Process method for synthesizing 4-site heteroatom-substituted cyclohexenyl halide

A technology of cyclohexenyl and process method, which is applied in the field of synthesis of organic compounds, can solve the problems of harsh reaction conditions and difficult control, and achieve the effects of mild process conditions, easy operation, avoiding ultra-low temperature reaction and column chromatography purification

Active Publication Date: 2011-05-25
DALIAN NETCHEM CHIRAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Based on the above analysis, it is found that the current various reaction routes have the problem of harsh reaction conditions and difficult control.

Method used

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  • Process method for synthesizing 4-site heteroatom-substituted cyclohexenyl halide
  • Process method for synthesizing 4-site heteroatom-substituted cyclohexenyl halide
  • Process method for synthesizing 4-site heteroatom-substituted cyclohexenyl halide

Examples

Experimental program
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Effect test

Embodiment 1

[0034] The first step: Tetrahydropyran-4-hydrazine ( 2a , X = O) to synthesize

[0035] Under argon protection, add 70-80% hydrazine hydrate (10 moles) and 400 ml of ethanol to a 1-liter reaction flask equipped with a constant-pressure addition funnel, and stir at room temperature for 20 minutes. Cool down to -10 o C. Slowly add tetrahydropyran-4-one (0.5 mole) in ethanol (100 ml) solution dropwise, the dropwise addition is completed in 8-10 hours, keep warm and continue to react for 3-5 hours. After the complete reaction of the raw materials was detected by TLC (using the exclusive color reagent 2,4-dinitrophenylhydrazine for color development). After rotary evaporation of the solvent and vacuum distillation, 52 grams of the product tetrahydropyran-4-hydrazylhydrazone were obtained with a yield of 91%.

[0036] The second step: tetrahydropyran-4-enyl chloride ( 3a ) and tetrahydropyran-4-dichloro ( 4a ) (X = O, X' = Cl) synthesis:

[0037] Under the protection of argon,...

Embodiment 2

[0041] The first step: tetrahydrosulfone pyran-4-hydrazine ( 2b , X = SO 2 )synthesis

[0042] Under argon protection, add tetrahydrosulfone pyran-4-one (0.5 mol) and 450 ml of ethylene glycol dimethyl ether to a 1-liter reaction flask equipped with a condenser tube and a constant pressure addition funnel, and stir at room temperature After 20 minutes, start to slowly add 70-80% hydrazine hydrate (20 moles) dropwise. After the dropwise addition is complete, heat up to reflux for 3-5 hours. After the complete reaction of the raw materials was detected by TLC (using the exclusive color reagent 2,4-dinitrophenylhydrazine for color development). After rotary evaporation of the solvent and distillation under reduced pressure, 75 grams of the product tetrahydrosulfonepyran-4-hydrahydrazone were obtained, with a yield of 93%.

[0043] The second step: tetrahydrothiopyran-4-enyl bromide ( 3b ) and tetrahydrothiopyran-4-dibromo ( 4b ) (X = S, X’ = Br) synthesis:

[0044] Under ar...

Embodiment 3

[0048] The first step: nitrogen benzyl cyclohexyl-4-hydrazine ( 2c , X = NBn) to synthesize

[0049] Under argon protection, add nitrogen benzylcyclohexyl-4-one (0.5 mol) and 400 ml of toluene to a 1-liter reaction flask equipped with a constant pressure addition funnel, and stir at room temperature for 20 minutes. Cool down to -20 o C, Start to slowly add anhydrous hydrazine (2.0 mol) dropwise, the dropwise addition is completed in 8-10 hours, keep warm and continue the reaction for 3-5 hours, then rise to room temperature and stir overnight. After the complete reaction of raw materials was detected by TLC (UV lamp 254 nm). After rotary evaporation of the solvent and distillation of excess hydrazine hydrate under reduced pressure, n-hexane was added to make a slurry to obtain 100 g of the product nitrogen benzylcyclohexyl-4-one, with a yield of 98%.

[0050] The second step: azbutoxycarbonyl cyclohex-4-enyl chloride ( 3c ) and Azebutoxycarbonylcyclohexyl-4-dichloro ( 4c ...

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Abstract

The invention relates to a method for synthesizing organic compounds, in particular to a process method for synthesizing 4-site heteroatom-substituted cyclohexenyl halide. The method comprises the following steps of: performing refluxing reaction on 4-site heteroatom-substituted cyclohexanone (1) and 1 to 50 equivalents of anhydrous hydrazine or hydrazine hydrate in a solvent at the temperature of -20 DEG C; filtering or spin-drying the solvent to obtain corresponding hydrazone; reacting the hydrazone with a CuX2 / alkali mixture in an alcohol solvent at the temperature of between -20 and 40 DEG C; adding aqueous alkali and a solvent after the reaction; performing separation to obtain mixed solution; adding organic alkali and performing the refluxing reaction; adding 1N acid to remove excessive alkali; adding saturated NaHSO3 to react; and removing the solvent to obtain the 4-site heteroatom-substituted cyclohexenyl halide (3). The method has the advantages of original and simple synthesis process and mild process condition, is easy and convenient to operate, avoids super-low temperature reaction and column chromatography purification involved in literatures, and is suitable for industrial scale-up production.

Description

technical field [0001] The invention relates to a method for synthesizing organic compounds, in particular to a method for synthesizing a 4-heteroatom substituted cyclohexenyl halide. Background technique [0002] The cyclohexene structure with a heteroatom at the 4th position is often introduced into drug molecules as an important structural unit, or used for coupling reactions to obtain pharmaceutically active compounds. As the precursor of this type of structure, there are few reports on the synthesis of cyclohexenyl halides substituted by heteroatoms at the 4-position, and all of them inevitably require ultra-low temperature operation and column chromatography purification, which greatly limits their industrialization. aspects of application. existing literature [1] The synthetic route is as follows: starting from commercially available 4-position protected (such as NCbz, NBoc) cyclohexanone, using LiHMDS as base in THF solvent, -78 o After the reaction at C, maintain...

Claims

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Application Information

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IPC IPC(8): C07D309/28C07D335/02C07D211/74
Inventor 刘启宾
Owner DALIAN NETCHEM CHIRAL TECH
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