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A kind of preparation method of chiral fluoroalkyl substituted piperidine ring compound

A compound and fluoroalkyl technology, applied in the field of preparation of piperidine ring compounds, can solve problems such as lack of fluoroalkyl-substituted substrate chiral catalysts, and achieve high yield, simple preparation method and high stereoselectivity Effect

Active Publication Date: 2019-02-12
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, due to the lack of fluoroalkyl-substituted substrates and suitable chiral catalysts, how to synthesize chiral fluoroalkyl-substituted piperidine rings is still a very challenging issue at present.

Method used

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  • A kind of preparation method of chiral fluoroalkyl substituted piperidine ring compound
  • A kind of preparation method of chiral fluoroalkyl substituted piperidine ring compound
  • A kind of preparation method of chiral fluoroalkyl substituted piperidine ring compound

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preparation example Construction

[0058] The present invention also provides a preparation method of the chiral fluoroalkyl-substituted piperidine ring compound of the present invention, comprising:

[0059] reacting the compound of the formula (II) and the compound of the formula (III) under the action of the catalyst shown in the formula (IV-a), to obtain the compound of the formula (I-a);

[0060]

[0061] Among them, R 1 for hydrogen, C 1 -C 30 Alkyl, C 1 -C 30 Alkoxy, halogen, nitro or C 4 ~C 30 the aryl group;

[0062] R 2 is trifluoromethyl, difluoromethyl, monofluoromethyl or pentafluoroethyl;

[0063] R 3 for C 1 ~C 30 Alkyl or C 4 ~C 30 aromatic group;

[0064] R 4 for C 1 ~C 30 Alkyl or C 4 ~C 15 aromatic group;

[0065] R 5 for C 1 ~C 30 Alkyl or C 4 ~C 30 Aromatic group;

[0066] Or react the compound of formula (II) structure with the compound of formula (III) structure under the action of catalyst shown in formula (IV-b), obtain the compound of formula (I-b) structur...

Embodiment 1

[0089] In a 20mL reaction tube, the catalyst (2S,3S)-2-amino-N-((S)-1-phenyl-3-hydroxypropan-2-yl) represented by the formula (IV-a-3) was added )-3-methylphenylpropanamide (0.06mmol, 15.9mg), p-nitrobenzoic acid (0.06mmol, 10.0mg), fluoroalkyl-substituted aminal 3-(three Fluoromethyl) 3-hydroxy-5-methyl 2,3-dihydrophenylpropane[d]isothiazole 1,1-diox (0.3mmol, 80.2mg), enone (E)-4-(3- Methylphenyl)-but-3-en-2-one (0.6mmol, 96.1mg) and chloroform (3.0mL), stirred and reacted at 30°C. After the reaction was completed (TLC tracking detection), the residue obtained by spin drying was used as an eluent to pass through the chromatographic column to obtain the product (7R, 10aR)-2-methyl-7-(3-methyl Phenyl)-10a-(trifluoromethyl)-10,10a-dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-9(8H)-one 5,5 -Dioxygen, 99% yield.

[0090] The absolute configuration of the product was determined by XRD single crystal diffraction, the results can be found in figure 1 , figure 1 It is the XRD ...

Embodiment 2

[0104] In a 20mL reaction tube, add catalyst (S)-2-amino-N-((S)-1-phenyl-3-hydroxypropan-2-yl)-3 shown in formula (IV-a-1) -Phenylpropionamide (0.06mmol, 17.9mg), p-nitrobenzoic acid (0.06mmol, 10.0mg), fluoroalkyl-substituted aminal 3-(trifluoromethyl)3 represented by formula (II-1) -Hydroxy-2,3-dihydrophenylpropane[d]isothiazole 1,1-diox (0.3mmol, 76.0mg), enone (E)-4-phenyl-but-3-en-2-one (0.6mmol, 87.7mg) and chloroform (3.0mL), stirred at 30°C. After the reaction was completed (TLC tracking detection), the residue obtained by spin drying was used as an eluent to cross the chromatographic column to obtain the product (7R, 10aR)-7-phenyl-10a-(trifluoromethyl )-10,10a-dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-9(8H)-one 5,5-diox in a yield of 90%.

[0105] By using a nuclear magnetic resonance spectrometer to analyze the addition product, the results can be found in Figure 4~5 , Figure 4 For the addition product that the embodiment of the present invention 2 provid...

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Abstract

The present invention provides a preparation method of a chiral fluoroalkyl substituted piperidine ring compound, wherein a compound having a structure represented by a formula (II) and a compound having a structure represented by a formula (III) are subjected to a reaction under the action of a catalyst having a structure represented by a formula (IV-a) or formula (IV-b) to obtain a compound having a structure represented by a formula (I-a) or formula (I-b). According to the present invention, with the preparation method, the fluoroalkyl substituted piperidine ring compound containing the two chiral centers is prepared through the one-step reaction by using the catalyst and the raw materials of the present invention, such that the preparation method is simple, the obtained product has the high stereoselectivity, and the yield is high.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for preparing chiral fluoroalkyl-substituted piperidine ring compounds. Background technique [0002] Asymmetric synthesis research is a key method and means for the creation of chiral substances, and it is one of the most active fields of chemical research. It has important theoretical significance and application prospects. [0003] As a dominant structure, the piperidine ring widely exists in natural products and drug molecules (A.D.Elbein, R.Molyneux, In Alkaloids, Chemical and Biological Perspectives, (Ed.: S.W.Pelletier,) John Wiley & Sons: New York, 1987, 57) , it has been found that there are many drugs with piperidine rings, especially chiral piperidine ring compounds, such as: quinolizidine alkaloids ((+)-Lasubine II), (S)-piperidine acid, patent S .Rault, O.Renault, J.Guillon, P.Dallemagne, P.Renard, B.Pfeiffer, P.Lestage, M.Lebrun, E.P.Patent 1050530, Al di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04
CPCC07B2200/07C07D513/04
Inventor 汪志勇张胜李丽君
Owner UNIV OF SCI & TECH OF CHINA