CN114805019B - Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology - Google Patents

Abstract

The invention discloses a method for preparing 2-aryl-1-cyclohexanol based on a continuous flow reaction technology. Which relates to a continuous flow process for lithium halide exchange. And pumping bromobenzene or derivatives 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 perform lithium halide exchange, then pumping cyclohexene oxide to perform nucleophilic substitution reaction, and finally pumping boron trifluoride diethyl ether as a fourth component to perform ring opening reaction to obtain a 2-aryl-1-cyclohexanol product. The invention solves the problems of large energy consumption, amplification effect and the like of the traditional kettle type reaction by utilizing a continuous flow reaction technology under a low temperature condition; the dangerous coefficient of the active lithium reagent is reduced, the reaction obtains higher product purity under the controllable continuous condition, the reaction efficiency is improved, and the method has wide application prospect.

Description

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

Technical field

The invention belongs to the field of chemical synthesis technology, and in particular relates to a method for preparing 2-aryl-1-cyclohexanol based on continuous flow reaction technology.

Background technique

2-Aryl-1-cyclohexanol is an important intermediate in the synthesis of many biologically active molecules, drugs, and other materials. For 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 type of intravenous general anesthetic, clinically used as a general anesthetic or anesthesia induction agent, and has a bronchodilator effect, so it is also suitable for In the treatment of asthma patients, it can also be used as a dilator of cerebral blood vessels. 2-(2-Methylphenyl)-2-nitrocyclohexan-1-one has good effects in the treatment of neurological diseases. 2-Aryl-1-cyclohexanol is an important intermediate in the synthesis of the above compounds, so it is of great significance to develop a rapid and efficient synthesis method for it.

By using three-membered epoxy compounds to oxidize cyclohexene and aryl bromide under the action of metallic lithium reagents (such as n- and tert-butyllithium), 2-aryl-1-cyclohexanols can be obtained in a relatively ideal yield. Compounds are an efficient means of synthesizing such compounds. For example, Zhang Fumin et al. used o-chlorobromobenzene and cyclohexene oxide as raw materials, and used tert-butyllithium as the lithium reagent. Under low temperature conditions, 2-(2-chlorophenyl)cyclohexanol could be synthesized, and finally ketamine was synthesized. ; Xue Tao et al. synthesized 2-(2-methylphenyl)-2-nitrocyclohexan-1-one using 2-(2-methylphenyl)cyclohexanol as raw material. This drug has the effect of treating the nervous system. Function; Tang Shizhong et al. used phenylcyclohexanol as raw material, oxidized it, and then used PTSA to catalyze the fluorination of a-branchone, which can be used to construct the fluorinated quaternary carbon center.

However, although the above reaction to synthesize 2-aryl-1-cyclohexanol has a high yield and relatively good effect, it requires the use of highly dangerous tert-butyllithium/butyllithium; in addition, the tert-butyllithium/butyllithium used in the system Butyllithium and boron trifluoride ether solutions are sensitive to water and air, and the reaction needs to be carried out at low temperatures such as minus 80°C, which places high requirements on reaction operations. At the same time, due to the danger of the reaction and the strict requirements on temperature, the reaction is difficult to scale up. Currently, there are many problems in the existing technology for the synthesis of 2-aryl-1-cyclohexanol, including risk factors, high energy consumption, and cumbersome operations. Therefore, the development of new synthesis technologies for this type of compounds has important research significance and application value.

Contents of the invention

In order to solve the shortcomings of the existing technology, including risk factor, large energy consumption, cumbersome operation, etc., the present invention proposes a method for rapidly preparing 2-aryl-1-cyclohexanol based on continuous flow reaction technology and its application. .

The invention provides a method for rapidly preparing 2-aryl-1-cyclohexanol based on continuous flow reaction technology. The process relies on nitrogen to balance the system pressure and utilizes continuous flow experimental pump equipment to achieve continuous feeding and discharging. Chemical production, using material 1 as the reactant, the product 2-aryl-1-cyclohexanol is prepared through lithium halide exchange reaction, nucleophilic substitution reaction, and Lewis acid ring-opening reaction.

The method of the invention utilizes bromobenzene, butyllithium, epoxy, boron trifluoride ether and continuous flow chemical technology to synthesize the target product of 2-aryl-1-cyclohexanol. By sequentially adding materials, this reaction undergoes lithium halide exchange between butyllithium and aryl bromide to obtain an aryllithium intermediate, which is further nucleophilically substituted with epoxy, and then ring-opened under the action of boron trifluoride. Finally, By quenching the reaction with water, the target product 2-aryl-1-cyclohexanol is obtained.

The reaction route of the method of the present invention is:

Among them, R means that the substituent group on the aromatic ring is methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, Any one or more substituents such as amino, hydroxyl, and trifluoromethyl.

The methods include:

(1) Lithium halide exchange

Before starting the reaction, first fill the pipeline with tetrahydrofuran so that there is no air in the pipeline. Then, under nitrogen protection, pump material 1 and lithium reagent into the continuous flow reaction device in equivalent proportions. In the first solvent, at -60 At a temperature of ℃ ~ -80 ℃, react for 5-8 minutes to perform lithium halide exchange to generate intermediate 2;

(2) Nucleophilic substitution

Continue to pass the active intermediate 2 generated in step (1) into the continuous flow reaction device, and then pump the cyclohexene oxide solution into the continuous flow reaction device in proportion, in the second solvent, at -60°C~- At 80°C, react for 5-7 minutes to perform nucleophilic substitution to generate active intermediate 3;

(3) Lewis acid ring opening

Continue to pass the active intermediate 3 generated in step (2) into the continuous flow reaction device, and then pump the boron trifluoride ether solution into the continuous flow reaction device in proportion, in the third solvent, at -70°C~ At a temperature of -85°C, react for 8-10 minutes, a ring-opening reaction occurs, and the 2-aryl-1-cyclohexanol product is obtained.

In some embodiments, the steps include:

First, fill the pipeline with tetrahydrofuran so that there is no air in the pipeline. Then, under nitrogen protection, pump material 1 and butyl lithium into the continuous flow reaction device in a certain equivalent ratio. The reaction is carried out at -80°C for 5 to 8 minutes. Lithium halide exchange, the generated active intermediate 2 continues to pass through the continuous flow device; then the cyclohexene oxide solution is pumped into the continuous flow reaction device according to a certain proportion, and reacts at -80°C for 5 to 7 minutes to perform nucleophilic substitution to generate Intermediate 3; the generated active intermediate 3 continues to flow into the continuous flow reaction device, and then the boron trifluoride ether solution is pumped into the continuous flow reaction device according to a certain proportion, and the reaction is carried out at -80°C for 8 minutes to 10 minutes, and the Lewis reaction is carried out The acid rings open to give 2-aryl-1-cyclohexanol.

In step (1), the first solvent used in the solution of material 1 in the synthesis of intermediate 2 is at least one of toluene, tetrahydrofuran and anhydrous ether, with a concentration of 0.8 mol/L to 1.5 mol/L, and a flow rate of 6.0mL/min～10.0mL/min;

The equivalent ratio of material 1 to butyllithium in the synthesis intermediate 2 is 1:1 to 1.5, and the above temperature is -60°C to -80°C;

The reaction time of lithium halide exchange in the synthesis intermediate 2 is 5min~8min;

The organolithium reagent is one of butyllithium, sec-butyllithium and tert-butyllithium, and its flow rate is 4mL/min~6mL/min;

In step (2), the second solvent used in the cyclohexene oxide solution in the synthesis intermediate 3 is at least one of toluene, tetrahydrofuran and anhydrous ether, and its concentration is 0.8mol/L to 1.5mol/L. The flow rate is 5mL/min~8mL/min;

The equivalent ratio of material 1 in the synthesis intermediate 3 to cyclohexene oxide is 1:0.9~1; the above-mentioned temperature is -60°C~-80°C;

The reaction time of nucleophilic substitution in synthetic intermediate 3 is 3 to 5 minutes;

In step (3), the third solvent used in the boron trifluoride diethyl ether solution used to synthesize the target product 4, that is, the product 2-aryl-1-cyclohexanol, is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether. species, its concentration is 1.2mol/L~2.0mol/L, and the flow rate is 6.5mL/min~10.0mL/min;

When synthesizing target product 4, the equivalent ratio of material 1 to boron trifluoride ether is 1:1.5~2, and the above-mentioned temperature is -70°C~-85°C;

The reaction time of the Lewis ring-opening reaction when synthesizing the target product 4 is 5 to 10 minutes.

In the method of the present invention, the continuous flow reaction device includes: a continuous flow reaction pipe, which is a PTFE Teflon pipe or a 316L stainless steel pipe; a micro-mixing mixer; a temperature control system; a continuous flow reaction experimental pump connected to the inlet of the reactant; The continuous flow reaction voltage stabilizing device is connected to the outlet of the product; the continuous flow product collection device is connected to the outlet of the voltage stabilizing device.

In the method of the present invention, the continuous flow reaction experimental pump includes pump 1-pump 4; wherein,

Continuous flow reaction experiment pump 1 allows the tetrahydrofuran and toluene solution of material 1 to pass into the pipeline, where the solution concentration is 0.5mol/L~1mol/L, and the flow rate is 6.0mL/min~10.0mL/min;

The continuous flow reaction experimental pump 2 allows the lithium reagent to pass into the pipeline, and its flow rate is 4mL/min~6mL/min;

The continuous flow reaction experiment pump 3 passes the tetrahydrofuran solution of cyclohexene oxide into the pipeline, the concentration is 0.8mol/L~1.5mol/L, and the flow rate is 5mL/min~8mL/min;

The continuous flow reaction experimental pump 4 passes the toluene solution of boron trifluoride-diethyl ether into the pipeline, with a concentration of 1.2 mol/L to 2.0 mol/L and a flow rate of 6.5 to 10.0 mL/min.

The overall reaction temperature of the reaction is -80°C, and the overall retention time of the reaction is 20 to 30 minutes.

The present invention further includes post-processing steps:

Step 4) Separate the product through extraction to obtain an organic phase, then dry the organic phase with anhydrous sodium sulfate, and spin the organic phase to dryness using a rotary evaporator to obtain a white waxy solid; and/or,

Step 5) The collected product is monitored by GC, and the purity is 80-90%.

The present invention also proposes intermediate 2 shown below,

Among them, R means that the substituent group on the aromatic ring is methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, Any one or more substituents such as amino, hydroxyl, and trifluoromethyl.

The present invention also proposes an intermediate 3, whose structure is:

Among them, R means that the substituent group on the aromatic ring is methyl, methoxy, halogen (fluorine, chlorine), alkyl, aryl, heteroaryl, alkoxy, Any one or more substituents such as amino, hydroxyl, and trifluoromethyl.

The innovative beneficial effects of the present invention include combining a low-cost synthesis path with continuous flow technology, solving the amplification effect of the kettle test reaction, reducing the dangerous operating coefficient of the active lithium reagent, reducing the energy consumption required for the reaction, and saving cost, providing an efficient, safe and low-cost process for the synthesis of 2-aryl-1-cyclohexanol, allowing the reaction to obtain a higher purity crude product (GC purity 80 %~90%), which is higher than the purity of the kettle test (GC purity is 65%~70%). The method of the present invention combines the better heat and mass transfer effect of the continuous flow reaction. The continuous flow reaction has no amplification effect and avoids losses caused by the amplification effect. The continuous flow reaction has the advantages of simple operation and low risk factor, including The continuous flow reaction device has the advantages of good heat and mass transfer, short reaction time, and relatively low energy consumption. The method proposed by the present invention for synthesizing 2-aryl-1-cyclohexanol using a continuous flow method has important significance and application value in the field of synthesis technology.

Description of the drawings

Figure 1 is a schematic process flow diagram of the method for synthesizing 2-aryl-1-cyclohexanol according to the present invention: 1, 2, 3, and 4 are prepared materials; 5, 6, 7, and 8 are continuous flow experimental pumps. ; 9, 10, 11, 12 are pre-cooling tubes; 13, 16, 19 are micro-mixing devices; 14, 17, 20 are temperature control device detection points; 15, 18, 21 are reaction tubes; 22 the system Voltage stabilizing device; 23 is the receiving device of the system.

Figures 2 and 3 are physical diagrams of the process flow.

Detailed ways

The invention will be further described in detail with reference to the following specific embodiments and drawings. The process, conditions, experimental methods, etc. for implementing the present invention, except those specifically mentioned below, are common knowledge and common sense in the field, and the present invention has no special limitations.

Example 1

As shown in Figure 1, put the THF solution of bromobenzene into the three-necked flask 1, put nBuLi into the three-necked flask 2, put the THF solution of cyclohexene oxide into the three-necked flask 3, and put the toluene solution of boron trifluoride ether into into the three-necked flask 4, the temperature control device is set to -60°C, and the THF solution and nBuLi of bromobenzene are driven in by the continuous flow experimental pumps 5 and 6 respectively, so that the lithium halide exchange is performed in the reaction tube 15 for 6 minutes; then the above The obtained intermediate 2 and the THF solution of cyclohexene oxide were subjected to nucleophilic substitution in reaction tube 18 for 4 minutes; finally, the intermediate 3 obtained in the second step and the toluene solution of boron trifluoride ether were placed in reaction tube 21 Carry out ring opening with a retention time of 7 minutes; then pass the reactant into 23 (containing 1/3 of the ice-water mixture) for quenching, then separate the reaction solution, wash once with brine, dry, spin dry and pass through GC After analysis, the purity of the crude product was 90.3%;

¹ HNMR (400MHz, CDCl ₃ ) δ7.32 (t, J = 7.5 Hz, 2H), 7.24 (dd, J = 7.6, 2.6 Hz, 3H), 3.65 (td, J = 10.0, 4.2 Hz, 1H), 2.41(m,1H),2.14-2.05(m,1H),1.85(dd,J＝12.2,3.4Hz,2H),1.79-1.70(m,1H),1.59-1.27(m,6H).

Example 2

The specific synthesis process is the same as in Example 1 of the present invention, except that bromobenzene is replaced by 2-methylbromobenzene, and the temperature control device is set to -65°C; the purity of the obtained product is 87.2%;

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).

Example 3

The specific synthesis process is the same as Example 2 of the present invention, except that 2-methylbromobenzene is replaced by 3-methylbromobenzene; the purity of the obtained product is 85.9%;

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).

Example 4

The specific synthesis process is the same as in Example 1 of the present invention, except that bromobenzene is replaced by 2-fluorobromobenzene, and the purity of the product obtained is 88.7%;

¹ H NMR (400MHz, CDC1 ₃ ), δ7.28(m,1H),7.20(m,1H),7.12(m,1H),7.04(m,1H),3.79(m,1H),2.83(m ,1H),2.17-2.10(m,1H),1.94-1.81(m,2H),1.81-1.69(m,1H),1.66-1.18(m,4H),0.93-0.79(m,1H).

Example 5

The specific synthesis process is the same as Example 4 of the present invention, except that 2-fluorobromobenzene is replaced by 3-fluorobromobenzene; the purity of the obtained product is 89.8%;

¹ H NMR (400MHz, CDC1 ₃ ) δ 87.32-7.27 (m, 1H), 7.03 (d, J = 7.5Hz, 1H), 6.94 (dd J = 16.8, 9.1Hz, 2H), 3.64 (td, J ＝9.9,4.2Hz,1H),2.49-2.38(m,1H),2.12(d,J＝8.0Hz,1H), 1.86(d,J＝10.2Hz,2H)

Example 6

The specific synthesis process is the same as Example 1 of the present invention, except that bromobenzene is replaced with 2-chlorobromobenzene and the temperature control device is set to -78°C; the purity of the obtained product is 82.3%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.39 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.26 (q, J = 8.0, 7.5 Hz, 2H), 7.21 –7.10(m,2H),3.90–3.78(m,1H),3.12(m,1H),2.36(m,1H),2.16(m,1H),1.97–1.65(m,4H),1.55–1.18 (m,4H).

Example 7

The specific synthesis process is the same as Example 1 of the present invention, except that bromobenzene is replaced with 4-phenylbromobenzene, and the temperature control device is set to -82°C; the purity of the obtained product is 83.7%

¹ H NMR (400MHz, CDCl ₃ ): δ7.61-7.68(m,4H),7.48-7.05(m,2H),7.37-7.44(m,3H),3.70-3.78(m,1H),2.50- 2.58(m,1H),2.17-2.21(m,1H),1.93-1.98(m,2H),1.85(s,2H),1.38-1.67(m,4H).

The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art, simple technical modifications or equivalent substitutions of the present invention by those skilled in the art, have been included in the present invention, and are included in the appended The claims represent the scope of protection.

Claims (4)

1. A method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction is characterized in that the method relies on nitrogen balance system pressure, continuous flow experimental pump equipment is utilized to realize continuous production through continuous feeding and discharging, material 1 is used as a reactant, and the product 2-aryl-1-cyclohexanol is prepared through lithium halogen exchange reaction, nucleophilic substitution reaction and Lewis acid ring opening reaction in sequence; the reaction route of the method is as follows:

wherein R represents an alkyl group, an aryl group, fluorine or chlorine;

the method comprises the following steps:

(1) Lithium halide exchange

Before the reaction starts, filling a pipeline with tetrahydrofuran to ensure that no air exists in the pipeline, pumping the material 1 and a lithium reagent into a continuous flow reaction device according to an equivalent proportion under the protection of nitrogen, and reacting for 5-8 minutes in a first solvent at the temperature of minus 60 ℃ to minus 80 ℃ to perform lithium halogen exchange to generate an active intermediate 2; the lithium reagent is an organolithium reagent, and is n-butyllithium;

(2) Nucleophilic substitution

Continuously introducing the active intermediate 2 generated in the step (1) into a continuous flow reaction device, then pumping cyclohexene oxide solution into the continuous flow reaction device in proportion, and carrying out nucleophilic substitution in a second solvent at the temperature of minus 60 ℃ to minus 80 ℃ for 5-7 minutes to generate an active intermediate 3;

(3) Ring opening of Lewis acids

Continuously introducing the active intermediate 3 generated in the step (2) into a continuous flow reaction device, then pumping boron trifluoride diethyl etherate solution into the continuous flow reaction device in proportion, and reacting for 8-10 minutes in a third solvent at the temperature of-70 ℃ to-85 ℃ to perform ring opening reaction to obtain a 2-aryl-1-cyclohexanol product;

the continuous flow reaction apparatus comprises:

the continuous flow reaction pipeline is a PTFE Teflon pipe or a 316L stainless steel pipe;

a micro-mixer;

a temperature control system;

a continuous flow reaction experiment pump connected with the inlet of the reactant; the continuous flow reaction experimental pump comprises a pump 1-a pump 4; wherein,

the continuous flow reaction experiment pump 1 leads tetrahydrofuran and toluene solution of the material 1 to be introduced into a pipeline, wherein the concentration of the solution is 0.5-1 mol/L, and the flow rate is 6.0-10.0 mL/min;

the continuous flow reaction experiment pump 2 leads the lithium reagent to be led into a pipeline, and the flow speed is 4 mL/min-6 mL/min;

the continuous flow reaction experiment pump 3 leads the tetrahydrofuran solution of cyclohexene oxide to be led into a pipeline, the concentration of the tetrahydrofuran solution is 0.8 mol/L-1.5 mol/L, and the flow rate is 5 mL/min-8 mL/min;

the continuous flow reaction experiment pump 4 leads toluene solution of boron trifluoride-diethyl etherate into a pipeline, the concentration of the toluene solution is 1.2 mol/L-2.0 mol/L, and the flow rate is 6.5-10.0 mL/min;

the continuous flow reaction pressure stabilizing device is connected with the outlet of the product;

and the continuous flow product collecting device is connected with the outlet of the pressure stabilizing device.

2. The method of claim 1, wherein the step of determining the position of the substrate comprises,

in the step (1), the first solvent used in the solution of the material 1 is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether;

in the step (2), the second solvent used in the cyclohexene oxide solution is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether;

in the step (3), the third solvent used in the boron trifluoride diethyl etherate solution is at least one of toluene, tetrahydrofuran and anhydrous diethyl ether.

3. The method of claim 1, wherein the step of determining the position of the substrate comprises,

in the step (1), the equivalent ratio of the material 1 to the lithium reagent is 1:1 to 1.5;

in the step (2), the equivalent ratio of the material 1 to cyclohexene oxide is 1:0.9 to 1;

in the step (3), the equivalent ratio of the material 1 to the boron trifluoride diethyl etherate is 1:1.5 to 2.

4. The method of claim 1, further comprising the post-processing step of:

step 4) extracting and separating the product to obtain an organic phase, then drying the organic phase by using anhydrous sodium sulfate, and spin-drying the organic phase by using a rotary evaporator to obtain a white waxy solid;

and/or the product collected in step 5) is monitored by GC and has a purity of 80 to 90%.