Preparation method of amino protection (R)-3-amino piperidine

A technology of amino protection and aminopiperidine is applied in the field of preparation of optically active intermediates, can solve problems such as long steps, unsuitable for industrialized production and the like, and achieves the effects of high yield, readily available raw materials, and concise process steps

Active Publication Date: 2014-08-13
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The method for preparing 3-aminopiperidine disclosed in Chinese patent application CN101955457A (Route 5) uses low raw material prices, high safety, and simple post-treatment and purification operations, but this method has long steps and is not suitable for industrial production

Method used

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  • Preparation method of amino protection (R)-3-amino piperidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Preparation of (R)-2-(tert-butoxycarbonyl) glutaric acid (a compound of formula III)

[0045]

[0046] 3-liter three-necked bottle, into which DMF / H 2O (volume ratio 3:2) mixed solvent 1.55 liters, while stirring, slowly add 142 grams of D-glutamic acid to the system, stir for 10 minutes until the system is clear, keep the system at 20°C to 30°C, add dicarbonic acid dropwise 161 grams of di-tert-butyl ester was stirred for 1 hour after dripping. Rotate distillation at about 55°C to remove most of the solvent, add 1 liter of ethyl acetate to it, separate the layers, wash the organic phase with 200 ml of 1 mole per liter of hydrochloric acid solution, extract the water phase with 200 ml of ethyl acetate, combine the organic phases, The organic phase was washed with 300 ml of water, and then washed with 300 ml of saturated brine, the organic phase was separated, dried with an appropriate amount of anhydrous sodium sulfate for 1 hour, filtered, and the filtrat...

Embodiment 2

[0047] Example 2 Preparation of (R)-2-(phthaloyl)aminoglutaric acid (a compound of formula III)

[0048]

[0049] 3-liter three-necked bottle, into which DMF / H 2 O (volume ratio 3:2) mixed solvent 1.55 liters, while stirring, slowly add 147 grams of D-glutamic acid to the system, stir for 10 minutes until the system is clear, keep the system at 15°C to 20°C, add o-benzene 178 grams of diformic anhydride, after dropping, stirred for 2 hours. Rotate distillation at about 55°C to remove most of the solvent, add 1 liter of ethyl acetate to it, separate the layers, wash the organic phase with 200 ml of 1 mole per liter of hydrochloric acid solution, extract the water phase with 200 ml of ethyl acetate, combine the organic phases, The organic phase was washed with 300 ml of water, and then washed with 300 ml of saturated brine, the organic phase was separated, dried with an appropriate amount of anhydrous sodium sulfate for 1 hour, filtered, and the filtrate was spin-dried to ob...

Embodiment 3

[0050] Example 3 Preparation of (R)-2-tert-butyloxycarbonylamino-1,5-pentanediol (a compound of formula IV)

[0051]

[0052] In a 5-liter three-necked flask, replace the system with nitrogen three times, add 2 liters of dry tetrahydrofuran to it, add 200 grams of (R)-2-(tert-butoxycarbonyl) glutaric acid prepared in Example 1 while stirring, and cool down to -5°C About 197 grams of borane dimethyl sulfide was added dropwise therein (the molar concentration was 10 moles per liter), keeping the temperature of the system not exceeding 0°C, rising to about 50°C after dropping, and stirring for 10 hours. Cool down to below 10°C, slowly add 200 ml of methanol dropwise, after the drop is completed, transfer the system to rotary distillation, spin dry, add 1 liter of ethyl acetate to the system, and use 0.5 moles per liter of sodium hydroxide aqueous solution 200 Wash the organic phase with 1 ml, then wash the organic phase with 200 ml of saturated brine, separate the organic phas...

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Abstract

The invention discloses a preparation method of amino protection (R)-3-amino piperidine, and the preparation method comprises the following steps: (1) in the presence of a first solvent or absence of a solvent, reacting a compound of formula V with benzylamine to obtain a compound of formula VI; (2) in the presence of a second solvent, performing catalytic hydrogenation of the compound of formula VI to remove benzyl to obtain the amino protection (R)-3-amino piperidine. According to the method, the defects of use of expensive metal catalysts and use of high-pressure hydrogenation and various splitting for synthesis of a chiral amino piperidine ring can be avoided, at the same time, the synthetic route is short, the process is simple, the yield is high, and the method is suitable for industrial mass production.

Description

technical field [0001] The invention relates to a preparation method of an optically active intermediate, in particular to a preparation method of an optically active amino-protected (R)-3-aminopiperidine. Background technique [0002] Piperidine derivatives are widely used in the field of medicine. At present, such compounds are used as intermediates to synthesize a wide variety of drugs. Some drugs have wide application, fast curative effect, and small side effects. They are widely used in clinical treatment and have irreplaceable effects of other drugs. . Optically active (R)-3-aminopiperidine is an important chemical and pharmaceutical synthetic intermediate, especially a key intermediate for the synthesis of chiral drugs or pesticides, and is mainly used to synthesize dipeptidyl peptidase IV ( DPP-IV) inhibitors. Although the output of (R)-3-aminopiperidine is not large, its price is high and its added value is very considerable. At present, the introduction of amino...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCY02P20/55C07D211/56
Inventor 李朝龙魏彦君王华
Owner SHANGHAI VIWIT PHARMA CO LTD
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