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Method for preparing chiral N-tert-butyloxycarboryl-3-hydroxypiperidine

A technology of tert-butoxycarbonyl and hydroxypiperidine, which is applied in the field of preparation of chiral N-tert-butoxycarbonyl-3-hydroxypiperidine, which can solve problems that are difficult to apply to industrial production, difficult to obtain a large amount of catalysts, and insufficient optical purity of products Advanced problems, to achieve the effect of large industrial application value, cheap raw materials, simple and easy operation

Inactive Publication Date: 2014-02-12
SYNCOZYMES SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The root of the ground wild carrot is used as a biocatalyst to reduce N-tert-butoxycarbonyl-3-piperidone to obtain (S)-N-tert-butoxycarbonyl-3-hydroxypiperidine. There are a large amount of catalysts in this method Difficulty in obtaining and insufficient optical purity of the product lead to low reaction efficiency and high production cost, making it difficult to be applied in industrial production

Method used

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  • Method for preparing chiral N-tert-butyloxycarboryl-3-hydroxypiperidine
  • Method for preparing chiral N-tert-butyloxycarboryl-3-hydroxypiperidine
  • Method for preparing chiral N-tert-butyloxycarboryl-3-hydroxypiperidine

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Embodiment 1

[0029] 1. Synthesis of N-tert-butoxycarbonyl-3-hydroxypiperidine

[0030] At room temperature, add 100mL of 3-hydroxypiperidine into the reaction flask, add 500ml of water, then add 200g of di-tert-butyl dicarbonate, stir for 12h, add dichloromethane for extraction, and the obtained dichloromethane solution is directly used in the next reaction .

[0031] Two, the synthesis of N-tert-butoxycarbonyl-3-piperidone

[0032] At room temperature, to the dichloromethane solution of the above-mentioned N-tert-butoxycarbonyl-3-hydroxypiperidine, add 500 ml of water and 5 g of 2,2,6,6-tetramethylpiperidine-N-oxide, Adjust the pH value to 9.0 with sodium hydroxide solution, add 100 ml of saturated sodium hypochlorite solution dropwise under stirring, stir for 12 h, separate the dichloromethane layer, and concentrate to obtain a residue that is directly used in the next reaction.

[0033] 3. Synthesis of (R)-N-tert-butoxycarbonyl-3-hydroxypiperidine

[0034] At room temperature, add 50...

Embodiment 2

[0036] 1. Synthesis of N-tert-butoxycarbonyl-3-hydroxypiperidine

[0037] As described in Example 1.

[0038] Two, the synthesis of N-tert-butoxycarbonyl-3-piperidone

[0039] As described in Example 1.

[0040] 3. Synthesis of (S)-N-tert-butoxycarbonyl-3-hydroxypiperidine

[0041] At room temperature, add 500 ml of water, 10 g of ketoreductase KRED198 enzyme powder (Shangke Biomedicine (Shanghai) Co., Ltd.), 90 g of glucose, 0.05 g of NADP, and glucose dehydrogenation GDH105 enzyme powder to the residue obtained above at room temperature (Shangke Biopharmaceutical (Shanghai) Co., Ltd.) 10 g, control the pH value to 7.0, stir for 24 hours, filter, add ethyl acetate to extract three times, combine the organic layer, dry, filter, and concentrate to obtain the crude product; Crystallization in medium yielded 143 g of (S)-N-tert-butoxycarbonyl-3-hydroxypiperidine with a molar yield of 72% and an optical purity of 99.1%.

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Abstract

The invention discloses a method for preparing chiral N-tert-butyloxycarboryl-3-hydroxypiperidine. The method comprises the following steps: a) enabling racemic 3-hydroxypiperidine and di-tert-butyl dicarbonate ester to react to generate racemic N-tert-butyloxycarboryl-3-hydroxypiperidine; b) oxidizing the racemic N-tert-butyloxycarboryl-3-hydroxypiperidine into racemic N-tert-butyloxycarboryl-3-piperidone under the action of an oxidizing agent; c) reducing the racemic N-tert-butyloxycarboryl-3-piperidone by using a ketoreductase into the chiral N-tert-butyloxycarboryl-3-hydroxypiperidine. Compared with the prior art, the method provided by the invention can be used to prepare the chiral N-tert-butyloxycarboryl-3-hydroxypiperidine with the optical purity of 99% by using the racemic 3-hydroxypiperidine as a raw material, in addition, the material is cheap and easy to get, the reaction condition is mild, the operation is simple and feasible, the production cost is greatly lowered, and great industrial application value is achieved.

Description

technical field [0001] The invention relates to a method for preparing chiral N-tert-butoxycarbonyl-3-hydroxypiperidine by combining chemical reaction and biotransformation reaction, and belongs to the field of pharmaceutical industry biotechnology. Background technique [0002] 3-Hydroxypiperidine derivatives, especially chiral N-tert-butoxycarbonyl-3-hydroxypiperidine, are a class of compounds with important research value in the field of medicine. It is an important drug intermediate and is widely used in the synthesis of analgesic, antipsychotic, antitumor and other drugs. [0003] At present, the methods for preparing chiral N-tert-butoxycarbonyl-3-hydroxypiperidine mainly include chemical resolution and biotransformation. [0004] Chemical resolution method, as follows: [0005] [0006] Mainly, the racemic 3-hydroxypiperidine is salted and precipitated under the action of a chiral acid to obtain a chiral salt, and then the protecting group is freed to obtain a ch...

Claims

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Application Information

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IPC IPC(8): C12P41/00C12P17/12
Inventor 竺伟吴会王波
Owner SYNCOZYMES SHANGHAI
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