Method for preparing 1-(3-methoxypropyl)-4-piperidinamine

Abstract

The invention discloses a method for preparing 1-(3-methoxypropyl)-4-piperidinamine. The method includes the following steps: the raw material, namely 4-aminopiperdine is adopted, primary amine is selectively protected by benzophenone based on the difference of chemical properties of primary amine and secondary amine, free secondary amine is subjected to proton abstraction, then the free secondary amine subjected to proton abstraction reacts with 3-methoxy-bromopropane, under the acid condition, the protecting group is removed, and finally, the product is obtained. The synthetic process is simple to operate, besides, the removed protecting group subjected to simple treatment can be recycled, and industrial enlarged production is facilitated.

Description

technical field

[0001] The invention relates to a method for preparing 1-(3-methoxypropyl)piperidin-4-amine, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique

[0002] In recent years, with the impact of many factors such as living standards, lifestyles, and dietary structure, coupled with the rapid increase of the elderly population, the incidence of constipation in my country is on the rise. Prucalopride (English name: Prucalopride), as a selective, high-affinity serotonin (5-HT4) receptor agonist, increases gastrointestinal motility and provides a safer, more effective and more symptomatic treatment . After being approved in Europe in October 2009, Prucalopride was launched in Germany in January 2010 and in the UK in March 2010.

[0003]

[0004] 1-(3-methoxypropyl)piperidin-4-amine is used as a key intermediate in the synthesis of prucalopride, and the existing synthetic methods mainly include: starting from piperidin-4-on...

Examples

Embodiment 1

[0021] Synthesis of N-(dibenzylidene)piperidin-4-amine:

[0022] Add 4-aminopiperidine (50.1g, 0.5mol) and benzophenone (100.2g, 0.55mol) into a 500mL reaction flask with a separator, add 260mL of toluene and BF 3 -Et 2 After O (3.6g, 0.025mol), water was separated for 8-10 hours under reflux conditions. After the reaction was completed, the reaction solution was directly spin-dried, and the condensation dehydration intermediate N-( Dibenzylidene)piperidin-4-amine 103.1g, yield 78%.

[0023] Synthesis of 1-(3-methoxypropyl)piperidin-4-amine:

[0024] Under the protection of nitrogen, take the above intermediate (26.4g, 0.1mol) in a 500mL three-necked flask equipped with a temperature agent and a dropping funnel, and add 120mL of anhydrous tetrahydrofuran to completely dissolve it. 60% solid sodium hydride (6.0 g, 0.15 mol) was added in 5 batches, and after the addition was completed, the reaction was maintained at 0° C. for 30 minutes. Subsequently, 3-methoxybromopropane (...

Embodiment 2

[0026] Synthesis of N-(dibenzylidene)piperidin-4-amine:

[0027] Add 4-aminopiperidine (20.0g, 0.2mol) and benzophenone (36.4g, 0.2mol) into a 250mL reaction flask with a water separator, add 150mL of toluene and 4A molecular sieves (30g), reflux conditions Divide the water for 8-10 hours. After the reaction is completed, spin the reaction solution to dryness, add ethanol / heptane mixed solvent for recrystallization, and obtain the condensation dehydrated intermediate N-(dibenzylidene)piperidin-4-amine 36.4 g, yield 69%.

[0028] Synthesis of 1-(3-methoxypropyl)piperidin-4-amine:

[0029] Under the protection of nitrogen, take the above intermediate (26.4g, 0.1mol) in a 500mL three-neck flask equipped with a temperature agent and a dropping funnel, add 120mL of anhydrous tetrahydrofuran to dissolve completely, cool the reaction solution to 0°C, and slowly add After the addition of 2.5Mn-BuLi (48mL, 0.12mol), the reaction was maintained at 0°C for 30 minutes. Then, 3-methoxyb...

technical field

[0001] The invention relates to a method for preparing 1-(3-methoxypropyl)piperidin-4-amine, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique

[0002] In recent years, with the impact of many factors such as living standards, lifestyles, and dietary structure, coupled with the rapid increase of the elderly population, the incidence of constipation in my country is on the rise. Prucalopride (English name: Prucalopride), as a selective, high-affinity serotonin (5-HT4) receptor agonist, increases gastrointestinal motility and provides a safer, more effective and more symptomatic treatment . After being approved in Europe in October 2009, Prucalopride was launched in Germany in January 2010 and in the UK in March 2010.

[0003]

[0004] 1-(3-methoxypropyl)piperidin-4-amine is used as a key intermediate in the synthesis of prucalopride, and the existing synthetic methods mainly include: starting from piperidin-4-on...

Examples

Embodiment 1

[0021] Synthesis of N-(dibenzylidene)piperidin-4-amine:

[0022] Add 4-aminopiperidine (50.1g, 0.5mol) and benzophenone (100.2g, 0.55mol) into a 500mL reaction flask with a separator, add 260mL of toluene and BF 3 -Et 2 After O (3.6g, 0.025mol), water was separated for 8-10 hours under reflux conditions. After the reaction was completed, the reaction solution was directly spin-dried, and the condensation dehydration intermediate N-( Dibenzylidene)piperidin-4-amine 103.1g, yield 78%.

[0023] Synthesis of 1-(3-methoxypropyl)piperidin-4-amine:

[0024] Under the protection of nitrogen, take the above intermediate (26.4g, 0.1mol) in a 500mL three-necked flask equipped with a temperature agent and a dropping funnel, and add 120mL of anhydrous tetrahydrofuran to completely dissolve it. 60% solid sodium hydride (6.0 g, 0.15 mol) was added in 5 batches, and after the addition was completed, the reaction was maintained at 0° C. for 30 minutes. Subsequently, 3-methoxybromopropane (...

Embodiment 2

[0026] Synthesis of N-(dibenzylidene)piperidin-4-amine:

[0027] Add 4-aminopiperidine (20.0g, 0.2mol) and benzophenone (36.4g, 0.2mol) into a 250mL reaction flask with a water separator, add 150mL of toluene and 4A molecular sieves (30g), reflux conditions Divide the water for 8-10 hours. After the reaction is completed, spin the reaction solution to dryness, add ethanol / heptane mixed solvent for recrystallization, and obtain the condensation dehydrated intermediate N-(dibenzylidene)piperidin-4-amine 36.4 g, yield 69%.

[0028] Synthesis of 1-(3-methoxypropyl)piperidin-4-amine:

[0029] Under the protection of nitrogen, take the above intermediate (26.4g, 0.1mol) in a 500mL three-neck flask equipped with a temperature agent and a dropping funnel, add 120mL of anhydrous tetrahydrofuran to dissolve completely, cool the reaction solution to 0°C, and slowly add After the addition of 2.5Mn-BuLi (48mL, 0.12mol), the reaction was maintained at 0°C for 30 minutes. Then, 3-methoxyb...

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