CN101235026B - 4'-dialkoxymethyldicyclohexyl-4-methanol and preparation method thereof - Google Patents

4'-dialkoxymethyldicyclohexyl-4-methanol and preparation method thereof Download PDF

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CN101235026B
CN101235026B CN 200810008844 CN200810008844A CN101235026B CN 101235026 B CN101235026 B CN 101235026B CN 200810008844 CN200810008844 CN 200810008844 CN 200810008844 A CN200810008844 A CN 200810008844A CN 101235026 B CN101235026 B CN 101235026B
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bis cyclohexane
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CN101235026A (en
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岩窪昌幸
楠本哲生
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DIC Corp
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Dainippon Ink and Chemicals Co Ltd
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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

4'-dialkoxy methyl bicycle hexane-4-base methyl alcohol and method of manufacture thereof
Technical field
The present invention relates to a kind ofly making useful as intermediates and method of manufacture 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 liquid-crystal compsn of dielectric anisotropy value as negative value.Dielectric constant anisotropy is that the liquid-crystal compsn of negative value has been reported many kinds, as one of them, has reported a kind ofly have 2, the compound (with reference to patent documentation 1) of formula (5) expression of 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.
Figure S2008100088445D00011
Recently, disclose and a kind ofly had 2 of thiazolinyl as side chain, 3-difluoro hydroquinone derivatives (with reference to patent documentation 2).In this citing document, specifically disclose as side chain and have 2 of thiazolinyl, 3-difluoro hydroquinone derivatives is also relevant for the record of method of manufacture.But, in the method for manufacture of this citing document record, have following problem, as the poor yields of making compound shown in the following chemical formula that midbody uses, through purifies and separates yield variation more, the practical method of manufacture of therefore can not saying so.In addition, in the method for manufacture of this citing document record, need to make in addition 4-(2-thiazolinyl)-2,3-difluorophenol verivate.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 verivate.
Figure S2008100088445D00021
In sum, seeking to develop have thiazolinyl on effective manufacturing side chain have 2, the method for the compound of 3-difluoro quinhydrones skeleton and make midbody.
Patent documentation 1: No. 89/08637 pph of International Publication
Patent documentation 2: No. 06/93102 pph of International Publication
Summary of the invention
The problem that the present invention wants to solve is, provide a kind of to make have thiazolinyl on the side chain have 2, the useful manufacturing midbody of compound of 3-difluoro quinhydrones skeleton, 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; The result finds instead, and is 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 accomplished the present invention.
The present invention provides the anti-of a kind of formula (4) expression, the method for manufacture of anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives, wherein; Anti-with formula (1) expression, the carboxyl reduction of anti--4-(carbalkoxy) bis cyclohexane-4-yl carboxylic acid verivate converts the anti-of 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 formula (3) expression to, anti--4-(dialkoxy methyl) bis cyclohexane-4-yl carboxylic acid ester derivative; Its carbalkoxy is reduced; Make the anti-of formula (4) expression thus, anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives
Figure S2008100088445D00031
(in the formula, R 3The expression carbon number is 1～12 alkyl),
Figure S2008100088445D00032
(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),
Figure S2008100088445D00034
(in the formula, R 1And R 2Expression and general formula (3) identical meanings).
In addition, the present invention also provides the compound of general formula (1), general formula (2) and general formula (3) expression as manufacturing midbody of the present invention simultaneously.
The manufacturing midbody of the application of the invention, the synthesis path below using, can make effectively have thiazolinyl on the side chain have 2, the compound of 3-difluoro quinhydrones skeleton.
Figure S2008100088445D00041
Method of manufacture 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 compound effectively with various side chains, manufacturing is had 2, the compound of 3-difluoro quinhydrones skeleton is useful.
That utilizes that midbody of the present invention can make has 2, and the compound of 3-difluoro quinhydrones skeleton is useful as the component parts of the liquid crystal display device of vertical orientation mode.And, through with instead, anti--4-(carbalkoxy) bis cyclohexane-4-yl carboxylic acid verivate is the method for manufacture of the present invention of starting substance, can make manufacturing midbody of the present invention effectively.
Embodiment
Below, describe 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 through utilizing chlorizating agent that carboxylic acid is converted to.As being used for the chlorating reaction solvent, so long as the solvent that reaction is carried out smoothly can use can give an example halogen solvent, ether solvent or varsol etc.As halogen solvent can give an example methylene dichloride, chloroform, 1,2-ethylene dichloride etc. can give an example 1 as ether solvent; 4-diox, 1; 3-diox, THF, diethyl ether or t-butyl methyl ether etc. are as varsol can give an example pentane, hexane, hexanaphthene, heptane or toluene etc., wherein; Preferably as the methylene dichloride or 1 of halogen solvent, the 2-ethylene dichloride.
As chlorizating agent can give an example oxalyl chloride, THIONYL CHLORIDE 97, sulfuryl chloride etc., consider that from the easy property viewpoint that obtains and handle preferred oxalyl chloride, THIONYL CHLORIDE 97 are considered from the easy property viewpoint of the chloride of acid purifying that obtains, more preferably oxalyl chloride.When using THIONYL CHLORIDE 97, if do not carry out distillation purifying, the reduction reaction after then 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, therefore preferably.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 needs to produce this moment is 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, in reaction soln, adds alkali and the method for chemically supplying hydrogen chloride gas; Consider from the viewpoint of reaction yield, more preferably use the method for alkali.As the alkali that adds to give an example tertiary amine or pyridine derivate.As tertiary amine can give an example Trimethylamine 99, triethylamine, diisopropylethylamine etc., as pyridine derivate can give an example pyridine, 2-picoline, 2,6-lutidine etc. are considered from the viewpoint of reaction yield, preferred diisopropylethylamine or 2,6-lutidine.As the reaction solvent that uses, so long as the solvent that reaction is carried out smoothly can use can give an example ether solvent, esters solvent or varsol etc.Can give an example 1 as ether solvent; 4-diox, 1; 3-diox, THF, diethyl ether or t-butyl methyl ether etc. are as esters solvent can give an example ritalin or vinyl acetic monomer, as varsol can give an example pentane, hexane, hexanaphthene, heptane or toluene etc.; Wherein, preferred 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 the give an example method of 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 are considered from the easy property of reagent acquisition and the easy property viewpoint of processing, preferred especially two (2-methoxy ethoxy) sodium aluminum hydrides.As the reaction solvent that uses, so long as the solvent that reaction is carried out smoothly can use can give an example ether solvent or varsol etc.Can give an example 1 as ether solvent, 4-diox, 1,3-diox, THF, diethyl ether or t-butyl methyl ether etc.; As varsol can give an example pentane, hexane, hexanaphthene, heptane or toluene etc.; Wherein, preferred 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 give an example and use the method for 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 method of manufacture of the present invention, as the compound that the general formula (4) of title product is represented, the more specifically manufacturing of compound preferred as follows.
As preferred especially compound, the compound as follows of can giving an example.
Figure S2008100088445D00062
As the compound that the general formula (3) of compound of the present invention is represented, preferred particularly compound as follows.
Figure S2008100088445D00071
(in the formula, R 3The expression carbon number is 1～8 alkyl).
As preferred especially compound, the compound as follows of can giving an example.
Figure S2008100088445D00072
(in the formula, R 3The expression carbon number is 1～8 alkyl).
(application examples) used the manufacturing of the liquid crystalline cpd of manufacturing midbody of the present invention
Convert anti-, anti--4-(dialkoxy methyl) bis cyclohexane-4-base carbinol derivatives of formula (4) expression the compound of formula (7) expression to.Make itself and 2,3-difluorophenol reaction obtains the compound of formula (8) expression.Introduce hydroxyl, deriving is the phenols of formula (9) expression, and the compound reaction that itself and formula (10) are represented obtains the compound that formula (11) is represented.Under acidic conditions,, derive the aldehyde of formula (12) expression, make ylide (ylide) reaction, can obtain the compound of formula (13) expression thus by the methyltriphenylphosphonium bromide preparation with the acetal deprotection.The compound of formula (13) expression is that the component parts of the liquid-crystal compsn of negative value is useful as dielectric constant anisotropy.
Figure S2008100088445D00073
(in the formula, R 1And R 2The alkyl or alkenyl of representing Wasserstoffatoms, 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);
Figure S2008100088445D00081
(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);
Figure S2008100088445D00082
(in the formula, R 1And R 2Expression and general formula (4) identical meanings);
Figure S2008100088445D00083
(in the formula, R 1And R 2Expression and general formula (1) identical meanings);
Figure S2008100088445D00084
(in the formula, R 4The alkyl or alkenyl of expression carbon number 1～12, n representes 0 or 1, X 2Expression and general formula (7) identical meanings);
Figure S2008100088445D00085
(in the formula, R 1And R 2Expression and general formula (4) identical meanings, R 4And n representes and general formula (10) identical meanings);
Figure S2008100088445D00086
(in the formula, R 4And n representes and general formula (10) identical meanings);
Figure S2008100088445D00091
(in the formula, R 4And n representes 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 starting substance expression, can be through making the anti-of formula (14) expression, anti--4 ', a carbalkoxy hydrolysis of 4-bis cyclohexane dicarboxylic diester and obtaining.
Figure S2008100088445D00092
(in the formula, R 3Expression and general formula (1) identical meanings).
Embodiment
Below, the present invention will be described in more detail for the embodiment that gives an example, 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.
The THF THF
The LDA LDA
The i-Pr sec.-propyl
DIAD di-isopropyl azodicarboxylate
The Ph phenyl
(embodiment 1) is anti-, the manufacturing of anti--4 '-(methoxycarbonyl) bis cyclohexane-4-yl carboxylic acid
Figure S2008100088445D00101
Instead, anti--4 ', in 4-bis cyclohexane dimethyl dicarboxylate's (15.8g) methyl alcohol (46mL)/THF (46mL) solution, 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 removes and desolvates 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, anti--4 ', it is anti-that 4-bis cyclohexane dimethyl dicarboxylate and complete hydrolysis form, anti--4 ', 4-bis cyclohexane dicarboxylicacid 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 in embodiment 1, obtain 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 underpressure distillation removes and desolvates, and obtains brown solid.Make this compound and palladium charcoal (3.6g), 2,6-lutidine (19g) is suspended in the THF (240mL), under 25 ℃, atmosphere of hydrogen, stirs 10 hours.Carry out diatomite filtration, will filtrate with the washing of 10% salt solution, with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and 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
Figure S2008100088445D00111
Anti-with what obtain in (2-1), the basic formaldehyde (45g) of anti--4-(methoxycarbonyl) bis cyclohexane-4-, terepthaloyl moietie (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 underpressure distillation then, obtain brown solid except that desolvating.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
Figure S2008100088445D00112
What in (2-2), obtain 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 pair (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.Obtain organic layer, use the extracted in toluene water layer.Organic layer is merged, and anhydrous sodium sulfate drying is used in water, saturated common salt water washing successively, carries out underpressure distillation then except that desolvating, and 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
Figure S2008100088445D00121
What in (2-3), obtain is anti-, in methylene dichloride (54mL) solution of the basic methyl alcohol (Ia, 18g) of anti--4-(1,3-dioxolane-2-yl) bis cyclohexane-4-, pyridine (8mL), splashes into methylsulfonyl chloride (7.7mL) under 25 ℃.After 5 hours, splash into saturated sodium bicarbonate aqueous solution 35 ℃ of stirrings.Obtain 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 underpressure distillation then except that desolvating, and 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, N (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 entry and extract with toluene.With organic layer water successively, saturated common salt water washing, use anhydrous sodium sulfate drying, carry out underpressure distillation then except that desolvating, 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-under Nei Wen-40～-55 ℃, to splash into 1-; 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, obtain organic layer after, use the extracted in toluene water layer.In the organic layer that merges, slowly add 15% ydrogen peroxide 50 (12.7g), stirred 2 hours down at 40 ℃.Add entry and stir a little while, extract with toluene.With organic layer water and saturated common salt water washing, use anhydrous sodium sulfate drying, carry out underpressure distillation except that desolvating, 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 under 5 ℃, splash into di-isopropyl azodicarboxylate (7.88g)., concentrate and remove THF after 1 hour in stirring at room.Add 67% methanol aqueous solution solid matter is disperseed,, obtain 6-(3-butenyloxy)-3-(anti-, anti--4 '-(1,3-dioxolane-2-yl) bis cyclohexane-4-ylmethoxy)-1,2-two fluorobenzene (Ie, 14.3g) crystallization filtration, drying.
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 entry and saturated aqueous common salt is obtained organic layer; Water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, underpressure distillation removes and desolvates, and 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, stirred 30 minutes at 5 ℃.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.Underpressure distillation is except that desolvating after adding entry 10mL, and adding 50% methanol aqueous solution and hexane are obtained organic layer in residue.With organic layer with 50% methanol aqueous solution and saturated common salt water washing; Underpressure distillation removes and desolvates; 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 C64.5 N119.5I
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).
Through 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
Figure S2008100088445D00141
(R-1-1) 1-(2-butylene oxygen base)-2, the manufacturing of 3-two fluorobenzene
2, in 2-butanone (600ml) solution of 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.Distillation removes and desolvates, and carries out underpressure distillation (155-160 ℃, 50kPa), 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% ydrogen peroxide 50 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.Distillation removes and desolvates, and 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
Figure S2008100088445D00151
(R-2-1) 4; The manufacturing of 4 '-dimethoxy methylene-bis hexanaphthene is scattered in chlorination methoxymethyl triphenyl
Figure 2008100088445_0
882.3g among the THF2600mL, is 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 entry then and make reaction terminating.After underpressure distillation removes and desolvates, add hexane and carry out vigorous stirring, filtration (2 times).50% methanol aqueous solution, saturated common salt water washing are used in the merging of will filtrating successively, use anhydrous magnesium sulfate drying.Distillation removes and desolvates, and 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.With the organic layer that merges with the saturated common salt water washing after, use anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and 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 entry, the solid of separating out through the suction filtration leaching.With the solid that obtains water successively, methanol wash, drying, 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) solution of the solid 120.0g that under interior temperature 5-10 ℃, obtains to (R-2-2) drips.In keeping, stirred 1 hour in the temperature, add entry 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 removes and desolvates 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 Peng Qinghuana 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.Stirred 2 hours after being warming up to room temperature, add entry, ETHYLE 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 ETHYLE ACETATE.The organic layer that merges is used the saturated common salt water washing, use anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and 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.In ice bath cooling down,, be warming up to after the room temperature stirring 6 hours, placement a whole night with methylene dichloride (6mL) solution that dripped methylsulfonyl chloride 6.3mL in 30 minutes.Reaction soln is joined in 10% hydrochloric acid, obtain 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.Underpressure distillation removes desolvates, and residue is utilized column chromatography (silica gel/toluene) and recrystallize (hexane/toluene) purifying 3 times, 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)
Figure S2008100088445D00171
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, append 4-(3-butenyloxy)-2,3-difluorophenol, restir 3 hours at 100-130 ℃.Reaction mixture is added in the entry, extract with toluene, anhydrous magnesium sulfate drying is used in water and saturated common salt water washing successively.Underpressure distillation removes and desolvates, and utilizes column chromatography and recrystallize to carry out purifying residue, obtains 2, the colourless crystallization of 3-two fluoro-1-(3-butenyloxy)-4-(anti-, anti--4-vinyl bis cyclohexane-4-yl) anisole (R).
In not using the existing method of manufacture of midbody 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 method for manufacture of comparative example, must make 4-(2-thiazolinyl)-2,3-difluorophenol verivate in addition.Its result when making the side chain different compounds, needs to make various 4-(2-thiazolinyl)-2,3-difluorophenol verivate, thereby efficient is poor.

Claims (1)

1. a formula (1) expression is anti-, anti--4-(carbalkoxy) bis cyclohexane-4-yl carboxylic acid verivate,
Figure FSB00000904608900011
In the formula (1), R 3The expression carbon number is 1～12 alkyl.
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