Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology

Abstract

The invention discloses a method for preparing 2-aryl-1-cyclohexanol based on a continuous flow reaction technology. Wherein the invention relates to a continuous flow process for lithium halide exchange. The preparation method comprises the following steps: pumping bromobenzene or a derivative thereof and n-butyllithium into a continuous flow reaction device according to a certain proportion, reacting for a period of time under a specific low-temperature condition to carry out lithium-halogen exchange, then pumping cyclohexene oxide to carry out nucleophilic substitution reaction, and finally pumping a fourth component boron trifluoride diethyl etherate to carry out ring-opening reaction to obtain a 2-aryl-1-cyclohexanol product. According to the invention, a continuous flow reaction technology under a low-temperature condition is utilized, so that the problems of high energy consumption, amplification effect and the like of the traditional kettle type reaction are solved; the danger coefficient of the active lithium reagent is reduced, so that the reaction obtains higher product purity under a controllable continuous condition, the reaction efficiency is improved, and the method has a wide application prospect.

Description

technical field

[0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for preparing 2-aryl-1-cyclohexanol based on continuous flow reaction technology. Background technique

[0002] 2-Aryl-1-cyclohexanol is an important intermediate in the synthesis of many biologically active molecules, drugs, and other materials. Example: 4-Cycloalkoxybenzonitrile is an androgen receptor modulator. It can effectively reduce sebum secretion and stimulate hair growth, thus bringing good news to patients with hair loss; Ketamine is a kind of intravenous general anesthetic, clinically used as general anesthetic or anesthesia inducer, and has the effect of bronchodilator, so it is also suitable for The treatment of asthma patients can also be used for cerebral vasodilators. 2-(2-methylphenyl)-2-nitrocyclohexan-1-one has a good effect in the treatment of nervous system diseases. And 2-aryl-1-cyclohexanol is an important intermediate in the synthe...

Examples

Embodiment 1

[0051] like figure 1 As shown, the THF solution of bromobenzene is packed in there-necked flask 1, nBuLi is packed in there-necked flask 2, the THF solution of cyclohexene oxide is packed in there-necked flask 3, and the toluene solution of boron trifluoride ether is packed into there-necked flask 3 In 4, the temperature control device is set to -60 ℃, and the THF solution of bromobenzene and nBuLi are pumped in by continuous flow experimental pumps 5 and 6 respectively, so that it is carried out lithium halide exchange 6min in reaction tube 15; The THF solution of intermediate 2 and cyclohexene oxide was subjected to nucleophilic substitution in reaction tube 18 for 4 min; finally, the intermediate 3 obtained in the second step and the toluene solution of boron trifluoride ether were subjected to ring opening in reaction tube 21 , the retention time was 7min; then the reactant was passed into 23 (with 1 / 3 of the ice-water mixture) for quenching, and then the reaction solution...

Embodiment 2

[0054] The concrete synthesis process is the same as the embodiment of the present invention 1, except that bromobenzene is replaced with 2-methylbromobenzene, and the temperature control device is set to -65°C; the purity of the obtained product is 87.2%;

[0055] 1 HNMR (400MHz, CDC1 3 )δ7.27-7.23(m,1H),7.22-7.14(m,2H),7.13-7.08(m,1H),3.83-3.71(m,1H),2.83-2.68(m,1H),2.36( s,3H),2.18-2.07(m,1H),1.94-1.70(m,3H),1.69-1.59(m,1H),1.51-1.27(m,4H).

Embodiment 3

[0057] The specific synthesis process is the same as the embodiment of the present invention 2, except that 2-methyl bromobenzene is replaced with 3-methyl bromobenzene; the purity of the obtained product is 85.9%;

[0058] 1 HNMR(400MHZ,CDC1 3 )δ7.26-7.18(m,1H),7.09-7.01(m,3H),3.70--3.58(m,1H),2.43-2.35(m,1H),2.34(s,3h),2.14-2.06 (m,1h),1.88-1.71(m,3H),1.68-1.60(m,1H),1.56-1.28(m,4h).

technical field

[0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for preparing 2-aryl-1-cyclohexanol based on continuous flow reaction technology. Background technique

[0002] 2-Aryl-1-cyclohexanol is an important intermediate in the synthesis of many biologically active molecules, drugs, and other materials. Example: 4-Cycloalkoxybenzonitrile is an androgen receptor modulator. It can effectively reduce sebum secretion and stimulate hair growth, thus bringing good news to patients with hair loss; Ketamine is a kind of intravenous general anesthetic, clinically used as general anesthetic or anesthesia inducer, and has the effect of bronchodilator, so it is also suitable for The treatment of asthma patients can also be used for cerebral vasodilators. 2-(2-methylphenyl)-2-nitrocyclohexan-1-one has a good effect in the treatment of nervous system diseases. And 2-aryl-1-cyclohexanol is an important intermediate in the synthe...

Examples

Embodiment 1

[0051] like figure 1 As shown, the THF solution of bromobenzene is packed in there-necked flask 1, nBuLi is packed in there-necked flask 2, the THF solution of cyclohexene oxide is packed in there-necked flask 3, and the toluene solution of boron trifluoride ether is packed into there-necked flask 3 In 4, the temperature control device is set to -60 ℃, and the THF solution of bromobenzene and nBuLi are pumped in by continuous flow experimental pumps 5 and 6 respectively, so that it is carried out lithium halide exchange 6min in reaction tube 15; The THF solution of intermediate 2 and cyclohexene oxide was subjected to nucleophilic substitution in reaction tube 18 for 4 min; finally, the intermediate 3 obtained in the second step and the toluene solution of boron trifluoride ether were subjected to ring opening in reaction tube 21 , the retention time was 7min; then the reactant was passed into 23 (with 1 / 3 of the ice-water mixture) for quenching, and then the reaction solution...

Embodiment 2

[0054] The concrete synthesis process is the same as the embodiment of the present invention 1, except that bromobenzene is replaced with 2-methylbromobenzene, and the temperature control device is set to -65°C; the purity of the obtained product is 87.2%;

[0055] 1 HNMR (400MHz, CDC1 3 )δ7.27-7.23(m,1H),7.22-7.14(m,2H),7.13-7.08(m,1H),3.83-3.71(m,1H),2.83-2.68(m,1H),2.36( s,3H),2.18-2.07(m,1H),1.94-1.70(m,3H),1.69-1.59(m,1H),1.51-1.27(m,4H).

Embodiment 3

[0057] The specific synthesis process is the same as the embodiment of the present invention 2, except that 2-methyl bromobenzene is replaced with 3-methyl bromobenzene; the purity of the obtained product is 85.9%;

[0058] 1 HNMR(400MHZ,CDC1 3 )δ7.26-7.18(m,1H),7.09-7.01(m,3H),3.70--3.58(m,1H),2.43-2.35(m,1H),2.34(s,3h),2.14-2.06 (m,1h),1.88-1.71(m,3H),1.68-1.60(m,1H),1.56-1.28(m,4h).

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