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Preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate

A technology of tert-butyl carboxylate and methylpiperidine, which is applied in the new preparation field of compound-3-amino-4-methylpiperidine-1-tert-butyl carboxylate, can solve the problem of long synthetic route and three-dimensional Poor selectivity and other problems, to achieve the effect of long synthetic route, poor stereoselectivity and high ee value

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

AI Technical Summary

Problems solved by technology

It mainly solves the problems of long synthetic routes and poor stereoselectivity of such compounds reported in previous literatures

Method used

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  • Preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate
  • Preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate
  • Preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Example 1 : Operation steps: In a 100 ml single-necked bottle, triphenylmethylphosphonium bromide (1.3 g, 3.6 mmol) was dissolved in 20 ml of chloroform, and potassium hydroxide (0.37 g, 6.63 mg Moore). (R)-1-(1-tert-butoxycarbonyl)-4-oxo-3-piperidinylhydrazine-1,2-dicarboxylate dibenzyl ester was dissolved in (1.5 g, 3.01 mmol) in 15 mL of Slowly add chloroform into the reaction flask, stir at room temperature (20-30°C) for 20 hours, pour the reaction solution into ice water to quench, add dichloromethane for extraction, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate , purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 5:1, and 0.25 g of a white solid product was obtained with a yield of 16%.

Embodiment 2

[0029] Example 2 : Operation steps: In a 100-ml single-necked bottle, triphenylmethylphosphonium bromide (1.3 g, 3.6 mmol) was dissolved in 20 ml of chloroform, and sodium methoxide (0.36 g, 6.63 mg Moore). (R)-1-(1-tert-butoxycarbonyl)-4-oxo-3-piperidinylhydrazine-1,2-dicarboxylate dibenzyl ester was dissolved in (1.5 g, 3.01 mmol) in 15 mL of Slowly add chloroform into the reaction flask, stir at room temperature (20-30°C) for 20 hours, pour the reaction liquid into ice water to quench, add ethyl acetate for extraction, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate , purified by column chromatography, the eluent was petroleum ether: ethyl acetate = 5:1, and 0.15 g of a white solid product was obtained with a yield of 10.6%.

Embodiment 3

[0030] Example 3 : Operation steps: In a 100 ml three-necked flask, triphenylmethylphosphonium bromide (2.6 g, 7.2 mmol) was dissolved in 36 ml of tetrahydrofuran, and sodium hydrogen (0.26 g, 6.63 mmol) was added at zero degrees Celsius. Dibenzyl (R)-1-(1-tert-butoxycarbonyl)-4-oxo-3-piperidinylhydrazine-1, 2-dicarboxylate was dissolved in 50 ml of THF and slowly added to the reaction flask , stirred at room temperature (20-30°C) for 4 hours, the reaction solution was quenched by pouring into ice water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, purified by column chromatography, and the eluent was petroleum Ether: ethyl acetate = 5:1, 0.5 g of white solid product was obtained, yield 30%.

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Abstract

The invention discloses a high-stereoselectivity preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate, which is mainly used for solving the problems that compounds reported by conventional documents have long synthesis routes and poor stereoselectivity. The preparation method comprises the following steps: carrying out ylide reaction under an alkaline condition by taking a compound R)-1-(1-tert-butyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dibenzyl dicarboxylate as a starting material to obtain (S)-1-(1-tert-butyloxycarbonyl)-4-methylene -3-piperidyl hydrazine-1,2-dibenzyl dicarboxylate; then, obtaining (3S, 4R)-3- diazanyl-4-methyl piperidine-1-tertiary butyl carboxylate by catalytic hydrogenation under action of a metal hydrogenation catalyst and hydrogen gas; and finally, reducing under action of the metal hydrogenation catalyst and hydrogen gas to obtain the (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate. And the total yield is 34.5%.

Description

technical field [0001] The invention relates to a new preparation method of compound (3S, 4R)-3-amino-4-methylpiperidine-1-carboxylic acid tert-butyl ester. Background technique [0002] Piperidine and substituted piperidine compounds have long attracted the attention of synthetic chemists. For a long time, organic chemists have been committed to developing new methods to efficiently synthesize piperidine compounds. Because piperidine compounds are widely used in the synthesis intermediates of other complex organic heterocyclic compounds and drugs. And some molecules containing piperidine units have good biological activity. However, so far there are only a few very efficient synthetic methods for the synthesis of 3-amino-4-substituted piperidines. [0003] For example, in the literature Organic Chemistry Communications (Org. Lett., 2002, 25, 4499-4502), a method for synthesizing trans-(3S)-amino-4-substituted piperidines was reported, which uses protected serine as The r...

Claims

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Application Information

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