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A kind of process method of synthesizing 4-heteroatom substituted cyclohexenyl halides

A technology of cyclohexenyl group and process method, applied in the field of organic compound synthesis, can solve problems such as difficult control and harsh reaction conditions, and achieve the effects of simple operation, mild process conditions and simple synthesis route

Active Publication Date: 2016-04-27
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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  • A kind of process method of synthesizing 4-heteroatom substituted cyclohexenyl halides
  • A kind of process method of synthesizing 4-heteroatom substituted cyclohexenyl halides
  • A kind of process method of synthesizing 4-heteroatom substituted cyclohexenyl halides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[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, and the dropwise addition is completed in 8-10 hours, and keep warm for another 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, add 150 mL of anhy...

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 argon pro...

Embodiment 3

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

[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, and the dropwise addition is completed in 8-10 hours, keep warm and continue to react for 3-5 hours, then rise to room temperature and stir overnight. TLC detected the complete reaction of raw materials (ultraviolet lamp 254nm). 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 ) (X=NBoc,X’...

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Abstract

The present invention relates to a method for synthesizing organic compounds. A process for synthesizing 4-heteroatom substituted cyclohexenyl halides, from cyclohexanone substituted by 4-heteroatom ( 1 ) starting with 1-50 equivalents of anhydrous hydrazine or hydrazine hydrate in a solvent, -20? oC to reflux reaction, after filtering or spin-drying the solvent to obtain the corresponding hydrazone, and then react with CuX2 / alkali mixture in alcohol solvent, the reaction temperature is -20? cC~40? oC, add alkaline aqueous solution and solvent after the reaction, obtain a mixed solution after liquid separation, add an organic base for reflux reaction, add 1N acid to remove the excess alkali, add saturated NaHSO3 for reaction, and remove the solvent to obtain a 4-position heteroatom Substituted cyclohexenyl halides ( 3 ). The synthesis process route of the present invention has originality, simple route, mild process conditions, simple and convenient operation, avoids the ultra-low temperature reaction and column chromatography purification involved in the literature, 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/28C07D335/02C07D211/74
Inventor 刘启宾
Owner DALIAN NETCHEM CHIRAL TECH