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Production method of N-protection pipradrol

A production method and a technology for piperidinol, which are applied in the production field of N-protected piperidinol, can solve the problems of low efficiency, high industrialization cost, harsh reaction conditions and the like, and achieve the effects of high efficiency, simplicity and good industrial application value.

Active Publication Date: 2014-05-14
SHANGHAI RES & DEV CENT OF INDAL BIOTECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

(S)-N-tert-butoxycarbonyl-3-hydroxypiperidine can be obtained by chemical catalysis or resolution, but due to low efficiency and harsh reaction conditions, more three wastes are produced, and the industrialization cost is higher
Biocatalytic asymmetric synthesis of chiral alcohols has been widely used. Although the biocatalytic asymmetric synthesis of (S)-N-tert-butoxycarbonyl-3-hydroxypiperidine has been reported, there is no efficient method so far, such as : The conversion rate reported in the literature (Lacheretz R et al.Daucus carota Mediated-Reduction of Cyclic3-Oxo-amines.Organic Letters, 2009,11(6):1245-1248) is only 73%, and the ee value is only 95%. Has industrial application value; although CN201310173088.2 discloses that biocatalysis can achieve high-efficiency conversion, it does not disclose specific catalytic enzymes

Method used

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  • Production method of N-protection pipradrol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1, N-tert-butoxycarbonyl-3-piperidone is used as a substrate for enzyme screening

[0050] Synthesize the gene sequences of 19 alcohol dehydrogenases and ADH-A from different sources and design restriction enzyme sites at both ends of the genes, and then subclone them into the corresponding sites of the vector pET24a (purchased from Novagen). The obtained recombinant plasmid was transformed into Escherichia coli host cell BL21(DE3) for expression.

[0051] Weigh 0.4g of N-tert-butoxycarbonyl-3-piperidone and add them to 19 250ml shake flasks, then add 2ml of isopropanol and 10ml of water, adjust the pH to about 8.0 with ammonia water, and adjust the pH according to the final concentration of 40000U / L (enzyme activity assay scheme refers to literature Levin I, Meiri G, Peretz M, et al. The ternary complex of Pseudomonas aeruginosa alcohol dehydrogenase with NADH and ethylene glycol[J]. Protein science, 2004, 13(6): 1547-1556 The method in ) was added to ADH-...

Embodiment 2

[0057] Embodiment 2, N-tert-butoxycarbonyl-3-piperidone is the conversion of substrate

[0058] 2.1. Transformation of cpsADH broken solution

[0059] Weigh 100g of the substrate N-tert-butoxycarbonyl-3-piperidone, 200ml of isopropanol, add it to a 2000ml fermenter, add 200ml of water, adjust the pH to about 8.0 with ammonia water, and then add the enzyme according to the final concentration of 40000U / L Liquid ADH-A, according to the final concentration of 1g bacteria / L (converted according to the weight of the bacteria before crushing), add cpsADH crushing liquid, set the volume to 1000ml volume, adjust the pH to 8.0 with ammonia water, add 0.03g / L NAD + The reaction was started, and air was introduced at 0.5vvm, and the conversion result was detected by GC method after 3 hours of conversion, and the conversion rate reached 98.9%; the ee value of the product detected by chiral HPLC was greater than 99.5%.

[0060] 2.2. Transformation of cpsADH cells

[0061] Weigh 100g of...

Embodiment 3

[0066] Embodiment 3,1-benzyl-3-piperidone is the conversion of substrate

[0067] 3.1. Transformation of cpsADH cells

[0068] Weigh 100g of the substrate 1-benzyl-3-piperidone, 200ml of isopropanol, add it to a 2000ml fermenter, add 200ml of water, adjust the pH to about 8.0 with ammonia water, and then add the enzyme solution ADH according to the final concentration of 40000U / L -A, add cpsADH cells at a final concentration of 1g cells / L, set the volume to 1000ml, adjust the pH to 8.0 with ammonia water, add 0.03g / L NAD at 40°C and rotate at 500rpm + The reaction was started, and air was introduced at 0.5vvm, and the conversion result was detected by GC method after 5 hours of conversion, and the conversion rate reached 99.0%; the ee value of the product detected by chiral HPLC was greater than 99.5%.

[0069] 3.2. Transformation of cmADHmut cells

[0070] Weigh 100g of the substrate 1-benzyl-3-piperidone, 200ml of isopropanol, add it to a 2000ml fermenter, add 200ml of wat...

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Abstract

The invention discloses a production method of N-protection pipradrol. The structural formula of the N-protection pipradrol is shown in the specification, wherein R is tert-butyloxycarbonyl or benzyl. The production method is characterized in that the N-protection piperidone is taken as a substrate, and is obtained through a reaction in the presence of alcohol dehydrogenase, ADH-A, isopropyl alcohol and NAD<+1>; the alcohol dehydrogenase is cpsADH or cmADHmut. The method disclosed by the invention is efficient and simple and has relatively high value in industrial application.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to a production method of N-protected piperidinol. Background technique [0002] (S)-N-tert-butoxycarbonyl-3-hydroxypiperidine ((S)-1-Boc-3-hydroxypiperidine) can be used to synthesize the anti-congestive heart failure drug carmorelin (Philip A Carpino et al.Pyrazolinone -piperidine dipeptide growth hormone secretagogues (GHSs): Discovery of capromorelin. Bioorganic & Medicinal Chemistry, 2003, 11(4):581-590), which can also be used in the synthesis of new lymphoma drug ibrutinib. (S)-N-tert-butoxycarbonyl-3-hydroxypiperidine can be obtained by chemical catalysis or resolution, but due to low efficiency and harsh reaction conditions, more three wastes are produced and the industrialization cost is higher. Biocatalytic asymmetric synthesis of chiral alcohols has been widely used. Although the biocatalytic asymmetric synthesis of (S)-N-tert-butoxycarbonyl-3-hydroxypiperidine ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/12
Inventor 陶荣盛
Owner SHANGHAI RES & DEV CENT OF INDAL BIOTECH
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