 or 2, characterized in that, in the step of preparing compound III from compound II, glycine ethyl ester hydrochloride, The molar ratio of di-tert-butyl dicarbonate and alkali is 1:1~1.1:1~2.0. 4. A kind of synthetic method of 1-amino-2-methyl-2-propanol according to claim 1, characterized in that, in the step of preparing compound III from compound II, in an ice bath, in an organic solvent 1 , add glycine ethyl ester hydrochloride and triethylamine, then add di-tert-butyl dicarbonate dropwise, control the dropping speed so that the temperature of the reaction solution does not exceed 20°C, and stir the reaction; Wherein, the organic solvent 1 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl tertiary ether, and toluene. 5. A kind of synthetic method of 1-amino-2-methyl-2-propanol according to claim 1, characterized in that, in the step of preparing compound IV from compound III, in an organic solvent under an ice bath, Add compound III to 2, replace the reaction system with nitrogen, add Grignard reagent dropwise to the reaction solution, so that the reaction temperature does not exceed room temperature, and stir the reaction; Wherein, the organic solvent 2 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl tertiary ether, and toluene. 6. the synthetic method of a kind of 1-amino-2-methyl-2-propanol according to claim 1 or 5, is characterized in that, described Grignard reagent is: methylmagnesium bromide, methyl Magnesium iodide or CH ₃ X reacts with metallic magnesium to form CH ₃ XMg, where X is Cl, Br or I. 7. The synthesis method of 1-amino-2-methyl-2-propanol according to any one of claims 1, 5, and 6, characterized in that the molar ratio of compound III to Grignard reagent is: 1 :2.2. 8. A kind of synthetic method of 1-amino-2-methyl-2-propanol according to claim 1, characterized in that, in the step of preparing compound I from compound IV, in an ice bath, in an organic solvent 3 Add compound IV, add trimethylsilyl chloride dropwise so that the reaction temperature does not exceed room temperature, and stir the reaction; Wherein, the organic solvent 3 is one or more of dichloromethane, tetrahydrofuran, methanol, n-hexane, n-heptane, methyl tertiary ether, and toluene. 9. A method for synthesizing 1-amino-2-methyl-2-propanol according to claim 8, characterized in that the molar ratio of compound IV to trimethylchlorosilane is 1:1.1-2.