CN103183591A - 4'-dialkoxymethylbicyclohexyl-4-ylmethanol and method for producing it - Google Patents
4'-dialkoxymethylbicyclohexyl-4-ylmethanol and method for producing it Download PDFInfo
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Abstract
The invention provides a manufacture intermediate which is useful for manufacturing compounds which is provided with 2,3-difluoro-hydroquinone frame and whose branched chain is provided with alkenyl. The invention also provides a method of effectively manufacturing the compounds. The invention provides a method of a manufacture general formula (4) expressing trans-trans-4-(dialkyloxymeth) Di cyclohexane-4-methanol derivative, which is processed via following steps. Moreover, the invention also provides intermediate compounds expressed by a general formula (1), a general formula (2) and a general formula (3). Using the manufacture method and the manufacture intermediate of the invention can effectively manufacture the compounds which is provided with 2,3-difluoro-hydroquinone frame and whose branched chain is provided with alkenyl.
Description
The application be that January 25, application number in 2008 are 200810008844.5 the applying date, denomination of invention divides an application for the application for a patent for invention of " 4'-dialkoxy methyl bicycle hexane-4-base methyl alcohol and manufacture method thereof ".
Technical field
The present invention relates to a kind ofly making useful as intermediates and manufacture method thereof aspect the liquid crystal material.
Background technology
At present, liquid crystal display device is owing to advantageous feature such as low voltage startup, slim demonstration are widely used.As the display mode of liquid crystal display device, vertical orientation mode is by up-to-date practicability in recent years.Vertical orientation mode is to utilize the vertical orientated expectation of liquid crystal molecule to improve the mode at visual angle, can use the dielectric anisotropy value to be the liquid-crystal composition of negative value.Dielectric constant anisotropy is that the liquid-crystal composition of negative value has been reported many kinds, as one of them, has reported a kind of compound (with reference to patent documentation 1) with formula (5) expression of 2,3-difluoro quinhydrones skeleton.But, the compound that side chain has saturated alkyl is only disclosed in this citing document, do not mention that compound with formula (6) expression is the compound that has thiazolinyl on the side chain of representative.Availability when therefore, using about the rerum natura of the compound that has thiazolinyl on the side chain and as liquid crystalline cpd is still unknown.
Recently, disclose and a kind ofly had 2 of thiazolinyl as side chain, 3-difluoro hydroquinone derivatives (with reference to patent documentation 2).Specifically disclose as side chain in this citing document and have 2 of thiazolinyl, 3-difluoro hydroquinone derivatives is also relevant for the record of manufacture method.But in the manufacture method of this citing document record, there are the following problems, as the poor yields of making compound shown in the following chemical formula that intermediate uses, by purifies and separates yield variation more, the practical manufacture method of therefore can not saying so.In addition, in the manufacture method of this citing document record, need to make in addition 4-(2-thiazolinyl)-2,3-difluorophenol derivative.Therefore, when making the different homologue of side chain, need to make various 4-(2-thiazolinyl)-2, there is the problem of production efficiency difference in 3-difluorophenol derivative.
In sum, seeking to develop method and the manufacturing intermediate of the compound with 2,3-difluoro quinhydrones skeleton that has thiazolinyl on effective manufacturing side chain.
Patent documentation 1: the international brochure that discloses No. 89/08637
Patent documentation 2: the international brochure that discloses No. 06/93102
Summary of the invention
The problem that the present invention wants to solve is, provides a kind of and has the useful manufacturing intermediate of compound with 2,3-difluoro quinhydrones skeleton of thiazolinyl to making on the side chain, and a kind of method of effective this compound of manufacturing is provided.
The inventor concentrates on studies in order to solve above-mentioned problem, found that anti-, anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives, to make have thiazolinyl on the side chain have 2, the compound of 3-difluoro quinhydrones skeleton is useful, thereby has finished the present invention.
The invention provides the anti-of a kind of following general formula (4) expression; instead-manufacture method of 4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives; wherein; anti-with following general formula (1) expression; instead-carboxyl reduction of 4-(carbalkoxy) bis cyclohexane-4-yl carboxylic acid derivative; convert the anti-of following general formula (2) expression to; instead-4-(carbalkoxy) bis cyclohexane-4-base formaldehyde derivatives; its formyl radical is carried out the acetal protection; convert the anti-of following general formula (3) expression to; instead-4-(dialkoxy methyl) bis cyclohexane-4-yl carboxylic acid ester derivative; its carbalkoxy is reduced; make the anti-of following general formula (4) expression thus, anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives
(in the formula, R
3The expression carbon number is 1 ~ 12 alkyl),
(in the formula, R
3Expression and general formula (1) identical meanings),
(in the formula, R
1And R
2Represent the alkyl of carbon number 1 ~ 12 or the thiazolinyl of carbon number 1 ~ 12 respectively independently, R
1And R
2Also can represent R
1And R
2The formation ring texture-CH
2CH
2-or-CH
2CH
2CH
2-, R
3Expression and general formula (1) identical meanings),
(in the formula, R
1And R
2Expression and general formula (3) identical meanings).
In addition, the present invention also is provided as the compound of general formula (1), general formula (2) and general formula (3) expression of manufacturing intermediate of the present invention simultaneously.
The manufacturing intermediate of the application of the invention, the following synthesis path of use can be made the compound with 2,3-difluoro quinhydrones skeleton that has thiazolinyl on the side chain effectively.
Manufacture method of the present invention does not contain the operation of the non-constant of yield in manufacturing processed.And, since be in the end the stage introduce side chain, therefore can make the compound with various side chains effectively, the compound that manufacturing is had 2,3-difluoro quinhydrones skeleton is useful.
The compound with 2,3-difluoro quinhydrones skeleton that utilizes intermediate of the present invention to make is useful as the component parts of the liquid crystal display device of vertical orientation mode.And, by with instead, anti--4-(carbalkoxy) bis cyclohexane-4-yl carboxylic acid derivative is the manufacture method of the present invention of initial substance, can make manufacturing intermediate of the present invention effectively.
Embodiment
Below, be described in detail about the present invention.
The oxidation of the compound of general formula (1) expression can be carried out rosenmund reduction (Rosenmund reduction) behind the chloride of acid and carries out by utilizing chlorizating agent that carboxylic acid is converted to.Reaction solvent as being used for chlorination so long as the solvent that reaction is carried out smoothly can use, can exemplify halogen solvent, ether solvent or varsol etc.Can exemplify methylene dichloride, chloroform, 1 as the halogen solvent, 2-ethylene dichloride etc., can exemplify 1 as ether solvent, 4-diox, 1,3-diox, tetrahydrofuran (THF), diethyl ether or t-butyl methyl ether etc. can exemplify pentane, hexane, hexanaphthene, heptane or toluene etc. as varsol, wherein, preferably as methylene dichloride or 1, the 2-ethylene dichloride of halogen solvent.
Can exemplify oxalyl chloride, thionyl chloride, sulfuryl chloride etc. as chlorizating agent, consider from the easiness viewpoint that obtains and handle, preferred oxalyl chloride, thionyl chloride are considered from the easiness viewpoint of the chloride of acid purifying that obtains, more preferably oxalyl chloride.When using thionyl chloride, if do not carry out distillation purifying, then Zhi Hou reduction reaction just can not be carried out smoothly, and with respect to this, when using oxalyl chloride, even do not carry out purifying, reduction reaction also can be carried out, and is therefore preferred.Temperature of reaction during chlorination is preferably 0 ℃ ~ 150 ℃, considers more preferably 0 ℃ ~ 80 ℃ from the heat-staple viewpoint of chloride of acid.If under higher temperature, heat, isomerization reaction then takes place, the trans/cis stereoselectivity variation on the carbon of the root of cyclohexane ring and chloro carbonyl, therefore not preferred.
When rosenmund reduction, carry out hydrogenation reaction with the palladium charcoal as catalyzer, the hydrogen chloride gas that produce this moment need be removed from reaction system.As the method for removing hydrogen chloride gas, have and hydrogen is bubbled in reaction soln and hydrogen chloride gas physically is discharged to method outside the solution, adds alkali and the method for chemically supplying hydrogen chloride gas in reaction soln, consider from the viewpoint of reaction yield, more preferably use the method for alkali.Can exemplify tertiary amine or pyridine derivate as the alkali that adds.Can exemplify Trimethylamine 99, triethylamine, diisopropylethylamine etc. as tertiary amine, can exemplify pyridine, 2-picoline, 2 as pyridine derivate, 6-lutidine etc. are considered from the viewpoint of reaction yield, preferred diisopropylethylamine or 2,6-lutidine.Reaction solvent as using so long as the solvent that reaction is carried out smoothly can use, can exemplify ether solvent, esters solvent or varsol etc.Can exemplify 1 as ether solvent, 4-diox, 1,3-diox, tetrahydrofuran (THF), diethyl ether or t-butyl methyl ether etc., can exemplify ritalin or vinyl acetic monomer as esters solvent, can exemplify pentane, hexane, hexanaphthene, heptane or toluene etc. as varsol, wherein, preferred tetrahydrofuran (THF) or vinyl acetic monomer.Temperature of reaction is preferably 0 ℃ ~ 60 ℃, more preferably 15 ℃ ~ 35 ℃.
The method of carbalkoxy as reduction general formula (3), can exemplify the method for using metal, the method for using metal hydride, hydrogenation reaction etc., the preferred metal hydride that uses, further preferred lithium aluminium hydride, lithium borohydride, diisobutylaluminium hydride or two (2-methoxy ethoxy) sodium aluminum hydride, consider preferred especially two (2-methoxy ethoxy) sodium aluminum hydrides from the easiness of reagent acquisition and the easiness viewpoint of processing.Reaction solvent as using so long as the solvent that reaction is carried out smoothly can use, can exemplify ether solvent or varsol etc.Can exemplify 1,4-diox, 1 as ether solvent, 3-diox, tetrahydrofuran (THF), diethyl ether or t-butyl methyl ether etc., can exemplify pentane, hexane, hexanaphthene, heptane or toluene etc. as varsol, wherein, preferred tetrahydrofuran (THF) or toluene, more preferably toluene.When the water termination reaction, insoluble sodium aluminate is separated out, and makes aftertreatment become difficulty, and problem often takes place.As the method that prevents this problem, can exemplify the method for using hydrochloric acid or aqueous sodium hydroxide solution place of water, consider preferred aqueous sodium hydroxide solution from the viewpoint of the stability of the acetal radical of the compound that obtains.In addition, consider that from the deliquescent viewpoint of sodium aluminate the concentration of aqueous sodium hydroxide solution is preferably more than 20%.
In general formula (1), general formula (2) and general formula (3), preferred R
3The alkyl of expression carbon number 1 ~ 12, particularly, preferred-CH
3,-CH
2CH
3,-(CH
2)
2CH
3,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
6CH
3Or-(CH
2)
7CH
3
In general formula (3) and general formula (4), preferred R
1And R
2Be the alkyl of carbon number 1 ~ 12 simultaneously, particularly, preferred expression-CH
3,-CH
2CH
3,-(CH
2)
2CH
3Or-(CH
2)
3CH
3, preferred R
1And R
2Expression-CH
2CH
2-or-CH
2CH
2CH
2-and have ring texture.
In manufacture method of the present invention, as the compound that the general formula (4) of target product is represented, the manufacturing of the compound shown in more specifically being preferably as follows.
As particularly preferred compound, can exemplify compound as follows.
As the compound that the general formula (3) of compound of the present invention is represented, the compound shown in being preferably as follows particularly.
(in the formula, R
3The expression carbon number is 1 ~ 8 alkyl).
As particularly preferred compound, can exemplify compound as follows.
(in the formula, R
3The expression carbon number is 1 ~ 8 alkyl).
(application examples) uses the manufacturing of the liquid crystalline cpd of manufacturing intermediate of the present invention
Convert anti-, anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives of following general formula (4) expression the compound of following general formula (7) expression to.Itself and 2,3-difluorophenol are reacted, obtain the compound of following general formula (8) expression.Introduce hydroxyl, deriving is the phenols of following general formula (9) expression, and the compound that itself and following general formula (10) are represented reacts, and obtains the compound of following general formula (11) expression.Under acidic conditions, with the acetal deprotection, derive the aldehyde of following general formula (12) expression, make ylide (ylide) reaction by the methyltriphenylphosphonium bromide preparation, can obtain the compound of following general formula (13) expression thus.The compound of following general formula (13) expression is that the component parts of the liquid-crystal composition of negative value is useful as dielectric constant anisotropy.
(in the formula, R
1And R
2The alkyl or alkenyl of representing hydrogen atom, carbon number 1 ~ 12 respectively independently, R
1And R
2Also can represent-CH
2CH
2-or-CH
2CH
2CH
2-, in addition, R
3Expression and general formula (2) identical meanings);
(in the formula, R
1And R
2Expression and general formula (4) identical meanings, X
1Expression chlorine, bromine, iodine, phenylsulfonyloxy, tolysulfonyl oxygen base, mesyloxy or trifluoro-methanesulfonyl oxy);
(in the formula, R
1And R
2Expression and general formula (4) identical meanings);
(in the formula, R
1And R
2Expression and general formula (1) identical meanings);
(in the formula, R
4The expression carbon number 1 ~ 12 alkyl or alkenyl, n represent 0 or 1, X2 represent and general formula (7) identical meanings);
(in the formula, R
1And R
2Expression and general formula (4) identical meanings, R
4And n represents and general formula (10) identical meanings);
(in the formula, R
4And n represents and general formula (10) identical meanings);
(in the formula, R
4And n represents and general formula (10) identical meanings).
The compound of the application of the invention can be made effectively and is difficult to the liquid crystalline cpd made in the past.
In the present invention, as the compound of the general formula (1) of initial substance expression, can be by making the anti-of following general formula (14) expression, a carbalkoxy hydrolysis of anti--4 ', 4-bis cyclohexane dicarboxylic diester and obtaining.
(in the formula, R
3Expression and general formula (1) identical meanings).
Embodiment
Below, the present invention will be described in more detail to exemplify embodiment, but the present invention is not limited to these embodiment.The structure of compound utilizes nuclear magnetic resonance spectrum (NMR), mass spectrum (MS) etc. to confirm.
Use following abbreviation in the compound record.
(embodiment 1) is anti-, the manufacturing of anti--4 '-(methoxycarbonyl) bis cyclohexane-4-yl carboxylic acid
Instead, in methyl alcohol (46mL)/tetrahydrofuran (THF) (46mL) solution of anti--4 ', 4-bis cyclohexane dimethyl dicarboxylate (15.8g), splash into 20% aqueous sodium hydroxide solution (11.7mL) under 15 ℃.After stirring 2 hours under 25 ℃, make its pH=3 with 10% hydrochloric acid, distillation desolventizing, the solid that leaching is separated out.Solid is disperseed washing with methylene dichloride, washings is concentrated, carry out recrystallize, obtain thus instead, the water white transparency crystallization (fusing point 204-207 ℃) of anti--4 '-(methoxycarbonyl) bis cyclohexane-4-yl carboxylic acid (7.35g).
1H-NMR(400MHz,CDCl
3)
δ：0.95-1.13(m,6H),1.33-1.45(m,4H),1.79(bs,4H),2.01(t,J=13.6Hz,4H),2.22(ddt,J=3.6Hz,12.4Hz,20.8Hz,2H),3.66(s,3H).
Need to prove that unreacted anti-in the present embodiment, it is anti-that anti--4 ', 4-bis cyclohexane dimethyl dicarboxylate and complete hydrolysis form, anti--4 ', 4-bis cyclohexane dicarboxylic acid can utilize manipulation of regeneration at an easy rate as the raw material of this reaction.
(embodiment 2) are anti-, the manufacturing of anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-base methyl alcohol
The manufacturing of (2-1) anti-, anti--4-(methoxycarbonyl) bis cyclohexane-4-base formaldehyde
What obtain in embodiment 1 is anti-, in methylene dichloride (222mL) solution of anti--4 '-(methoxycarbonyl) bis cyclohexane-4-yl carboxylic acid (44g), splashes into oxalyl chloride (22mL) under 25 ℃.Stirring is after 3 hours down at 35 ℃, and the underpressure distillation desolventizing obtains brown solid.Make this compound and palladium charcoal (3.6g), 2,6-lutidine (19g) is suspended in the tetrahydrofuran (THF) (240mL), stirs 10 hours under 25 ℃, atmosphere of hydrogen.Carry out diatomite filtration, with filtrate with 10% salt solution wash, with behind the anhydrous sodium sulfate drying, the underpressure distillation desolventizing obtains the yellow solid of anti-, anti--4-(methoxycarbonyl) bis cyclohexane-4-base formaldehyde (45g).
1H-NMR(400MHz,CDCl
3)
δ：0.95-1.12(m,7H),1.20-1.29(m,1H),1.38-1.45(m,2H),1.76-2.00(m,4H),2.00-2.07(m,4H),2.11-2.25(m,2H),3.66(s,1H),9.60(s,1H).
(2-2) anti-, the manufacturing of anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-yl carboxylic acid methyl esters
Anti-with what obtain in (2-1), the basic formaldehyde (45g) of anti--4-(methoxycarbonyl) bis cyclohexane-4-, ethylene glycol (12g) and sal enixum (4.6g) are dissolved in the toluene (135mL), Yi Bian carry out azeotropic dehydration, Yi Bian stirred 3 hours down at 115 ℃.After being cooled to 25 ℃, reaction soln successively with 5% sodium bicarbonate aqueous solution, water and the washing of 10% salt solution, is used anhydrous sodium sulfate drying, carry out the underpressure distillation desolventizing then, obtain brown solid.Carry out purifying with column chromatography, obtain anti-the yellow solid of anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-yl carboxylic acid methyl esters (42g).
MS?m/z：296(M
+)、265
1H-NMR(400MHz,CDCl
3)
δ：0.93-1.15(m,8H),1.32-1.50(m,3H),1.73-1.87(m,6H),1.96-2.00(m,2H),2.21(tt,J=3.6Hz,12.2Hz,1H),3.65(s,3H),3.82-3.88(m,2H),3.90-3.95(m,2H),4.58(d,J=5.2Hz,1H).
The manufacturing of (2-3) anti-, anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-base methyl alcohol
What obtain in (2-2) is anti-, in the toluene (120mL) of anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-yl carboxylic acid methyl esters (20g), splashes into two (2-methoxy ethoxy) sodium aluminum hydrides (70%wt toluene solution, 23g) under 5 ℃.After 1 hour, under 5 ℃, splash into 20% aqueous sodium hydroxide solution (45mL) 25 ℃ of stirrings.Divide and get organic layer, use the toluene aqueous layer extracted.Organic layer is merged, and anhydrous sodium sulfate drying is used in water, saturated common salt water washing successively, carries out the underpressure distillation desolventizing then, obtains the light yellow solid of anti-, anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-base methyl alcohol (18g).
MS?m/z：268(M
+)、250
1H-NMR(400MHz,CDCl
3)
δ：0.85-1.15(m,10H),1.32-1.52(m,3H),1.73-1.86(m,8H),3.43(t,J=6.2Hz,2H),3.82-3.88(m,2H),3.90-3.95(m,2H),4.59(d,J=4.8Hz,1H).
(application examples) 2, the manufacturing of 3-two fluoro-1-(3-butenyloxy)-4-(anti-, anti--4 '-vinyl bis cyclohexane-4-yl) anisole
What obtain in (2-3) is anti-, in methylene dichloride (54mL) solution of anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-base methyl alcohol (Ia, 18g), pyridine (8mL), splashes into methylsulfonyl chloride (7.7mL) under 25 ℃.After 5 hours, splash into saturated sodium bicarbonate aqueous solution 35 ℃ of stirrings.Divide and get organic layer, use the dichloromethane extraction water layer.Organic layer is merged, and anhydrous sodium sulfate drying is used in water, saturated common salt water washing successively, carries out the underpressure distillation desolventizing then, obtains yellow solid.Carry out purifying with column chromatography and recrystallize, it is anti-to obtain methylsulfonic acid, the colourless crystallization of anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-base methyl esters (Ib, 21g).
Methylsulfonic acid is anti-, anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-base methyl esters (Ib, 21g), 2, dimethyl formamide (125mL) solution of 3-difluorophenol (8.7g) and salt of wormwood (11g) stirred 7 hours down at 85 ℃.After naturally cooling to room temperature, add water with toluene and extract.With organic layer water successively, saturated common salt water washing, use anhydrous sodium sulfate drying, carry out the underpressure distillation desolventizing then, obtain yellow solid.Carry out purifying with column chromatography and recrystallize, obtain 1-(anti-, anti--4 '-(1,3-dioxolane-2-yl) bis cyclohexane-4-ylmethoxy)-2, the colourless crystallization of 3-two fluorobenzene (Ic, 21g).
Adjustment LDA (0.37M, 135mL, THF: hexane=75:25), it is (anti-to splash into 1-under Nei Wen-40 ~-55 ℃, instead-4 '-(1,3-dioxolane-2-yl) bis cyclohexane-4-ylmethoxy)-2, THF (42mL) solution of 3-two fluorobenzene (Ic, 14.0g) stirred 2 hours under the condition of temperature in keeping.Under Nei Wen-50 ~-55 ℃, splash into triisopropyl borate ester (10.5g), be warming up to 0 ℃.Add the aqueous ammonium chloride solution termination reaction, after branch is got organic layer, use the toluene aqueous layer extracted.In the organic layer that merges, slowly add 15% hydrogen peroxide (12.7g), stirred 2 hours down at 40 ℃.Add water stirring a little while, extract with toluene.With organic layer water and saturated common salt water washing, use anhydrous sodium sulfate drying, carry out the underpressure distillation desolventizing, obtain 4-(anti-, anti--4 '-(1,3-dioxolane-2-yl) bis cyclohexane-4-ylmethoxy)-2,3-difluorophenol (Id, 13.1g).
4-is (anti-, instead-4 '-(1,3-dioxolane-2-yl) bis cyclohexane-4-ylmethoxy)-2,3-difluorophenol (Id, 12.9g), 3-butenol (2.81g), triphenylphosphine (10.6g) and THF (58mL) mix, and splash into di-isopropyl azodicarboxylate (7.88g) under 5 ℃., concentrate and remove THF after 1 hour in stirring at room.Add 67% methanol aqueous solution solid matter is disperseed, with crystallization filtration, drying, obtain 6-(3-butenyloxy)-3-(anti-, anti--4 '-(1,3-dioxolane-2-yl) bis cyclohexane-4-ylmethoxy)-1,2-two fluorobenzene (Ie, 14.3g).
With 6-(3-butenyloxy)-3-(anti-, anti--4 '-(1,3-dioxolane-2-yl) bis cyclohexane-4-ylmethoxy)-1,2-two fluorobenzene (Ie, 14.3g) are dissolved in the toluene (70mL), add formic acid (28mL), stir 5 hours down at 50 ℃.After being cooled to room temperature; add water and saturated common salt moisture is got organic layer; water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing; the underpressure distillation desolventizing; it is (anti-to obtain 6-(3-butenyloxy)-3-; instead-4 '-and formyl radical bis cyclohexane-4-ylmethoxy)-1,2-two fluorobenzene (If, 12.8g).
Methyltriphenylphosphonium bromide (14.4g) is scattered among the THF (43mL), adds potassium tert.-butoxide (4.50g) down at 5 ℃, stirred 30 minutes.Then, splash into 6-(3-butenyloxy)-3-(anti-, anti--4 '-formyl radical bis cyclohexane-4-ylmethoxy)-1, THF (25mL) solution of 2-two fluorobenzene (If, 12.6g) stirred 30 minutes.Add water underpressure distillation desolventizing behind the 10mL, in residue, add 50% methanol aqueous solution and the hexane branch is got organic layer.With organic layer with 50% methanol aqueous solution and saturated common salt water washing, the underpressure distillation desolventizing, utilize recrystallize and column chromatography that residue is carried out purifying, obtain 2, the colourless crystallization of 3-two fluoro-1-(3-butenyloxy)-4-(anti-, anti--4 '-vinyl bis cyclohexane-4-yl) anisole (Ig, 10.5g).
Phase transition temperature C 64.5N 119.5I
MS?m/z：404(M
+)
1H-NMR(400MHz,CDCl
3)
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=6.4Hz,10.4Hz,17.2Hz,1H),5.83-5.95(m,1H),6.55-6.70(m,2H).
By with 4 '-dialkoxy methyl bicycle hexane of the present invention-4-base methyl alcohol as starting raw material, can make effectively and have 2 of 2 thiazolinyl side chains, 3-two fluoro-1-(3-butenyloxy)-4-(anti-, anti--4 '-vinyl bis cyclohexane-4-yl) anisole.
(comparative example) 2, the manufacturing of 3-two fluoro-1-(3-butenyloxy)-4-(anti-, anti--4-vinyl bis cyclohexane-4-yl) anisole (R)
(R-1) 4-(2-butylene oxygen base)-2, the manufacturing of 3-difluorophenol
(R-1-1) 1-(2-butylene oxygen base)-2, the manufacturing of 3-two fluorobenzene
In 2-butanone (600ml) solution of 2,3-difluorophenol 77.2g, behind the adding Anhydrous potassium carbonate 122g, add 1-bromo-2-butylene 90.0ml (E/Z is than=92/8).After the reflux 4 hours, be cooled to room temperature, drip water and make reaction terminating.Extract (3 times) with hexane, the organic layer of collecting is used 3M hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing successively, use anhydrous magnesium sulfate drying.Underpressure distillation (155-160 ℃, 50kPa) is carried out in the distillation desolventizing, obtains 1-(2-butylene oxygen base)-2 thus, 3-two fluorobenzene (E/Z ratio=82/18, utilization
1The H-NMR analysis) colourless transparent liquid of 106g.
(R-1-2) 4-(2-butylene oxygen base)-2, the manufacturing of 3-difluorophenol
Below-50 ℃ to 1-(2-butylene oxygen base)-2, THF (500ml) solution of 3-two fluorobenzene 96.0g carries out in the vigorous stirring, in keeping, drip 2.67M n-buli hexane solution 225ml in the temperature after, continue stirring 1 hour down at-50 ℃.In keeping, drip THF (60ml) solution of trimethyl borate 63.3g in the temperature, after continuing to stir 30 minutes under the condition that keeps its temperature, be warming up to 0 ℃.After in keeping, dripping water 120ml in the temperature, further drip 15% hydrogen peroxide 160ml, continue to stir 1 hour down at 0 ℃.Be warming up to room temperature, continue again to stir after 2 hours, add saturated aqueous common salt, separate organic layer, from water layer, extract (2 times) with toluene.After the organic layer collection, use 10% sodium thiosulfate solution, 3M hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, saturated common salt water washing successively, use anhydrous magnesium sulfate drying.The distillation desolventizing utilizes column chromatography to carry out purifying, recrystallize the residue that obtains, and obtains 4-(2-butylene oxygen base)-2 thus, 3-difluorophenol (E/Z ratio=99/1, utilization
1The H-NMR analysis) the light yellow needle crystal of 42.7g.
(R-2) 1-((E)-2-butylene oxygen base)-2, the manufacturing of 3-two fluoro-4-(anti--4-(anti--4-vinyl cyclohexyl) cyclohexyl) anisole
(R-2-1) 4, the manufacturing of 4 '-dimethoxy methylene-bis hexanaphthene
With chlorination methoxymethyl triphenyl
882.3g be scattered among the THF2600mL, be cooled to-10 ℃.In keeping, add potassium tert.-butoxide 313.2g in the temperature.In keeping, stirred 1 hour in the temperature, drip bis cyclohexane-4 then, the THF of 4 '-diketone 200.0g (800mL) solution.In keeping, stirred 1 hour in the temperature, add water then and make reaction terminating.After the underpressure distillation desolventizing, add hexane and carry out vigorous stirring, filtration (2 times).Filtrate is merged, use 50% methanol aqueous solution, saturated common salt water washing successively, use anhydrous magnesium sulfate drying.The distillation desolventizing obtains white solid 231.8g.
(R-2-2) anti-, anti--bis cyclohexane-4, the manufacturing of 4 '-dicarbaldehyde
In the THF of the solid 231.8g that (R-2-1) obtains (930mL) solution, add 10% hydrochloric acid 700mL, reflux 1 hour.Behind the reaction solution naturally cooling, organic layer is separated, from water layer, extract (4 times) with toluene.After the organic layer usefulness saturated common salt water washing that merges, use anhydrous magnesium sulfate drying.The underpressure distillation desolventizing obtains reddish-brown liquid 204.5g.It is dissolved among the methyl alcohol 800mL, under-10 ℃, carries out in the vigorous stirring, in keeping, drip 10% aqueous sodium hydroxide solution 80ml under the condition of temperature.In keeping, stirred 2 hours under the condition of temperature.Add water the solid of separating out by the suction filtration leaching.With the solid that obtains water, methanol wash, drying successively, obtain white solid 189.4g.
(R-2-3) manufacturing of 4 '-vinyl bis cyclohexane-4-formaldehyde
Methyltriphenylphosphonium bromide 192.5g is scattered among the THF580mL, under-10 ℃, carries out in the vigorous stirring, in keeping, add potassium tert.-butoxide 66.6g in the temperature.In keeping, stirred 1 hour in the temperature, then, THF (1800mL) the solution dropping of the solid 120.0g that under interior temperature 5-10 ℃, obtains to (R-2-2).In keeping, stirred 1 hour in the temperature, add water then and make reaction terminating.Reaction soln is washed with 5% aqueous ammonium chloride solution.The solvent of organic layer is removed in distillation, adds hexane and toluene, washs with 50% methanol-water.Use anhydrous magnesium sulfate drying, underpressure distillation desolventizing then obtains almost colourless solid 60.1g.
(R-2-4) manufacturing of anti--4-(anti--4-vinyl cyclohexyl) hexahydrobenzyl alcohol
In under-10 ℃, ethanol (120mL) solution of sodium borohydride 1.65g being stirred, THF (180mL) solution of the almost colourless solid 60.1g that in keeping, obtains in the dropping (R-2-3) in the temperature.Be warming up to after the room temperature and stirred 2 hours, add water, ethyl acetate, aqueous ammonium chloride solution, make reaction terminating.In reaction solution, add saturated aqueous common salt, organic layer is separated, from water layer, extract (2 times) with ethyl acetate.With the organic layer saturated common salt water washing that merges, use anhydrous magnesium sulfate drying.The underpressure distillation desolventizing utilizes column chromatography to carry out purifying, obtains the white solid 15.4g of anti--4-(anti--4-vinyl cyclohexyl) hexahydrobenzyl alcohol.
(R-2-5) methylsulfonic acid anti--manufacturing of 4-(anti--4-vinyl cyclohexyl) cyclohexyl methyl esters
Anti--4-(anti--4-vinyl cyclohexyl) hexahydrobenzyl alcohol 15.1g, pyridine 8.2mL and 4-dimethylaminopyridine 0.41g are dissolved among the methylene dichloride 50mL.Under ice bath cooling,, stirred 6 hours placement a whole night after being warming up to room temperature with methylene dichloride (6mL) solution that dripped methylsulfonyl chloride 6.3mL in 30 minutes.Reaction soln is joined in 10% hydrochloric acid, divide and get organic layer, use the dichloromethane extraction water layer.The saturated common salt water washing is used in the organic layer merging, used anhydrous magnesium sulfate drying.The underpressure distillation desolventizing utilizes column chromatography (silica gel/toluene) and recrystallize (hexane/toluene) purifying 3 times with residue, obtain methylsulfonic acid anti--the colourless crystallization 9.8g of 4-(anti--4-vinyl cyclohexyl) cyclohexyl methyl esters.
(R-3) 2, the manufacturing of 3-two fluoro-1-(3-butenyloxy)-4-(anti-, anti--4-vinyl bis cyclohexane-4-yl) anisole (R)
The methylsulfonic acid that (R-2) obtained is anti--4-(anti--4-vinyl cyclohexyl) cyclohexyl methyl esters and the 4-(3-butenyloxy)-2 that (R-1) obtains, and the 3-difluorophenol is dissolved among the DMF.Wherein add Tripotassium phosphate, stirred 3 hours down at 100-130 ℃, append 4-(3-butenyloxy)-2,3-difluorophenol, restir 3 hours.Reaction mixture is added to the water, extracts with toluene, anhydrous magnesium sulfate drying is used in water and saturated common salt water washing successively.The underpressure distillation desolventizing utilizes column chromatography and recrystallize to carry out purifying residue, obtains the colourless crystallization of 2,3-, two fluoro-1-(3-butenyloxy)-4-(anti-, anti--4-vinyl bis cyclohexane-4-yl) anisole (R).
In not using the existing manufacture method of intermediate of the present invention, because the selectivity of the reaction (R-2-3) is low, therefore, the 4 '-vinyl bis cyclohexane-4-formaldehyde 120g that is obtained by (R-2-3) can only obtain anti--4-(anti--4-vinyl cyclohexyl) hexahydrobenzyl alcohol of about 15g, and separation yield is low to moderate about 13% in two operations.And, in the manufacture method of comparative example, must make 4-(2-thiazolinyl)-2,3-difluorophenol derivative in addition.Its result when making the different compound of side chain, needs to make various 4-(2-thiazolinyl)-2,3-difluorophenol derivative, thereby efficient is poor.
Claims (6)
1. a following general formula (4) expression is anti-; instead-manufacture method of 4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives; wherein; anti-with following general formula (1) expression; instead-carboxyl reduction of 4-(carbalkoxy) bis cyclohexane-4-yl carboxylic acid derivative; convert the anti-of following general formula (2) expression to; instead-4-(carbalkoxy) bis cyclohexane-4-base formaldehyde derivatives; its formyl radical is carried out the acetal protection; convert the anti-of following general formula (3) expression to; instead-4-(dialkoxy methyl) bis cyclohexane-4-yl carboxylic acid ester derivative; its carbalkoxy is reduced; make the anti-of following general formula (4) expression thus, anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives
In the formula (1), R
3The expression carbon number is 1 ~ 12 alkyl,
In the formula (2), R
3Expression and general formula (1) identical meanings,
In the formula (3), R
1And R
2The alkyl of representing carbon number 1 ~ 12 respectively independently, R
1And R
2Also can represent R
1And R
2The formation ring texture-CH
2CH
2-or-CH
2CH
2CH
2-, R
3Expression and general formula (1) identical meanings,
In the formula (4), R
1And R
2Expression and general formula (3) identical meanings.
2. a following general formula (4) expression is anti-; instead-manufacture method of 4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives; wherein; convert the anti-of following general formula (2) expression to; instead-4-(carbalkoxy) bis cyclohexane-4-base formaldehyde derivatives; its formyl radical is carried out the acetal protection; convert the anti-of following general formula (3) expression to; instead-4-(dialkoxy methyl) bis cyclohexane-4-yl carboxylic acid ester derivative; its carbalkoxy is reduced; make the anti-of following general formula (4) expression thus, anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives
In the formula (2), R
3The expression carbon number is 1 ~ 12 alkyl,
In the formula (3), R
1And R
2The alkyl of representing carbon number 1 ~ 12 respectively independently, R
1And R
2Also can represent R
1And R
2The formation ring texture-CH
2CH
2-or-CH
2CH
2CH
2-, R
3Expression and general formula (2) identical meanings,
In the formula (4), R
1And R
2And R
3Expression and general formula (3) identical meanings.
3. manufacture method as claimed in claim 1; wherein; with the compound reduction of general formula (1) expression, convert the method for the compound of general formula (2) expression to, convert the method for carrying out rosenmund reduction behind the chloride of acid to for the compound that makes general formula (1) expression and chlorination reaction.
4. manufacture method as claimed in claim 3 wherein, uses oxalyl chloride as chlorizating agent.
5. manufacture method as claimed in claim 3, wherein, the reaction conditions of described rosenmund reduction is to add alkali.
6. manufacture method as claimed in claim 1 or 2, wherein, with the compound reduction of general formula (3) expression, convert in the method for compound of general formula (4) expression, use metal hydride as reductive agent.
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| FR2342282A1 (en) * | 1976-02-25 | 1977-09-23 | Rhone Poulenc Ind | PROCESS FOR THE PREPARATION OF SULPHONES ACETALS AND THEIR USE FOR THE PREPARATION OF ETHYLENIC ALDEHYDES |
| DE3807801A1 (en) * | 1988-03-10 | 1989-09-21 | Merck Patent Gmbh | DERIVATIVES OF 2,3-DIFLUORHYDROQUINONE |
| US5185098A (en) * | 1990-04-05 | 1993-02-09 | Hoffmann-La Roche Inc. | Liquid crystalline mixtures containing 3,4-difluorophenyl-substituted bicyclohexyls |
| DE59106113D1 (en) * | 1990-05-21 | 1995-09-07 | Hoffmann La Roche | Bicyclohexyl derivatives. |
| AU7587896A (en) * | 1995-11-20 | 1997-06-11 | Chisso Corporation | Liquid-crystal compounds bearing vinyl linkages and liquid-crystal composition |
| TW386106B (en) * | 1996-03-28 | 2000-04-01 | Chisso Corp | Alkenyl compounds, liquid crystal compositions, and liquid crystal display devices |
| TWI378139B (en) * | 2005-01-27 | 2012-12-01 | Dainippon Ink & Chemicals | A difluorobenzene derivative and a nematic liquid crystal composition using the same |
| JP5051418B2 (en) * | 2006-04-28 | 2012-10-17 | Ｄｉｃ株式会社 | Cyclohexyl methanol derivative and method for producing the same |
| JP5157154B2 (en) * | 2006-12-20 | 2013-03-06 | Ｄｉｃ株式会社 | 4 '-(alkoxycarbonyl) bicyclohexyl-4-ylcarboxylic acid and process for producing the same |
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| CN103183591B (en) | 2016-01-20 |
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