阅读说明：本技术 一种一锅两相法合成n-(苄氧羰基)琥珀酰亚胺的方法 (Method for synthesizing N- (benzyloxycarbonyl) succinimide by one-pot two-phase method ) 是由 王玉琴 刘文庆 仲崇超 詹玉进 于 2019-11-20 设计创作，主要内容包括：本发明涉及有机化学技术领域,具体涉及一种一锅两相法合成N-(苄氧羰基)琥珀酰亚胺的方法,包括如下步骤：向反应容器中加入纯化水、硫酸羟胺,并在搅拌下滴加液碱,滴加结束后,分批加入丁二酸酐,在酸催化下高温真空脱水,直至无水采出,制成N-羟基丁二酰亚胺溶液；向N-羟基丁二酰亚胺溶液中加入碱调节反应液pH,控制温度为0~60℃,滴加氯甲酸苄；滴加完毕后分出有机层浓缩至干,经重结晶得到N-(苄氧羰基)琥珀酰亚胺成品。本发明提供的方法避免了N-羟基丁二酰亚胺合成后的分离及提纯步骤,直接采用两相法,一锅合成N-(苄氧羰基)琥珀酰亚胺,有效的降低的工艺成本,缩减了操作步骤,有利于开展大规模工业化的生产。(The invention relates to the technical field of organic chemistry, in particular to a method for synthesizing N- (benzyloxycarbonyl) succinimide by a one-pot two-phase method, which comprises the following steps of adding purified water and hydroxylamine sulfate into a reaction container, dropwise adding liquid alkali under stirring, after dropwise adding, adding succinic anhydride in batches, dehydrating at high temperature and in vacuum under acid catalysis until no water is extracted, preparing N-hydroxysuccinimide solution, adding alkali into the N-hydroxysuccinimide solution, adjusting the pH of the reaction solution, controlling the temperature to be 0 ~ 60 ℃, dropwise adding benzyl chloroformate, separating out an organic layer after dropwise adding, concentrating to be dry, and recrystallizing to obtain an N- (benzyloxycarbonyl) succinimide finished product.)

1. A method for synthesizing N- (benzyloxycarbonyl) succinimide by a one-pot two-phase method is characterized by comprising the following steps:

(1) adding purified water and hydroxylamine sulfate into a reaction container, dropwise adding liquid alkali under stirring, after dropwise adding, adding succinic anhydride in batches, and carrying out high-temperature vacuum dehydration under acid catalysis until no water is extracted to prepare an N-hydroxysuccinimide solution;

(2) adding alkali into the N-hydroxysuccinimide solution obtained in the step (1) to adjust the pH of the reaction solution, controlling the temperature to be 0-60 ℃, and dropwise adding benzyl chloroformate; separating out an organic layer after the dropwise addition is finished, concentrating to be dry, and recrystallizing to obtain a finished product of N- (benzyloxycarbonyl) succinimide; the specific reaction formula is as follows:

2. the method for synthesizing N- (benzyloxycarbonyl) succinimide according to claim 1, wherein the heating temperature for the high-temperature vacuum dehydration in step (1) is 100-160 ℃; the vacuum degree is 1000-2000 Pa.

3. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to claim 1, wherein the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid in step (1) is 1: 1-4: 2-6: 0.01 to 0.1.

4. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to claim 1, wherein the catalyst acid in step (1) is selected from sulfuric acid and phosphoric acid.

5. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to any of claims 1 to 4 by the one-pot two-phase method, wherein before the addition of benzyl chloroformate in step (2), a water-carrying agent is added to the N-hydroxysuccinimide solution obtained in step (1) and the mixture is heated and refluxed until no water is separated out.

6. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to claim 5, wherein the water-carrying agent in step (2) is selected from organic solvents that can be azeotroped with water, such as toluene or xylene; the dosage of the water-carrying agent is 0.5-1 time of the total mass of the water added in the step (1).

7. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to any of claims 1 to 4, wherein the reaction solution in step (2) is adjusted to pH 9 to 11 by the addition of a base.

8. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to any of claims 1 to 4, wherein the molar ratio of benzyl chloroformate, N-hydroxysuccinimide and base in step (2) is 1: 1-3: 0.5 to 3.

9. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to any one of claims 1 to 4, wherein the base in step (2) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine; the base is added in the form of an aqueous solution; the mass concentration of the alkali aqueous solution is 10-30%.

10. The method for synthesizing N- (benzyloxycarbonyl) succinimide according to any one of claims 1 to 4, wherein the solvent used in the recrystallization step in step (2) is dichloromethane, cyclohexane or ethyl acetate.

Technical Field

The invention relates to the technical field of organic chemistry, in particular to a method for synthesizing N- (benzyloxycarbonyl) succinimide by a one-pot two-phase method.

Background

N- (carbobenzoxy) succinimide is a high-efficiency amino acid protective agent and is widely applied to the synthesis of polypeptide. The synthesis route of N- (benzyloxycarbonyl) succinimide is mainly synthesized by reacting N-hydroxysuccinimide with benzyloxycarbonyl chloride.

The existing synthesis method of N-hydroxysuccinimide is mature, and the commonly adopted method is that succinic anhydride reacts with hydroxylamine (hydroxylamine is obtained by dissociating hydroxylamine hydrochloride or hydroxylamine sulfate), and the finished product of the N-hydroxysuccinimide is obtained through a series of post-treatments. Such as Henan chemical, 1995(5) 18; application chemistry 2003.20(6) 611; jiangxi chemical 2002(11)37, etc.; another method is to react succinic acid with hydroxylamine, which is obtained by dissociating hydroxylamine hydrochloride or hydroxylamine sulfate, and then obtain a finished product of N-hydroxysuccinimide by treatment, such as the patent applied by Tanakesair chemical science and technology Co., Ltd: CN 108558728A, the method can obtain the N-hydroxysuccinimide finished product with better quality, but has the problems of complicated steps and high process cost.

At present, two general methods for synthesizing N- (benzyloxycarbonyl) succinimide exist, one is that an organic system is adopted, such as the reaction of French Antenis M.J.O in 1987 and French impurity BULL.SOC.Chim96(10). p775, which uses triethylamine as alkali and in tetrahydrofuran, and the crude product of N- (benzyloxycarbonyl) succinimide is obtained by filtering and desalting, but the yield is only 25%; the other method is to react benzyl chloroformate with N-hydroxysuccinimide in an alkaline aqueous solution to obtain a product, and both methods have higher quality requirements on the raw material N-hydroxysuccinimide.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: the method for synthesizing the N- (benzyloxycarbonyl) succinimide by the one-pot two-phase method is provided, and the technical problems of complicated synthesis steps, high process cost and high requirement on raw material purity of the N- (benzyloxycarbonyl) succinimide in the prior art are solved.

The technical scheme for solving the technical problems is as follows:

a method for synthesizing N- (benzyloxycarbonyl) succinimide by a one-pot two-phase method comprises the following steps:

(1) adding purified water and hydroxylamine sulfate into a reaction container, dropwise adding liquid alkali under stirring, after dropwise adding, adding succinic anhydride in batches, and carrying out high-temperature vacuum dehydration under acid catalysis until no water is extracted to prepare an N-hydroxysuccinimide solution;

(2) adding alkali into the N-hydroxysuccinimide solution obtained in the step (1) to adjust the pH of the reaction solution, controlling the temperature to be 0-60 ℃, and dropwise adding benzyl chloroformate; separating out an organic layer after the dropwise addition is finished, concentrating to be dry, and recrystallizing to obtain a finished product of N- (benzyloxycarbonyl) succinimide; the specific reaction formula is as follows:

preferably, the heating temperature for high-temperature vacuum dehydration in the step (1) is 100-160 ℃; the vacuum degree is 1000-2000 Pa.

Preferably, the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid in the step (1) is 1: 1-4: 2-6: 0.01 to 0.1; further, the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid in the step (1) is 1: 1-3: 2-6: 0.05 to 0.1; further, in the step (1), the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid is 1: 2-2.4: 2.6-4: 0.06-0.08.

Preferably, the catalyst acid in step (1) is selected from sulfuric acid or phosphoric acid.

Preferably, before adding the benzyl chloroformate in the step (2), adding a water-carrying agent into the N-hydroxysuccinimide solution obtained in the step (1), and heating and refluxing until no water is separated out.

Preferably, the water-carrying agent in step (2) is selected from organic solvents capable of azeotroping with water, such as toluene or xylene; the dosage of the water-carrying agent is 0.5-1 time of the total mass of the water added in the step (1); and (2) calculating the total mass of the water added in the step (1) by the sum of the mass of the added purified water and the mass of the water in the liquid caustic soda.

Preferably, alkali is added in the step (2) to adjust the pH of the reaction solution to 9-11.

Preferably, the molar ratio of the benzyl chloroformate, the N-hydroxysuccinimide and the base in the step (2) is 1: 1-3: 0.5 to 3; further, in the step (2), the molar ratio of the benzyl chloroformate to the N-hydroxysuccinimide to the base is 1: 1-2: 0.5 to 2; further, in the step (2), the molar ratio of the benzyl chloroformate to the N-hydroxysuccinimide to the base is 1: 1.7-2: 1.1 to 1.8. The amount of the N-hydroxysuccinimide is calculated according to the feeding amount of the succinic anhydride in the step (1).

Preferably, the base in the step (2) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine; the base is added in the form of an aqueous solution; the mass concentration of the aqueous solution of the alkali is 10-30%; further, the mass concentration of the alkali aqueous solution is 8-30%.

Preferably, the solvent used in the recrystallization step in step (2) is dichloromethane, cyclohexane or ethyl acetate.

The Chinese naming of the compounds of the present invention conflicts with the structural formula, whichever is more.

The method for synthesizing the N- (benzyloxycarbonyl) succinimide by the one-pot two-phase method avoids the steps of separation and purification after the synthesis of the N-hydroxysuccinimide, directly adopts the two-phase method, synthesizes the N- (benzyloxycarbonyl) succinimide by one pot, effectively reduces the process cost, reduces the operation steps, and is beneficial to the development of large-scale industrial production.

Detailed Description

The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.