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(s)-1-tert-butoxycarbonyl-3-hydroxypiperidine preparation method and device thereof

A technology of tert-butoxycarbonyl and hydroxypiperidine, which is applied in the field of preparation of -1-tert-butoxycarbonyl-3-hydroxypiperidine, can solve the problems of large amount of ketoreductase, non-recycling, troublesome post-processing, etc.

Active Publication Date: 2018-09-11
JIANGSU JIMING PHARMA TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] But at the same time, this technology also has disadvantages, such as a large amount of ketoreductase and cannot be recycled, and the production cost is high; post-processing is troublesome, and a large amount of diatomaceous earth is required to filter out ketone reductase; the production cycle is long and labor-intensive

Method used

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  • (s)-1-tert-butoxycarbonyl-3-hydroxypiperidine preparation method and device thereof
  • (s)-1-tert-butoxycarbonyl-3-hydroxypiperidine preparation method and device thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Stir 5 liters of phosphate buffer solution (0.1M, pH 6.8), 90 grams of ketoreductase enzyme powder and 180 grams of NAD, and then pump them into a reactor equipped with a filter membrane with a molecular weight cut off of >3000.

[0036] Add 3.0 kg of N-Boc-3-piperidone into the first 50-liter reaction kettle, add 3 liters of isopropanol, stir until dissolved, then add 21 liters of phosphoric acid buffer solution (0.1M, pH 6.8), 30 After stirring evenly at ℃. The above-mentioned reaction solution was pumped into the membrane filter reactor at a rate of 2 liters / hour by a flow pump, and the reaction solution coming out of the membrane filter reactor was received by the second reaction tank. The reaction was monitored by GC after pumping, conversion 99.3%, 99.0% ee.

[0037] Add 24 kg of ethyl acetate to the second reaction kettle, stir and let stand to separate the liquid, wash the organic phase twice with saturated brine and concentrate, add 30 liters of petroleum ethe...

Embodiment 2

[0040] Stir 5 liters of phosphate buffer solution (0.1M, pH 6.8), 90 grams of ketoreductase enzyme powder and 180 grams of NAD, and then pump them into a reactor equipped with a filter membrane with a molecular weight cut off of >3000.

[0041] Add 30.0 kg of N-Boc-3-piperidone into 500 liters of the first reaction kettle, add 30 liters of isopropanol, stir until dissolved, add 210 liters of phosphate buffer solution (0.1M, pH 6.8), 30 ℃ After stirring evenly. The above-mentioned reaction solution was pumped into the membrane filter reactor at a rate of 2 liters / hour by a flow pump, and the reaction solution coming out of the membrane filter reactor was received by the second reaction tank. GC detects every time 30 liters of reaction solution is received, and the conversion rate results are as follows:

[0042]

[0043] Add 120 kg of ethyl acetate to the second reaction kettle, stir and let it stand for liquid separation, wash the organic phase twice with saturated brine a...

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Abstract

The invention discloses a method for preparing (S)-1-tert-Boc (butoxycarbonyl)-3-hydroxypiperidine. The method comprises following steps: firstly, ketoreductase powder and coenzyme are mixed and added to a filter membrane reactor; N-Boc-3-piperidone and isopropyl alcohol are stirred and dissolved in a first reaction kettle and are added with a buffer solution for stirring and mixing at the temperature of 30 DEG C; the solution is pumped into the filter membrane reactor through a flow pump for a mixing reaction; a reaction liquid of the filter membrane reactor flows through a second reaction kettle for after-treatment; a treated mixture is extracted, concentrated and crystalized, and the (S)-1-tert-Boc-3-hydroxypiperidine is prepared. According to the method, the ketoreductase powder and the coenzyme can be recycled and applied simply and conveniently by the filter membrane reactor according to the features that molecular weight of the ketoreductase powder and the coenzyme is larger and molecular weight of a reaction substrate and a product is smaller; the reaction time is shortened by controlling the moving speed of a reaction liquid material; an after-treatment process of (S)-1-tert-Boc-3-hydroxypiperidine production is simplified; accordingly, the preparation cost of (S)-1-tert-Boc-3-hydroxypiperidine is greatly reduced.

Description

technical field [0001] The present invention relates to a preparation method of (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine, in particular to a preparation method of (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine using an enzyme membrane reactor pyridine method. Background technique [0002] (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine is an important pharmaceutical intermediate, and this compound can be used to synthesize a kind of anti-congestive heart failure drug carmorelin (Bio.Med.Chem., 2003,11,581-590), selectively inhibit the Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib (Ibrutinib), the natural substance Isonitramine (Isonitramine) and Nitraquinine ( Sibirine) and other prodrugs (Tetrahedron Lett., 1989, 30, 2301-2304). In particular, ibrutinib has been approved for the treatment of rare aggressive blood cancers - mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenstrom's macroglobulinemia. As one of the four drugs approved for anti-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/12C12M1/00C12M1/12
Inventor 何牧李斌峰张喜通陈剑戈
Owner JIANGSU JIMING PHARMA TECH
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