Method for preparing 4-Boc-aminopiperidine

A technology of aminopiperidine and piperidinone, which is applied in the field of preparing 4-Boc-aminopiperidine, can solve the problems of high price of 4-aminopiperidine and difficult industrialized mass production, and avoid the use and operation of metal reducing agents. Simple and shortened production cycle effect

Active Publication Date: 2018-03-16
SHANGHAI HOBOR CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The used raw material 4-aminopiperidine of this method is expensive, is difficult to carry out industrialized batch production

Method used

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  • Method for preparing 4-Boc-aminopiperidine
  • Method for preparing 4-Boc-aminopiperidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Step 1: Into a 1L three-necked flask, add 189.2g (1.00mol) of N-benzyl-4-piperidone, 1.72g (10mmol) of p-toluenesulfonic acid, 159.2g (1.50mol) of trimethyl orthoformate and Methanol 400mL, heated to reflux for 2 hours, after the methanol was distilled off at normal pressure, 117.1g (1.00mol) of tert-butyl carbamate (1.00mol) and toluene 600mL were added, heated to 80-100°C, and the methanol produced by the reaction was distilled off while reacting to accelerate the reaction. After reacting for 3 hours, the residual raw material in GC was less than 1%, lowered the temperature, concentrated the solvent under reduced pressure, added ethanol, lowered the temperature to 0°C and stirred for 1 hour, a white solid was precipitated, filtered to obtain 240.5g white solid product, the yield was 83.4%, Purity 99.1%, LCMS (ESI) m / z: [M+H] + 289.18.

[0026] Step 2: Into a 5L autoclave, add 240.5g (0.834mol) of the product obtained in the previous step and 2.4L of methanol, add 24....

Embodiment 2

[0028] Step 1: Add 189.2g (1.00mol) of N-benzyl-4-piperidone, 0.53g (10mmol) of ammonium chloride, 106.1g (1.00mol) of trimethyl orthoformate and methanol into a 1L three-necked flask 400mL, heated to reflux for 2 hours, after distilling off methanol at normal pressure, add 140.6g (1.20mol) of tert-butyl carbamate and 600mL of toluene, heat to 80-100°C, and distill off the methanol generated during the reaction to accelerate the reaction. After 3 hours, the remaining raw material in GC was less than 1%, lowered the temperature, concentrated the solvent under reduced pressure, added ethanol, lowered the temperature to 0°C and stirred for 1 hour, a white solid precipitated, filtered to obtain 235.3g white solid product, the yield was 81.6%, the purity 99.0%.

[0029] Step 2: Add 235.3g (0.816mol) of the product obtained in the previous step and 2.3L of methanol to a 5L autoclave, add 11.8g of 5% Pd / C, replace the system with nitrogen three times, and feed hydrogen to control the...

Embodiment 3

[0031] Step 1: Into a 1L three-necked flask, add 189.2g (1.00mol) of N-benzyl-4-piperidone, 8.60g (50mmol) of p-toluenesulfonic acid, 296.4g (2.00mol) of triethyl orthoformate and 400mL of ethanol, heated to reflux for 2 hours, after distilling off the ethanol at normal pressure, add 128.9g (1.10mol) of tert-butyl carbamate and 600mL of toluene, heat to 90-110°C, and distill off the ethanol generated during the reaction to accelerate the reaction. After reacting for 3 hours, the remaining raw materials were controlled in GC <1%. Cool down, concentrate the solvent under reduced pressure, add ethanol, cool down to 0°C and stir for 1 hour, a white solid precipitated, filtered to obtain 242.0 g of white solid product, yield 83.9%, 99.2% purity.

[0032] Step 2: Add 242.0g (0.839mol) of the product obtained in the previous step and 2.4L of methanol to a 5L autoclave, add 12.1g of 10% Pd / C, replace the system with nitrogen three times, and feed hydrogen to control the pressure at 0....

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Abstract

The invention discloses a method for preparing 4-Boc-aminopiperidine. The method includes: allowing N-benzyl-4-piperidone to have reaction with ortho-formate in an alcoholic solution under acid catalysis to form ketal, allowing the ketal to have reaction with tert-butyl carbamate to generate imine, and subjecting the imine to Pd/C catalytic hydrogenation reduction to obtain the 4-Boc-aminopiperidine. The method is short in synthesizing route, easy in raw material obtaining, cheap, simple to operate, high in reaction yield, easy in product separation and purification and promising in application prospect.

Description

Technical field: [0001] The invention relates to a method for preparing 4-Boc-aminopiperidine, which belongs to the technical field of organic synthesis. Background technique: [0002] 4-Boc-aminopiperidine is an important intermediate for the synthesis of 1,4-disubstituted piperidine derivatives, which are muscarinic M3 receptor antagonists and can be used to treat or prevent respiratory diseases such as chronic obstructive pulmonary disease muscarinic diseases, chronic bronchitis, asthma and rhinitis; digestive disorders such as irritable bowel syndrome, convulsive colitis, diverticulitis and pain associated with contraction of digestive smooth muscles; urinary disorders such as urinary incontinence and neurogenic Frequent urination, neurogenic bladder, nocturnal enuresis, bladder instability, bladder spasm and chronic cyst frequency; motion sickness and other diseases, has a wide range of uses in the pharmaceutical industry. [0003] The relevant synthesis method of this...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58
CPCC07D211/58
Inventor 帅小华董伟
Owner SHANGHAI HOBOR CHEM CO LTD
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