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N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof

A technology of n-boc-3- and -n-boc-3- is applied in the synthesis field of intermediate N-Boc-3-aminopiperidine and optical isomers thereof, and can solve the problems that hydrogenation is not easy to complete and after-treatment Difficulty, difficult to industrialize and other problems, to achieve the effect of low production cost, easy industrialized scale production, and simple operation

Active Publication Date: 2011-08-10
NOVOCODEX BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this synthetic route, the pressure required for the reduction reaction is relatively high, and the hydrogenation is not easy to complete, there are many by-products, the post-processing is difficult, and it is not easy to industrialize

Method used

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  • N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof
  • N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof
  • N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof

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Embodiment 1

[0031] Embodiment 1: the synthesis of ethyl N-Boc-3-piperidinecarboxylate (3)

[0032] Dissolve ethyl 3-piperidinecarboxylate (2) (31.4g, 0.2mol) and triethylamine (55.8mL, 0.4mol) in dichloromethane (150mL), cool to below 0°C, add di-tert-dicarbonate dropwise A solution of butyl ester (52.4 g, 0.24 mol) in dichloromethane (100 mL) was controlled at a temperature between 0 and 10°C. After the dropwise addition, wash with saturated potassium carbonate solution (3×50mL), 5% HCl (3×50mL) and saturated brine (3×50mL) successively, dry the organic phase over anhydrous sodium sulfate for 6h, filter and evaporate to dryness under reduced pressure The solvent was used to obtain ethyl N-Boc-3-piperidinecarboxylate (3), 49.3 g, 95%.

Embodiment 2

[0033] Embodiment 2: the synthesis of N-Boc-3-piperidine carboxamide (4)

[0034] Ethyl N-Boc-3-piperidinecarboxylate (3) (41.1g, 0.16mol), 28% ammonia water was dissolved in 1,4-dioxane (300mL), sealed, and the external temperature was set at 85-90 ℃, heat preservation reaction for 1.5h, after the reaction was completed, the solvent was evaporated to dryness under reduced pressure, recrystallized from petroleum ether (340mL), and dried to obtain N-Boc-3-piperidinecarboxamide (4), 35g, 96%.

Embodiment 3

[0035] Embodiment 3: the synthesis of N-Boc-3-aminopiperidine (1)

[0036] Cool NaOH (18g, 0.45mol) and 10% sodium hypochlorite solution (30mL, 0.3mol) to below 0°C, add N-Boc-3-piperidinecarboxamide (4) (34.2g, 0.15mol) in one go, and stir After 30 min, the ice bath was removed. Heat up to 70°C and keep warm for 45 minutes. Cool to room temperature, extract with ether (3×50 mL), combine the organic phases, wash with saturated brine (3×50 mL), and dry over anhydrous sodium sulfate for 6 h. The solvent was evaporated to dryness under reduced pressure to obtain N-Boc-3-aminopiperidine (1), 26.7 g, 89%.

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Abstract

The invention discloses an intermediate N-Boc-3-aminopiperidine and a synthesizing method of optical isomer thereof. The prior synthesizing route has the disadvantages of high requirements on reactionconditions, high possibility of racemization, a great number of byproducts, as well as difficult post-treatment and difficult industrialization. The synthesizing method comprises the following steps:taking halogenated hydrocarbon as a solvent and organic alkali as an acid-binding agent, 3-piperidine ethyl formate is added with di-tert-butyl dicarbonate by dripping at temperature of 0-10 DEG C toobtain N-Boc-3-piperidine ethyl formate; 1,4-dioxane is used as a solvent, the N-Boc-3-piperidine ethyl formate undergoes ammonolysis reaction to obtain N-Boc-3-piperidine formamide; and the N-Boc-3-piperidine formamide is added by dripping in a solution with sodium hypochlorite and sodium hydroxide to obtain N-Boc-3-aminopiperidine. The invention has the advantages of no racemization during thereaction, high optical purity of the product, relatively moderate reaction conditions, simple operation, low total production cost, and easy large-scale industrial production.

Description

technical field [0001] The invention relates to the field of organic chemistry, in particular to a method for synthesizing an intermediate N-Boc-3-aminopiperidine and an optical isomer thereof. Background technique [0002] N-Boc-3-aminopiperidine and its optical isomers are important intermediates, mainly used as pharmaceutical intermediates, organic synthesis intermediates, organic solvents, and can also be used in dye production, pesticide production and spices, etc. . [0003] The existing synthetic methods are as follows: [0004] 1. Using 3-hydroxypiperidine as a raw material reported by Brian R. de Costa, etc., N-Boc-3-aminopiperidine was prepared through protection, mesylation, azidation, and reduction reactions (Journal of Medicinal Chemistry, 35(23):4334-4343, 1992; PCT Int. Appl., 2005000305, 06 Jan 2005). This route has long steps, low yield (total yield 58%), and high price of raw material 3-hydroxypiperidine; the reagent sodium azide used in azidation reacti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/56C07B53/00
Inventor 沈大冬张伯引刘正俊
Owner NOVOCODEX BIOPHARMACEUTICALS CO LTD
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