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Preparation method for 3-aminopiperidine and optical isomer thereof

A technology of optical isomers and aminopiperidine, which is applied in the field of preparation of heterocyclic compounds, can solve the problems of cumbersome synthesis process and achieve the effects of high optical purity, mild reaction conditions and less by-products

Inactive Publication Date: 2013-10-30
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route requires multiple steps of removal and conversion of protecting groups and hydrogenolysis under palladium-carbon catalytic conditions, and the synthesis process is cumbersome.

Method used

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  • Preparation method for 3-aminopiperidine and optical isomer thereof
  • Preparation method for 3-aminopiperidine and optical isomer thereof
  • Preparation method for 3-aminopiperidine and optical isomer thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1. Preparation of (R)-1-allyl-3-(benzyloxycarbonylamino)piperidine

[0044] Weigh allylamine (22.55g, 0.41mol) in a one-necked bottle, and add (R)-2-((benzyloxycarbonyl)amino)pentane-1,5-dimesylate [Heterocycles, 44(1), 213-225, 1997; Syn.Comm.28(21), 3919-3926, 1998; Eur.J.Org.Chem., (9), 1765-1776, 2005] (40.9g, 0.1 mol), the added solid dissolves slowly, after adding, heat up to 50°C and stir, and a large amount of solid (allylamine methanesulfonate) appears instantly after about 1h, stop stirring, keep warm for 30min, add ethyl acetate to dissolve the product, and heat up to Stir at 70°C until it is evenly stirred, filter off the solid, wash the organic phase three times with water, dry, filter, spin dry to obtain a yellow solid, recrystallize to obtain 22.3g of a white solid, which is (R)-1-allyl-3 -(Benzyloxycarbonylamino)piperidine (yield 81.3%).

[0045] 1 H-NMR (CDCl3, 400MHz): δ1.53-1.69(m, 4H), 2.23-2.45(m, 4H), 2.93(d, 2H), 3.78-3.81(m, 1H), 5.06(s, 2H) ...

Embodiment 2

[0059] 1. Preparation of (R)-1-(4-methylbenzyl)-3-(benzyloxycarbonylamino)piperidine

[0060] Weigh 4-methylbenzylamine (49.61g, 0.41mol) in a single-necked bottle, add (R)-2-((benzyloxycarbonyl)amino)pentane-1,5-dimethylsulfonic acid in batches under stirring Esters (40.9g, 0.1mol), the added solids were slowly dissolved, after the addition was complete, the temperature was raised to 50°C and stirred, and a large amount of solids (4-methylbenzylamine methanesulfonate) appeared instantly after about 1h, the stirring was stopped, and the temperature was kept for 30min , add ethyl acetate to dissolve the product, heat up to 70°C and stir until evenly stirred, filter off the solid, wash the organic phase three times with water, dry, filter, spin dry to obtain a yellow solid, recrystallize to obtain 30.5g of a white solid, as ( R)-1-(4-methylbenzyl)-3-(benzyloxycarbonylamino)piperidine (yield 90.3%).

[0061] 1 H-NMR (CDCl 3 , 400MHz): δ1.89-1.98(m, 2H), 2.00-2.05(m, 2H), 2.35(...

Embodiment 3

[0066] 1. Preparation of (R)-1-(4-methylbenzyl)-3-(tert-butoxycarbonylamino)piperidine

[0067]Weigh 4-methylbenzylamine (49.61g, 0.41mol) in a single-necked bottle, add (R)-2-((tert-butoxycarbonyl)amino)pentane-1,5-dimethylsulfonate in batches under stirring Ester (37.5g, 0.1mol), the added solid dissolved slowly, after the addition was completed, the temperature was raised to 50°C and stirred, and a large amount of solid (4-methylbenzylamine methanesulfonate) appeared instantly after about 1h, the stirring was stopped, and the temperature was kept After 30 minutes, add ethyl acetate to dissolve the product, raise the temperature to 70°C and stir until it is evenly stirred, filter off the solid, wash the organic phase three times with water, dry, filter, and spin dry to obtain a yellow solid, which is recrystallized to obtain 27.1g of a white solid. (R)-1-(4-methylbenzyl)-3-(tert-butoxycarbonylamino)piperidine (yield 89.4%).

[0068] 1 H-NMR (CDCl 3 , 400MHz): δ1.41(s, 9H)...

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Abstract

The invention discloses a preparation method for 3-aminopiperidine and an optical isomer thereof. The preparation method comprises the following steps of: reacting a compound shown in formula (I) with R2NH2 to obtain a compound shown in formula (II) or a compound shown in formula (III); removing an amino protecting group from the compound shown in formula (II) under the action of a metal catalyst to obtain the compound shown in formula (III) or a compound shown in formula (IV); and removing a primary amine protecting group from the compound shown in formula (III) to obtain the compound shown in formula (IV) or corresponding salts. According to the method, starting materials are low in the prices, simple and easily-available; reaction in each step is high in yield and few in by-products; reaction conditions are moderate, and racemized 3-aminopiperidine or 3-aminopiperidine with a single optical isomer can be obtained via the same method and only by changing the optical rotation of carbon atoms in the starting materials; moreover, the obtained optical isomer can achieve a high optical purity.

Description

technical field [0001] The present invention relates to the preparation of heterocyclic compounds, in particular to the preparation method of 3-aminopiperidine and its optical isomer (R)-3-aminopiperidine or (S)-3-aminopiperidine. Background technique [0002] 3-aminopiperidine and its optical isomers are widely used in the production of medicines, dyes, pesticides and spices, among which (R)-3-aminopiperidine is an important intermediate in the preparation of DPPIV antidiabetic drugs Alogliptin and Linagliptin body [WO2003004496; CN1926128A; J.Med.Chem., 50(10), 2297-2230, 2007; J.Med.Chem., 50(26), 6451-6453, 2007]. [0003] The existing synthetic method of 3-aminopiperidine is as follows: [0004] Method 1: Using 3-hydroxypiperidine as a raw material, 3-aminopiperidine is obtained by adding a protective group to the amino group, mesylation, azidation, reduction reaction, and removal of the protective group [J.Med.Chem, 35(23), 4334-4343, 1992]. Obviously, this method u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCY02P20/55
Inventor 赵传生吕辉陆成樑刘文中张锐
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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