阅读说明：本技术 一种1-Boc-4-氨甲基哌啶的合成方法 (Synthesis method of 1-Boc-4-aminomethyl piperidine ) 是由 杨少强 陆毅 鲁斌斌 徐本全 周广 熊灵丽 吴林艳 陈国庆 于 2021-08-19 设计创作，主要内容包括：本发明公开了一种1-Boc-4-氨甲基哌啶的合成方法,属于有机合成技术领域,该方法以1-Boc-4-氰基哌啶为原料,在路易斯酸的催化下,加入含氢硅油进行还原反应,即可得到1-Boc-4-氨甲基哌啶。该方法的原料易得,安全系数高,反应过程温和,同时通过使用路易斯酸降低反应物的活化能,提高了反应活性,总收率可达到80％,能够有效地实现规模化生产。(The invention discloses a synthesis method of 1-Boc-4-aminomethyl piperidine, belonging to the technical field of organic synthesis, and the method comprises the steps of taking 1-Boc-4-cyano piperidine as a raw material, and adding hydrogen-containing silicone oil to carry out reduction reaction under the catalysis of Lewis acid to obtain the 1-Boc-4-aminomethyl piperidine. The method has the advantages of easily available raw materials, high safety factor and mild reaction process, and simultaneously reduces the activation energy of reactants by using the Lewis acid, improves the reaction activity, has the total yield up to 80 percent, and can effectively realize large-scale production.)

1. A method for synthesizing 1-Boc-4-aminomethyl piperidine is characterized by comprising the following steps:

(a) taking a compound I as a raw material, and adding Lewis acid into a toluene or tetrahydrofuran solvent;

(b) heating the reaction solution, dripping hydrogen-containing silicone oil, and carrying out reduction reaction;

(c) dropwise adding a citric acid solution or a potassium hydroxide solution into the reaction solution for quenching;

(d) vacuum distilling to obtain pure 1-Boc-4-aminomethyl piperidine

2. The method of claim 1, wherein the volume ratio of compound I to toluene or tetrahydrofuran is from 1:5 to 1: 8.

3. The method according to claim 1, wherein the Lewis acid is selected from any one of boron trifluoride diethyl etherate, tetraisopropyl titanate, or bismuth trichloride.

4. The synthesis method according to claim 1 or 3, wherein the molar ratio of the compound I to the Lewis acid is 1:1 to 1:2.2, and the temperature at which the Lewis acid is added is 20 to 30 ℃.

5. The synthesis method according to claim 1, wherein the temperature for heating up before dropping the hydrogen-containing silicone oil is 60 to 70 ℃.

6. The synthesis method according to claim 1, wherein the hydrogen-containing silicone oil is selected from polymethylhydrosiloxane or 1,1,3, 3-tetramethyldisiloxane.

7. The synthesis method according to claim 1 or 6, wherein the molar ratio of the compound I to the hydrogen-containing silicone oil is 1:2-1: 3.

8. The method of claim 1, wherein the molar ratio of compound I to citric acid or potassium hydroxide is 1:3 to 1: 5.

9. The synthesis method as claimed in claim 1, wherein the reduced pressure distillation temperature is 120-130 ℃ and the pressure is 20-70 Pa.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 1-Boc-4-aminomethyl piperidine.

Background

The 1-Boc-4-aminomethyl piperidine is an important intermediate for synthesizing various medicaments, can be used for preparing antimalarial medicaments and medicaments for regulating metabolism and treating cardiovascular diseases, is also one of raw materials of a light-emitting diode and a chiral preparation column, and has good pharmaceutical value and market prospect.

The following synthetic routes are reported in the European Journal of Medicinal Chemistry,2018,150,2018,698-718:

the route takes 1-boc-4-piperidine formaldehyde as an initial raw material, and obtains a target product through reduction reaction after nucleophilic reaction of mesylate and sodium azide. The use of azide in the above route is liable to cause explosion by heating during the reaction, and therefore, the use thereof has a high risk factor and is difficult in industrial production.

International patent WO2004002483a1 discloses a route to 1-Boc-4-aminomethylpiperidine, which is prepared by reducing 1-Boc-4-cyanopiperidine as a starting material in a solvent of diethyl ether or tetrahydrofuran with lithium aluminum hydride to give the final product in 47.7% yield.

1-Boc-4-cyanopiperidine is cheap and easy to obtain, is an ideal raw material for synthesizing 1-Boc-4-aminomethyl piperidine, but lithium aluminum hydride is expensive, is easy to cause fire when meeting humid air, is difficult to control and is not beneficial to large-scale production. Finding a hydrogen source with high safety factor and low cost to carry out reduction reaction with 1-Boc-4-cyanopiperidine and simultaneously improving the reaction yield is a technical problem to be solved at present.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provides a synthesis method of 1-Boc-4-aminomethyl piperidine, which has the advantages of short route, mild reaction, capability of effectively improving the reaction yield and suitability for industrial production.

The invention is realized by the following technical means:

a method for synthesizing 1-Boc-4-aminomethyl piperidine comprises the following steps:

(a) taking a compound I as a raw material, and adding Lewis acid into a toluene or tetrahydrofuran solvent;

(b) heating the reaction solution, dripping hydrogen-containing silicone oil, and carrying out reduction reaction;

(c) dropwise adding a citric acid solution or a potassium hydroxide solution into the reaction solution for quenching;

(d) the pure product of 1-Boc-4-aminomethyl piperidine is obtained by reduced pressure distillation.

Expressed by the reaction formula:

the volume ratio of the compound I to the toluene or tetrahydrofuran is 1:5-1: 8.

The Lewis acid is selected from any one of boron trifluoride ethyl ether, tetraisopropyl titanate or bismuth trichloride.

The molar ratio of the compound I to the Lewis acid is 1:1-1:2.2, and the temperature when the Lewis acid is dripped is 20-30 ℃.

Heating to 60-70 ℃ before dripping the hydrogen-containing silicone oil.

The hydrogen-containing silicone oil is selected from polymethylhydrosiloxane or 1,1,3, 3-tetramethyldisiloxane.

The molar ratio of the compound I to the hydrogen-containing silicone oil is 1:2-1: 3.

The molar ratio of the compound I to the citric acid or the potassium hydroxide is 1:3-1: 5.

The reduced pressure distillation temperature is 120-130 ℃, and the pressure is 20-70 Pa.

Has the advantages that: the raw material 1-Boc-4-cyanopiperidine is sufficient in market supply, hydrogen-containing silicone oil such as polymethylhydrosiloxane is used as a hydrogen source for hydrogenation reaction to reduce the 1-Boc-4-cyanopiperidine, the process is mild, the reaction can be carried out at high temperature, and the reaction rate is further improved; the reactivity is increased by the addition of Lewis acids such as boron trifluoride etherate, tetraisopropyl titanate or bismuth trichloride. The technology is safe and easy to control, has low cost, can achieve the yield of 80 percent, and can realize large-scale production.

Detailed Description

In order to facilitate the technical solution of the present application, some concepts related to the present application will be described below.

The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.

Example 1

In a 1000 ml four-mouth bottle, 320g of toluene is added, 60g (0.29mol, 1.0eq) of 1-boc-4-cyanopiperidine is added, the temperature is controlled to be 20 ℃, 49.4g (0.348mol, 1.2eq) of boron trifluoride diethyl etherate is added dropwise, after the dropwise addition is finished, the mixture is stirred for 20 minutes at 25 ℃, then the temperature is raised to 70 ℃, 40g (0.620mol, 2.2eq) of polymethylhydrosiloxane is added dropwise, and after the dropwise addition is finished, the stirring is continued for 8 hours.

85g of a saturated aqueous citric acid solution was added dropwise thereto, followed by quenching at 20 ℃ or lower. Adding 200 ml of water, stirring, standing for layering, separating to obtain an organic phase, adding 150 ml of toluene into the aqueous phase solution for extraction, combining the organic phases, adding 150 ml of saturated saline solution for washing, spin-drying the organic phase, and then carrying out reduced pressure distillation at the temperature of 130 ℃ under the pressure of 50Pa to obtain 49g of a product with the yield of 80.13%.

Example 2

In a 1000 ml four-neck flask, 420g of tetrahydrofuran, 66g (0.31mol, 1.0eq) of 1-boc-4-cyanopiperidine, 136.4g (0.480mol, 1.5eq) of tetraisopropyl titanate were added dropwise at a temperature of 30 ℃, after the addition, the mixture was stirred at 30 ℃ for 20 minutes, then the temperature was raised to 65 ℃, 48g (0.744mol, 2.4eq) of polymethylhydrosiloxane was added dropwise, and after the addition, the stirring was continued for 8 hours.

100g of a saturated aqueous citric acid solution was added dropwise thereto, followed by quenching at 20 ℃ or lower. Adding 200 ml of water, stirring, standing for layering, separating to obtain an organic phase, adding 180 ml of toluene into the aqueous phase solution for extraction, combining the organic phases, adding 180 ml of saturated saline solution for washing, spin-drying the organic phase, and then carrying out reduced pressure distillation at the temperature of 120 ℃ and under the pressure of 70Pa to obtain 52g of a product, wherein the yield is 77.31%.

Example 3

In a 1000 ml four-neck flask, 250g of tetrahydrofuran was added, 60g (0.29mol, 1.0eq) of 1-boc-4-cyanopiperidine was added, the temperature was controlled at 20 ℃, 91.4g (0.290mol, 1.0eq) of bismuth trichloride was added dropwise, after the addition was completed, the mixture was stirred at 20 ℃ for 20 minutes, then the temperature was raised to 60 ℃, 78g (0.581mol, 2.0eq) of 1,1,3, 3-tetramethyldisiloxane was added dropwise, and after the addition was completed, the mixture was stirred for 8 hours.

100g of a saturated aqueous citric acid solution was added dropwise thereto, followed by quenching at 20 ℃ or lower. Adding 200 ml of water, stirring, standing for layering, separating to obtain an organic phase, adding 150 ml of toluene into the aqueous phase solution for extraction, combining the organic phases, adding 150 ml of saturated saline solution for washing, spin-drying the organic phase, and then carrying out reduced pressure distillation, wherein the temperature is controlled to be 125 ℃, the pressure is 20Pa, and the product is 46g, and the yield is 75.22%.

Example 4

In a 1000 ml four-neck flask, 390g of toluene was added, 52g (0.25mol, 1.0eq) of 1-boc-4-cyanopiperidine was added, the temperature was controlled at 25 ℃, 88.7g (0.290mol, 1.0eq) of boron trifluoride diethyl etherate was added dropwise, after the dropwise addition was completed, the mixture was stirred at 20 ℃ for 20 minutes, then the temperature was raised to 65 ℃, 100g (0.744mol, 3.0eq) of 1,1,3, 3-tetramethyldisiloxane was added dropwise, and after the dropwise addition was completed, the mixture was stirred for 8 hours.

85g of a saturated aqueous potassium hydroxide solution was added dropwise thereto, followed by quenching at 20 ℃ or lower. Adding 200 ml of water, stirring, standing for layering, separating to obtain an organic phase, adding 150 ml of toluene into the aqueous phase solution for extraction, combining the organic phases, adding 150 ml of saturated saline solution for washing, spin-drying the organic phase, and then carrying out reduced pressure distillation at the temperature of 120 ℃ under the pressure of 50Pa to obtain 39g of a product with the yield of 73.59%.