阅读说明：本技术 一种合成环丙氨的新方法和工艺 (Novel method and process for synthesizing cyclopropylammonia ) 是由 王可为 刘威 唐培昆 蔡小川 韩建国 于 2021-06-30 设计创作，主要内容包括：本发明公开了一种环丙氨合成路线合成工艺路线,该工艺路线中,先以氰基乙酸酯和二氯乙烷为起始原料,通过环化生成1-氰基环丙烷-1-甲酸酯(1),(1)在强碱的作用下水解生成1-氰基环丙烷-1-甲酸(2),(2)脱羧生成环丙基氰(3),(3)在强碱的作用下生成环丙烷甲酰胺(4),(4)经过霍夫曼重排得到目标产物环丙氨。本工艺路线虽然较现阶段生产工艺,反应路线长,但避免了高温高压的使用,降低了危险性,提高了安全性,降低了对反应设备的要求,所使用的原料易得,易于操作,安全环保,可以实现工业化生产。(The invention discloses a synthetic process route of a cyclopropane ammonia synthetic route, which comprises the steps of firstly using cyanoacetate and dichloroethane as starting raw materials, generating 1-cyanocyclopropane-1-formic ester (1) through cyclization, (1) hydrolyzing under the action of strong base to generate 1-cyanocyclopropane-1-formic acid (2), (2) decarboxylating to generate cyclopropyl cyanide (3), (3) generating cyclopropane formamide (4) under the action of strong base, and (4) obtaining a target product of the cyclopropane ammonia through Hofmann rearrangement. Although the process route is longer than the existing production process, the reaction route avoids the use of high temperature and high pressure, reduces the danger, improves the safety, reduces the requirements on reaction equipment, has easily obtained used raw materials, is easy to operate, is safe and environment-friendly, and can realize industrial production.)

1. The synthesis process of cyclopropanamine includes the following steps:

(1) preparation of 1-cyanocyclopropane-1-carboxylate (1): putting cyanoacetate, dichloroethane, alkali and a phase transfer catalyst into a reaction bottle, heating until reflux and water diversion, and monitoring by GC until the reaction is complete; filtering, evaporating excessive dichloroethane from the filtrate under reduced pressure, and obtaining 1-cyanocyclopropane-1-formic ester (1) as residual liquid; in the experiment, strong base is found to generate side reaction, so that cyanoacetate is decomposed, and the yield of the product is reduced, therefore, weak base is selected as the raw material; wherein the molar ratio of cyanoacetate: 1, 2-dichloroethane: weak base: phase transfer catalyst =1:5-15-1:0.8-5: 0.01-0.1;

(2) preparation of 1-cyanocyclopropane-1-carboxylic acid (2): adding 1-cyanocyclopropane-1-formic ether (1), alkali and water into a reaction flask, heating to 15-110 ℃, detecting by GC that the reaction of (1) is finished, and neutralizing by hydrochloric acid until the pH is 4-6 to obtain an aqueous solution of 1-cyanocyclopropane-1-formic acid (2), wherein the molar ratio of 1-cyanocyclopropane-1-formic ether: base =1: 1-5;

(3) preparation of cyclopropyl cyanide (3): putting the aqueous solution of the 1-cyanocyclopropane-1-formic acid (2) obtained in the previous step into a reaction bottle, acidifying until the pH is 3-4, heating to 15-110 ℃, detecting by GC (gas chromatography) that the reaction is finished, neutralizing until the pH is 7, extracting EA, and spirally distilling off EA to obtain cyclopropyl cyanide;

(4) preparation of cyclopropanecarboxamide (4): adding cyclopropyl cyanide (3), ethanol, water and sodium hydroxide into a reaction bottle, heating to 50-110 ℃, detecting by GC (gas chromatography) that the reaction of (3) is finished, neutralizing until the PH is 7, extracting EA, and rotationally evaporating EA to obtain cyclopropane carboxamide (4);

(5) preparation of cyclopropylammonia: the cyclopropane carboxamide (4) is subjected to Hofmann rearrangement to obtain a target product cyclopropylamine, and the process route is as follows:

。

2. the process of claim 1, wherein in step (1) the ratio of cyanoacetate: 1, 2-dichloroethane: weak base: phase transfer catalyst =1:5-15-1:0.8-5:0.01-0.1, preferably 1:8:3: 0.015.

3. The process of claim 1 wherein the addition of a phase transfer catalyst in step (1) accelerates the rate of reaction.

4. The process of claim 1, wherein the weak base in step (1) comprises one or more of potassium carbonate, sodium carbonate, potassium acetate and sodium acetate.

5. The process of claim 1, wherein in step (1) the cyanoacetic acid ester comprises methyl cyanoacetate and ethyl cyanoacetate, and ethyl cyanoacetate is used as the starting material for cost reasons.

6. The process of claim 1, wherein the base in step (2) is sodium hydroxide or potassium hydroxide.

7. The process according to claim 1, wherein the reaction temperature in step (2) is 15-110 ℃, preferably 15-30 ℃.

8. The process according to claim 1, wherein the reaction temperature in step (3) is 15-110 ℃, preferably 65-95 ℃.

9. The process according to claim 1, wherein the reaction temperature in step (4) is 15-110 ℃, preferably 80-100 ℃.

10. The process of claim 1, wherein in step (4) the molar ratio of cyclopropyl cyanide: the molar ratio of sodium hydroxide is =1:1.5-5, preferably 1: 2.1.

Technical Field

The invention relates to a synthesis process route of cyclopropylammonia, belonging to the chemical class.

Background

Cyclopropylamine is an important intermediate for fine chemical engineering and medicine, and is mainly used for synthesizing ciprofloxacin, cyclopropane fluazinic acid and Spathiacin.

The existing industrial production route is to carry out ammonolysis on cyclopropyl formate and ammonia water under the high pressure of 160atm to obtain cyclopropyl formamide, and then obtain cyclopropylamine through Hofmann rearrangement.

Disclosure of Invention

The invention aims to provide a synthesis process of cyclopropylammonia, which comprises the following steps:

1. a process for the synthesis of cyclopropylammonia, which process comprises:

(1) preparation of 1-cyanocyclopropane-1-carboxylate (1): putting cyanoacetate, dichloroethane, alkali and a phase transfer catalyst into a reaction bottle, heating to reflux, and monitoring by GC until the reaction is complete; filtering, evaporating excessive dichloroethane from the filtrate under reduced pressure, and obtaining 1-cyanocyclopropane-1-formic ester (1) as residual liquid; in the experiment, the side reaction is found to occur by using strong base, so that cyanoacetate is decomposed, and the product yield is reduced, therefore, weak base is selected as the raw material, wherein the molar ratio of cyanoacetate: 1, 2-dichloroethane: weak base: phase transfer catalyst =1:5-15-1:0.8-5: 0.01-0.1;

(2) preparation of 1-cyanocyclopropane-1-carboxylic acid (2): adding 1-cyanocyclopropane-1-formic ether (1), alkali and water into a reaction flask, heating to 15-110 ℃, detecting by GC that the reaction of (1) is finished, and neutralizing by hydrochloric acid until the pH is 4-6 to obtain an aqueous solution of 1-cyanocyclopropane-1-formic acid (2), wherein the molar ratio of 1-cyanocyclopropane-1-formic ether: base =1: 1-5;

(3) preparation of cyclopropyl cyanide (3): putting the aqueous solution of the 1-cyanocyclopropane-1-formic acid (2) obtained in the previous step into a reaction bottle, acidifying until the pH is 3-4, heating to 15-110 ℃, detecting by GC (gas chromatography) that the reaction of the (2) is finished, neutralizing until the pH is 7, extracting by EA, and rotationally evaporating EA to obtain cyclopropyl cyanide;

(4) preparation of cyclopropanecarboxamide (4): adding cyclopropyl cyanide (3), ethanol, water and sodium hydroxide into a reaction bottle, heating to 50-110 ℃, detecting by GC (gas chromatography) that the reaction of (3) is finished, neutralizing until the PH is 7, extracting EA, and rotationally evaporating EA to obtain cyclopropane carboxamide (4);

(5) preparation of cyclopropylammonia: cyclopropane carboxamide (4) is subjected to Hofmann rearrangement to obtain a target product of cyclopropylamine,

the process of claim 1, wherein in step (1) the ratio of cyanoacetate: 1, 2-dichloroethane: the weak base is present in a molar ratio of =1:5-15:0.8-5, preferably 1:8: 3.

The process of claim 1, wherein the weak base in step (1) comprises potassium carbonate, sodium carbonate, potassium acetate and sodium acetate, and wherein the reaction is carried out at a slow rate by adding sodium carbonate, potassium acetate and sodium acetate as raw materials, thereby selecting potassium carbonate as the raw material in view of cost.

The process of claim 1, wherein in step (1) the cyanoacetic acid ester comprises methyl cyanoacetate and ethyl cyanoacetate, and ethyl cyanoacetate is used as the starting material for cost reasons.

The process of claim 1, wherein the base in step (2) is sodium hydroxide or potassium hydroxide.

The process according to claim 1, wherein the reaction temperature in step (2) is 15-110 ℃, preferably 15-30 ℃.

The process according to claim 1, wherein the reaction temperature in step (3) is 15-110 ℃, preferably 65-95 ℃.

The process according to claim 1, wherein the reaction temperature in step (4) is 15-110 ℃, preferably 80-100 ℃.

The process of claim 1, wherein in step (4) the molar ratio of cyclopropyl cyanide: the molar ratio of sodium hydroxide is =1:1.5-5, preferably 1: 2.1.

Compared with the existing production process, the synthesis process has more reaction steps, avoids the application of high pressure, reduces the danger of reaction, has mild equipment requirement, is simple to operate, easily obtains raw materials, has mild reaction conditions and low cost, and is easy to industrialize.

Detailed Description

The invention is illustrated by the following specific examples.

[ example 1 ] preparation of ethyl 1-cyanocyclopropane-1-carboxylate (1)

Putting 1mol of ethyl cyanoacetate, 8mol of dichloroethane, 2.5mol of potassium carbonate and 0.015mol of tetrabutylammonium bromide into a 2L four-mouth reaction bottle with a water separator, and heating until reflux and water diversion are carried out; GC monitored until ethyl cyanoacetate was completely reacted; filtration and rotary evaporation of excess dichloroethane from the filtrate gave 86.2g (62% yield) of ethyl 1-cyanocyclopropane-1-carboxylate (1).

Example 2 preparation of ethyl 1-cyanocyclopropane-1-carboxylate (1)

Putting 1mol of ethyl cyanoacetate, 8mol of dichloroethane, 2.5mol of sodium acetate and 0.015mol of tetrabutylammonium bromide into a 2L four-mouth reaction bottle with a water separator, and heating until reflux and water diversion are carried out; GC monitored until ethyl cyanoacetate was completely reacted; filtration and rotary evaporation of excess dichloroethane from the filtrate gave 128.3g (92.3% yield) of ethyl 1-cyanocyclopropane-1-carboxylate (1).

Example 3 preparation of 1-cyanocyclopropane-1-carboxylic acid (2)

0.2mol of 1-cyanocyclopropane-1-carboxylic acid ethyl ester (1), 0.24mol of sodium hydroxide and 100mL of water are put into a reaction flask, and reacted at room temperature, and after the reaction of (1) is detected by GC, the reaction is neutralized to pH 4-6 with hydrochloric acid to obtain an aqueous solution of 1-cyanocyclopropane-1-carboxylic acid (2).

[ example 4 ] preparation of Cyclopropylcyanide (3)

Putting the aqueous solution of the 1-cyanocyclopropane-1-formic acid (2) obtained in the previous step into a reaction bottle, acidifying until the pH is 3-4, heating to 80 ℃, detecting by GC that the reaction of the (2) is finished, neutralizing until the pH is 7, extracting by EA, and performing rotary evaporation on the EA to obtain 11.5g of cyclopropyl cyanide (yield is 85.8%).

[ example 5 ] preparation of Cyclopropanecarboxamide (4)

0.17 mol of cyclopropylcyanide (3), 20mL of ethanol, 50mL of water and 0.36mol of sodium hydroxide were put into a reaction flask, the temperature was raised to 100 ℃, GC detected that the reaction of (3) was completed, the reaction was neutralized to pH 7, EA was extracted, and EA was rotary-distilled off to obtain 13.4g (yield 92%) of cyclopropanecarboxamide (4).

[ example 6 ] preparation of Cyclopropanamine

The cyclopropane carboxamide (4) utilizes classical Hofmann rearrangement reaction to obtain the target product cyclopropylamine with the yield of 83 percent.