CN102344434A - Method for preparing difluorobenzene derivatives - Google Patents
Method for preparing difluorobenzene derivatives Download PDFInfo
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- CN102344434A CN102344434A CN2011102082036A CN201110208203A CN102344434A CN 102344434 A CN102344434 A CN 102344434A CN 2011102082036 A CN2011102082036 A CN 2011102082036A CN 201110208203 A CN201110208203 A CN 201110208203A CN 102344434 A CN102344434 A CN 102344434A
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Abstract
To provide a method for efficiently producing conventionally hardly producible difluorobenzene derivatives having alkenyl on a side chain thereof, and to provide an intermediate usable for the production method. The production method for difluorobenzene comprises steps represented by general formulae (2a), (2b) and (2c). And each production intermediate compound thereof is provided.
Description
It is on March 30th, 2007, Application No. 200710091376.8, the divisional application of entitled " preparation method of difluoro bezene derivative " applying date that the present invention, which is,.
Technical field
The present invention relates to a kind of preparation method of difluoro bezene derivative and its prepare intermediate.
Background technology
The advantages of liquid crystal display cells are due to the operation of its low pressure, slim display, is nowadays widely used.The display mode of liquid crystal display cells had TN (twisted-nematic), STN (super twisted nematic), or active-matrix (active-matrix) (TFT that TN is formed on substrate in the past：Thin film transistor (TFT)) etc., they are to utilize dielectric constant anisotropy value for positive liquid-crystal composition.But these display modes have one disadvantage in that i.e. its visual angle is narrower, desired raising of being maximized recently as liquid crystal board improves this problem as larger problem.
As its solution, the display mode such as vertical orientation mode, IPS (In Plane Switching transverse electric fields effect) started to be practical in recent years.Vertical orientation mode is the vertical orientated method to improve visual angle using liquid crystal molecule, and it is negative liquid-crystal composition to use dielectric constant anisotropy value.Other IPS, is, to improve the method at visual angle, to use the liquid-crystal composition that dielectric constant anisotropy value is negative or positive in the horizontal direction of relative glass substrate using transverse electric switched liquid crystal molecule.Thus, the liquid-crystal compounds and liquid-crystal composition that are required to dielectric constant anisotropy value in it can improve the vertical orientation mode of effective display mode at visual angle and IPS to bear, highly desirable to be achieved.
Be the liquid-crystal compounds used in negative liquid-crystal composition as dielectric constant anisotropy value, 2,3- difluorophenyls derivative can be enumerated (with reference to patent document 1).But, the compound that side chain is amino is only disclosed in patent document 1, the compound that side chain is alkenyl is not disclosed completely, its preparation method is not also known.Additionally, it is known that therefore 1 of the phenyl ring and 4 upper compound with alkoxy does not use (with reference to non-patent literature 1) due to chemically unstable as liquid crystal material, therefore do not have progress to the exploitation of the compounds process for production thereof.
Patent document 1：Special public affairs table 2-503568 publications
Non-patent literature 1：Natural pond field, " trend of liquid crystal material ", monthly magazine デ イ ス プ レ イ, in March, 1998, volume 4, No. 3 (page 5)
The content of the invention
Having on present invention offer side chain prepare intermediate used by the effective preparation method and the preparation method of the difluoro bezene derivative of alkenyl.
The present inventor is attentively studied to solve above-mentioned problem, as a result the method by the way that compound shown in formula (1) to be converted to compound shown in formula (2) is found, the difluoro bezene derivative on side chain with alkenyl can be effectively prepared, so as to complete the present invention.
The present invention relates to,
Compound represented by formula (1) carries out reacting compound shown in the formula of obtaining (2) with the phenates made from 2,3- difluorophenols；
Compound shown in formula (13) is obtained after compound oxidation shown in the formula (2)；
The compound shown in formula (7) of phenates made from compound is reacted as shown in the formula (13), obtains compound shown in formula (16)；
Compound shown in formula (17) is obtained after the deprotection of compound shown in the formula (16)；
Compound shown in the formula (17) obtains compound shown in formula (18) with hydrolyzable after reactant salt in methoxy phosphine；
Compound shown in the formula (18) obtains the preparation method of compound shown in formula (9) with reactant salt in alkylphosphines,
And,
Compound shown in formula (1) obtains compound shown in formula (2) with the phenates reaction made from 2,3- difluorophenols；
Compound shown in formula (3) is obtained after the deprotection of compound shown in the formula (2)；
Compound shown in the formula (3) obtains compound shown in formula (4) with hydrolyzable after reactant salt in methoxy phosphine；
Compound shown in the formula (4) obtains compound shown in formula (5) with reactant salt in alkylphosphines；
Compound shown in formula (6) is obtained after compound oxidation shown in the formula (5)；
The compound shown in formula (7) of phenates made from compound is reacted as shown in the formula (6), obtains the preparation method of compound shown in formula (9).
Wherein,
In formula (1), (2), (13), (16), R1And R2Respective independent methyl, ethyl or propyl group are represented, or, R1And R2Expression-CH2CH2-、-CH2CH2CH2- or-CH2C(CH3)2CH2-；
In formula (1), X1Represent chlorine, bromine, iodine, phenylsulfonyloxy, tolysulfonyl epoxide, methanesulfonyloxy group or trifluorometanesulfonyloxy；
In formula (5), (6), (9), R3Represent the alkyl of hydrogen atom or carbon number 1 to 5；
In formula (7), X2Represent chlorine, bromine, iodine, phenylsulfonyloxy, tolysulfonyl epoxide, methanesulfonyloxy group or trifluorometanesulfonyloxy；
In formula (7), (9), (16), (17), (18), R4Represent the alkenyl or expression (8) of carbon number 2 to 12；
In formula (8), R5For the alkyl of carbon number 1 to 12, the alkenyl of carbon number 2 to 12, the alkoxy of carbon number 1 to 12, carbon number 2 to 12 alkenyloxy group.
Further, the present invention to provide and prepare intermediate used by preparation process of the present invention, the compound as shown in formula (2), (3), (4), (5), (6), (13), (16), (17) and (18).
The preparation method of the present invention, it is very useful as the preparation method of difluoro bezene derivative.In addition, the preparation method of the present invention due to introducing side chain R in a final step3Or R4, can extremely be readily synthesized only R3Or R4Compound group shown in different formulas (9).
Embodiment
In the preparation method of the present invention, then 2,3- difluorophenols and alkali effect generation phenates obtain compound shown in formula (2), the alkali used can enumerate metal hydride, metal carbon with the reaction of compound shown in formula (1)
Hydrochlorate, metal phosphate, metal hydroxides, metal carboxylate, metal amide and metal etc., wherein preferred as alkali hydride, alkali metal phosphate, alkali metal phosphate, alkali carbonate, alkali metal hydroxide, alkali metal amide, alkali metal；Further preferred alkali metal phosphate, alkali metal hydride, alkali carbonate.The preferred lithium hydride of alkali metal hydride, sodium hydride, hydrofining, alkali metal phosphate preferably phosphoric acid tripotassium, the preferred sodium carbonate of alkali carbonate, sodium acid carbonate, cesium carbonate, potassium carbonate, saleratus.
As reaction dissolvent, as long as the progress for being adapted to reaction is any, but ether solvent, chlorine class solvent, varsol, fragrant same clan solvent, polar solvent etc. are preferably used.As ether solvent, Isosorbide-5-Nitrae-two can be enumerated
Alkane, 1,3- bis-
Alkane, tetrahydrofuran, Anaesthetie Ether, t-butyl methyl ether etc., dichloromethane, 1 can be enumerated as chlorine class solvent, 2- dichloroethanes, four salinization carbon etc., amylene, hexene, cyclohexene, heptane, octane etc. can be enumerated as varsol, benzene,toluene,xylene, trimethylbenzene, chlorobenzene, dichloro-benzenes etc. can be enumerated as fragrant same clan's solvent, polar solvent can enumerate the preferably example such as DMF, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), sulfolane.The polar solvent of ether solvent, the DMF of wherein more preferred tetrahydrofuran, Anaesthetie Ether etc. etc..In addition, each solvent of preceding note can be used alone, can also 2 kinds or more be used in mixed way.
Though reaction temperature can be carried out in from the freezing point of solvent to reflow temperature range, preferably 0 DEG C to 150 DEG C, further preferred 30 DEG C to 120 DEG C.In addition, the phenates of generation can react after first separation with compound shown in formula (1), it can not also separate and be reacted, but consider that progress reacts preferable without separation from the difficulty or ease of operation.
The deprotection of compound, is preferably carried out in acid condition shown in formula (2) or formula (16).The acid used, can enumerate the Bronsted acid of formic acid, acetic acid, trifluoroacetic acid, oxalic acid, p-methyl benzenesulfonic acid etc., lewis acid of boron trifluoride element etc. etc., but preferably use formic acid.
Reaction dissolvent, any one can be used as long as being adapted to the progress of reaction, preferably use ether solvent, chlorine class solvent, ketones solvent, varsol, fragrant same clan's solvent, polar solvent etc., lower can also be reacted solvent-free.Ether solvent, can enumerate Isosorbide-5-Nitrae-two
Alkane, 1,3- bis-
Alkane, tetrahydrofuran, Anaesthetie Ether, t-butyl methyl ether etc., chlorine class solvent has dichloromethane, 1,2- dichloroethanes, chloroform, four salinization carbon etc., ketones solvent can enumerate acetone, 2- butanone etc., varsol can enumerate amylene, hexene, cyclohexene, heptane, octane etc., fragrant same clan's solvent can enumerate benzene,toluene,xylene, trimethylbenzene, chlorobenzene, dichloro-benzenes etc., and polar solvent can enumerate the preferably example such as acetonitrile, dimethyl sulfoxide (DMSO).Wherein, the varsol of more preferred amylene, hexene, cyclohexene, heptane, octane etc., benzene,toluene,xylene
Deng fragrant same clan's solvent etc..In addition, each solvent of preceding note can be used alone, solvent that can also be 2 kinds or more is used in mixed way.
Though reaction temperature can be carried out in from the freezing point of solvent to reflow temperature range, preferably 0 DEG C to 100 DEG C, further preferred 30 DEG C to 60 DEG C.
Compound shown in formula (3) or formula (17) and hydrolyzable after reactant salt in methoxy phosphine, compound shown in formula (4) is can obtain from formula (3), compound shown in formula (18) is can obtain from formula (17).Methoxy phosphine inner salt can be made from phosphonium salt, phosphate etc., be preferably made from methoxymethyl triphenylphosphonium phosphonium salt.
Acted on when preparing inner salt using methoxymethyl triphenylphosphonium phosphonium salt with alkali, the preferred potassium tert-butoxide of alkali, n-BuLi, phenyl lithium, sodium hydride for using etc., more preferred potassium tert-butoxide.Reaction dissolvent preferably uses ether solvent, fragrant same clan solvent, polar solvent etc..Ether solvent can enumerate Isosorbide-5-Nitrae-two
Alkane, 1,3- bis-
Alkane, tetrahydrofuran, Anaesthetie Ether, t-butyl methyl ether etc., fragrant same clan's solvent can enumerate benzene,toluene,xylene, trimethylbenzene etc., and polar solvent can enumerate DMF etc..Wherein more preferred tetrahydrofuran, toluene.In addition, each solvent of preceding note can be used alone, solvent that can also be 2 kinds or more is used in mixed way.
Reaction temperature can from the freezing point of solvent to reflow temperature range in carry out, but preferably -40 DEG C to 30 DEG C, further preferably -20 DEG C to 20 DEG C.Obtained inner salt reacts preferably under unseparated situation with compound shown in formula (3).In addition, alkali can also be added in the mixture of compound shown in methoxymethyl triphenylphosphonium phosphonium salt, formula (3).
Hydrolyzable can be carried out under an acid catalysis.The acid used, can enumerate watery hydrochloric acid, aqueous sulfuric acid etc..Reaction dissolvent, any one can be used as long as being adapted to the progress of reaction, preferably use ether solvent, varsol, fragrant same clan's solvent etc., lower can also be reacted solvent-free.Ether solvent, can enumerate Isosorbide-5-Nitrae-twoAlkane, 1,3- bis-
Alkane, tetrahydrofuran, Anaesthetie Ether, t-butyl methyl ether etc., varsol can enumerate amylene, hexene, cyclohexene, heptane, octane etc., and fragrant same clan's solvent can enumerate benzene,toluene,xylene, trimethylbenzene, chlorobenzene, dichloro-benzenes etc..Wherein, more preferred tetrahydrofuran.In addition, each solvent of preceding note can be used alone, solvent that can also be 2 kinds or more is used in mixed way.
Reaction temperature can from the freezing point of solvent to reflow temperature range in carry out, preferably 0 DEG C to 80 DEG C.
Compound shown in so obtained formula (4) or formula (18), what is obtained for cyclohexene ring is cis with trans mixture, but as liquid-crystal compounds intermediate use it is preferred trans.For formula (4) or formula (18)
The cyclohexene ring of the combination formyl side of shown compound, by the way that its cis-trans isomerization can be made with alkali effect, so that trans surplus.The preferred NaOH of alkali, potassium hydroxide for now using etc., the preferred methanol of reaction dissolvent, ethanol, tetrahydrofuran etc., preferably -40 DEG C to 20 DEG C, further preferably -20 DEG C to 10 DEG C of reaction temperature.
Compound shown in formula (4) or formula (18) and reactant salt in alkylphosphines, formula (5) can be obtained from formula (4), compound shown in final goal product formula (9) is obtained from formula (18).In the reaction, alkylphosphines inner salt can be made from phosphonium salt, phosphate etc., be preferably made from alkyl triphenyl phosphonium phosphonium salt.
Acted on when inner salt is made using alkyl triphenyl phosphonium phosphonium salt with alkali, the preferred potassium tert-butoxide of alkali, n-BuLi, phenyl lithium, sodium hydride for using etc., more preferred potassium tert-butoxide.Reaction dissolvent preferably uses ether solvent, fragrant same clan solvent, polar solvent etc..Ether solvent, can enumerate Isosorbide-5-Nitrae-two
Alkane, 1,3- bis-
Alkane, tetrahydrofuran, Anaesthetie Ether, t-butyl methyl ether etc., fragrant same clan's solvent can enumerate benzene,toluene,xylene, trimethylbenzene etc., and polar solvent can enumerate DMF etc., wherein more preferred tetrahydrofuran, toluene.In addition, each solvent of preceding note can be used alone, solvent that can also be 2 kinds or more is used in mixed way.Reaction temperature can from the freezing point of solvent to reflow temperature range in carry out, preferably from -40 DEG C to 30 DEG C, further preferably -20 DEG C to 20 DEG C.The inner salt of gained reacts preferably under unseparated situation with compound shown in formula (4).In addition, alkali can also be added in the mixture of compound shown in alkyl triphenyl phosphonium phosphonium salt, formula (4).Alkyl triphenyl phosphonium phosphonium salt preferably uses methyl triphenyl phosphonium salt.
The oxidation of compound shown in formula (2) or formula (5), it is possible to use obtain boron compound with trialkyl borate reaction after organometallic reagent deprotonation, then acted on oxidant.Reaction dissolvent, can be can enumerate ether solvent, varsol etc. as long as the progress for being adapted to reaction is any.As ether solvent, Isosorbide-5-Nitrae-two can be enumerated
Alkane, 1,3- bis-
Alkane, tetrahydrofuran, Anaesthetie Ether, t- butyl methyl ethers etc., varsol can enumerate amylene, hexene, cyclohexene, heptane, octane etc., wherein it is preferred that tetrahydrofuran.Organometallic reagent can enumerate n-BuLi, s-butyl lithium, tert-butyl lithium, lithium methide, lithium diisopropylamide etc., from the aspect of obtaining and operating difficulty or ease preferred n-BuLi, s-butyl lithium, due to can the effective more preferred s-butyl lithium of deprotonation.In addition, during deprotonation, the potassium tert-butoxide as additive can also be added together with above-mentioned organometallic reagent, the alkali such as tetramethylethylened.Preferably -100 DEG C to -20 DEG C, further preferably -78 DEG C to -40 DEG C of reaction temperature during deprotonation.
Trialkyl borate, preferably uses trimethylborate.Preferably -100 DEG C to -20 DEG C, further preferably -78 DEG C to -40 DEG C of reaction temperature during boronation.Obtained boron compound can be with first separation, can also be regardless of
From direct and oxidant reaction.Again can also with oxidant reaction in addition, being changed into after obtained boron compound hydrolyzable after boronic acid compounds.
Oxidant, preferably uses hydrogen peroxide, peracetic acid or performic acid.Preferably -78 DEG C to 70 DEG C, further preferred 0 DEG C to 50 DEG C of reaction temperature.In addition, during with oxidant reaction, solvent is aqueous also to have no relations.
Carbonyl utilizes R in formula (1), formula (2), formula (13) and compound shown in formula (16)1And R2Protected.R1And R2Methyl, ethyl or propyl group each are stood alone as, or, R1And R2Expression-CH2CH2- ,-CH2CH2CH2- or-CH2C(CH3)2CH2-, work as R1And R2For-CH2CH2- ,-CH2CH2CH2- or-CH2C(CH3)2CH2- when, the specific formula described in formula (1) is as follows.
In formula (1), preferably R1And R2It is methyl, or R1And R2For-CH2CH2- or-CH2CH2CH2-。X1And X2For chlorine, bromine, iodine, phenylsulfonyloxy, preferably tolysulfonyl epoxide, methanesulfonyloxy group or trifluorometanesulfonyloxy, bromine or methanesulfonyloxy group.R4For the alkenyl of carbon number 2 to 12, preferably 3- cyclobutenyls and 4- pentenyls.R5For the alkyl of carbon number 1 to 12, the alkenyl of carbon number 2 to 12, the alkoxy of carbon number 1 to 12, the alkyl of the alkenyloxy group of carbon number 2 to 12, preferably carbon number 1 to 12 or the alkenyl of carbon number 2 to 12, the alkyl of further preferred carbon number 1 to 7.
The present invention formula (2) prepare intermediate be further specifically preferably as follows as described in compound.
Wherein further preferred formula (2a), formula (2b) or compound shown in formula (2d).
R in formula (5)3For hydrogen atom or the alkyl of carbon number 1 to 5, preferably hydrogen atom or methyl, more preferably hydrogen atom.
R in formula (6)3For hydrogen atom or the alkyl of carbon number 1 to 5, preferably hydrogen atom or methyl, more preferably hydrogen atom.
Prepare intermediate of the present invention such as formula (13) is further specifically preferably as follows shown compound.
Wherein further preferred formula (13a), formula (13b) or compound shown in formula (13d).
The present invention prepares intermediate compound further preferably as shown in following formula (16a) to formula (16l) as shown in formula (16).
In formula, R6For the alkenyl of carbon number 2 to 12.
Formula (16a) is arrived in formula (16f), R6It is preferably specifically 3- cyclobutenyls, 3- pentenyls, 4- pentenyls or 4- hexenyls, further preferred 3- cyclobutenyls or 4- pentenyls.
In formula, R5For the alkenyloxy group of the alkyl of carbon number 1 to 12, the alkenyl of carbon number 2 to 12, the alkoxy of carbon number 1 to 12 or carbon number 2 to 12.
Formula (16g) is arrived in formula (16l), R5The preferably alkenyloxy group of the alkyl of carbon number 1 to 7, the alkenyl of carbon number 2 to 7, the alkoxy of carbon number 1 to 7 or carbon number 2 to 7, the alkyl of further preferred carbon number 1 to 5, the alkenyl of carbon number 2 to 5, the alkenyloxy group of the alkoxy of carbon number 1 to 5 or carbon number 2 to 5, the alkyl of particularly preferred carbon number 1 to 5 or the alkenyl of carbon number 2 to 5.Alkenyl preferred vinyl, 1- acrylic, 3- cyclobutenyls or 3- pentenyls, particularly preferred vinyl.
Prepare intermediate of the present invention as shown in formula (17) is further specifically preferably as follows compound shown in formula (17a) and formula (17b).
In formula, R6For the alkenyl of carbon number 2 to 12, R5For the alkenyloxy group of the alkyl of carbon number 1 to 12, the alkenyl of carbon number 2 to 12, the alkoxy of carbon number 1 to 12 or carbon number 2 to 12.
In formula (17a), R6It is preferably specifically 3- cyclobutenyls, 3- pentenyls, 4- pentenyls or 4- hexenyls, further preferred 3- cyclobutenyls or 4- pentenyls.
In formula (17b), R5The preferably alkoxy or carbon number of the alkenyloxy group of the alkyl of carbon number 1 to 7, the alkenyl of carbon number 2 to 7, the alkoxy of carbon number 1 to 7 or carbon number 2 to 7, the more preferably alkyl of carbon number 1 to 5, the alkenyl of carbon number 2 to 5, carbon number 1 to 5
The alkyl of 2 to 5 alkenyloxy group, particularly preferably carbon number 1 to 5 or the alkenyl of carbon number 2 to 5.Alkenyl preferred vinyl, 1- acrylic, 3- cyclobutenyls or 3- pentenyls, particularly preferred vinyl.
Prepare intermediate of the present invention as shown in formula (18) is specifically preferably as follows compound shown in formula (18a) and formula (18b).
In formula, R6For the alkenyl of carbon number 2 to 12, R5For the alkenyloxy group of the alkyl of carbon number 1 to 12, the alkenyl of carbon number 2 to 12, the alkoxy of carbon number 1 to 12 or carbon number 2 to 12.
In formula (17a), R6It is preferably specifically 3- cyclobutenyls, 3- pentenyls, 4- pentenyls or 4- hexenyls, more preferably 3- cyclobutenyls or 4- pentenyls.
In formula (17b), R5The preferably alkenyloxy group of the alkyl of carbon number 1 to 7, the alkenyl of carbon number 2 to 7, the alkoxy of carbon number 1 to 7 or carbon number 2 to 7, the alkenyloxy group of the more preferably alkyl of carbon number 1 to 5, the alkenyl of carbon number 2 to 5, the alkoxy of carbon number 1 to 5 or carbon number 2 to 5, the alkyl of particularly preferred carbon number 1 to 5 or the alkenyl of carbon number 2 to 5.Alkenyl preferred vinyl, 1- acrylic, 3- cyclobutenyls or 3- pentenyls, particularly preferred vinyl.
Embodiment
Hereinafter, enumerate embodiment and the present invention is described in further detail, but the present invention is not restricted to these embodiments.The structure of compound, it is possible to use nuclear magnetic resonance (NMR), mass spectral analysis (MS) etc. is confirmed.
Compound is described using following abbreviation.
THF：Tetrahydrofuran
DMF：DMF
Me：Methyl
Et：Ethyl
Bu：Butyl
Ph：Phenyl
Ms：Methane sulfonyl
Reference example
The initial substance of the present invention is compound shown in formula (1), it is possible to use prepared by for example following method.
In formula, R1And R2For expression and formula (1) identical meaning, Ms is methane sulfonyl.
Embodiment 1：The synthesis 1 of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (If)
1-1：The synthesis of 3- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -1,2- difluorobenzene (Ia)
Loprazolam (4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl) methyl, 2,3- difluoromethane sulfonic acid (4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl) methyl esters 122.9g, 2,3- difluorophenol 49.5g, tripotassium phosphate 235.4g and DMF 690mL are mixed, the 3 stirring hour at 80 DEG C.Reactant mixture is filtered, solid constituent is cleaned using DMF, filtering.Merging filtrate adds frozen water, and leaching separates out solid, is dissolved in acetic, hexene, the mixed solvent of toluene.It is loaded into column chromatography, decompression evaporates solvent, residue recrystallizes 3- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -1, the 2- difluorobenzene (Ia) for being refining to obtain 111.6g.Compound (Ia), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：366(M+)
1H-NMR (60MHz, CDCl3)
δ：1.3-2.0 (m, 19H), 3.8-4.0 (m, 6H), 6.4-6.6 (m, 2H), 6.8-7.0 (m, 1H)
1-2：The synthesis of 4- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -2,3- difluorophenol (Ig)
90g 3- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -1,2- difluorobenzene (Ia) is dissolved in 540mL THF.Secondary BuLi (1.0M cyclohexene solution) 260mL is added at -60 DEG C of temperature inside, is stirred 2 hours.Trimethylborate 29g is added at -60 DEG C of temperature inside, 20 DEG C are warming up to.15% hydrogen peroxide 72mL is added, is stirred 5 hours at 35 DEG C.Add and 10% is utilized after 10% aqueous solution of sodium bisulfite
Hydrochloric acid is neutralized, and is divided and is taken after organic layer, and water layer is extracted with 400mL toluene, is merged organic layer and is cleaned using 10% saline solution 250mL and water 250mL, utilizes anhydrous sodium sulfate drying.Decompression evaporates solvent, and residue recrystallization is refining to obtain 4- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -2,3- difluorophenol (Ib) 87.9g.Compound (Ib), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：382(M+)
1H-NMR (60MHz, CDCl3)
δ：1.3-2.2 (m, 19H), 3.8-4.0 (m, 6H), 4.0-6.0 (s, 1H), 6.3-6.5 (m, 2H)
1-3：The synthesis of fluoro- 1- (the 4- amylenes oxygen) benzene (Ih) of 4- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -2,3- bis-
The bromo- 1- amylenes of 5-, 4- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -2,3- difluorophenol (Ig), tripotassium phosphate and DMF are mixed, stirred 2 hours at 130 DEG C.Add water, extracted with toluene, cleaning decompression after organic layer with water and saturated aqueous common salt evaporates solvent.Residue is refined using column chromatography and recrystallization, obtains fluoro- 1- (the 4- amylenes oxygen) benzene (Ih) of 4- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -2,3- bis-.Compound (Ih), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：450(M+)
1H-NMR (60MHz, CDCl3)
δ：1.3-2.2 (m, 23H), 3.8-4.0 (m, 8H), 4.9-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.3-6.5 (m, 2H)
1-4：The synthesis of 4- (- 4 '-yl of bicyclic hex- 4- ketone) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (Ii)
Toluene and formic acid are added in fluoro- 1- (the 4- amylenes oxygen) benzene (Ih) of 4- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -2,3- bis-, is stirred 2 hours at 50 DEG C.It is cooled to after room temperature, adding water point takes organic layer, utilizes toluene to extract water layer.After merging organic layer is cleaned using water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, decompression evaporates solvent after being dried using anhydrous magnesium sulfate.Residue recrystallization be refining to obtain 4- (it is bicyclic oneself
- 4 '-yl of -4- ketone) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (Ii).Compound (Ii), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：406(M+)
1H-NMR (60MHz, CDCl3)
δ：1.6-2.0 (m, 19H), 2.0-2.4 (m, 4H), 3.8-4.0 (m, 4H), 4.9-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.3-6.5 (m, 2H)
1-5：The synthesis of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- formyls-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (Ij)
4- (- 4 '-yl of bicyclic hex- 4- ketone) methoxyl group -2, the fluoro- 1- of 3- bis- (4- amylenes oxygen) benzene (Ii) and methoxymethyl triphenylphosphonium phosphine chloride are scattered in THF, the THF solution of potassium tert-butoxide is added at 0~5 DEG C of temperature inside, is stirred 2 hours.After adding water decompression evaporate in solvent, residue add hexene be separated by filtration solid constituent.Filtrate utilizes 50% methanol aqueous solution, and water and saturated aqueous common salt are cleaned, dried with anhydrous magnesium sulfate.Decompression, which evaporates, adds 10% hydrochloric acid and THF in solvent, residue, add backflow 1 hour.Divide and take organic layer, utilize toluene to extract water layer.Merge organic layer to clean using saturated aqueous common salt, solvent is evaporated with decompression after anhydrous sodium sulfate drying.Triethylamine, THF and methanol are added in residue.Then wherein add 30% sodium hydrate aqueous solution, at 5 DEG C stir 3 hours.Neutralized after adding water with 10% hydrochloric acid, add THF and toluene.Divide and take organic layer, decompression evaporates solvent after being dried with anhydrous magnesium sulfate, obtain 4- (anti-, the trans- bicyclic hex- 4 ' of 4- formyls-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (Ij).Compound (Ij), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：420(M+)
1H-NMR (60MHz, CDCl3)
δ：1.3-2.0 (m, 23H), 2.2-2.4 (m, 1H), 3.8-4.0 (m, 4H), 4.9-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.4-6.6 (m, 2H), 9.6-9.8 (m, 1H)
1-6：The synthesis of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (If)
Methyl triphenyl phosphine bromide is scattered in THF, and potassium tert-butoxide is added below 0 DEG C, stirs 30 points of stirrings.The THF solution of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- formyls-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (Ij) is instilled, is stirred 1 hour.Add decompression after acetone and water and evaporate addition hexene leaching solid constituent in solvent, residue.Filtrate is cleaned using 50% methanol aqueous solution, water and saturated aqueous common salt, is dried with anhydrous magnesium sulfate.Decompression evaporates solvent, and residue is refined using column chromatography and recrystallization, obtains 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (If).Compound (If), it is very useful as the component parts of liquid-crystal composition.
Embodiment 2：The synthesis 2 of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (If)
2-1：3- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -1,2- difluorobenzene (Ia) is synthesized using method same 1-1 in be the same as Example 1.
2-2：The synthesis of 3- (- 4 '-yl of bicyclic hex- 4- ketone) methoxyl group -1,2- difluorobenzene (Ib)
3- [4,4- (ethylidene dioxy) bicyclic hex- 4 '-yl] methoxyl group -1,2- difluorobenzene (Ia) 111g is dissolved in toluene 330mL, is added after formic acid 270mL and is stirred 2 hours at 50 DEG C.It is cooled to after room temperature, the 200mL that adds water points take organic layer, and water layer is extracted with toluene 300mL.Merge and cleaned after organic layer using water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, decompression evaporates solvent after being dried with anhydrous magnesium sulfate.Residue recrystallization is refining to obtain 3- (- 4 '-yl of bicyclic hex- 4- ketone) methoxyl group -1,2- difluorobenzene (Ib) 95g.Compound (Ib), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：322(M+)
1H-NMR (60MHz, CDCl3)
δ：1.6-2.0 (m, 15H), 2.0-2.4 (m, 4H), 3.8-4.0 (m, 2H), 6.4-6.6 (m, 2H), 6.8-7.0 (m, 1H)
2-3：The synthesis of 3- (anti-, the trans- bicyclic hex- 4 ' of 4- formyls-yl) methoxyl group -1,2- difluorobenzene (Ic)
3- (- 4 '-yl of bicyclic hex- 4- ketone) methoxyl group -1,2- difluorobenzenes (Ib) 95g and methoxymethyl triphenylphosphonium phosphine chloride 132g are scattered in THF 650mL, potassium tert-butoxide 44g THF (180mL) solution is added at 0~5 DEG C of temperature inside, is stirred 2 hours.The decompression after 25mL that adds water evaporates addition hexene 700mL leaching solid constituents in solvent, residue.Filtrate utilizes 50% methanol aqueous solution, and water and saturated aqueous common salt are cleaned, dried with anhydrous magnesium sulfate.Decompression, which evaporates, adds 10% hydrochloric acid 300mL and THF400mL in solvent, residue, be heated to reflux 1 hour.Divide and take organic layer, utilize toluene 300mL to extract water layer.Merge and cleaned after organic layer using saturated aqueous common salt, solvent is evaporated with decompression after anhydrous sodium sulfate drying.Triethylamine 8mL, THF 250mL and methanol 400mL are added in residue.30% sodium hydrate aqueous solution 20mL is wherein added, is stirred 3 hours at 5 DEG C.Add water and neutralized with 10% hydrochloric acid after 600mL, add THF 300mL and toluene 700mL.Divide and take organic layer, decompression evaporates solvent after being dried with anhydrous magnesium sulfate, obtain 3- (anti-, the trans- bicyclic hex- 4 ' of 4- formyls-yl) methoxyl group -1,2- difluorobenzene (Ic) 99g.Compound (Ic), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：336(M+)
1H-NMR (60MHz, CDCl3)
δ：1.3-2.0 (m, 19H), 2.2-2.4 (m, 1H), 3.8-4.0 (m, 2H), 6.4-6.6 (m, 2H), 6.8-7.0 (m, 1H), 9.6-9.8 (m, 1H)
2-4：The synthesis of 3- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -1,2- difluorobenzene (Id)
Methyl triphenyl phosphine bromide 136g is scattered in THF 340mL, and potassium tert-butoxide 46g is added below 0 DEG C, stirs 30 points.3- (anti-, the trans- bicyclic hex- 4 ' of 4- formyls-yl) methoxyl group -1,2- difluorobenzene (Ic) 99g THF (200mL) solution is added dropwise, stirs 1 hour.Add decompression after acetone 15mL and water 15mL and evaporate addition hexene 500mL leaching solid constituents in solvent, residue.Filtrate is cleaned using 50% methanol aqueous solution, water and saturated aqueous common salt, is dried with anhydrous magnesium sulfate.Decompression evaporates solvent, and residue is refined using column chromatography and recrystallization, obtains 3- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -1,2- difluorobenzene (Id) 81g.Compound (Id), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：334(M+)
1H-NMR (60MHz, CDCl3)
δ：1.3-2.2 (m, 20H), 3.8-4.0 (m, 2H), 4.8-5.0 (m, 2H), 5.7-5.9 (m, 1H), 6.4-6.6 (m, 2H), 6.8-7.0 (m, 1H)
2-5：The synthesis of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- difluorophenol (Ie)
3- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -1,2- difluorobenzene (Id) 39g is dissolved in THF 320mL.Secondary BuLi (0.95M cyclohexene solution) 196mL is added at -60 DEG C of temperature inside, is stirred 2 hours.Trimethylborate 21g THF (42mL) solution is added at -60 DEG C of temperature inside, 0 DEG C is warming up to.The 7.2mL that adds water is stirred after 10 points, adds 30% hydrogen peroxide 34mL, is stirred 5 hours at 35 DEG C.Add after 10% aqueous solution of sodium bisulfite and neutralized with 10% hydrochloric acid, divide and take organic layer.Water layer is extracted using 120mL toluene, merges and cleaned after organic layer using 10% saline solution, utilize anhydrous sodium sulfate drying.Decompression evaporates solvent, and residue recrystallization is refining to obtain 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- difluorophenol (Ie) 36g.Compound (Ie), as liquid-crystal compounds to prepare intermediate very useful.
MS m/z：350(M+)
1H-NMR (60MHz, CDCl3)
δ：1.3-2.2 (m, 20H), 3.8-4.0 (m, 2H), 4.8-5.0 (m, 2H), 5.7-5.9 (m, 1H), 6.3-6.5 (m, 2H), 4.0-6.0 (s, 1H)
2-6：The synthesis of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (If)
The bromo- 1- amylenes of 5-, 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- difluorophenol (Ie), tripotassium phosphate and DMF mixing, are stirred 2 hours at 130 DEG C.Add water, extracted using toluene, decompression evaporates solvent after organic layer is cleaned using water and saturated aqueous common salt.Residue is refined using column chromatography and recrystallization, obtains 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (4- amylenes oxygen) benzene (If).
Compound (If), it is very useful as the constituting portion material of liquid-crystal composition.
Phase inversion temperature：C 75.6 N 195.2 I
MS m/z：418(M+)
1H-NMR (400MHz, CDCl3)
δ：0.95-1.15 (m, 10H), 1.65-2.00 (m, 12H), 2.20-2.30 (m, 2H), 3.76 (d, J=6.4Hz, 2H), 3.98 (t, J=6.8Hz, 2H), 4.87 (d, J=10.0Hz, 1H), 4.95 (d, J=17.2Hz, 1H), 5.00 (d, J=10.4Hz, 1H), 5.05 (d, J=17.2Hz, 1H), 5.77 (ddd, J=17.2Hz, J=10.4Hz, J=6.4Hz, 1H), 5.84 (ddt, J=16.8Hz, J=13.6Hz, J=6.8Hz, 1H), 6.55-6.65 (m, 2H)
Embodiment 3：The synthesis of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (3- butylene oxygen) benzene (IIf)
In embodiment 1 or 2, the bromo- 1- butylene of 4- is used instead of the bromo- 1- amylenes of 5-, same reaction is carried out, 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (3- butylene oxygen) benzene (IIf) is obtained.
The I of 64.5 N of phase inversion temperature C 119.5
MS m/z：404(M+), 55 (100)
1H-NMR (400MHz, CDCl3)
δ：0.95-1.15 (m, 10H), 1.65-2.00 (m, 10H), 2.50-2.60 (m, 2H), 3.76 (d, J=6.4Hz, 2H), 4.03 (t, J=6.8Hz, 2H), 4.80-5.30 (m, 4H), 5.79 (ddd, J=17.2Hz, J=10.4Hz, J=6.4Hz, 1H), 5.83-5.95 (m, 1H), 6.55-6.70 (m, 2H)
Embodiment 4：The synthesis of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (trans- 4- ethylcyclohexyls) methoxybenzene (IIIf)
In embodiment 1 or 2, trans- 4- (ethylcyclohexyl) bromomethane is used instead of the bromo- 1- amylenes of 5-, carry out same reaction, obtain 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (trans- 4- ethylcyclohexyls) methoxybenzene (IIIf).
The I of 94.1 N of phase inversion temperature C 197.5
MS m/z：474(M+), 146 (100)
1H-NMR (400MHz, CDCl3)
δ：0.88 (t, J=7.2Hz, 3H), 0.90-1.30 (m, 17H), 1.65-2.00 (m, 15H), 3.70-3.80 (m, 4H), 4.80-5.00 (m, 2H), 5.77 (ddd, J=16.8Hz, J=10.4Hz, J=6.4Hz, 1H), 6.59 (d, J=5.6Hz, 2H)
Embodiment 5：The synthesis of 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (trans- 4- vinyl cyclohexyls) methoxybenzene (IVf)
In embodiment 1 or 2, Loprazolam trans- 4- (vinyl cyclohexyl) methyl is used instead of the bromo- 1- amylenes of 5-, carry out same reaction, obtain 4- (anti-, the trans- bicyclic hex- 4 ' of 4- vinyl-yl) methoxyl group -2,3- bis- fluoro- 1- (trans- 4- vinyl cyclohexyls) methoxybenzene (IVf).
The I of 86.5 N of phase inversion temperature C 205.8
MS m/z：472(M+), 146 (100)
1H-NMR (400MHz, CDCl3)
δ：0.95-1.25 (m, 14H), 1.65-2.00 (m, 16H), 3.77 (t, J=7.2Hz, 4H), 4.85-5.05 (m, 4H), 5.70-5.85 (m, 2H), 6.60 (d, J=5.6Hz, 2H)
Industrial utilizability
The inventive method is very useful as the preparation method of liquid-crystal compounds.In addition the compound of the present invention as liquid-crystal compounds to prepare intermediate also very useful.
Claims (3)
1. one kind compound as shown in formula (2),
In formula, R1And R2Respective independent methyl, ethyl or propyl group are represented, or, shown in the specific formula such as following formula (2a) of formula (2), formula (2b) or formula (2c),
2. one kind compound as shown in formula (13)：
In formula, R1And R2Respective independent methyl, ethyl or propyl group are represented, or, shown in the specific formula such as following formula (13a) of formula (13), formula (13b) or formula (13c),
3. one kind compound as shown in formula (16),
In formula (16), R1And R2Respective independent methyl, ethyl or propyl group are represented, or, shown in the specific formula such as following formula (16a) of formula (16), formula (16b) or formula (16c), R4The alkenyl or expression (8) of carbon number 2 to 12 are represented,
In formula (8), R5For the alkyl of carbon number 1 to 12, the alkenyl of carbon number 2 to 12, the alkoxy of carbon number 1 to 12, carbon number 2 to 12 alkenyloxy group.
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