Preparation method of trans-N-Boc-3-amino-4-hydroxypiperidine

A technology of -n-boc-3-, n-boc-4-, applied in the field of preparation of compound trans-N-Boc-3-amino-4-hydroxypiperidine, capable of solving positional isomerism and stereoselection Problems such as low sex, to achieve the effect of high ee value

Inactive Publication Date: 2014-03-26
上海药明康德新药开发有限公司 +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the problems of positional isomerism and low stereoselectivity in the existing preparation methods

Method used

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  • Preparation method of trans-N-Boc-3-amino-4-hydroxypiperidine
  • Preparation method of trans-N-Boc-3-amino-4-hydroxypiperidine
  • Preparation method of trans-N-Boc-3-amino-4-hydroxypiperidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 : Procedure: In a 100 ml single-necked bottle, N-Boc-4-piperidone (1.0 g, 5.1 mmol) and cis-tert-butyldimethylsilylhydroxy-L-proline (39 mg, 0.34 mmol) was dissolved in 67 ml of 1,2-dichloroethane, and dibenzyl azodicarboxylate (1 g, 3.35 mmol) was added under stirring, and stirred at room temperature (20-30°C) for 40 hours, The 1,2-dichloroethane was removed by vacuum rotary evaporation, and the residue was purified by silica gel column (petroleum ether: ethyl acetate volume ratio = 10:1) to obtain 1 g of the compound. The yield is 30%.

Embodiment 2

[0027] Example 2 : Procedure: In a 100 ml single-necked bottle, N-Boc-4-piperidone (1.0 g, 5.1 mmol) and cis-tert-butyldimethylsilylhydroxy-L-proline (39 mg, 0.34 mmol) was dissolved in 67 ml of tetrahydrofuran, and dibenzyl azodicarboxylate (1 g, 3.35 mmol) was added under stirring, stirred at room temperature (20-30°C) for 18 hours, and tetrahydrofuran was removed by rotary evaporation in vacuum, leaving The compound was purified by silica gel column (petroleum ether: ethyl acetate volume ratio = 10:1) to obtain 0.5 g of the compound. The yield is 20%.

Embodiment 3

[0028] Example 3 : Operating steps: In a 100 ml single-necked bottle, N-Boc-4-piperidone (1.0 g, 5.1 mmol) and camphorsulfonic acid (12 mg, 0.51 mmol) were dissolved in 67 ml of tetrahydrofuran, stirred Dibenzyl azodicarboxylate (1 g, 3.35 mmol) was added under low temperature, stirred at room temperature (20-30°C) for 18 hours, and the tetrahydrofuran was removed by rotary evaporation under vacuum. =10:1) Purified by column to obtain 0.3 g of the compound. Yield 19%.

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Abstract

The invention discloses a preparation method of trans-N-Boc-3-amino-4-hydroxypiperidine, mainly aiming to solve the problem that the compound is needed to be chirally resolved because of having stereoisomerisms. The preparation method comprises the following steps: firstly, with a compound N-Boc-4-piperidone as a starting raw material, enabling N-Boc-4-piperidone to react with dibenzyl diazene-1, 2-dicarboxylate in the presence of a catalyst amino acid to obtain (R)-3-[N, N'-bis(carbobenzoxy)hydrazine]-N-Boc piperidine-1-ketone; secondly, enabling (R)-3-[N, N'-bis(carbobenzoxy)hydrazine]-N-Boc piperidine-1-ketone to react with a reducing reagent at the temperature of 0 DEG C to obtain (R)-3-[N, N'-bis(carbobenzoxy)hydrazine]-N-Boc piperidine-1-aocohol; thirdly, enabling (R)-3-[N, N'-bis(carbobenzoxy)hydrazine]-N-Boc piperidine-1-aocohol to react in the presence of a metal hydrogenation catalyst or samarium diiodide to obtain (R)-3-[N-(carbobenzoxy)amino]-N-Boc piperidine-1-aocohol; fourthly, reducing (R)-3-[N-(carbobenzoxy)amino]-N-Boc piperidine-1-aocohol in the presence of the metal hydrogenation catalyst or hydrogen gas to obtain the trans-N-Boc-3-amino-4-hydroxypiperidine. The total yield of the trans-N-Boc-3-amino-4-hydroxypiperidine is 33%.

Description

technical field [0001] The invention relates to a preparation method of compound trans-N-Boc-3-amino-4-hydroxypiperidine. Background technique [0002] 3-amino-4-hydroxypiperidine compounds occupy an important position in synthetic drugs due to their unique structure and properties, and are often found in natural products. On the one hand, 3-amino-4-hydroxypiperidine compounds contain electron Negative heteroatoms such as O and N have strong intermolecular forces with other molecules, and are good medical molecular skeletons; on the other hand, this type of compound contains functional groups such as amino and hydroxyl, which also makes it It is easily introduced into the substrate molecule through acid amine condensation, reductive amination and other classic reactions, resulting in different physiological activities or effects. [0003] For example, the literature (J. Med. Chem. 2011, 54, 5362–5372) reported an example in which the cyclohexyl group was substituted by 3-am...

Claims

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Application Information

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IPC IPC(8): C07D211/56
CPCC07D211/56
Inventor 孙海燕彭宣嘉汪秀吴颢马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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