CN108033931B

CN108033931B - Synthesis method of N-Boc piperazine

Info

Publication number: CN108033931B
Application number: CN201711465168.XA
Authority: CN
Inventors: 梁辉; 朱义胜; 张庆涛
Original assignee: SHANDONG BOYUAN PHARMACEUTICAL CO Ltd
Current assignee: Shandong Baoyuan Pharmaceutical Co ltd
Priority date: 2017-12-28
Filing date: 2017-12-28
Publication date: 2020-03-10
Anticipated expiration: 2037-12-28
Also published as: CN108033931A

Abstract

The invention discloses N-Boc piperazineA method for synthesizing oxazine. The method takes diethylaminoalcohol as a starting material, and N-Boc piperazine is synthesized through three steps of chlorination, Boc protection and aminolysis cyclization. The method has the advantages of easily available raw materials, mild reaction conditions, low product cost, high yield and high purity, and is suitable for industrial production.

Description

Synthesis method of N-Boc piperazine

Technical Field

The invention relates to a synthesis method of N-Boc piperazine, belonging to the technical field of organic synthesis.

Background

N-Boc piperazine, Chinese alias: n-tert-butoxycarbonylpiperazine, piperazine-1-carboxylic acid tert-butyl ester; molecular formula C₉H₁₈N₂O₂Molecular weight: 186.25. the chemical structural formula is as follows:

N-Boc piperazine belongs to piperazine monosubstituted compounds. The piperazine monosubstituted compounds become key intermediates in the synthesis of numerous drugs due to their special structures, such as: glucocorticoids such as palbociclib, ranolazine, dexamethasone, and the like. Therefore, the synthesized piperazine monosubstituted compound has very important pharmaceutical value and economic value.

The current method for synthesizing N-Boc piperazine mainly comprises the following two methods:

the method comprises the following steps: anhydrous piperazine is adopted to drop di-tert-butyl dicarbonate for selective reaction, and nitrogen at one end of piperazine is protected, so that amino at the other end reacts with another group. In the method, both ends of piperazine are connected with di-tert-butyl dicarbonate, and a large amount of water is needed for washing during purification, so that the yield of the product is reduced; the cost of three wastes treatment is increased, and the process has high raw material cost.

The second method comprises the following steps: starting from piperazine, carrying out a salt forming reaction with glacial acetic acid, adding di-tert-butyl dicarbonate for an acylation reaction, and finally extracting with toluene to obtain a crude product of N-tert-butoxycarbonylpiperazine; in the post-treatment, the unreacted raw materials and other impurities are removed by taking ethyl acetate as an extracting agent, and finally the qualified N-Boc piperazine product is obtained. Although the method improves the selectivity of N on piperazine, the method takes anhydrous piperazine as a main raw material, has high cost, and uses toluene, thereby posing a threat to the health of workers.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a synthetic method of N-Boc piperazine. The method takes diethanolamine as a starting material, and N-Boc piperazine is synthesized through three steps of chlorination, Boc protection and aminolysis cyclization. The method has the advantages of easily available raw materials, mild reaction conditions, low product cost, high yield and high purity, and is suitable for industrial production.

The technical scheme of the invention is as follows: a synthetic method of N-Boc piperazine is characterized by comprising the following steps:

1) diethanolamine (compound II) and a chlorinating agent react to generate bis (2-chloroethyl) amine (compound III);

2) bis (2-chloroethyl) amine and BOC anhydride react to generate bis (2-chloroethyl) carbamic acid tert-butyl ester (compound IV).

3) And (3) carrying out cyclization reaction on the bis (2-chloroethyl) carbamic acid tert-butyl ester and ammonia water to generate N-Boc piperazine (compound I).

The chlorinating agent in the step 1) is as follows: SOCl₂、POCl₃、PCl₃、PCl₅Etc., preferably SOCl₂。

The molar ratio of the chlorinating agent to the diethanol amine in the step 1) is 2-5:1, and preferably 3: 1.

The mole ratio of Boc anhydride to diethanolamine in the step 2) is 0.95-1.05:1, preferably 1: 1.

NH in ammonia water in the step 3)₃The molar ratio to diethanolamine is from 2 to 4:1, preferably 3: 1.

Preferably, the step 1) is performed under reflux conditions.

Preferably, the step 2) is carried out under alkaline conditions.

Preferably, the ammonia water in the step 3) is in a dropwise adding mode, and the reaction temperature is 55-65 ℃.

The reaction equation is as follows:

further, the method specifically comprises the following steps:

1) dropping diethanolamine into thionyl chloride for reflux reaction for 3-5h, and cooling to below 10 ℃ after the reaction is finished;

2) adding purified water, adding inorganic base to adjust the pH value to be more than 10, then dropwise adding Boc anhydride, reacting at 10-30 ℃ for at least 12 hours after dropwise adding, and keeping the reaction system alkaline in the process;

3) heating to 55-65 ℃, and slowly dripping ammonia water; reacting for 2-5h at 55-65 ℃ after dripping, cooling to below 25 ℃, extracting with ethyl acetate, drying, concentrating under reduced pressure and evaporating ethyl acetate to obtain N-Boc piperazine.

The adding amount of the purified water in the step 2) is 2-3 times of the mass of the feed liquid in the step 1), the inorganic base is preferably sodium carbonate, and the reaction time is preferably 12-16 hours.

The ammonia water dropping time in the step 3) is preferably 2.5-3.5 h.

The invention has the beneficial effects that: the method has the advantages of simple and easily obtained raw materials, mild reaction conditions, low product cost, high yield (more than or equal to 93.5%), high purity and environmental friendliness, and is suitable for industrial production.

Detailed Description

Example 1:

1) 357g (3mol) of thionyl chloride is added into a 2000ml reaction bottle, 105g (1mol) of diethanolamine is added dropwise, and the temperature is raised and the reflux reaction is carried out for 4 hours; cooling to below 10 ℃, adding 1000ml of purified water, and stirring until heat is not released;

2) adding 636g (6mol) of sodium carbonate to dissolve, wherein the pH value is more than 10; controlling the temperature within 10-20 ℃, dripping 218g (1mol) of Boc anhydride, reacting for 12 hours at 25 ℃, and keeping the reaction system alkaline;

3) raising the temperature to 60 ℃, slowly dripping 182g (3mol) of ammonia water for about 3 hours; controlling the temperature to be 60 ℃ for reaction for 3h, then cooling to below 25 ℃, extracting reaction liquid (300 ml each time) by three times by using 900ml of ethyl acetate, drying an ethyl acetate layer by using anhydrous sodium sulphate, filtering, concentrating and evaporating the ethyl acetate under reduced pressure at below 60 ℃, and cooling to obtain 174.8g of N-Boc piperazine with the yield of 94.0% and the purity of 99.63%.

Example 2:

1) 327g (2.75mol) of thionyl chloride is added into a 2000ml reaction bottle, 105g (1mol) of diethanolamine is added dropwise, and the temperature is raised and the reflux is carried out for 4.5 h; cooling to below 10 ℃, adding 1000ml of purified water, and stirring until heat is not released;

2) 583g (5.5mol) of sodium carbonate are added to dissolve, the pH value is more than 10; controlling the temperature within 10-20 ℃, dripping 214g (0.98mol) of Boc anhydride, reacting for 14 hours at 25 ℃, and keeping the reaction system alkaline;

3) heating to 60 ℃, slowly dripping 170g (2.8mol) of ammonia water for about 3 hours; controlling the temperature to be 60 ℃ for reaction for 3.5h, reducing the temperature to be below 25 ℃, extracting reaction liquid by 900ml of ethyl acetate for three times, drying an ethyl acetate layer by using anhydrous sodium sulphate, filtering, concentrating under reduced pressure at the temperature of below 60 ℃ and evaporating the ethyl acetate to dryness, and cooling to obtain 174.5g of N-Boc piperazine, wherein the yield is 93.8 percent, and the purity is 99.72 percent.

Example 3:

1) adding 387g (3.25mol) of thionyl chloride into a 2000ml reaction bottle, dropwise adding 105g (1mol) of diethanolamine, and heating and refluxing for 3.5 h; cooling to below 10 ℃, adding 1000ml of purified water, and stirring until heat is not released;

2) 689g (6.5mol) of sodium carbonate are added to dissolve at a pH > 10. Controlling the temperature within 10-20 ℃, dripping 222g (1.02mol) of Boc anhydride, reacting for 12 hours at 25 ℃, and keeping the reaction system alkaline;

3) the temperature is raised to 60 ℃, 194g (3.2mol) of ammonia water is slowly dropped into the solution, and the dropping is finished for about 3 hours. Controlling the temperature to be 60 ℃ for reaction for 2.5h, reducing the temperature to be below 25 ℃, extracting reaction liquid by using 900ml of ethyl acetate for three times, drying an ethyl acetate layer by using anhydrous sodium sulphate, filtering, concentrating under reduced pressure at the temperature of below 60 ℃ and evaporating the ethyl acetate to dryness, and cooling to obtain 175.3g of N-Boc piperazine, wherein the yield is 94.3%, and the purity is 99.42%.

Claims

1. A synthetic method of N-Boc piperazine is characterized by comprising the following steps:

1) diethanolamine and thionyl chloride react to generate di (2-chloroethyl) amine;

2) reacting bis (2-chloroethyl) amine with BOC anhydride to generate bis (2-chloroethyl) carbamic acid tert-butyl ester;

3) performing cyclization reaction on bis (2-chloroethyl) carbamic acid tert-butyl ester and ammonia water to generate N-Boc piperazine;

the method specifically comprises the following steps:

2) adding purified water, adding inorganic base sodium carbonate to adjust the pH value to be more than 10, then dropwise adding Boc anhydride, reacting at 10-30 ℃ for at least 12 hours after dropwise adding, and keeping the reaction system alkaline in the process;

3) heating to 55-65 ℃, slowly dripping ammonia water, and reacting for 2-5h at 55-65 ℃ after dripping; cooling to below 25 ℃, extracting with ethyl acetate, drying, decompressing, concentrating and evaporating the ethyl acetate to obtain the N-Boc piperazine.

2. The method for synthesizing N-Boc piperazine according to claim 1, wherein the molar ratio of thionyl chloride to diethanolamine in step 1) is 2.75-3.25: 1.

3. The method for synthesizing N-Boc piperazine according to claim 1, wherein the mole ratio of Boc anhydride to diethanolamine in step 2) is 0.95-1.05: 1.

4. The method for synthesizing N-Boc piperazine according to claim 1, wherein NH is added into ammonia water in step 3)₃The molar ratio of the compound to the diethanol amine is 2-4: 1.

5. The method for synthesizing N-Boc piperazine according to claim 1, wherein the amount of the purified water in the step 2) is 2-3 times of the mass of the feed liquid in the step 1), the inorganic base is sodium carbonate, and the reaction time is 12-16 hours.