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Synthesis method of 3-bromocyclohex-2-enone

A synthesis method and technology of cyclohexanedione, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as unfavorable industrial production, difficult control of reaction safety, harsh reaction conditions and production equipment requirements, and achieve easy control of safety and equipment requirements. The effect of low and high yield

Active Publication Date: 2016-01-06
LEPU PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, the synthesis method of 3-bromocyclohex-2-en-1-one 1 mainly uses benzene as solvent, 1,3-cyclohexanone , triphenylphosphine and liquid bromine are the reaction reagents. This method requires the reaction below 5°C. Because the reaction is violently exothermic, and the solvent benzene is a highly toxic reagent, the reaction reagent liquid bromine is highly corrosive, so the reaction is safe. Difficult to control, harsh reaction conditions and production equipment, not conducive to industrial production

Method used

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  • Synthesis method of 3-bromocyclohex-2-enone

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Experimental program
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Effect test

Embodiment 1

[0017] A kind of synthetic method of 3-bromocyclohex-2-en-1-one, comprises the steps:

[0018] Dissolve 17.7g (1.2eq.) of carbon tetrabromide in 10mL of toluene; take a 100mL three-necked flask, add 30mL of toluene, and stir, mix 5.0g (1.0eq.) of 1,3-cyclohexanedione and 11.7g Add (1.0eq.) triphenylphosphine into the three-necked flask, replace the nitrogen protection, cool down to 0-5°C, slowly add the toluene solution of carbon tetrabromide into the three-necked flask; dropwise, at 0-5°C Stir the reaction for 12 hours; filter the reaction solution, wash the filter cake 3 times with n-hexane, combine the filtrate, concentrate the filtrate to about 15 mL, and use a silica gel chromatography column (the eluent is petroleum ether: ethyl acetate volume ratio = 8:1) 7.5 g of 3-bromocyclohex-2-en-1-one was isolated as a colorless liquid with a yield of 96%. h 1 NMR (500MHz, CDCl 3 ) δ (ppm) 6.47 (m, 1H), 2.83 (m, 2H), 2.42 (m, 2H), 2.09 (m, 2H).

Embodiment 2

[0020] A kind of synthetic method of 3-bromocyclohex-2-en-1-one, comprises the steps:

[0021] Dissolve 41.4g (2.0eq.) of carbon tetrabromide in 15mL of cyclohexane; take a 100mL three-necked flask, add 40mL of cyclohexane, and stir to dissolve 7.0g (1.0eq.) of 1,3-cyclohexane Add ketone and 33.0g (2.0eq.) triphenylphosphine into the three-necked flask, replace the argon protection, control the temperature at 25-30°C, and slowly drop the cyclohexane solution of carbon tetrabromide into the three-necked flask. After dropping, the temperature was controlled at 25-30° C., and the reaction was stirred for 8 hours. Filter the reaction solution, wash the filter cake three times with n-hexane, combine the filtrates, remove the solvent by rotary evaporation, and then distill under reduced pressure (b.p.78-82°C, 1mmHg) to obtain 9.2g of 3-bromocyclohex-2-ene-1 Ketone, colorless liquid, yield 92%.

Embodiment 3

[0023] A kind of synthetic method of 3-bromocyclohex-2-en-1-one, comprises the steps:

[0024] Dissolve 53.2g (3.0eq.) of carbon tetrabromide in 15ml of cyclohexane; take a 250mL three-necked flask, add 100mL of toluene, and stir to dissolve 6.0g (1.0eq.) of 1,3-cyclohexanedione Add 56.0g (4.0eq.) triphenylphosphine into the three-necked flask, replace the argon protection, heat the water bath to 60-70°C, and slowly add the cyclohexane solution of carbon tetrabromide into the three-necked flask; After completion, control the temperature at 45-60°C, stir and react for 3 hours; after the reaction is completed, cool down to room temperature, filter the reaction solution, wash the filter cake with n-hexane for 3 times, combine the filtrate, remove the solvent by rotary evaporation, and then distill under reduced pressure (b.p.78-82°C, 1 mmHg) 8.9 g of 3-bromocyclohex-2-en-1-one was obtained as a colorless liquid, yield 95%.

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Abstract

The invention discloses a synthesis method of 3-bromocyclohex-2-enone, and belongs to the technical field of drug intermediate preparation. The synthesis method includes the steps that 1,3-cyclohexanedione, triphenylphosphine and carbon tetrabromide are dissolved in organic solvent under protection of inert gas, the mixture is reacted for 2-12 h at 0-70 DEG C, a quenching reaction and filtration are performed, and then 3-bromocyclohex-2-enone is obtained through column chromatography isolation or reduced pressure distillation. The synthesis method is safe and mild, no liquid bromine reagent is used, and high-yield 3-bromocyclohex-2-enone is obtained through the low-cost raw materials. Safety is easy to control in the synthesis process, equipment requirements are low, and the synthesis method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, in particular to a synthesis method of 3-bromocyclohex-2-en-1-one. Background technique [0002] 3-Bromocyclohex-2-en-1-one, American Chemical Abstracts registration number CAS56671-81-9, its structure is shown in formula 1. [0003] [0004] 3-Bromocyclohex-2-en-1one is a very important organic intermediate, especially an important starting material for the synthesis of some drugs, such as the synthesis of the cardiovascular drug Vorapaxar sulfate and its derivatives ( M. Clasby, J. Med. Chem., 2007, 50, 129; [0005] S. Chackalamannil, J. Med. Chem., 2008, 51, 3061) etc. [0006] Currently, literature reports about 3-bromocyclohex-2-en-1-one 1 The synthetic method of this method mainly uses benzene as solvent, 1,3-cyclohexanone, triphenylphosphine and liquid bromine as reaction reagents. This method requires reaction below 5°C, because the reaction is violently...

Claims

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Application Information

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IPC IPC(8): C07C49/687C07C45/63
CPCC07C45/63C07C49/687
Inventor 刘志康郭海波于梅艳李莹
Owner LEPU PHARMACEUTICAL CO LTD
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