CN112661656A - Preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol - Google Patents
Preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol Download PDFInfo
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Abstract
The invention relates to a preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol. In the preparation method, limonene is reacted with a halogenated reagent to obtain an intermediate shown in a formula (1), then the intermediate shown in the formula (1) is reacted with a tertiary amine compound to obtain an intermediate shown in a formula (2), and finally the intermediate shown in the formula (2) is subjected to pyrolysis elimination reaction to obtain (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol. The system isThe preparation method has mild conditions, does not need the oxidation process of hydrogen peroxide with high preparation condition requirements and higher safety risk, does not need expensive catalysts, has high yield and product purity, has simple steps, and can be suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of (1S,4R) -1-methyl-4- (1-methylethenyl) -2-cyclohexene-1-alcohol.
Background
Cannabidiol (CBD) is the main chemical component in medicinal plant marijuana, is extracted from female marijuana plant, is a non-addictive component in marijuana, and has pharmacological effects of resisting spasm, anxiety, inflammation, pain and the like. CBD can not only help control the consumption of GABA neurotransmitter, inhibit cerebral excitation, reduce epileptic seizure, but also help improve the curative effect of other antiepileptic drugs. Even the hallucinogenic effect of Tetrahydrocannabinol (THC) on the human body can be effectively eliminated, and is called as "anti-drug compound" (anti-marijuana compound).
The traditional preparation method of the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-ol is one of important intermediates for preparing CBD, limonene is usually taken as a raw material to obtain the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-ol through four steps of reactions of epoxidation, addition (selective ring opening), oxidation and elimination, and expensive selective ring opening catalysts such as zirconyl sulfate and the like are usually adopted in earlier literature reports, so that the preparation cost is high, and the industrial production is not facilitated.
The skilled person has been trying to develop new and inexpensive catalysts for selective ring-opening reaction, for example, Peddinti R.K uses unstable chloride as catalyst to catalyze the ring-opening reaction, and Saidi M.R uses easily deliquescent heteropoly acid such as phosphotungstic acid as catalyst to carry out the ring-opening reaction, so as to prepare (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-ol. All have the defects of unstable catalytic effect, non-recyclability and low yield. In addition, a technical scheme discloses a cheaper alkali solution as a ring-opening catalyst, but in the technical scheme, the ring-opening reaction needs to be refluxed for 18 hours, and then the steps of extraction, drying, concentration and the like are carried out, and the total yield can only reach about 60%. The other technical proposal discloses that the ring-opening reaction is carried out in the presence of sodium borohydride and diphenyl diselenide under the conditions of nitrogen protection, temperature reduction and the like, but the total reaction yield from 1, 2-epoxy limonene to (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-ol is not more than 67 percent. Although the technique adopts the ring-opening catalyst with better stability, the technique still has the defects of long process time, complicated steps and lower yield.
Meanwhile, in the conventional technology for preparing (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, four steps of epoxidation reaction, ring-opening addition reaction, oxidation reaction and elimination reaction are required, the whole process comprises two steps of oxidation reaction, the requirement on reaction conditions is high, great safety risk exists during industrial production, the steps are multiple, and the preparation cost is further increased.
Therefore, the development of a preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol with simple preparation process and high yield has important significance.
Disclosure of Invention
Based on the above, the invention provides a preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, which has high yield and simple process, thereby reducing the preparation cost of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol and being suitable for industrial production.
The invention provides a preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, which comprises the following steps:
reacting limonene, a halogenated reagent and water to obtain an intermediate of a formula (1);
reacting the intermediate of formula (1) with a tertiary amine compound to obtain an intermediate of formula (2);
carrying out pyrolysis elimination reaction on the intermediate of the formula (2) to obtain (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol;
wherein X is halogen; and R is independently selected from a straight-chain alkyl group with 1-20 carbon atoms, a branched-chain alkyl group with 3-20 carbon atoms, a cycloalkyl group with 3-20 carbon atoms, an aryl group with 5-20 carbon atoms, a heteroaryl group with 5-20 carbon atoms or a combination of the systems at each occurrence.
In some of these embodiments, the limonene is at least one of D-limonene and R-limonene.
In some of these embodiments, the limonene, the halogenating agent, and water undergo a double halogenation reaction and a hydrolysis reaction; the steps of the double halogenation addition and hydrolysis reaction are as follows: mixing the limonene and the halogenated reagent with water, and reacting at 30-120 ℃.
In some embodiments, an organic solvent is further added into the double-halogenation addition and hydrolysis reaction system, the mixture is cooled and layered after the reaction is finished, and an organic phase is taken for reduced pressure distillation to obtain the intermediate of the formula (1).
In some of these embodiments, the ratio of the amount of material of the halogenating agent to the limonene is (0.7-5): 1; the mass ratio of the water to the limonene is (0.5-2) to 1; the mass ratio of the tertiary amine compound to the intermediate of the formula (1) is (1-5): 1.
In some of these embodiments, the step of reacting limonene, a halogenating agent, and water is performed with a catalyst for the halogenation addition and a phase transfer catalyst.
In some of these embodiments, the halogenation addition catalystThe agent is selected from Cu (OAc)2·H2O and Mn (OAc)3·2H2At least one of O; and/or
The phase transfer catalyst is selected from quaternary ammonium salt type phase transfer catalysts.
In some of these embodiments, the conditions of the pyrolytic elimination reaction are: reacting for 0.5-5 h at 120-180 ℃.
In some of these embodiments, the conditions under which the intermediate of formula (1) is reacted with a tertiary amine compound are: reacting for 1-10 h at 10-90 ℃.
In some of these embodiments, the halogenating agent is selected from chlorine, bromine, hypobromite, hypochlorite, or elemental iodine.
Advantageous effects
In the preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, the traditional preparation method is broken through the inherent route that limonene is epoxidized and then selectively opened, and then oxidation and elimination reaction are carried out, and limonene, a halogenated reagent and water are creatively reacted firstly to obtain an intermediate of a formula (1); then the intermediate of the formula (1) reacts with a tertiary amine compound, the intermediate of the formula (2) can be obtained by one-pot reaction under mild conditions, and finally the intermediate of the formula (2) is subjected to pyrolysis elimination reaction to obtain (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol. The preparation method does not need the oxidation process of hydrogen peroxide with high preparation condition requirements and high safety risk, does not need expensive catalysts, has high yield and high product purity, has simple steps, and is suitable for industrial production.
Further, in the preparation method of the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, the limonene is D-limonene or R-limonene, and the D-limonene or the R-limonene is chiral dextrolimonene, and the chiral (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol is obtained directly through double-halogenation hydrolysis, reaction with a tertiary amine compound and pyrolysis reaction. The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol can reach more than 70%, and the purity is more than 95%.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol obtained in example 1.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The traditional preparation method is that limonene is usually used as a raw material, epoxidation is carried out, then selective ring opening is carried out, and then oxidation and elimination reactions are carried out to obtain (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol.
For example, one of the technical solutions employs an expensive oxide such as zirconyl sulfate as a catalyst to perform the selective ring-opening reaction, and the oxide such as zirconyl sulfate used in the process is expensive, resulting in high preparation cost and unfavorable for industrial production.
After a large amount of experimental researches, technicians of the invention obtain the preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, which has high yield and simple process and is suitable for industrial production.
The structure of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol is shown below:
one embodiment of the present invention provides a method for preparing (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol, comprising the following steps S10 to S30.
Step S10, reacting limonene, a halogenated reagent and water to obtain an intermediate of the formula (1);
wherein X is halogen.
Carrying out double halogenation and hydrolysis reaction on the limonene and a halogenating reagent to obtain the intermediate shown in the formula (1).
It is understood that the limonene can be levo-limonene or dextro-limonene, or a mixture of the two.
In some preferred embodiments, the limonene is selected from at least one of D-limonene and R-limonene.
D-limonene or R-limonene is chiral dextrolimonene to obtain chiral (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol. The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol can reach more than 70%, and the purity is more than 95%.
In some of these embodiments, in step S10, the limonene, the halogenating agent, and the water are subjected to a double halogenation addition and hydrolysis reaction; further, the step of the double halogenation addition and hydrolysis reaction is as follows S11
S11, mixing the limonene, the halogenated reagent and water, and reacting for 1-10 hours at 30-120 ℃.
In some embodiments, in step S11, the ratio of the amount of the halogenated agent to the amount of limonene is (0.7-5): 1; the mass ratio of water to limonene is (0.5-2) 1.
The yield of the reaction is improved by controlling the dosage of the halogenating reagent, the limonene and the water to ensure that the reaction is carried out in a direction favorable for generating the intermediate shown in the formula (1).
In some embodiments, the double-halogenation addition and hydrolysis reaction system in the step S10 further includes adding an organic solvent, and further includes the following step S12.
And step S12, after the double-halogenation addition and hydrolysis reaction is finished, cooling and layering, and taking an organic phase for reduced pressure distillation to obtain the intermediate of the formula (1).
Further, the organic solvent is at least one selected from the group consisting of methanol, toluene, cyclohexane, dichloromethane, dichloroethane, chloroform and carbon tetrachloride. Further, the organic solvent can be recovered by distillation under reduced pressure.
In some of these examples, the distillation under reduced pressure is carried out at an absolute pressure of 150Pa to 160Pa, receiving a fraction at a temperature of 120 ℃ to 130 ℃ to obtain the intermediate of formula (1).
It is understood that when water is directly used as the reaction solvent in step S10, the crude product containing the intermediate of formula (1) is an organic phase after the reaction is completed and the layers are separated by cooling.
Further, the step of reacting limonene, a halogenating agent and water in step S10 is performed by the action of a catalyst for halogenation addition and a phase transfer catalyst.
Under the action of the catalyst for halogenation addition, the reaction is carried out in the direction favorable for generating the intermediate of the formula (1), and meanwhile, the phase transfer catalyst can reduce the surface energy between materials and ensure that the materials are fully contacted, thereby improving the yield of the reaction.
In some of these embodiments, the catalyst for the halogenation addition is selected from Cu (OAc)2·H2O and Mn (OAc)3·2H2At least one of O.
The copper acetate may be anhydrous copper acetate or copper acetate hydrate; the manganese acetate can be anhydrous manganese acetate salt or manganese acetate hydrate.
In some of these embodiments the phase transfer catalyst is selected from quaternary ammonium salt type phase transfer catalysts.
In some of these embodiments, the quaternary ammonium salt-based catalyst has the following structure:
(R1)4N+X-
wherein X has the meaning as defined above.
Specifically, X is selected from Cl, Br or I;
R1independently selected from a linear alkyl group having 1 to 20 carbon atoms, a branched alkyl group having 3 to 20 carbon atoms, a cycloalkyl group having 3 to 20 carbon atoms, or a combination thereof. In particular, R1Are all the same and are selected from-CH3、-C2H5、-C3H7or-C4H9。
In some of the examples, the ratio of the amount of the substance of the catalyst for halogenation addition to the amount of the limonene ranges from (0.005-0.1): 1.
In some of these embodiments, the weight ratio of phase transfer catalyst to limonene is (0.001-0.01): 1.
In some of these embodiments, X is Cl, Br, or I; further, in step S10, the halogenating agent is selected from chlorine, bromine, hypobromite, hypochlorite or iodine; specifically, the hypobromite is selected from sodium hypobromite or potassium hypobromite; the hypochlorite is selected from sodium hypochlorite or potassium hypochlorite.
Step S20 of reacting the intermediate of formula (1) obtained in step S10 with a tertiary amine compound to obtain an intermediate of formula (2):
wherein R is independently selected from a linear alkyl group with 1-20 carbon atoms, a branched alkyl group with 3-20 carbon atoms, a cycloalkyl group with 3-20 carbon atoms, an aryl group with 5-20 carbon atoms, a heteroaryl group with 5-20 carbon atoms, or a combination of the above systems.
In the step S20, the intermediate of formula (1) and the tertiary amine compound are subjected to a one-pot reaction, and the intermediate of formula (1) is subjected to a one-pot reaction under the action of the tertiary amine compound, so that the intermediate of formula (2) containing a quaternary ammonium salt group can be obtained under mild reaction conditions, thereby overcoming the defects of severe preparation conditions and high safety risk caused by using hydrogen peroxide for oxidation reaction in the conventional preparation technology.
It can be understood that, in step S20, the tertiary amine compound has a structure represented by formula (3):
NR3 (3)
wherein R has the meaning as defined above.
Further, in the formula (3), each R is the same and is selected from a straight-chain alkyl group with 1-10 carbon atoms or a branched-chain alkyl group with 3-10 carbon atoms, and further R is selected from-CH3、-C2H5、-C3H7or-C4H9。
In some of these embodiments, the conditions under which the intermediate of formula (1) is reacted with the tertiary amine compound in step S20 are: reacting for 1-10 h at 10-90 ℃.
In some embodiments, in step S20, the ratio of the amount of tertiary amine compound to the amount of material of the intermediate of formula (1) is (1-5): 1.
Further, in step S20, the ratio of the amount of the tertiary amine compound to the amount of the substance of the intermediate of formula (1) is (1-2): 1.
In some of the embodiments, the reaction of the above tertiary amine compound with the intermediate of formula (1) is performed in an organic solvent in step S20, further, the organic solvent is at least one selected from the group consisting of acetonitrile, methanol, toluene, cyclohexane, dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; filtering to obtain a filter cake after the reaction is finished, and repeatedly washing the filter cake by using an organic solvent to obtain the intermediate of the formula (2). Specifically, the organic solvent is acetonitrile.
And step S30, carrying out pyrolytic elimination reaction on the intermediate of the formula (1) obtained in the step S20 to obtain (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol.
In some of these embodiments, the conditions of the pyrolysis elimination reaction are: reacting for 0.5-5 h at 120-180 ℃.
Further, in step S30, after the pyrolytic elimination reaction, the product obtained by the pyrolytic elimination reaction is distilled under reduced pressure to obtain (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol; further, reduced pressure distillation is carried out under the absolute pressure of 150Pa to 160Pa, and a fraction with the temperature of 70 ℃ to 74 ℃ is received, so as to obtain the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol.
In some embodiments, in step S30, the pyrolytic elimination reaction is performed at an absolute pressure of 150Pa to 160 Pa; at this time, rectification under reduced pressure was carried out while the reaction was being carried out.
In the preparation method of the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, limonene and a halogenating reagent are subjected to double halogenation addition reaction and hydrolysis to obtain an intermediate shown in the formula (1), then the intermediate shown in the formula (1) is subjected to reaction with a tertiary amine compound to obtain an intermediate shown in the formula (2) containing a quaternary ammonium salt group, and finally the intermediate shown in the formula (1) is subjected to pyrolysis elimination reaction to obtain the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol. The preparation method does not need the oxidation process of hydrogen peroxide with preparation conditions and high risk, does not need expensive catalysts, has high yield and high product purity, has simple steps, and can be suitable for industrial production.
While the present invention will be described with respect to particular embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but is intended to cover by the appended claims the scope of the invention, and that certain changes in the embodiments of the invention will be suggested to those skilled in the art and are intended to be covered by the appended claims.
Example 1
1) Preparation of intermediate 1: into a 500mL three-necked flask were placed 81.6g of D-limonene, 100mL of dichloroethane, and 100mL of water, 70.0g of sodium hypochlorite, Cu (OAc)2·H2Heating to 80 ℃ to perform reflux reaction when O is 1.2g and TMABB is 0.2g, sampling for 6h for reaction to test, wherein the result shows that the content of D-limonene is less than 1%, stopping the reaction, cooling and layering, performing reduced pressure distillation on an organic layer to recover dichloroethane to obtain a crude product containing an intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol with the mass of 111.5g, further performing reduced pressure distillation at the absolute pressure of 150 Pa-160 Pa, receiving a fraction at the temperature of 120 ℃ -124 ℃, obtaining 103.9g of the intermediate 1, the yield is 88.6%, and the purity of the intermediate 1 obtained by testing is 88.6%96.2％。
2) Preparation of intermediate 2: into a 250mL reaction vessel were charged 90.0g of the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, 126mL of acetonitrile, and 84.9g of trimethylamine, and the temperature was raised to 80 ℃ to react for 8 hours. After the reaction is finished, sampling for detection, stopping the reaction, cooling to room temperature, filtering, washing a filter cake for 2 times by using acetonitrile, and drying to obtain 111.4g of an intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethyl ammonium salt, wherein the yield is 91.9%, and the purity of the intermediate 2 is 93.8% through detection.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: weighing 90.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexane) -trimethyl ammonium salt in a 250mL three-neck flask, connecting a 30cm rectifying column and a condenser pipe, starting to perform reduced pressure distillation reaction (absolute pressure is 150 Pa-160 Pa), heating until the oil bath temperature reaches 130 ℃, melting the intermediate 2 into transparent liquid which is slightly yellow, receiving fraction when the oil bath temperature is 150 ℃, the top temperature of the rectifying column is stabilized at 72 ℃, distilling out colorless transparent liquid (49.0 g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, the yield is 90.3 percent, and detecting that (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1- The alcohol purity was 95.7%.
Further performing nuclear magnetic hydrogen spectrum test on the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol prepared in the step 3), wherein a spectrogram is shown in the attached drawing 1, and a test result shows that the high-purity (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol is successfully obtained according to the technical scheme of the invention.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 88.6% 91.9% 90.3% to 73.5%
Example 2
1) Preparation of intermediate 1: into a 500mL three-necked flask were placed 81.6g of D-limonene, 100mL of dichloroethane, 100mL of water, 111.8g of sodium hypobromite, Cu (OAc)2·H21.2g of O and 0.2g of TMABB, heating to 80 ℃ for reflux reaction, sampling for 6 hours for reaction, and testing, wherein the result shows that the content of D-limonene is less than or equal to that of D-limonene1 percent, stopping reaction, cooling, layering, taking an organic layer, carrying out reduced pressure distillation to recover dichloroethane to obtain 137.5g of crude product containing the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, further carrying out reduced pressure distillation under the absolute pressure of 150 Pa-160 Pa, receiving fraction at the temperature of 126-129 ℃, obtaining 128.5g of intermediate 1, wherein the yield is 88.3 percent, and the purity of the intermediate 1 is 96.1 percent.
2) Preparation of intermediate 2: a250 mL reaction vessel was charged with 120.0g of the intermediate 1(1S,4R) -2-bromo-4- (1-methylvinyl) -1-methyl-cyclohexanol, 150mL of acetonitrile, and 84.9g of trimethylamine, and heated to 80 ℃ for reaction for 8 hours. After the reaction is finished, sampling and detecting, wherein the content of the raw material intermediate 1 is less than 1%. After the reaction is stopped, the reaction product is cooled to room temperature and then filtered, a filter cake is washed with acetonitrile for 2 times and dried to obtain 140.8g of intermediate 2 product (1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt, the yield is 91.6 percent, and the purity of the intermediate 2 is detected to be 93.7 percent.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: 100.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt was weighed into a 250mL three-necked flask, a 30cm rectifying column and a condenser tube were connected, and a reduced pressure distillation reaction (150 Pa to 160Pa absolute) was started. When the temperature was raised to 130 ℃ the intermediate 2 began to melt as a clear liquid, slightly yellowish. When the temperature of the oil bath was raised to 150 ℃ and the temperature at the top of the rectifying column was stabilized at 72 ℃, 46.2g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol as a colorless transparent liquid was distilled off, the yield was 90.2%, and the purity of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was determined to be 95.6%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 88.3% 91.6% 90.2% to 73.0%
Example 3
1) Preparation of intermediate 1: into a 500mL three-necked flask were placed 81.6g of D-limonene, 100mL of dichloroethane, 100mL of water, 111.8g of sodium hypobromite, Mn (OAc)3·2H21.4g of O and 0.2g of TMABB, heating to 90 ℃ for reflux reaction, sampling for 10 hours for reaction, and measuringThe test shows that the content of the D-limonene is less than 1%. Stopping the reaction, cooling, layering, taking an organic layer, carrying out reduced pressure distillation to recover dichloroethane, obtaining 132.4g of crude product containing the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, further carrying out reduced pressure distillation under the absolute pressure of 150 Pa-160 Pa, receiving fraction at the temperature of 126-129 ℃, obtaining 128.4g of intermediate 1, wherein the yield is 88.1%, and the purity of the intermediate 1 is 95.9% through detection.
2) Preparation of intermediate 2: a250 mL reaction vessel was charged with 120.0g of the intermediate 1(1S,4R) -2-bromo-4- (1-methylvinyl) -1-methyl-cyclohexanol, 150mL of acetonitrile, and 84.9g of trimethylamine, and heated to 60 ℃ for 10 hours. After the reaction is finished, sampling and detecting, wherein the content of the raw material intermediate 1 is less than 1%. After the reaction is stopped, the reaction product is cooled to room temperature and then filtered, a filter cake is washed with acetonitrile for 2 times and dried to obtain 140.7g of intermediate 2 product (1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt, the yield is 91.7 percent, and the purity of the intermediate 2 is detected to be 93.7 percent.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: 100.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt was weighed into a 250mL three-necked flask, a 30cm rectifying column and a condenser tube were connected, and a reduced pressure distillation reaction (150 Pa to 160Pa absolute) was started. When the temperature was raised to 130 ℃ the intermediate 2 began to melt as a clear liquid, slightly yellowish. When the temperature of the oil bath was raised to 150 ℃ and the temperature at the top of the rectifying column was stabilized at 72 ℃, 46.2g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol, a colorless transparent liquid, was distilled off, the yield was 90.4%, and the purity of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol, which was measured, was 95.8%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 87.6% 90.3% 88.7% to 73.0%
Example 4
1) Preparation of intermediate 1: a500 mL three-necked flask was charged with 81.6g of D-limonene, 100mL of cyclohexane and 100mL of water, 70.0g of sodium hypochlorite, Cu (OAc)2·H21.2g of O and 0.2g of TMABB, and heating to 70 DEG CAnd carrying out reflux reaction, reacting for 7 hours, sampling and testing, wherein the result shows that the content of the D-limonene is less than 1%. Stopping reaction, cooling, layering, taking an organic layer, distilling under reduced pressure to recover dichloroethane to obtain 113.5g of crude product containing the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, further distilling under reduced pressure at the absolute pressure of 150 Pa-160 Pa, receiving fraction at 120-124 ℃ to obtain 103.7g of intermediate 1, and testing to obtain the intermediate 1 with the purity of 95.8% and the yield of 88.1%.
2) Preparation of intermediate 2: into a 250mL reaction vessel were charged 90.0g of the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, 126mL of acetonitrile, and 84.9g of trimethylamine, and the temperature was raised to 80 ℃ to react for 8 hours. After the reaction is finished, sampling and detecting, wherein the content of the raw material intermediate 1 is less than 1%, stopping the reaction, cooling to room temperature, filtering, washing a filter cake for 2 times by using acetonitrile, and drying to obtain 111.0g of intermediate 2 product (1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethyl ammonium salt, wherein the purity of the intermediate 2 is 93.9% and the yield is 92.0%.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: 90.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt was weighed into a 250mL three-necked flask, a 30cm rectifying column and a condenser tube were connected, and a reduced pressure distillation reaction (150 Pa to 160Pa absolute) was started. When the temperature of the oil bath is raised to 130 ℃, the intermediate 2 begins to melt into transparent liquid which is slightly yellowish, when the temperature of the oil bath is raised to 150 ℃, the top temperature of a rectifying column is stabilized at 72 ℃, fractions are received, 49.1g of colorless transparent liquid (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol is distilled out, the yield is 90.4%, and the purity of the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol is detected to be 95.7%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 88.1% 90.0% 90.4% 73.3%
Example 5
1) Preparation of intermediate 1: a500 mL three-necked flask was charged with 81.6g of D-limonene, 100mL of cyclohexane and 100mL of water, 70.0g of sodium hypochlorite, Cu (OAc)2·H22.4g of O and 0.2g of TMAB, heating to 80 ℃ for reflux reaction, reacting for 6 hours, sampling and testing, wherein the D-limonene content is less than 1 percent. Stopping the reaction, cooling, layering, distilling an organic layer under reduced pressure to recover dichloroethane to obtain 113.5g of crude product containing the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, further distilling under reduced pressure at 150-160 Pa, receiving fraction at 120-124 ℃ to obtain 103.6g of intermediate 1, wherein the purity of the intermediate 1 is 95.8% and the yield is 88.0%.
2) Preparation of intermediate 2: into a 250mL reaction vessel were charged 90.0g of the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, 126mL of acetonitrile, and 145.3g of triethylamine, and the temperature was raised to 60 ℃ to react for 10 hours. After the reaction is finished, sampling for detection, stopping the reaction, cooling to room temperature, filtering, washing a filter cake for 2 times by using acetonitrile, and drying to obtain an intermediate 2 product (1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -triethylammonium salt (110.9 g), wherein the purity of the intermediate 2 is 94.0% and the yield is 92.0%.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: 90.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -triethylammonium salt was weighed into a 250mL three-necked flask, a 30cm rectifying column and a condenser tube were connected, and a reduced pressure distillation reaction (absolute pressure 150Pa to 160Pa) was started. When the temperature of the oil bath is raised to 143 ℃, the intermediate 2 begins to melt into transparent liquid which is slightly yellowish, when the temperature of the oil bath is raised to 150 ℃, the top temperature of a rectifying column is stabilized at 72 ℃, fractions are received, 49.1g of colorless transparent liquid (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol is distilled out, the yield is 90.3%, and the purity of the (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol is detected to be 95.7%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 88.0% 92.0% 90.3% 73.1%
Example 6
1) Preparation of intermediate 1: a500 mL three-necked flask was charged with D-limonene (81.6) g, 100mL dichloroethane and40.8mL of water, sodium hypochlorite (44.6) g, Cu (OAc)2·H2The content of O is 1.2g and TMABB is 0.2g, the temperature is increased to 80 ℃ for reflux reaction, the reaction is carried out for 6h, sampling is carried out for testing, the result shows that the content of D-limonene is less than 1%, the reaction is stopped, the reaction is cooled and layered, an organic layer is taken for vacuum distillation to recover dichloroethane, a crude product containing an intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol is obtained, the mass is 110.1g, the vacuum distillation is further carried out under the absolute pressure of 150 Pa-160 Pa, a fraction at the temperature of 120 ℃ -124 ℃ is received, 99.8g of the intermediate 1 is obtained, the yield is 84.8%, and the purity of the intermediate 1 obtained through testing is 95.8%.
2) Preparation of intermediate 2: into a 250mL reaction vessel were charged 90.0g of the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, 126mL of acetonitrile, and 56.6g of trimethylamine, and the temperature was raised to 80 ℃ to react for 8 hours. After the reaction is finished, sampling for detection, stopping the reaction, cooling to room temperature, filtering, washing a filter cake for 2 times by using acetonitrile, and drying to obtain an intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt 110.7g, wherein the yield is 91.7%, and the purity of the intermediate 2 is detected to be 93.8%.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: weighing 90.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexane) -trimethyl ammonium salt in a 250mL three-neck flask, connecting a 30cm rectifying column and a condenser pipe, starting to perform reduced pressure distillation reaction (absolute pressure is 150 Pa-160 Pa), heating until the oil bath temperature reaches 130 ℃, melting the intermediate 2 into transparent liquid which is slightly yellow, receiving fraction when the oil bath temperature is 150 ℃, the top temperature of the rectifying column is stabilized at 72 ℃, distilling out colorless transparent liquid (49.0 g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, the yield is 90.4 percent, and detecting that (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1- The alcohol purity was 95.8%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 84.8% 91.7% 90.4 ═ 70.3%
Example 7
1) Preparation of intermediate 1: the mixture is baked in 500mL three-portInto a bottle was added D-limonene 81.6g, 100mL dichloroethane and 163mL water, sodium hypochlorite 223.0g, Cu (OAc)2·H2The content of O is 2.4g and TMAB is-0.4 g, the temperature is increased to 60 ℃ for reflux reaction, the reaction is carried out for 9h, sampling is carried out for detection, the result shows that the content of D-limonene is less than 1%, the reaction is stopped, the reaction is cooled and layered, an organic layer is taken for vacuum distillation to recover dichloroethane, a crude product containing an intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol is obtained, the mass is 117.9g, the vacuum distillation is further carried out under the absolute pressure of 150 Pa-160 Pa, a fraction at the temperature of 120 ℃ -124 ℃ is received, 105.7g of the intermediate 1 is obtained, the yield is 90.2%, and the purity of the intermediate 1 obtained through testing is 96.3%.
2) Preparation of intermediate 2: into a 250mL reaction vessel were charged 90.0g of the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, 126mL of acetonitrile, and 141.5g of trimethylamine, and the temperature was raised to 80 ℃ to react for 8 hours. After the reaction is finished, sampling for detection, stopping the reaction, cooling to room temperature, filtering, washing a filter cake for 2 times by using acetonitrile, and drying to obtain 111.6g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt, wherein the yield is 92.3%, and the purity of the intermediate 2 is 94.2% through detection.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: weighing 90.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexane) -trimethyl ammonium salt in a 250mL three-neck flask, connecting a 30cm rectifying column and a condenser pipe, starting to perform reduced pressure distillation reaction (absolute pressure is 150 Pa-160 Pa), heating until the oil bath temperature reaches 130 ℃, melting the intermediate 2 into transparent liquid which is slightly yellow, receiving fraction when the oil bath temperature is 150 ℃, the top temperature of the rectifying column is stabilized at 72 ℃, distilling out colorless transparent liquid (49.3 g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, the yield is 90.5 percent, and detecting that (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1- The alcohol purity was 95.8%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 90.2% 92.3% 90.5% 75.4%
Example 8
1) Preparation of intermediate 1: into a 500mL three-necked flask were placed 81.6g of D-limonene, 100mL of dichloroethane, 81.6mL of water, 111.6g of sodium hypochlorite, Cu (OAc)2·H2The content of O is 1.2g and TMAB is-0.2 g, the temperature is increased to 80 ℃ for reflux reaction, the reaction is carried out for 6h, sampling is carried out for detection, the result shows that the content of D-limonene is less than 1%, the reaction is stopped, the reaction is cooled and layered, an organic layer is taken for vacuum distillation to recover dichloroethane, a crude product containing an intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol is obtained, the mass is 114.6g, the vacuum distillation is further carried out under the absolute pressure of 150 Pa-160 Pa, a fraction at the temperature of 120 ℃ -124 ℃ is received, 104.2g of the intermediate 1 is obtained, the yield is 88.9%, and the purity of the intermediate 1 obtained through testing is 96.2%.
2) Preparation of intermediate 2: into a 250mL reaction vessel were charged 90.0g of the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, 126mL of acetonitrile, and 84.9g of trimethylamine, and the temperature was raised to 80 ℃ to react for 8 hours. After the reaction is finished, sampling for detection, stopping the reaction, cooling to room temperature, filtering, washing a filter cake for 2 times by using acetonitrile, and drying to obtain 111.2g of an intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethyl ammonium salt, wherein the yield is 91.6%, and the purity of the intermediate 2 is 93.7% through detection.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: weighing 90.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexane) -trimethyl ammonium salt in a 250mL three-neck flask, connecting a 30cm rectifying column and a condenser pipe, starting to perform reduced pressure distillation reaction (absolute pressure is 150 Pa-160 Pa), heating until the oil bath temperature reaches 130 ℃, melting the intermediate 2 into transparent liquid which is slightly yellow, receiving fraction when the oil bath temperature is 150 ℃, the top temperature of the rectifying column is stabilized at 72 ℃, distilling out colorless transparent liquid (49.0 g of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol, the yield is 90.4 percent, and detecting that (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1- The alcohol purity was 95.7%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 88.9% 91.6% 90.4% 73.6%
Example 9
1) Preparation of intermediate 1: a500 mL three-necked flask was charged with 81.6g of L-limonene, 100mL of dichloroethane, and 100mL of water, 70.0g of sodium hypochlorite, Cu (OAc)2·H2The content of O is 1.2g and TMABB is 0.2g, the temperature is increased to 80 ℃ for reflux reaction, the reaction is carried out for 6h, sampling is carried out for testing, the result shows that the content of L-limonene is less than 1%, the reaction is stopped, the reaction is cooled and layered, an organic layer is taken for vacuum distillation to recover dichloroethane, a crude product containing an intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol is obtained, the mass is 114.1g, the vacuum distillation is further carried out under the absolute pressure of 150 Pa-160 Pa, a fraction at the temperature of 120 ℃ -124 ℃ is received, 100.8g of the intermediate 1 is obtained, the yield is 85.5%, and the purity of the intermediate 1 obtained through testing is 95.7%.
2) Preparation of intermediate 2: into a 250mL reaction vessel were charged 90.0g of the intermediate 1(1S,4R) -2-chloro-4- (1-methylvinyl) -1-methyl-cyclohexanol, 126mL of acetonitrile, and 84.9g of trimethylamine, and the temperature was raised to 80 ℃ to react for 8 hours. After the reaction is finished, sampling for detection, stopping the reaction, cooling to room temperature, filtering, washing a filter cake for 2 times by using acetonitrile, and drying to obtain an intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexyl) -trimethylammonium salt 110.6g, wherein the yield is 91.6%, and the purity of the intermediate 2 is 93.7% through detection.
3) Preparation of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol: weighing 90.0g of intermediate 2(1S,4R) (2-hydroxy-5- (1-methylvinyl) -2-methylcyclohexane) -trimethyl ammonium salt in a 250mL three-neck flask, connecting a 30cm rectifying column and a condenser pipe, starting to perform reduced pressure distillation reaction (absolute pressure is 150 Pa-160 Pa), heating until the oil bath temperature reaches 130 ℃, melting the intermediate 2 into transparent liquid which is slightly yellow, receiving fraction when the oil bath temperature is 150 ℃, the top temperature of the rectifying column is stabilized at 72 ℃, distilling 48.9g of colorless transparent liquid (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol out, wherein the yield is 90.1%, and detecting that (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1- The alcohol purity was 95.6%.
The total yield of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexen-1-ol was 85.5% 91.6% 90.1% to 70.6%
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A preparation method of (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol is characterized by comprising the following steps:
reacting limonene, a halogenated reagent and water to obtain an intermediate of a formula (1);
reacting the intermediate of formula (1) with a tertiary amine compound to obtain an intermediate of formula (2);
carrying out pyrolysis elimination reaction on the intermediate of the formula (2) to obtain (1S,4R) -1-methyl-4- (1-methylvinyl) -2-cyclohexene-1-alcohol;
wherein X is halogen; and R is independently selected from a straight-chain alkyl group with 1-20 carbon atoms, a branched-chain alkyl group with 3-20 carbon atoms, a cycloalkyl group with 3-20 carbon atoms, an aryl group with 5-20 carbon atoms, a heteroaryl group with 5-20 carbon atoms or a combination of the systems at each occurrence.
2. The method of claim 1, wherein the limonene is at least one of D-limonene and R-limonene.
3. The method of claim 1, wherein said limonene, a halogenating agent, and water undergo a double halogenation addition and hydrolysis reaction; the steps of the double halogenation addition and hydrolysis reaction are as follows: and mixing the limonene and the halogenated reagent with water, and reacting for 1-10 h at 30-120 ℃.
4. The preparation method according to claim 3, wherein an organic solvent is further added into the system of the double halogenation addition and hydrolysis reaction, the mixture is cooled and layered after the reaction is finished, and an organic phase is taken and subjected to reduced pressure distillation to obtain the intermediate of the formula (1).
5. The method of claim 4, wherein the ratio of the amount of said halogenating agent to said limonene species is (0.7-5): 1; the mass ratio of the water to the limonene is (0.5-2) to 1; the mass ratio of the tertiary amine compound to the intermediate of the formula (1) is (1-5): 1.
6. The method of claim 5, wherein the step of reacting limonene, a halogenating agent, and water is performed with a catalyst for the halogenation addition and a phase transfer catalyst.
7. The process according to claim 6, wherein the catalyst for the addition halogenation is selected from the group consisting of Cu (OAc)2·H2O and Mn (OAc)3·2H2At least one of O; and/or
The phase transfer catalyst is selected from quaternary ammonium salt type phase transfer catalysts.
8. The production method according to any one of claims 1 to 7, wherein the conditions of the pyrolysis elimination reaction are: reacting for 0.5-5 h at 120-180 ℃.
9. The method according to any one of claims 1 to 7, wherein the intermediate of formula (2) is prepared by reacting the intermediate of formula (1) with a tertiary amine compound under the conditions: reacting for 1-10 h at 10-90 ℃.
10. The method of any one of claims 1 to 7, wherein the halogenating agent is selected from chlorine, bromine, hypobromite, hypochlorite, and elemental iodine.
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| CN115724716A (en) * | 2022-10-27 | 2023-03-03 | 南京康立瑞生物科技有限公司 | Synthesis method of trans-menthyl-2, 8-diene-1-alcohol |
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