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

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Problems solved by technology

[0008] Based on the above analysis, it is found that the current various react

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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Example Embodiment

[0033] Example 1

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

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

[0036] Step 2: Tetrahydropyran-4-enyl chloride ( 3a ) And tetrahydropyran-4-dichloride ( 4a ) (X = O, X’ = Cl) composition:

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

Example Embodiment

[0040] Example 2:

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

[0042] Under the protection of argon, 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 and a constant-pressure addition funnel, and stir at room temperature After 20 minutes, slowly drip 70-80% hydrazine hydrate (20 mol). After the dripping is completed, the temperature is raised to reflux and react for 3-5 hours. TLC detects the complete reaction of the raw materials (using the exclusive color reagent 2,4-dinitrophenylhydrazine for color development). After rotating the solvent and distilling under reduced pressure, 75 grams of tetrahydrosulfone pyran-4-hydrazone were obtained with a yield of 93%.

[0043] Step 2: Tetrahydrothiopyran-4-enyl bromide ( 3b ) And tetrahydrothiopyran-4-dibromo ( 4b ) (X = S, X’ = Br) composition:

[0044] Under the protection of argon, add 250 mL of anhyd...

Example Embodiment

[0047] Example 3:

[0048] The first step: nitrobenzylcyclohexyl-4-hydrazone ( 2c , X = NBn) synthesis

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

[0050] The second step: azepine-tert-butoxycarbonyl cyclohex-4-enyl chloride ( 3c ) And azetyl cyclohexane-4-dichloro ( 4c ) (X = NBoc, X’...

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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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