Preparation method of (S)-N-Boc-3-hydroxypiperidine

A technology of hydroxypiperidine and -n-boc-3-, which is applied in the field of preparation of -N-Boc-3-hydroxypiperidine, can solve the problems of low yield of lipase resolution, expensive raw materials, easy inactivation, etc. , achieve good catalytic effect, reduce production cost, and facilitate contact

Inactive Publication Date: 2018-03-27
ITIC MEDCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The biocatalytic method mainly has the following approaches: (1) take N-Boc-3-piperidone as raw material, reduce and introduce chiral center by ketoreductase, although this method can utilize the substrate to the greatest extent, the ketone used Reductase, coenzyme and lactate dehydrogenase for regeneration are expensive and easily inactivated; (2) Selective resolution with lipase can distribute and obtain (S) and (R) type 3-hydroxypiperidine , but the resolution yield of lipase is still low, and the separation of products is m

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] A preparation method for (S)-N-Boc-3-hydroxypiperidine, comprising the following steps:

[0022] (1) Mix the activated carbon with the aqueous solution of polyvinyl alcohol, ultrasonically disperse for 4 hours, add glutaraldehyde, stir and mix evenly, adjust the pH to 2, heat to 60°C for 4 hours, then stand at room temperature for 12 hours, and break up with a stirrer , to prepare PVA composite particles,

[0023] (2) Mix ketoreductase, glucose dehydrogenase, coenzyme NADP and sodium phosphate buffer, adjust the pH to 7, add the PVA composite particles prepared in step (1), add sodium alginate solution during stirring, and After continuous stirring for 4 hours, cool down to 3°C and let stand for 12 hours, then filter to obtain immobilized mixed enzyme granules;

[0024] (3) Add N-Boc-3-piperidone and water into the reaction kettle, add sodium phosphate buffer and mix well, add glucose, adjust the pH to 7 with phosphoric acid, control the temperature at 25°C, and then a...

Embodiment 2

[0030] A preparation method for (S)-N-Boc-3-hydroxypiperidine, comprising the following steps:

[0031] (1) Mix the activated carbon with the aqueous solution of polyvinyl alcohol, ultrasonically disperse for 5 hours, add glutaraldehyde, stir and mix evenly, adjust the pH to 3, heat to 80°C for 6 hours, then stand at room temperature for 18 hours, and break up with a stirrer , to prepare PVA composite particles,

[0032] (2) Mix ketoreductase, glucose dehydrogenase, coenzyme NADP and sodium phosphate buffer, adjust the pH to 7, add the PVA composite particles prepared in step (1), add sodium alginate solution during stirring, and After continuous stirring for 6 hours, cool down to 3-8°C and let stand for 24 hours, then filter to obtain immobilized mixed enzyme granules;

[0033] (3) Add N-Boc-3-piperidone and water into the reaction kettle, add sodium phosphate buffer and mix well, add glucose, adjust the pH to 7 with phosphoric acid, control the temperature at 35°C, and then...

Embodiment 3

[0039] A preparation method for (S)-N-Boc-3-hydroxypiperidine, comprising the following steps:

[0040](1) Mix the activated carbon with the aqueous solution of polyvinyl alcohol, ultrasonically disperse for 4 hours, add glutaraldehyde, stir and mix evenly, adjust the pH to 3, heat to 60°C for 6 hours, then let it stand at room temperature for 12 hours, and break it up with a stirrer , to prepare PVA composite particles,

[0041] (2) Mix ketoreductase, glucose dehydrogenase, coenzyme NADP and sodium phosphate buffer, adjust the pH to 7, add the PVA composite particles prepared in step (1), add sodium alginate solution during stirring, and After continuous stirring for 6 hours, cool down to 3°C and let stand for 24 hours, then filter to obtain immobilized mixed enzyme granules;

[0042] (3) Add N-Boc-3-piperidone and water into the reaction kettle, add sodium phosphate buffer and mix well, add glucose, adjust the pH to 7 with phosphoric acid, control the temperature at 25°C, a...

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PUM

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Abstract

The invention discloses a preparation method of (S)-N-Boc-3-hydroxypiperidine, wherein the preparation method includes the following steps: adding N-Boc-3-piperidone and water into a reaction kettle,adding a sodium phosphate buffer solution, mixing and stirring evenly, adding glucose, then adjusting the pH to 7 with phosphoric acid, controlling the temperature to 25-35 DEG C, then adding immobilized mixed enzyme particles prepared in the step (2), stirring, carrying out a reaction for 24 h, followed by, filtering, recycling the immobilized mixed enzyme particles, extracting the filtrate withethyl acetate, carrying out reduced pressure distillation, and recrystallizing with petroleum ether to obtain (S)-N-Boc-3-hydroxypiperidine. The preparation method has the advantages of simple operation, mild conditions, fewer by-products, high product purity and relatively high product yield.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of (S)-N-Boc-3-hydroxypiperidine. Background technique [0002] Chirality is a basic attribute in nature, and many basic structural units in organisms have chirality. Chiral drugs refer to drugs containing chiral centers in their molecular structures, including single stereoisomers, unequal mixtures of two or more stereoisomers, and racemates. Piperidine is an important class of pharmaceutical intermediates and chemical intermediates. It plays an important role in the synthesis of chiral drugs. A variety of high value-added pharmaceutical intermediates. Among them, 3-hydroxypiperidine, which has a chiral structure, plays an important role in lowering blood pressure, anti-tumor, and anti-coccidiosis. [0003] N-Boc-3-hydroxypiperidine is an important derivative of 3-hydroxypiperidine, and it is also an important pharmaceutical intermediate. This compound ca...

Claims

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Application Information

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IPC IPC(8): C12P17/12C12N11/14C12N11/10C12N11/08
CPCC12N9/0006C12N9/0008C12N11/08C12N11/10C12N11/14C12P17/12C12Y101/01047
Inventor 胡海威
Owner ITIC MEDCHEM CO LTD
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