CN116178152A

CN116178152A - Preparation method of diethyl 2, 3-di-sec-butensuccinate

Info

Publication number: CN116178152A
Application number: CN202211439682.7A
Authority: CN
Inventors: 陈明明
Original assignee: Henan Kehong Biotechnology Co ltd
Current assignee: Henan Kehong Biotechnology Co ltd
Priority date: 2022-11-17
Filing date: 2022-11-17
Publication date: 2023-05-30

Abstract

The invention discloses a preparation method of diethyl 2, 3-di-sec-butensuccinate, which is characterized by comprising the following steps of deaminating L-isoleucine under the action of hydroxylamine sulfonic acid to obtain an intermediate 1; the intermediate 1 is esterified with ethanol under the action of sulfuric acid to obtain an intermediate 2; intermediate 2 is subjected to the action of lithium diisopropylamide and titanium tetrachloride to obtain the final product. The method provided by the invention is simple to operate, high in yield, low in cost and suitable for industrial production.

Description

Preparation method of diethyl 2, 3-di-sec-butensuccinate

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of diethyl 2, 3-di-sec-butensuccinate.

Background

The diethyl 2, 3-di-sec-butensuccinate can be used as a chemical product in various fields such as medicine, paint, preparation and the like as various intermediates, however, the synthesis method is complex, the process is difficult to control, a large amount of byproducts are easy to generate, the synthesis is difficult, the yield is low, and the requirements are far from being met.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a preparation method of diethyl 2, 3-di-sec-butensuccinate.

The aim of the invention is achieved by the following technical scheme: a preparation method of diethyl 2, 3-di-sec-butensuccinate comprises the following steps,

1) Deamination of L-isoleucine under the action of hydroxylamine sulfonic acid to obtain an intermediate 1;

2) The intermediate 1 is esterified with ethanol under the action of sulfuric acid to obtain an intermediate 2;

3) Intermediate 2 is subjected to the action of lithium diisopropylamide and titanium tetrachloride to obtain the final product.

Further, the method comprises the steps of,

1) Respectively and alternately adding a strong alkali solution and hydroxylamine sulfonic acid into L-isoleucine for reaction for multiple times, keeping the temperature of a reaction solution below 20 ℃, raising the temperature again for reflux reaction, then reducing the temperature to below 5 ℃ and adding concentrated sulfuric acid, finally extracting by using an organic solvent, drying and spin-drying to obtain an intermediate 1;

2) Adding ethanol and concentrated sulfuric acid into the intermediate 1, keeping the reflux reaction at 85 ℃, cooling to room temperature, neutralizing to pH=7, and obtaining white precipitate generated in the neutralization process as an intermediate 2;

3) The intermediate 2 is added into a solvent containing lithium diisopropylamide to react under stirring, then reacts with the solvent containing titanium tetrachloride at the temperature of minus 60 ℃ to the room temperature, is quenched, extracted, washed and dried, and finally the solvent is distilled out under reduced pressure, and the product is obtained by column chromatography.

Preferably, the L-isoleucine is dissolved in NaOH or KOH solution and cooled to 0-5 ℃, then hydroxylamine sulfonic acid with the temperature of 0-5 ℃ is gradually added into the reaction solution, the temperature of the reaction solution is kept below 10 ℃ in the adding process, the reaction is waited for 0.5h after the adding is finished, then NaOH or KOH solution is added, hydroxylamine sulfonic acid is gradually added, the temperature of the reaction solution is kept below 20 ℃ in the adding process, then stirring is carried out for 8h to room temperature, the temperature is raised to 100 ℃ again for reflux reaction for 3h, the temperature is reduced to 5 ℃ and concentrated sulfuric acid is added for stirring for 1h, dichloromethane solvent is used for extraction, and an organic phase is dried by anhydrous sodium sulfate and then is dried by a rotary evaporator to obtain an intermediate 1.

Preferably, intermediate 1 is added to ethanol and concentrated sulfuric acid, the reaction solution is refluxed at 85 ℃ for 5 hours, the reaction solution is cooled to room temperature, then neutralized to ph=7 with 5% NaOH or KOH solution, the white precipitate produced after neutralization is dissolved with water, then dissolved with ethyl acetate, the organic phase is washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried to obtain intermediate 2.

Preferably, the intermediate 2 is dissolved in tetrahydrofuran and added into lithium diisopropylamide dropwise, the mixture is stirred and reacted for 0.5h, then dichloromethane solution containing titanium tetrachloride is dropwise added at the temperature of minus 60 ℃, the temperature is gradually raised to room temperature, after stirring and reacting for 8h, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate solution is added for quenching, then ethyl acetate is used for extraction, saturated sodium chloride aqueous solution is used for washing, anhydrous sodium sulfate is used for drying, finally, the solvent is distilled out under reduced pressure, and petroleum ether and ethyl acetate are used as eluent for column chromatography to obtain the product.

The invention has the following advantages: the novel preparation method of the diethyl 2, 3-di-sec-butensuccinate product is simple to operate, low in cost and suitable for mass production, and various byproducts generated in the synthesis process are avoided by optimizing reaction raw materials and strictly controlling reaction conditions.

Drawings

FIG. 1 is a schematic illustration of the reaction process of the present invention.

Detailed Description

In order to make the purposes, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described.

The embodiment relates to a preparation method of diethyl 2, 3-di-sec-butene succinate, which comprises the following steps,

1) Dissolving 12.4g L-isoleucine in 180mL of 2.5mol NaOH solution, cooling to 5 ℃ in an ice bath, then cooling to 5 ℃, slowly adding 12.24g hydroxylamine sulfonic acid into a reaction bottle in batches, keeping the temperature of the solution not higher than 10 ℃ in the adding process, reacting the solution under the ice bath for 0.5h after the adding, adding 100mL of NaOH2.5mol solution after 0.5h, slowly adding 12.24g hydroxylamine sulfonic acid in batches, keeping the temperature of the reaction solution not higher than 20 ℃, stirring the reaction for 8h to reach the room temperature, heating the reaction solution to 100 ℃ after 8h to reflux for 3h, cooling to 0-5 ℃ after 3h, adding 40mL of concentrated sulfuric acid, cooling to 0-5 ℃ to prevent the vigorous heating during quenching reaction, stirring under the ice bath for 1h after the adding 100mL of CM (dichloromethane solvent), performing 6 times of extraction, drying the organic phase with anhydrous sodium sulfate, and spin-drying by a spin-drying instrument to obtain 6.36g of intermediate 1, wherein the KOH solution can be replaced by the KOH solution.

The nuclear magnetic data of the obtained intermediate 1 are as follows:

HNMR (nuclear magnetic resonance) (MeOD, 400 MHz) 0.92 (t, 3H), 0.94 (d, 3H), 1.25 (m, 1H), 1.39 (m, 1H) 1.84 (m, 1H), 2.07 (q, 1H) 2.28 (q, 1H)

2) 4g of intermediate 1 was placed in a 100mL three-necked flask, 20mL of ethanol and 0.2mL of concentrated sulfuric acid were added, the reaction solution was heated and refluxed in an oil bath at 85℃for 5 hours, after cooling the reaction solution to room temperature, the reaction solution was neutralized with a 5% NaOH solution or KOH solution until pH=7 or so, white precipitate was produced during the neutralization, the white precipitate produced after the neutralization was dissolved in water, then extracted 5 times with 30mLEtOAc (ethyl acetate), the organic phase was washed with 50mL of water, washed with 50mL of saturated sodium chloride, dried with anhydrous sodium sulfate and then spin-evaporated to dryness to obtain 3.1g of intermediate 2.

The obtained intermediate 2 nuclear magnetic data are as follows:

HNMR(MeOD，400MHz)0.85(m，6H)

3) 3.6mL of diisopropylethylamine is added into 60mL of THF (tetrahydrofuran) under the protection of nitrogen, the temperature is reduced to minus 78 ℃, 1.55mol of n-BuLi (n-butyllithium) 18mL of LDA (lithium diisopropylamide) is added dropwise, 3g of intermediate 2 is dissolved into 10mL of THF and added into the LDA, stirring reaction is carried out for 0.5h, 22mL of 1mol of dichloromethane solution of titanium tetrachloride is added dropwise at minus 60 ℃, the temperature is gradually increased to room temperature, stirring reaction is carried out for 8h, 2% sodium carbonate solution is added into ice bath for quenching, the sodium carbonate solution can be replaced by potassium carbonate, sodium bicarbonate and potassium bicarbonate for quenching, then 150mL of ethyl acetate is added for extraction three times, saturated sodium chloride aqueous solution is used for washing, anhydrous sodium sulfate is dried, finally, the solvent is distilled out under reduced pressure, and petroleum ether and ethyl acetate are used as eluent for column chromatography to obtain the product.

Claims

1. A preparation method of diethyl 2, 3-di-sec-butensuccinate is characterized by comprising the following steps,

2. The method for preparing diethyl 2, 3-di-sec-butensuccinate according to claim 1, comprising the steps of,

3. The method for preparing diethyl 2, 3-di-sec-butensuccinate according to claim 2, wherein the L-isoleucine is dissolved in NaOH or KOH solution and cooled to 0-5 ℃, then hydroxylamine sulfonic acid of 0-5 ℃ is gradually added into the reaction solution, the temperature of the reaction solution is kept below 10 ℃ in the adding process, after the completion of the adding, the reaction is waited for 0.5h, then NaOH or KOH solution is added, hydroxylamine sulfonic acid is gradually added, the temperature of the reaction solution is kept below 20 ℃ in the adding process, then stirring is carried out for 8h to room temperature, reflux reaction is carried out for 3h at the temperature of 100 ℃ again, the temperature is reduced to 0-5 ℃ and concentrated sulfuric acid is added for 1h, dichloromethane solvent is used for extraction, and an organic phase is dried by anhydrous sodium sulfate and then dried by a rotary evaporator to obtain an intermediate 1.

4. The process for preparing diethyl 2, 3-di-sec-butensuccinate according to claim 2, wherein the intermediate 1 is added to ethanol and concentrated sulfuric acid, the reaction solution is refluxed at 85 ℃ for 5 hours, the reaction solution is cooled to room temperature and then neutralized to ph=7 with 5% NaOH or KOH solution, white precipitate generated after the neutralization is dissolved with water and then dissolved with ethyl acetate, the organic phase is washed with water, and dried with anhydrous sodium sulfate after washing with saturated sodium chloride to obtain intermediate 2.

5. The preparation method of diethyl 2, 3-di-sec-butensuccinate according to claim 2, wherein the intermediate 2 is dissolved in tetrahydrofuran and added into lithium diisopropylamide dropwise, stirring and reacting for 0.5h, then adding dichloromethane solution containing titanium tetrachloride dropwise at-60 ℃ and gradually heating to room temperature, stirring and reacting for 8h, adding sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate solution for quenching, extracting with ethyl acetate, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, finally distilling and unscrewing solvent under reduced pressure, and obtaining the product by using petroleum ether and ethyl acetate as eluent for column chromatography.