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Preparation method of 1-cyclohexylpiperazine

A technology of cyclohexylpiperazine and cyclohexyl is applied in the field of synthesis of small molecule drug intermediates, and can solve problems such as troublesome post-processing, complicated steps and the like

Inactive Publication Date: 2021-04-13
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The first step of the above-mentioned synthetic method needs to carry out nucleophilic substitution reaction under acidic conditions, and use sodium triacetoxy borohydride to carry out reduction, and step is comparatively loaded down with trivial details, and aftertreatment is more troublesome (sodium hydroxide neutralization and organic solvent extraction etc. repeatedly extraction step)

Method used

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  • Preparation method of 1-cyclohexylpiperazine
  • Preparation method of 1-cyclohexylpiperazine
  • Preparation method of 1-cyclohexylpiperazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026]

[0027] Add 4.8kg of cyclohexyl bromide (29.5mol) into a 50L reactor, add anhydrous acetonitrile 30kg, 1-Boc-piperazine 5kg (26.84mol), and 4.08kg (29.5mol) of potassium carbonate under stirring. Heat up to react, reflux for 2 hours, TLC monitors the reaction process, after the reaction is completed, cool to room temperature, filter, and the filtrate is concentrated to dryness to obtain 7.0 kg of intermediate 1 red oil. The purity of the product as determined by GC is 98.5%. The rate is 96.6%.

Embodiment 2

[0028] Embodiment 2: the preparation of intermediate 2 cyclohexylpiperazine hydrochloride

[0029]

[0030] At room temperature, put 7kg of intermediate 1 obtained in the previous step into a 50L reactor, add 26kg of absolute ethanol and 6.6L of concentrated hydrochloric acid, pay attention to controlling the speed when adding concentrated hydrochloric acid, the reaction will generate a lot of bubbles and exotherm, pay attention to safety, After adding the hydrochloric acid, gradually heat up to the reflux temperature, and control the temperature rise rate not to be too fast. If the temperature rise rate is too fast, the reaction will be uncontrollable and dangerous. After the reflux reaction for about 4 hours, monitor the reaction process by TLC. After the reaction is completed, distill under reduced pressure. Evaporate the solvent to dryness, then cool down and add 8kg of isopropanol for beating, cool down to room temperature and continue to stir for 2 hours. After fully s...

Embodiment 3

[0031] Embodiment 3: Preparation of 1-cyclohexylpiperazine

[0032]

[0033] Add the product from the previous step into a 20L reaction kettle, add 6kg of pure water to stir and dissolve, adjust the pH to 14 with 20% sodium hydroxide solution, and add 6kg of dichloromethane to extract at the same time, and extract the water layer with dichloromethane after liquid separation 2 times, each 2kg, and keep the pH of the water layer is 14, merge the dichloromethane layer, dry over anhydrous sodium sulfate, after filtering, evaporate to dryness under reduced pressure, obtain semi-solid and semi-oily product after evaporation to dryness, then the product Distillation under reduced pressure gave 3.1 kg of an oil with a melting point of 34°C.

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Abstract

The invention discloses a preparation method of 1-cyclohexylpiperazine. The method comprises the steps of carrying out reflux reaction on cyclohexyl halide, 1-Boc-piperazine and inorganic base in an organic solvent, filtering after the reaction is finished, and concentrating to obtain an intermediate 1; removing Boc from the intermediate 1 under an acidic condition, drying by distillation after the reaction is finished, pulping with isopropanol, and filtering to obtain solid 1-cyclohexyl piperazine hydrochloride; dissolving with water, adding an inorganic base to adjust the pH value to 12 to 14, extracting with an extraction solvent, drying the solvent by distillation to obtain a crude product of 1-cyclohexylpiperazine, and carrying out reduced pressure distillation on the crude product through an oil pump to obtain a pure product of 1-cyclohexylpiperazine. In the synthesis process of the intermediate 1, use of sodium triacetoxyborohydride and sodium hydroxide is avoided, the production cost is greatly saved, meanwhile, only filtering is needed for aftertreatment, the method is very simple, and time and labor are saved.

Description

technical field [0001] The invention relates to a synthesis method of a small molecule drug intermediate, in particular to a preparation method of 1-cyclohexylpiperazine. Background technique [0002] 1-cyclohexylpiperazine (CAS: 17766-28-8), aliases: cyclohexylpiperazine, N-cyclohexylpiperazine, molecular formula is C 10 h 20 N 2 , the molecular weight is 168.279, and the structural formula is as follows. [0003] [0004] 1-Cyclohexylpiperazine is a small fragment in the middle of a drug molecule. Although it is used in a small amount, it is also a vital and indispensable raw material. At present, there are basically no reports about 1-cyclohexylpiperazine in China. WO2010051374 (A1) (patent family AU2009308854 (A1) CA2779178 (A1) EP2498599 (A1) EP2498599 (A4) EP2498599 (B1) ES2516740 (T3) US2010279997 (A1)) discloses a synthetic method of 1-cyclohexylpiperazine, Specifically: use cyclohexanone and 1-Boc-piperazine as starting materials to carry out nucleophilic su...

Claims

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Application Information

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IPC IPC(8): C07D295/023C07D295/033
CPCC07D295/023C07D295/033
Inventor 赵弦苏曼
Owner SHANDONG BOYUAN PHARM CO LTD
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