Synthesis method of 4-substituted piperidine derivatives

A synthesis method and technology of derivatives, applied in the direction of organic chemistry and the like, can solve the problems of poor stability of intermediates, expensive sulfonylation reagent-trifluoromethanesulfonic anhydride, etc., and achieve low synthesis cost, improved synthesis efficiency, and suitable wide range of effects

Active Publication Date: 2014-07-23
中国人民解放军63975部队
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method has disadvantages such as intermediate stability is poor and

Method used

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  • Synthesis method of 4-substituted piperidine derivatives
  • Synthesis method of 4-substituted piperidine derivatives
  • Synthesis method of 4-substituted piperidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Preparation of α, α-bis(2-hydroxyethyl)valeronitrile and 2-(2-hydroxyethyl)-2-propyliminobutyrolactone

[0063]

[0064] Dissolve diisopropylamine (16.80mL, 120mmol) in 200mL of anhydrous tetrahydrofuran, lower the temperature to -30°C under the protection of argon, add 2.4mol / L n-butyl lithium (50mL, 120mmol) dropwise, and react for 0.5h; Add valeronitrile (4.16g, 50mmol) and continue stirring for 0.5h; add ethylene oxide (5.28g, 120mmol) dropwise and react for 0.5h; slowly rise to 0°C for 1h, add 5mL of water to terminate the reaction; distill THF off , adding 200mL dichloromethane and 50mL water for extraction, the aqueous phase was extracted again with 50mL dichloromethane; the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and distilled under reduced pressure to obtain a white solid with a yield of 58% .

[0065] NMR data of α,α-bis(2-hydroxyethyl)valeronitrile:

[0066] 1 H NMR (400MHz, ...

Embodiment 2

[0074] Preparation of α, α-bis(2-hydroxyethyl)phenylacetonitrile and 2-phenyl-2-(2-hydroxyethyl)iminobutyrolactone

[0075]

[0076] Dissolve diisopropylamine (7.70mL, 55mmol) in 50mL of anhydrous tetrahydrofuran, cool down to -30°C under argon protection, drop in 2.4mol / L n-butyllithium (23mL, 55mmol), and react for 0.5h; Add phenylacetonitrile (2.92g, 25mmol), continue to stir for 0.5h; add dropwise ethylene oxide (2.42g, 55mmol), react for 0.5h; slowly rise to 0°C for 1h, add 5mL of water to terminate the reaction; evaporate tetrahydrofuran , adding 100mL dichloromethane and 50mL water for extraction, the aqueous phase was extracted again with 50mL dichloromethane; the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and separated by silica gel column chromatography to obtain a white solid, the yield 68%.

[0077] NMR data of α,α-bis(2-hydroxyethyl)phenylacetonitrile:

[0078] 1 H NMR (400MHz, CDCl ...

Embodiment 3

[0086] Preparation of α, α-bis(2-hydroxyethyl)-p-methoxyphenylacetonitrile and 2-p-methoxyphenyl-2-(2-hydroxyethyl)iminobutyrolactone

[0087]

[0088] Dissolve diisopropylamine (3.30mL, 24mmol) in 20mL of anhydrous tetrahydrofuran, lower the temperature to -30°C under the protection of argon, add 2.4mol / L n-butyllithium (10mL, 24mmol) dropwise, and react for 0.5h; Add p-methoxyphenylacetonitrile (1.47g, 10mmol), continue to stir for 0.5h; drop in ethylene oxide (1.06g, 24mmol), react for 0.5h; slowly rise to 0°C for 1h, add 5mL of water to terminate the reaction ; Evaporate tetrahydrofuran, add 50mL dichloromethane and 20mL water for extraction, the water phase is extracted again with 50mL dichloromethane; combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and separate by silica gel column chromatography to obtain white Solid, yield 66%.

[0089] NMR data of α,α-bis(2-hydroxyethyl)-p-methoxyphenylacetonitrile:

...

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Abstract

The invention relates to a synthesis method of 4-substituted piperidine derivatives. The synthesis method comprises the following steps: continuously reacting alpha-single substituted acetonitrile serving as a raw material with two-molecular ethylene oxide in the presence of a base I, thereby synthesizing compounds (2), wherein not one compound (2) is generated, and the compounds (2) are in tautomeric equilibrium with a compound (6); breaking the balance in the presence of a base II to generate an alcoxyl negative ion compound (3); reacting the compound (3) with R2SO2X or (R2SO2)2O to generate sulphonates (4); performing a cyclization reaction on the sulphonates (4) and primary amine to synthesize 4-substituted piperidine derivatives. Compared with a document reported method, the synthesis method has the advantages that the reaction steps are shortened and the synthetic efficiency is improved.

Description

technical field [0001] The invention relates to a synthesis method of 4-substituted piperidine derivatives. Background technique [0002] 4-substituted piperidine derivatives exist in the skeleton structure of many drug molecules, such as piperidine analgesics pethidine, piminodine or anilidine, and have the effect of reducing appetite and treating erectile dysfunction The MC4R receptor antagonist MB243 (Palucki BL, Park M K, Nargund RP, et al.Bioorg.Med.Chem.Lett.2005, 15, 171-175), etc., studied how to efficiently synthesize 4-substituted piperidine derivatives with important application value. [0003] [0004] Rinderknecht et al. (Bergel F, Morrison AL, Rinderknecht H.J. Chem.Soc.1944, 265-267.) used chloroethanol as raw material to synthesize intermediate α, α-bis(2-chloroethyl)phenylacetonitrile through 4-step reaction , This intermediate can be cyclized with primary amines to synthesize piperidine derivatives. This route has disadvantages such as long reaction s...

Claims

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Application Information

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IPC IPC(8): C07D211/64
CPCC07D211/64
Inventor 高振华邹传品钟辉何小伟刘利辉孟祥燕焦剑岚
Owner 中国人民解放军63975部队
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