CN109134229A - A method of preparing cypress oleyl alcohol - Google Patents
A method of preparing cypress oleyl alcohol Download PDFInfo
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- CN109134229A CN109134229A CN201711256954.9A CN201711256954A CN109134229A CN 109134229 A CN109134229 A CN 109134229A CN 201711256954 A CN201711256954 A CN 201711256954A CN 109134229 A CN109134229 A CN 109134229A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/32—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by introduction of halogenated alkyl groups into ring compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The present invention provides a kind of methods for preparing cypress oleyl alcohol, comprising: starting material compound cyclohexene and bromoform are carried out addition reaction and obtain the first compound of bicyclic [4.1.0] heptane of referred to as 7,7- dibromo；First compound obtains referred to as 3 through peroxidization, the second compound of bicyclic [4.1.0] the hept- 2- ketone of 7,7- tribromos；The second compound obtains the third compound of bicyclic [4.1.0] the hept- 3- alkene -2- ketone of the bromo- 3- hydroxyl of referred to as 7,7- bis- by substitution reaction；The third compound obtains the bromo- 2- hydroxyl cycloheptyl -2,4 of referred to as 4-, the fourth compound of 6- triolefin -1- ketone by ring expansion；The fourth compound obtains cypress oleyl alcohol by alkylated reaction.
Description
Technical field
The present invention relates to the industrialization of the preparation technical field of cypress oleyl alcohol more particularly to cypress oleyl alcohol and the systems of high-purity
Preparation Method.
Background technique
Cypress oleyl alcohol is also known as chamenol or Hinokitiol (Hinokitiol, β-Thujaplicin), is flat from TaiWan, China
A kind of native compound of the monoterpenes with seven ring Zhuo phenolic ketone skeletons extracted in cypress, the green gloomy cypress tree material of Japan, belongs to support phenol
Ketone compounds of group has good broad spectrum antibacterial, moisture retention and pest Repellency effect, is the plant component of high security, can
Raw material is prepared as antibacterial, insect-proof agent.As the main component of Taiwan Japan cypress essential oil, it has relatively broad bioactivity
It works well with stronger sterilizing ability, to general bacterium, minimal inhibitory concentration 10-100ppm, and fragrant, no
It is only capable of killing bacterium, mould in air, pest infestation human body can be also prevented, to inhibit mankind pathogeny bacterium；Especially for gold
Staphylococcus aureus (MRSA) has surprising inhibitory effect.The MRSA bacterium is often stored in the skin and respiratory tract of human body, often draws
The skin infections such as boil purulence ulcer are played, the seriously diseases such as septicemia, peritonitis, food poisoning are resulted even in.
In addition, application of the cypress oleyl alcohol in terms of beautifying whitening, has very strong inhibiting effect to tyrosinase bis-phenol enzyme,
Using DOPA as substrate, leading to the cypress oil determining alcohol (IC50) of enzyme activity decline 50% is 0.3 μm of ol/l.Tyrosinase is black
The key enzyme that element is formed, can be catalyzed light propylhomoserin, DOPA in human body and be converted to excellent melanocyte, brown pigment etc. by a plurality of approach, from
And cause the generation of freckle, chloasma, cyasma.Experiment in vitro shows that cypress oleyl alcohol inhibits tyrosinase vigor and will not lead
The permanent deactivation for causing enzyme, has substantial connection to the regulatory mechanism and its structure of tyrosinase in melanocyte.Tyrosinase is
A kind of oxidoreducing enzyme containing ketone, and 2 hydroxyls and 1 ketone structure be able to be with tyrosinases on cypress oleyl alcohol cycloheptatriene
Activated centre copper atom combines, and forms close complex compound, and so as to cause the active decline of tyrosinase catalysis, this is cypress
The major way of oleyl alcohol inhibition tyrosinase vigor.Meanwhile hydroxyl on cypress oleyl alcohol and ketone structure also can be with junket chloric acid enzymes
Substrate complex (ES) combines, and forms the formation of ternary complexes and then modulating melanin.
In recent years, it is generated around cypress oleyl alcohol tool broad-spectrum antiseptic anti-mildew, inhibition virus activity, inhibition tyrosinase and plant
The effects of ethylene and have the characteristics that assign cell activity, applied in pharmaceutical developments, amenities, cosmetics, hair care
It educates and is paid close attention in the exploitation of all multi-products such as hair, food fresh keeping by industry.
The preparation of traditional cypress oleyl alcohol, with methoxyl group cycloheptyl () triolefin, through isopropyl tropone, amido isopropyl
Base tropone process；Sheep's-parsley ketone epoxy-acetalation；Isopropyl pentylcyclohexanone (or alkene) cyanohydrination, and utilize bromine cycloheptyl
The methods of triolefin phenolic ketone and organo-tin compound effect, synthesis step is more, and raw material is difficult to obtain, it is virtually impossible to impose on industry
Production, therefore lack the practicability of industrialization production.
In recent years, the preparation of cypress oleyl alcohol is had following developing direction in mind around industrialization production and is implemented, and is with cyclopentadiene
Raw material and Grignard reagent diethyl magnesium bromide and isopropyl toluene sulfonic acid reactant salt, or it is anti-with acetone under alkaline condition
It answers, or the gas phase catalytic reaction with fatty lower alcohol or ethylene, or cyclopentadiene metallic compound is made through halogenation with alkali metal
The alkylations such as alkylation reaction obtain alkyl cyclopentadiene, the series methods such as preparation cypress oleyl alcohol.Due to making during these methods
The reagent prices such as Grignard, dialkylaluminum hydride, lithium alkylide are expensive, and during being gradually warmed up by low temperature control,
The apparatus and process of gas phase condition is required harsh；Due to polysubstituted alkyl body easily generated, cause monoalkyl body yield low, and produces
The equilibrium composition of object is essentially the equivalent isomer mixture of 1- isopropylcyclopentadiene and 2- isopropylcyclopentadiene, it is uncomfortable
Close the cypress oleyl alcohol of preparation high-purity.Further more, raw material cyclopentadiene belongs to energy-containing compound (propellant), and boiling point compared with
It is low, extremely unstable at room temperature, dimer easy to form, and release a large amount of heat during forming dimer and cause quick-fried
It is fried.Thus the preparation of cypress oleyl alcohol is caused not can be carried out large-scale industrialization and application.
Therefore, the technology of preparing of existing cypress oleyl alcohol needs to improve in the following areas:
(1) a kind of initial feed of the cyclopentadiene of substitution tool characteristic containing energy as preparation is looked for, can farthest be dropped
Low raw material saves cost and improves production security；
(2) the stronger compound of lithium alkylide/Grignard Reagent isoreactivity is avoided to participate in correlated response step, to eliminate cypress
Security risk during oleyl alcohol large-scale production；
(3) avoid occurring isomer during the preparation process, thus improve industrialization preparation cypress oleyl alcohol yield and
Purity.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of methods for preparing cypress oleyl alcohol, can farthest mention
The safety of high cypress oil alcohol industrialization production and the preservation cost for reducing material.
In order to solve the above-mentioned technical problems, the present invention provides a kind of methods for preparing cypress oleyl alcohol, comprising:
It is bicyclic that starting material compound cyclohexene and bromoform progress addition reaction are obtained into referred to as 7,7- dibromo
First compound of [4.1.0] heptane；First compound obtains referred to as 3 through peroxidization, and 7,7- tribromos are bicyclic [4.1.0]
The second compound of hept- 2- ketone；To obtain the bromo- 3- hydroxyl of referred to as 7,7- bis- bicyclic by substitution reaction for the second compound
The third compound of [4.1.0] hept- 3- alkene -2- ketone；The third compound obtains the bromo- 2- hydroxyl ring of referred to as 4- by ring expansion
Hept- 2,4, the fourth compound of 6- triolefin -1- ketone；The fourth compound obtains the of referred to as cypress oleyl alcohol by alkylated reaction
Five compounds.
Preferably, the preparation of the first compound specifically comprises the following steps:
Cyclohexene is mixed with bromoform and under the catalysis of triethylbenzene ammonium chloride and inorganic base carry out addition it is anti-
It answers, reaction temperature is -20 DEG C~30 DEG C, and the reaction time is 0.5~30 hour；Wherein, the volume ratio of cyclohexene and bromoform
It is 1: 0.5~1: 100, the volume ratio of cyclohexene and triethylbenzene ammonium chloride is 1000: 1~10: 1；
Addition reaction is finished with hydrochloric acid, and the concentration of the hydrochloric acid is 1M~10M；Then with dichloromethane solution extraction point
From collecting the first compound from the dichloromethane solution.
Preferably, the volume ratio of cyclohexene and bromoform is further to be selected as 1: 2~1: 10, cyclohexene and triethylbenzene
The volume ratio of ammonium chloride is further selected as 100: 1~50: 1；Inorganic base includes sodium hydroxide, any one in potassium hydroxide
Kind.
Preferably, the preparation of second compound specifically comprises the following steps:
First compound 1 and chromium trioxide are subjected to oxidation reaction under the auxiliary agent of ether, reaction temperature is -20 DEG C~40
DEG C, the reaction time is 0.5~8 hour；Wherein, the mass ratio of the first compound and the chromium trioxide is 1: 30~1: 2, first
The w/v of compound and the ether is 0.2g/ml~0.01g/ml；
The oxidation reaction, which finishes, is poured into reactant in water, is collected into second compound with ether extraction and separation.
Preferably, the mass ratio of the first compound and chromium trioxide is further selected as: 1: 5~1: 3；First compound and second
The w/v of ether selects a step to be selected as 0.1g/ml~0.04g/ml.
Preferably, the preparation of third compound specifically comprises the following steps:
Second compound and dimethyl sulfoxide, that is, DMSO organic solvent are carried out hydroxyl to replace instead under the catalysis of organic base
It answers, reaction temperature is 60 DEG C~150 DEG C, and the reaction time is 1~10 hour；Wherein, the bulking value of second compound and DMSO
Than for 0.5g/ml to 0.001g/ml；Second compound and the molar ratio of organic base are 1: 0.2~1: 30；
Hydroxyl substitution reaction is finished with hydrochloric acid, and the concentration of the hydrochloric acid is 0.5M~6M；Then dichloromethane solution is used
Extraction and separation are collected into third compound.
Preferably, the w/v of second compound and DMSO are further selected as 0.1g/ml~0.01g/ml；Second changes
The molar ratio for closing object and organic base is further selected as 1: 1~1: 10；Organic base include one of pyridine, triethylamine, sodium alkoxide or
It is a variety of.
Preferably, the preparation of fourth compound specifically comprises the following steps:
Under inert gas protection, by third compound and 1,11 carbon -7- alkene of 8- diazabicyclo (5.4.0) is in tetrahydro
Ring expansion is carried out in tetrahydrofuran solution, reaction temperature is -70 DEG C~0 DEG C, and the reaction time is 0.5~5 hour；Wherein, third
Object and 1 is closed, the molar ratio between 11 carbon -7- alkene of 8- diazabicyclo (5.4.0) is 1: 0.0001~1: 0.2；Third chemical combination
The w/v of object and tetrahydrofuran is 0.4g/ml~0.002g/ml；
Ring expansion finishes, and is quenched with the inorganic alkali solution that concentration is 0.1M~10M；Salt acid for adjusting pH is used after being quenched
To 4~5；Then it is extracted with dichloromethane and separates and collects fourth compound.
Preferably, inert gas includes nitrogen, any one in argon gas；Third compound and 1,8- diazabicyclo
Molar ratio between (5.4.0) 11 carbon -7- alkene is further selected as 1: 0.0005~1: 0.001；Third compound and tetrahydro furan
The w/v muttered further is selected as 0.08g/ml~0.01g/ml；Inorganic base includes sodium hydroxide, appointing in potassium hydroxide
It anticipates one kind.
Preferably, the preparation of the 5th compound specifically comprises the following steps:
Fourth compound and trimethacrylate base tin are blended in Isosorbide-5-Nitrae-dioxane, and in bi triphenyl phosphorus dichloride
Reaction is alkylated under the catalysis of palladium catalyst, reaction temperature is 70 DEG C~180 DEG C, and the reaction time is 0.5~5 hour；Its
In, the molar ratio between fourth compound and trimethacrylate base tin is 1: 0.5~1: 20；Fourth compound and Isosorbide-5-Nitrae-dioxy six
The w/v of ring is 0.2g/ml~0.001g/ml；
Alkylated reaction finishes, the solid being filtered to remove in reactant, and solvent is distilled off, and residue is dissolved in ethyl alcohol
In, hydro-reduction reaction is carried out under the palladium carbon catalysis of 0.5-10%, wherein the pressure of hydrogen is 0.1MPa~2MPa, the hydrogenation
The time of reduction reaction is 6~48 hours, and the w/v of residue and ethyl alcohol is 0.3g/ml~0.001g/ml, the hydrogenation
The temperature of reduction reaction is 0 DEG C~150 DEG C；
Hydro-reduction end of reaction is filtered to remove bi triphenyl phosphorus palladium chloride catalyst, and distillation removes ethyl alcohol, obtains
5th compound.
Preferably, the molar ratio between fourth compound and trimethacrylate base tin is further selected as 1: 0.8~1: 2；The
Four compounds and Isosorbide-5-Nitrae-dioxane w/v are more preferably 0.07g/ml~0.01g/ml；It is anti-in hydro-reduction
Ying Zhong is preferably carried out under 5% palladium carbon catalysis, and the pressure of hydrogen is further selected as 0.1MPa~0.5MPa；Also, the hydrogenation
The time of reduction reaction is further selected as 18~26 hours；The w/v of residue and ethyl alcohol is further selected as 0.07g/ml
~0.01g/ml；The temperature of hydro-reduction reaction is more preferably 20 DEG C~50 DEG C.
The method of industrialization provided by the invention preparation cypress oleyl alcohol, by using cyclohexene as initial feed, no matter
It is all greatly increased in the preservation cost of raw material or in terms of safety, solves to essence industry metaplasia
The safety issue of production；Due to the process that method of the invention is re-introduced into isopropyl by first preparing seven-members ring structure, avoid
The appearance of isomer ensures that the efficiency of large-scale production；Further more, method of the invention avoids lithium alkylide/lattice
The step of stronger compound of family name's reagent isoreactivity participates in correlated response, thus during eliminating cypress oleyl alcohol large-scale production
Security risk.
Detailed description of the invention
Fig. 1 is the reaction formula expression of the method for present invention preparation cypress oleyl alcohol；
Fig. 2 is that its reaction formula for preparing of compound 1 in the method for present invention preparation cypress oleyl alcohol is expressed；
Fig. 3 is that its reaction formula for preparing of compound 2 in the method for present invention preparation cypress oleyl alcohol is expressed；
Fig. 4 is that its reaction formula for preparing of compound 3 in the method for present invention preparation cypress oleyl alcohol is expressed；
Fig. 5 is that its reaction formula for preparing of compound 4 in the method for present invention preparation cypress oleyl alcohol is expressed；
Fig. 6 is that its reaction formula for preparing of target compound 5 in the method for present invention preparation cypress oleyl alcohol is expressed.
Specific embodiment
Technical solution of the present invention is set forth below in conjunction with preferred embodiment.
A kind of method preparing cypress oleyl alcohol provided by the invention, comprising: by starting material compound cyclohexene and tribromo
Methane carries out addition reaction and obtains compound 1 (i.e. bicyclic [4.1.0] heptane of 7,7- dibromo)；The compound 1 is through peroxidization
Obtain compound 2 (i.e. 3, bicyclic [4.1.0] the hept- 2- ketone of 7,7- tribromos)；The compound 2 obtains compound 3 by substitution reaction
(i.e. bicyclic [4.1.0] the hept- 3- alkene -2- ketone of the bromo- 3- hydroxyl of 7,7- bis-)；The compound 3 obtains compound 4 by ring expansion
(i.e. the bromo- 2- hydroxyl cycloheptyl -2,4 of 4-, 6- triolefin -1- ketone)；Finally the compound 4 obtains target compound by alkylated reaction
5 (i.e. cypress oleyl alcohol).
The reaction formula of the preparation is as shown in fig. 1.In the figure, label 1,2,3,4,5 respectively indicates compound 1, chemical combination
Object 2, compound 3, compound 4 and target compound 5.
In the method for preparation cypress oleyl alcohol of the invention, the preparation of compound 1 includes the following steps:
Cyclohexene is mixed with bromoform and under the catalysis of triethylbenzene ammonium chloride and inorganic base carry out addition it is anti-
It answers, reaction temperature is -20 DEG C~30 DEG C, and the reaction time is 0.5~30 hour；Wherein, the volume ratio of cyclohexene and bromoform
It is 1: 0.5~1: 100, preferably 1: 2~1: 10, the volume ratio of cyclohexene and triethylbenzene ammonium chloride is 1000: 1~10:
1, preferably 100: 1~50: 1；Inorganic base includes sodium hydroxide, any one in potassium hydroxide；
End of reaction hydrochloric acid, concentration of hydrochloric acid are 1M~10M；Then separation is extracted with dichloromethane, from the dichloro
Compound 1, yield 73% are collected in dichloromethane.
The reaction formula of the preparation is as shown in Figure 2.In the figure, label 1 indicates compound 1.
1 compound 1 of embodiment is synthetically prepared
10 milliliters of cyclohexene are dissolved in 50 milliliters of bromoforms, triethylbenzene ammonium chloride (phase transfer catalysis (PTC) is added
Agent) 0.1 gram, above-mentioned solution is cooled to 0 DEG C；24 gram 50% of sodium hydrate aqueous solution (necleophilic reaction is quickly added dropwise after stirring
Catalyst), stirred 2 hours at 0 DEG C, then at continue at room temperature stirring 22 hours；It is subsequently cooled to 0 DEG C, the hydrochloric acid of 6M is added dropwise
30 milliliters；Organic phase is isolated, remaining compound 1 is extracted with dichloromethane in water phase；It is organic by anhydrous magnesium sulfate drying
Phase removes desiccant, solvent；Colourless liquid compound 1 is obtained by vacuum distillation, and yield is up to 73%.
The structure of compound 1 is characterized by hydrogen nuclear magnetic resonance spectrum (HNMR) and mass spectrum (ESI-MS), and related data is such as
Under:
1H NMR(CDCl3, 300MHz), δ: 2.38 (t, 2H), 1.32-1.78 (m, 8H)；ESI-MS:251 (M+)。
In the method for preparation cypress oleyl alcohol of the invention, the preparation of compound 2 includes the following steps:
Compound 1 and chromium trioxide are subjected to oxidation reaction under the auxiliary agent of ether, reaction temperature is -20 DEG C~40 DEG C,
Reaction time is 0.5-8 hours；Wherein, the mass ratio of compound 1 and chromium trioxide is 1: 30~1: 2, preferably are as follows: 1: 5~1:
3；The w/v of compound 1 and ether is 0.2g/ml~0.01g/ml, preferably 0.1g/ml~0.04g/ml；
Reactant is poured into water by end of reaction, is collected into compound 2, yield 90% with ether extraction and separation.
The reaction formula of the preparation is as shown in Figure 3.In the figure, label 1,2 respectively indicates compound 1 and compound 2.
2 compound 2 of embodiment is synthetically prepared
7.6 g of compound 1 are added in the diethyl ether solution of 200 milliliters of chromium trioxides (30 grams) at 0 DEG C, and in 25-30
It is stirred 1 hour at DEG C, reactant is poured into 1 liter of water, separate organic phase, remaining compound 2 is extracted with ether in water phase；
The organic phase and extract liquor that hybrid separation goes out, and use aqueous sodium carbonate, saturated common salt water washing, with remove in organic phase it is residual
The impurity stayed；After anhydrous magnesium sulfate drying, ether is distilled off, obtains compound 2 (6.8 grams, yield 90%).
The structure of compound 2 is characterized by hydrogen nuclear magnetic resonance spectrum and mass spectrum, and related data is as follows:
1H NMR(CDCl3, 300MHz), δ: 4.32 (t, 1H), 4.08 (d, 1H), 3.91 (m, 1H), 2.42 (m, 2H),
1.96 (m, 2H)；ESI-MS:343 (M+)。
In the method for preparation cypress oleyl alcohol of the invention, the preparation of compound 3 includes the following steps:
By compound 2 and dimethyl sulfoxide (DMSO, Dimethyl sulfoxide) organic solvent organic base catalysis
Lower progress hydroxyl substitution reaction, reaction temperature are 60 DEG C~150 DEG C, and the reaction time is 1~10 hour；Wherein, compound 2 with
The w/v of DMSO is 0.5g/ml to 0.001g/ml, preferably 0.1g/ml~0.01g/ml；Compound 2 and organic base
Molar ratio be 1: 0.2~1: 30, preferably 1: 1~1: 10；Organic base used includes one of pyridine, triethylamine, sodium alkoxide
Or it is a variety of；
End of reaction is quenched with hydrochloric acid, and the concentration of hydrochloric acid is 0.5M~6M；Then separation is extracted with dichloromethane to receive
Collect compound 3, yield 87%.
The reaction formula of the preparation is as shown in Figure 4.In the figure, label 2,3 respectively indicates compound 2 and compound 3.
3 compound 3 of embodiment is synthetically prepared
By 9 grams of pyridines, 13 g of compound 2 are dissolved in 300 milliliters of DMSO, are heated to 90-95 DEG C, and keep this temperature 4
Hour；It is cooled to room temperature, 300 milliliters of hydrochloric acid of 200 milliliters of methylene chloride and 2M are added；After mixing evenly, organic phase is separated；
Remaining compound 3 is extracted with dichloromethane in water phase；The organic phase and extract liquor that hybrid separation goes out, are washed with water, dry, and remove
Methylene chloride obtains (11g) yield of compound 3 up to 87%.
The structure of compound 3 is characterized by hydrogen nuclear magnetic resonance spectrum and mass spectrum, and related data is as follows:
1H NMR (CDCl3,300MHz), δ: 5.98 (t, 1H), 3.18 (d, 1H), 2.92 (m, 1H), 1.96 (m, 2H)；
ESI-MS:279 (M+).
In the method for preparation cypress oleyl alcohol of the invention, the preparation of compound 4 includes the following steps:
Under inert gas protection, by compound 3 and 1,11 carbon -7- alkene of 8- diazabicyclo (5.4.0) is in tetrahydro furan
It mutters and carries out ring expansion in solution, reaction temperature is -70 DEG C~0 DEG C, and the reaction time is 0.5~5 hour；Wherein, inert gas
Including any one in nitrogen, argon gas；Compound 3 and 1, mole between 11 carbon -7- alkene of 8- diazabicyclo (5.4.0)
Than being 1: 0.0001~1: 0.2, preferably 1: 0.0005~1: 0.001；Compound 3 and the w/v of tetrahydrofuran are
0.4g/ml~0.002g/ml, preferably 0.08g/ml~0.01g/ml；
End of reaction is quenched with the inorganic alkali solution that concentration is 0.1M~10M, and inorganic base includes sodium hydroxide, hydrogen-oxygen
Change any one in potassium；With salt acid for adjusting pH to 4~5 after being quenched；Then it is extracted with dichloromethane and separates and collects compound
4, yield 62%.
The reaction formula of the preparation is as shown in Figure 5.In the figure, label 3,4 respectively indicates compound 3 and compound 4.
4 compound 4 of embodiment is synthetically prepared
By 1.4 milligrams of 1,8- diazabicyclo (5.4.0), 11 carbon -7- under the conditions of nitrogen protection and -40 DEG C of temperature
Alkene (DBU) was added in 50 milliliters of tetrahydrofuran solutions of 1.45 g of compound 3, and in low temperature 2 hours, then was added
Temperature is slowly risen to 0 DEG C by 0.7 milligram of DBU；The sodium hydroxide solution of 20 milliliters of 2M is added in above-mentioned reactant, is stirred
It mixes 5 minutes；It is acidified with the hydrochloric acid of 2M, and compound 4 remaining in water phase is extracted with dichloromethane；It is dry with anhydrous magnesium sulfate
Dry extract liquor removes desiccant, methylene chloride and obtains compound 4 (0.6 gram), and yield is up to 62%.
The structure of compound 4 is characterized by hydrogen nuclear magnetic resonance spectrum and mass spectrum, and related data is as follows:
1H NMR (CDCl3,300MHz), δ: 7.65 (s, 1H), 7.52 (d, 1H), 7.10 (d, 1H), 6.73 (d, 1H)；
ESI-MS:199 (M+).
In the method for preparation cypress oleyl alcohol of the invention, the preparation of compound 5 includes the following steps:
Compound 4 and trimethacrylate base tin are blended in Isosorbide-5-Nitrae-dioxane, and in bi triphenyl phosphorus palladium chloride
Reaction is alkylated under catalysis, reaction temperature is 70 DEG C~180 DEG C, and the reaction time is 0.5~5 hour；Wherein, compound 4
Molar ratio between trimethacrylate base tin is 1: 0.5~1: 20, preferably 1: 0.8~1: 2；Compound 4 and Isosorbide-5-Nitrae-dioxy
The w/v of six rings is 0.2g/ml~0.001g/ml, preferably 0.07g/ml~0.01g/ml；
End of reaction, the solid being filtered to remove in reactant, is distilled off solvent, in ethanol by residue dissolution,
Palladium carbon catalysis is lower to carry out hydro-reduction reaction；
The hydro-reduction end of reaction, Filtration of catalyst, distillation remove ethyl alcohol, obtain compound 5, yield is
53%.
During hydro-reduction, the palladium carbon of 0.5-10% is added, is preferably added 5%, the pressure of hydrogen be 0.1MPa~
2MPa, preferably 0.1MPa~0.5MPa；Hydrogenation time is 6~48 hours, preferably 18~26 hours；Residue and ethyl alcohol
W/v is 0.3g/ml~0.001g/ml, preferably 0.07g/ml~0.01g/ml；Hydrogenation temperature is 0 DEG C~150 DEG C,
Preferably 20 DEG C~50 DEG C.
The reaction formula of the preparation is as shown in Figure 6.In the figure, label 4,5 respectively indicates compound 4 and compound 5.
5 compound 5 of embodiment is synthetically prepared
0.3 gram of 2 g of compound 4,3 grams of trimethacrylate base tin and catalyst bi triphenyl phosphorus palladium chloride mixing are added
Into 100 milliliters of Isosorbide-5-Nitrae-dioxane, flows back 1 hour, be alkylated reaction；It is filtered to remove and is precipitated in reaction process
Solid, it is dry, remove Isosorbide-5-Nitrae-dioxane；Residue after removal solvent is added in 100 milliliters of ethyl alcohol, adds 5%
Palladium carbon, keep 1 atmospheric pressure of Hydrogen Vapor Pressure to carry out hydro-reduction reaction；After reacting 24 hours at room temperature, filtering removes solid
Catalyst and ethyl alcohol obtain compound 5 (0.94 gram), produce and reach rate 53%.
The structure of compound 5 is characterized by hydrogen nuclear magnetic resonance spectrum and mass spectrum, and related data is as follows:
1H NMR (CDCl3,300MHz), δ: 7.65 (s, 1H), 7.52 (d, 1H), 7.08 (d, 1H), 6.70 (d, 1H)；
ESI-MS:164 (M+).
To sum up, by the present invention in that using cyclohexene as initial feed, so that no matter in the preservation cost of raw material, still
It is all greatly increased in terms of safety, thus from essence solves the production of cypress oleyl alcohol industrialized scale metaplasia
Safety issue；In addition, being avoided due to the process that method of the invention is re-introduced into isopropyl by first preparing seven-members ring structure
The appearance of isomer, ensure that large-scale production yield and higher purity；Further more, method of the invention is avoided
The step of stronger compound of lithium alkylide/Grignard Reagent isoreactivity participates in correlated response, to eliminate cypress oleyl alcohol scale
Security risk during metaplasia production；.Therefore the highly significant of the beneficial effect of visible technical solution of the present invention acquirement.
Claims (11)
1. a kind of method for preparing cypress oleyl alcohol, comprising:
Starting material compound cyclohexene and bromoform are subjected to addition reaction and obtain referred to as 7,7- dibromo bicyclic [4.1.0] heptan
First compound of alkane；First compound obtains referred to as 3 through peroxidization, bicyclic [4.1.0] the hept- 2- ketone of 7,7- tribromos
Second compound；The second compound obtains bicyclic [4.1.0] the hept- 3- alkene-of the bromo- 3- hydroxyl of referred to as 7,7- bis- by substitution reaction
The third compound of 2- ketone；The third compound obtains the bromo- 2- hydroxyl cycloheptyl -2,4 of referred to as 4-, 6- triolefin-by ring expansion
The fourth compound of 1- ketone；The fourth compound obtains the 5th compound of referred to as cypress oleyl alcohol by alkylated reaction.
2. according to the method for claim 1, which is characterized in that the preparation of the first compound specifically comprises the following steps:
The cyclohexene is mixed with the bromoform and carries out institute under the catalysis of triethylbenzene ammonium chloride and inorganic base
Addition reaction is stated, reaction temperature is -20 DEG C~30 DEG C, and the reaction time is 0.5~30 hour；Wherein, the cyclohexene with it is described
The volume ratio of bromoform is 1: 0.5~1: 100, and the volume ratio of the cyclohexene and the triethylbenzene ammonium chloride is 1000
: 1~10: 1；
The addition reaction is finished with hydrochloric acid, and the concentration of the hydrochloric acid is 1M~10M；Then with dichloromethane solution extraction point
From collecting the first compound from the dichloromethane solution.
3. according to the method for claim 2, which is characterized in that
The volume ratio of the cyclohexene and the bromoform is further preferably 1: 2~1: 10, the cyclohexene with it is described
The volume ratio of triethylbenzene ammonium chloride is more preferably 100: 1~50: 1；The inorganic base includes sodium hydroxide, hydroxide
Any one in potassium.
4. according to the method for claim 1, which is characterized in that the preparation of second compound specifically comprises the following steps:
First compound 1 and chromium trioxide are subjected to oxidation reaction under the auxiliary agent of ether, reaction temperature is -20 DEG C~40 DEG C,
Reaction time is 0.5~8 hour；Wherein, the mass ratio of the first compound and the chromium trioxide is 1: 30~1: 2, and first changes
The w/v for closing object and the ether is 0.2g/ml~0.01g/ml；
The oxidation reaction, which finishes, is poured into reactant in water, is collected into second compound with ether extraction and separation.
5. according to the method for claim 4, which is characterized in that
The mass ratio of first compound and the chromium trioxide is further preferred are as follows: 1: 5~1: 3；First compound and ether
W/v is more preferably 0.1g/ml~0.04g/ml.
6. according to the method for claim 1, which is characterized in that the preparation of third compound specifically comprises the following steps:
Second compound and dimethyl sulfoxide, that is, DMSO organic solvent are subjected to hydroxyl substitution reaction under the catalysis of organic base, instead
Answering temperature is 60 DEG C~150 DEG C, and the reaction time is 1~10 hour；Wherein, the w/v of second compound and the DMSO
For 0.5g/ml to 0.001g/ml；Second compound and the molar ratio of the organic base are 1: 0.2~1: 30；
The hydroxyl substitution reaction is finished with hydrochloric acid, and the concentration of the hydrochloric acid is 0.5M~6M；Then dichloromethane solution is used
Extraction and separation are collected into third compound.
7. according to the method for claim 6, which is characterized in that
The w/v of second compound and the DMSO are more preferably 0.1g/ml~0.01g/ml；Second compound
Molar ratio with the organic base is more preferably 1: 1~1: 10；The organic base includes pyridine, triethylamine, in sodium alkoxide
It is one or more.
8. according to the method for claim 1, which is characterized in that the preparation of fourth compound specifically comprises the following steps:
Under inert gas protection, by third compound and 1,11 carbon -7- alkene of 8- diazabicyclo (5.4.0) is in tetrahydrofuran
Ring expansion is carried out in solution, reaction temperature is -70 DEG C~0 DEG C, and the reaction time is 0.5~5 hour；Wherein, third compound
Molar ratio between 1,8- diazabicyclo (5.4.0), the 11 carbon -7- alkene is 1: 0.0001~1: 0.2；Third chemical combination
The w/v of object and the tetrahydrofuran is 0.4g/ml~0.002g/ml；
The ring expansion finishes, and is quenched with the inorganic alkali solution that concentration is 0.1M~10M；Salt acid for adjusting pH is used after being quenched
To 4~5；Then it is extracted with dichloromethane and separates and collects fourth compound.
9. according to the method for claim 8, which is characterized in that the inert gas includes nitrogen, any one in argon gas
Kind；Molar ratio between third compound and 1,8- diazabicyclo (5.4.0), the 11 carbon -7- alkene is more preferably 1:
0.0005~1: 0.001；The w/v of third compound and the tetrahydrofuran be more preferably 0.08g/ml~
0.01g/ml；The inorganic base includes sodium hydroxide, any one in potassium hydroxide.
10. according to the method for claim 9, which is characterized in that the preparation of the 5th compound specifically comprises the following steps:
Fourth compound and trimethacrylate base tin are blended in Isosorbide-5-Nitrae-dioxane, and urged in bi triphenyl phosphorus palladium chloride
Reaction is alkylated under the catalysis of agent, reaction temperature is 70 DEG C~180 DEG C, and the reaction time is 0.5~5 hour；Wherein,
Molar ratio between four compounds and the trimethacrylate base tin is 1: 0.5~1: 20；Fourth compound and the Isosorbide-5-Nitrae-two
The w/v of six ring of oxygen is 0.2g/ml~0.001g/ml；
The alkylated reaction finishes, the solid being filtered to remove in reactant, and solvent is distilled off, and residue is dissolved in ethyl alcohol
In, hydro-reduction reaction is carried out under the palladium carbon catalysis of 0.5-10%, wherein the pressure of hydrogen is 0.1MPa~2MPa, the hydrogenation
The time of reduction reaction is 6~48 hours, and the w/v of the residue and the ethyl alcohol is 0.3g/ml~0.001g/
Ml, the temperature of hydro-reduction reaction are 0 DEG C~150 DEG C；
The hydro-reduction end of reaction is filtered to remove the bi triphenyl phosphorus palladium chloride catalyst, and distillation removes ethyl alcohol,
Obtain the cypress oleyl alcohol.
11. according to the method for claim 10, which is characterized in that
Molar ratio between fourth compound and the trimethacrylate base tin is more preferably 1: 0.8~1: 2；4th chemical combination
The w/v of object and the Isosorbide-5-Nitrae-dioxane is more preferably 0.07g/ml~0.01g/ml；In the hydro-reduction
In reaction, preferably carried out under 5% palladium carbon catalysis, the pressure of hydrogen is more preferably 0.1MPa~0.5MPa；Also,
The time of hydro-reduction reaction is more preferably 18~26 hours；The w/v of the residue and ethyl alcohol is further
Preferably 0.07g/ml~0.01g/ml；The temperature of hydro-reduction reaction is more preferably 20 DEG C~50 DEG C.
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| CN111280249A (en) * | 2020-03-23 | 2020-06-16 | 中国农业科学院农业环境与可持续发展研究所 | Preservative based on cypress oil alcohol and magnolia polyphenol and preparation method thereof |
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| JP2003201264A (en) * | 2001-12-28 | 2003-07-18 | Fujita Masao | Hinokitiol derivative and skin care preparation and hair cosmetic containing the same |
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| JP2003201264A (en) * | 2001-12-28 | 2003-07-18 | Fujita Masao | Hinokitiol derivative and skin care preparation and hair cosmetic containing the same |
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| CN111280249A (en) * | 2020-03-23 | 2020-06-16 | 中国农业科学院农业环境与可持续发展研究所 | Preservative based on cypress oil alcohol and magnolia polyphenol and preparation method thereof |
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