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Method for preparing chiral alpha-alkenyl(or alkynyl group)-alpha'-alkyl piperidine as well as N-Cbz derivatives and use thereof

A technology based on alkyl and alkenyl, applied in the field of preparation and application of chiral α-alkenyl (or alkynyl)-α'-alkylpiperidine and its N-Cbz derivatives, achieving high yield and easy operation easy effect

Inactive Publication Date: 2008-08-27
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In fact, there is no report on the general preparation method of chiral N-Cbz-α-(3-propanalyl)-α’-alkylpiperidine in the existing literature methods

Method used

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  • Method for preparing chiral alpha-alkenyl(or alkynyl group)-alpha'-alkyl piperidine as well as N-Cbz derivatives and use thereof
  • Method for preparing chiral alpha-alkenyl(or alkynyl group)-alpha'-alkyl piperidine as well as N-Cbz derivatives and use thereof
  • Method for preparing chiral alpha-alkenyl(or alkynyl group)-alpha'-alkyl piperidine as well as N-Cbz derivatives and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1, the preparation of (2R, 6R)-2-n-propyl-6-vinylpiperidine-1-benzyl carbonate (formula VI-a)

[0085]

[0086] A solution of compound formula IV-a (1.0 g, 2.59 mmol) with aqueous sodium hydroxide solution (6M, 1 mL), methanol (2 mL) and tetrahydrofuran (2 mL) was stirred and reacted at 60° C. for 2.0 hours. Then the system was cooled to room temperature and washed with CH 2 Cl 2 Moderately extract three times. The organic phases were combined and extracted with aqueous HCl (6.0 M, 5 x 5 mL) until compound V-a was completely salted and dissolved in the aqueous phase. Combine the aqueous phases with CH 2 Cl 2 Extract (3 x 10 mL) and discard the organic phase. Add NaOH aqueous solution (6.0M) dropwise to the remaining aqueous phase until the solution is alkaline (pH=10-12), and then use CH 2 Cl 2 Moderately extract three times. The combined organic phase containing compound formula V-a was washed with saturated brine, anhydrous NaSO 4 dry.

[0087]...

Embodiment 2

[0092] Embodiment 2, the preparation of (2R, 6R)-2-n-pentyl-6-vinylpiperidine-1-benzyl carbonate (formula VI-b)

[0093]

[0094] A solution of compound formula IV-b (1.0 g, 2.42 mmol), sodium hydroxide aqueous solution (6M, 1 mL), methanol (2 mL) and tetrahydrofuran (2 mL) was stirred and reacted at 60° C. for 2.0 hours. Then the system was cooled to room temperature and separated by column chromatography (silica gel, PE / EtOAc).

[0095] After evaporating most of the solvent from the resulting eluent containing compound formula V-b, add CH 2 Cl 2(20mL), Na 2 CO 3 (1.28g, 12.10mmol) and CbzCl (0.83g, 4.84mmol), mixed and stirred at room temperature for 5h. The system was cooled to room temperature, filtered to remove Na 2 CO 3 , the crude product obtained after evaporating the solvent was subjected to column chromatography (silica gel, PE / EtOAc) to obtain oily liquid formula VI-b (0.63 g, 82%).

[0096] [α] D 25 =+25.8° (c 1.5, CHCl 3 ).

[0097] 13 C NMR: δ 156...

Embodiment 3

[0100] Embodiment 3, the preparation of (2R, 6R)-2-n-hexyl-6-vinylpiperidine-1-benzyl carbonate (formula VI-c)

[0101]

[0102] Under the same conditions as in Example 2, the product formula VI-c was obtained from the compound formula IV-c with a yield of 80%.

[0103] [α] D 25 =+28.3° (c 1.4, CHCl 3 ).

[0104] 13 C NMR: δ 156.0, 139.7, 137.0, 128.4, 127.8, 114.8, 66.9, 51.7, 51.1, 34.1, 31.8, 29.2, 27.8, 27.7, 27.1, 22.6, 14.5, 14.1.

[0105] Elemental Analysis: Calcd.for C 21 h 31 NO 2 : C, 76.55; H, 9.48; N, 4.25. Found: C, 77.02; H, 9.41; N, 4.20.

[0106] Indicates that the obtained compound is correct.

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Abstract

The invention relates to a preparation method of chiral alpha-alkenyl (or alkynyl)-alpha'-alkyl piperidine and relative N-Cbz derivative and an application. The invention provides two compounds resprenseted as formula (V) and formula (VI). The preparation method comprises removing benzyl of the compound (IV0 in alkali condition to obtain the compound (V), reacting the compound (V) with benzyl chloroformate to obtain the compound (VI), wherein the compounds (V, VI) can be used to prepare 5-substituted-hydride indolizine natural alkaloids. The inventive method has simple operation and high yield, which can prepare chiral alpha-alkenyl (or alkynyl)-alpha'-alkyl piperidine in large scale with significant value in drug research or the like.

Description

technical field [0001] The invention relates to a preparation method and application of chiral α-alkenyl (or alkynyl)-α'-alkylpiperidine and N-Cbz derivatives thereof. Background technique [0002] Alkenyl- and alkynyl-substituted chiral α,α'-disubstituted piperidines and their N-derivatives are key intermediates in the synthesis of many natural alkaloids with important biological activities. For example: Indolizidine Alkaloids obtained from the skin secretions of tropical frogs are widely used in drug development due to their various important biological activities. For example: the natural products 167B (Formula I), 195H (Formula II) and 209D (Formula III) with a chiral alkyl substituent at the 5-position have non-competitive inhibitory activity on neuromuscular transmission. [0003] [0004] (-)-Indolizidine 167B (-)-Indolizidine 195H (-)-Indolizidine 209D [0005] (Formula I) (Formula II) (Formula III) [0006] Many synthetic routes for these compounds hav...

Claims

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Application Information

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IPC IPC(8): C07D211/08C07D471/04
Inventor 胡跃飞刘惠王歆燕程国林苏德泳
Owner TSINGHUA UNIV
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