CN101462939A - Preparation of trans substitute cyclohexane-carboxylic acid and trans/trans bicyclohexanedicarboxylic acid - Google Patents
Preparation of trans substitute cyclohexane-carboxylic acid and trans/trans bicyclohexanedicarboxylic acid Download PDFInfo
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Abstract
The present invention provides a method for preparing trans-substituted cyclohexane-carboxylic acids and trans/trans-bicyclohexane dicarboxylic acids. The invention is to provides a novel method for preparing trans-high-ratio substituted cyclohexane-carboxylic acids, wherein, in existence of strong acid, carboxyl of the substituted cyclohexane-carboxylic acids with a% (0<=a) ratio of trans-body is transferred into halogenated carbonyl, such that substituted cyclohexane-carboxylic acids with b% (a<b) ratio of trans-body is obtained, and then the halogenated carbonyl of obtained substituted cyclohexane-carboxylic acids acyl halide is hydrolyzed, such that substituted cyclohexane-carboxylic acids with c% (a<c) ratio of trans-body is obtained; and reaction of the obtained substituted cyclohexane-carboxylic acids acyl halide with compounds containing hydroxide or compounds containing amido or compounds nitrogen heterocyclic ring, such that substituted cyclohexane-carboxylic carboxylic ether or substituted cyclohexane-carboxylic amide with d% (a<d) ratio of trans-body is obtained.
Description
Technical field
The present invention relates to make the method for the high bicyclohexane omega-dicarboxylic acids of the ratio of the high substituted cyclohexane carboxylic-acid of the ratio of trans body and trans/trans body.
Background technology
Trans/trans the body of the trans body of hexahydrobenzoic acid and bicyclohexane dicarboxylic acid is useful as the intermediate in various fields such as liquid crystal material, pharmaceuticals, macromolecular material.Obtain hexahydrobenzoic acid trans body method and the cis/cis body of bicyclohexane dicarboxylic acid, the method that the cis/trans body is isomerizated into trans/trans body proposed the whole bag of tricks (for example, patent documentation 1～6 and non-patent literature 1).Therefore but any method of Ti Chuing all was to react under the reaction conditions of strictness in the past, wished to have the method for the trans/trans replacement body of the trans replacement body that obtains cyclohexane-carboxylic acid under gentle more condition and bicyclohexane omega-dicarboxylic acids.
Patent documentation 1: Japanese kokai publication hei 10-237015 communique
Patent documentation 2: TOHKEMY 2000-191602 communique
Patent documentation 3: TOHKEMY 2003-96026 communique
Patent documentation 4: TOHKEMY 2003-128620 communique
Patent documentation 5: TOHKEMY 2004-307468 communique
Patent documentation 6: Japanese Patent Publication 39-27244 communique
Non-patent literature 1:Tetrahedron Letters 2004,45,6669-72
Summary of the invention
Problem of the present invention provides the novel method of the high bicyclohexane omega-dicarboxylic acids of the ratio of the high cyclohexane-carboxylic acid of the ratio that can make trans body and trans/trans body.
The means that are used to solve above-mentioned problem are as described below.
[1] a kind of method of making the substituted cyclohexane carboxylic acid halides, wherein, in the presence of strong acid, with the ratio of trans body is that (wherein the carboxyl of 0≤a) substituted cyclohexane carboxylic acid changes halo carbonyl into to a%, thereby the ratio of making trans body is b% (the substituted cyclohexane carboxylic acid halides of a＜b) wherein.
[2] a kind of manufacture method of substituted cyclohexane carboxylic acid is characterized in that, this manufacture method comprises following operation:
The 1st operation, in this operation, in the presence of strong acid, with the ratio of trans body be a% (wherein the carboxyl of 0≤a) substituted cyclohexane carboxylic acid changes halo carbonyl into, thus obtain the substituted cyclohexane carboxylic acid halides and,
The 2nd operation, in this operation, with the halo carbonyl hydrolysis of the substituted cyclohexane carboxylic acid halides that obtains in the 1st operation, thereby the ratio that obtains trans body is c% (the substituted cyclohexane carboxylic acid of a＜c) wherein.
[3] manufacture method of a kind of substituted cyclohexane carboxylicesters or substituted cyclohexane carboxylic acid amide is characterized in that, this manufacture method comprises following operation:
The 1st operation, in this operation, in the presence of strong acid, with the ratio of trans body be a% (wherein the carboxyl of 0≤a) substituted cyclohexane carboxylic acid changes halo carbonyl into, thus obtain the substituted cyclohexane carboxylic acid halides and,
The 2nd operation, in this operation, make the substituted cyclohexane carboxylic acid halides that obtains in the 1st operation and contain the compound of hydroxyl or contain amino compound or the nitrogen-containing heterocycle compound reaction, thereby the ratio that obtains trans body is d% (wherein substituted cyclohexane carboxylicesters or the substituted cyclohexane acid amides of a＜d).
[4] a kind of method of making bicyclohexane dicarboxylic acid carboxylic acid halides, wherein, in the presence of strong acid, with the ratio of trans/trans body in 1 on the bicyclohexane ring and 4 and 1 ' and 4 ' 's the spatial relation is that (wherein the carboxyl of 0≤e) bicyclohexane dicarboxylic acid changes halo carbonyl into to e%, thereby the ratio of making trans/trans body is f% (the bicyclohexane dicarboxylic acid carboxylic acid halides of e＜f) wherein.
[5] a kind of manufacture method of bicyclohexane dicarboxylic acid is characterized in that, this manufacture method comprises following operation:
The 1st operation, in this operation, in the presence of strong acid, be that (wherein the carboxyl of 0≤e) bicyclohexane dicarboxylic acid changes halo carbonyl into to e% with the ratio of trans/trans body in 1 on the bicyclohexane ring and 4 and 1 ' and 4 ' 's the spatial relation, with
The 2nd operation, in this operation, with the halo carbonyl hydrolysis of the bicyclohexane dicarboxylic acid carboxylic acid halides that obtains in the 1st operation, thereby the ratio that obtains trans/trans body is g% (the bicyclohexane dicarboxylic acid of e＜g) wherein.
[6] manufacture method of a kind of bicyclohexane dicarboxylic diester or bicyclohexane dicarboxylic acid diamide is characterized in that this manufacture method comprises following operation:
The 1st operation, in this operation, in the presence of strong acid, with the ratio of trans/trans body in 1 on the bicyclohexane ring and 4 and 1 ' and 4 ' 's the spatial relation is that (wherein the carboxyl of 0≤e) bicyclohexane dicarboxylic acid changes halo carbonyl into to e%, thereby obtain bicyclohexane dicarboxylic acid carboxylic acid halides, with
The 2nd operation, in this operation, make the bicyclohexane dicarboxylic acid carboxylic acid halides that obtains in the 1st operation and contain the compound of hydroxyl or contain amino compound or the nitrogen-containing heterocycle compound reaction, thereby the ratio that obtains trans/trans body is h% (wherein bicyclohexane dicarboxylic diester or the bicyclohexane dicarboxylic acid diamide of e＜h).
[7] according to each described method in [1]～[6], it is characterized in that halo carbonyl is the chloro carbonyl.
[8] according to each described method in [1]～[7], it is characterized in that described strong acid is sulfuric acid or sulfonic acid.
[9] a kind of manufacture method of trans substituted cyclohexane carboxyl, it comprises: in the presence of strong acid, the carboxyl in the cis substituted cyclohexane carboxylic acid is changed into halo carbonyl and the halo carbonyl hydrolysis is formed carboxyl again.
[10] manufacture method of a kind of trans substituted cyclohexane carboxylicesters or trans substituted cyclohexane acid amides, it comprises: in the presence of strong acid, change the carboxyl in the cis substituted cyclohexane carboxylic acid into halo carbonyl, and make halo carbonyl and contain the compound of hydroxyl or contain amino compound or nitrogen-containing heterocycle compound reaction.
[11] a kind of trans/manufacture method of trans-bicyclohexane dicarboxyl, it comprises: in the presence of strong acid, with cis/cis-and/or cis/trans-bicyclohexane dicarboxylic acid in carboxyl change halo carbonyl into, and the halo carbonyl hydrolysis is formed carboxyl again.
[12] a kind of trans/manufacture method of trans-bicyclohexane dicarboxylic diester or trans/trans-bicyclohexane dicarboxylic acid diamide, it comprises: in the presence of strong acid, with cis/cis-and/or cis/trans-bicyclohexane dicarboxylic acid in carboxyl change halo carbonyl into, and make halo carbonyl and contain the compound of hydroxyl or contain amino compound or nitrogen-containing heterocycle compound reaction.
According to the present invention, can provide the novel method of the high bicyclohexane omega-dicarboxylic acids of the ratio of the high cyclohexane-carboxylic acid of the ratio that can make trans body and trans/trans body.
Embodiment
Below, the present invention is described in detail.In addition, use the numerical range of "～" expression to be meant the numerical value of the front and back record of "～" in this specification sheets as lower value and higher limit and the scope that included.
The present invention relates to by in the presence of strong acid, changing the carboxyl of substituted cyclohexane carboxylic acid into halo carbonyl, thereby make the method for the substituted cyclohexane carboxylic acid halides that the ratio of trans body is improved.In addition, also relate to the substituted cyclohexane carboxylic acid halides that utilization makes trans body by aforesaid method ratio is improved, make the method for the substituted cyclohexane carboxylic acid that the ratio of trans body is improved by hydrolysis.And then, the invention still further relates to following method: utilization is made the ratio of trans body be improved by aforesaid method substituted cyclohexane carboxylic acid halides, contain nitrogen-containing heterocycle compounds such as amino compound or piperidines, morpholine, thiodiphenylamine and react by making itself and aliphatics alcohols or phenols etc. contain aromatic amines such as aliphatics amine such as the compound of hydroxyl or Armeen or secondary aliphatic amine or aniline etc., thereby make substituted cyclohexane carboxylicesters or substituted cyclohexane acid amides.
2-replaces, 3-replaces and 4-substituted cyclohexane carboxylic acid for example can by with neighbour-replacements ,-replacement, right-substituted benzoic acid contact to reduce and obtain, at this moment, generally be to obtain as the mixture of cis body and trans body, 2-replaces and 4-substituted cyclohexane carboxylic acid is to obtain as the mixture of the trans height of ratio of cis body.Among the present invention, the mixture that uses the cis body of substituted cyclohexane carboxylic acid and trans body is as starting raw material, by carboxyl being changed into the ratio that halo carbonyl improves trans body in the presence of strong acid.As starting raw material, can certainly not use mixture, and only use the cis body of substituted cyclohexane carboxylic acid.
In the method for the present invention, the substituting group that the relevant substituted cyclohexane carboxylic acid that uses as starting raw material is had is not particularly limited.Only otherwise the carboxyl that can hinder in the substituted cyclohexane carboxylic acid changes halo carbonyl in the presence of strong acid, then can be any substituting group.The substituent example of substituted cyclohexane carboxylic acid comprises: halogen atom (Cl for example; Br; F; I); cyano group; carboxyl; sulfo group; carbonatoms is 1～20 a chain or cyclic alkyl (methyl for example; ethyl; sec.-propyl; normal-butyl; cyclohexyl; benzyl; styroyl; the 4-carboxybutyl; the 2-methoxy ethyl); carbonatoms is 1～20 an alkenyl (vinyl for example; allyl group; the 2-hexenyl); carbonatoms is 2～8 an alkynyl (ethynyl for example; the ethyl acetylene base; 3-hexin base); carbonatoms is 6～20 an aryl (phenyl for example; naphthyl; the 4-ethylphenyl; 3-Toluidrin phenyl; the 4-p-methoxy-phenyl; the 3-carboxyl phenyl); carbonatoms is 1～20 an acyl group (ethanoyl for example; benzoyl; propionyl; butyryl radicals); carbonatoms is 2～20 an alkoxy carbonyl (methoxycarbonyl for example; ethoxy carbonyl; cyclohexyloxy carbonyl); carbonatoms is 7～20 an aryloxycarbonyl (phenyloxycarbonyl for example; the naphthyloxy carbonyl); carbonatoms is 1～20 an alkoxyl group (methoxyl group for example; oxyethyl group; butoxy; methoxy ethoxy); carbonatoms is 6～20 an aryloxy (phenoxy group for example; 4-ethyl phenoxy group; 4-cyclohexyl phenoxy group; naphthyloxy); carbonatoms is 2～20 an acyloxy (acetoxyl group for example; cyclohexyl carbonyl oxygen base; benzoyloxy); carbonatoms is 1～20 an alkyl sulfenyl (hexyl sulfenyl for example; the octyl group sulfenyl); carbonatoms is 6～20 an artyl sulfo (phenyl sulfenyl for example; the naphthyl sulfenyl); carbonatoms is 1～20 an alkyl sulphonyl (methyl sulphonyl for example; the cyclohexyl alkylsulfonyl); carbonatoms is 7～20 an aryl sulfonyl (phenyl sulfonyl for example; 2-naphthyl alkylsulfonyl); heterocyclic radical (2-furyl for example; furfuryl group; the 2-thienyl; the 2-pyrryl; 1,3-two oxa-s penta ring-2-yl).
As starting raw material, also can use to have for example 1 of a plurality of carboxyls, 2-, 1,3-or 1,4-cyclohexane dicarboxylic acid.In addition, also can use the cyclohexane ring that has more than 2 (hydrogen atom of this cyclohexane ring can also further by replacements such as alkyl) as substituent substituted cyclohexane carboxylic acid.Above-mentioned trans body with substituent substituted cyclohexane carboxylic acid is useful as the intermediate of the compound that uses in the various fields.The example that can be used as the bicyclohexane carboxylic acid derivative of starting raw material utilization of the present invention comprises the compound of following formula (X) expression.
In the above-mentioned formula, R represents substituting group, and its object lesson is identical with above-mentioned substituent example.Preferred example comprises that carbonatoms is the alkyl of 1～20 straight or branched.In addition, as described later, R also can be a carboxyl.
Not only there is the isomer of trans body and cis body in the compound of above-mentioned formula (X) expression in 1 and 4 s' spatial relation, and also has the isomer of trans body and cis body in 1 ' and 4 ' 's spatial relation.Promptly, there are these 4 kinds of trans/trans body, trans/cis body, cis/trans body and cis/cis bodies (wherein, having trans/trans body, trans (cis)/cis (trans) body and these 3 kinds of isomer of cis/cis body in R is the compound of COOH) in above-claimed cpd in 1 and 4 and 1 ' and 4 ' 's spatial relation.The method according to this invention regardless of the trans body in 1 ' in the above-mentioned formula (X) and 4 ' 's the spatial relation and the ratio of cis body, can both improve the ratio of the trans body in 1 and 4 s' the spatial relation.Promptly, if with the trans body in 1 of starting raw material and 4 s' the spatial relation (promptly 1,4 trans/1 ', 4 ' trans body and 1,4 trans/1 ', 4 ' cis body sum) ratio is set at a ' %, and the overall proportion b ' % of the trans body in the spatial relation of halid 1 and 4 after then changing halo carbonyl under strong acid satisfies a '＜b '.
The invention still further relates to following method: in the presence of strong acid, change the carboxyl of the bicyclohexane dicarboxylic acid of following formula (I) expression into halo carbonyl, thereby make the bicyclohexane dicarboxylic acid carboxylic acid halides that the ratio of trans/trans body on the bicyclohexane ring 1 and 4 and 1 ' and 4 ' 's the spatial relation is improved.
In addition, the invention still further relates to following method: the bicyclohexane dicarboxylic acid carboxylic acid halides that utilizes the ratio that makes trans/trans body by aforesaid method to be improved, make the bicyclohexane dicarboxylic acid that the ratio of trans/trans body is improved by hydrolysis.And then, the invention still further relates to following method: utilization is made the ratio of trans/trans body be improved by aforesaid method bicyclohexane dicarboxylic acid carboxylic acid halides, contain nitrogen-containing heterocycle compounds such as amino compound or piperidines, morpholine, thiodiphenylamine and react by making itself and aliphatics alcohols or phenols etc. contain aromatic amines such as aliphatics amine such as the compound of hydroxyl or Armeen or secondary aliphatic amine or aniline etc., thereby make bicyclohexane dicarboxylic diester or cyclohexane dicarboxylic acid diamide.
The bicyclohexane dicarboxylic acid for example can be by with biphenyl-4, and 4 '-dicarboxylic acid contacts reduction and obtains, and at this moment, generally is to obtain as the mixture of cis/cis body, cis/trans body and trans/trans body.Among the present invention, the mixture of cis/cis body, cis/trans body and trans/trans body that uses the bicyclohexane dicarboxylic acid is as starting raw material, by carboxyl being changed into the ratio that halo carbonyl improves trans/trans body in the presence of strong acid.As starting raw material, can certainly not use mixture, and only use the cis/cis body or the cis/trans body of bicyclohexane dicarboxylic acid.
In the bicyclohexane dicarboxylic acid of above-mentioned formula (I) expression, on the bicyclohexane ring 1,1 ', 4 and 4 ' carbon atom in addition also can have substituting group.As this substituent example, the substituent example that is had with above-mentioned substituted cyclohexane carboxylic acid is identical.But, the ratio of/trans body trans in order to improve, the substituting group preferred volume of 2 and 2 ' 's carbon atom is little, more preferably unsubstituted.
Aforesaid method of the present invention is in the presence of strong acid, (COOH) changes the carboxyl in substituted cyclohexane carboxylic acid or the bicyclohexane dicarboxylic acid into halo carbonyl (COX) (X represents halogen atom).X is so long as halogen atom just can preferably use, but more preferably bromine or chlorine atom most preferably are the chlorine atom.As above-mentioned strong acid, can be any of organic acid, mineral acid, as its example, can list sulfuric acid, sulfonic acid, phosphoric acid, nitric acid etc.Wherein, if use sulfuric acid and sulfonic acid, then reaction can be carried out in the shorter time, thereby preferred.
Among the present invention, reagent and condition when changing carboxyl into halo carbonyl for example can adopt all ingredients and the condition put down in writing in synthetic and reaction (II), p1104～1120 at new experimental science lecture the 14th volume, organic compound (ball kind, clear and 59 years).Here the condition that changes the chloro carbonyl into is elaborated.
The present invention can use usually the condition of use in acyl chlorides synthetic, can synthesize trichloride with carboxylic acid and inorganic halides (for example thionyl chloride, SULPHURYL CHLORIDE, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride etc.), carboxylic acid and Organohalogen compounds (for example organophosphorus halogenide, α, α-dihalogenated ether etc.), carboxylic acid and oxalyl chloride, an alkali metal salt of carboxylic acid or the combination of amine salt and inorganic halides (for example phosphorus pentachloride, phosphoryl chloride, thionyl chloride etc.) etc.In addition, the suitable catalyzer of also preferred use.Other halo carbonyl also can utilize reagent and the condition put down in writing in the above-mentioned document to synthesize.
The temperature of carrying out halo carbonylization is according to reactive difference of employed reagent and difference, so preferably react under the temperature of each reagent being suitable for.Make the substituted cyclohexane carboxylic acid carry out isomerized temperature and be preferably 20 ℃～150 ℃, more preferably 30 ℃～130 ℃, more preferably 40 ℃～110 ℃.The strong acid that uses among the present invention can begin from the stage of carrying out halo carbonylization to add in advance, also strong acid can be added in the system in advance, reacts after wherein dripping mentioned reagent.In addition, also can after the halo carbonyl end, add.Be that the various organic synthesis that react of catalyzer are same with acid, among the present invention, strong acid is to add in the reaction system slightly.Addition is less, and then isomerized speed descends, and more, and the tendency of by product increase is then arranged in the reaction, so generally with respect to the carboxyl of the carboxylic acid that uses in the reaction, preferably add about 5～25 moles of %.
Be used for isomerized temperature of reaction as long as be fully, preferably about 20 ℃～140 ℃, carry out, more preferably about 50 ℃～120 ℃, carry out carrying out above-mentioned reaction.The needed reaction times of isomerization is promptly abundant with about 30 minutes～10 hours, can carry out in the relatively shorter time.By adjusting the addition of temperature of reaction or strong acid, and reaction system stirred etc., can in shorter time, react.
The method according to this invention, no matter use the substituted cyclohexane carboxylic acid or the bicyclohexane dicarboxylic acid of which type of stereoisomerism body burden, the ratio that can both obtain the ratio of trans body and trans/trans body be about 70～100% substituted cyclohexane carboxylic acid halides or bicyclohexane dicarboxylic acid carboxylic acid halides.
According to required, also substituted cyclohexane carboxylic acid halides or the hydrolysis of bicyclohexane dicarboxylic acid carboxylic acid halides that obtains can be formed substituted cyclohexane carboxylic acid or bicyclohexane dicarboxylic acid again.According to method of the present invention,, can improve the ratio of trans body, trans/trans body by via substituted cyclohexane carboxylic acid halides or bicyclohexane dicarboxylic acid carboxylic acid halides.
The hydrolysis of substituted cyclohexane carboxylic acid halides and bicyclohexane dicarboxylic acid carboxylic acid halides can be carried out under the condition identical with the hydrolysis of common carboxylic acid halides.For example, after above-mentioned reaction finishes,, wait the solvent removed in the system (being reaction reagent when the reaction reagent double as solvent), then,, halo carbonyl is decomposed by adding water by distillation according to required.
By the hydrolysis halo carbonyl, obtain substituted cyclohexane carboxylic acid or bicyclohexane dicarboxylic acid once more.In the operation of this hydrolysis, trans body can not be isomerizated into the cis body, trans/trans body can not be isomerizated into cis/cis body, cis/trans body, the ratio of the trans body of the substituted cyclohexane carboxylic acid that obtains or the trans/trans body of bicyclohexane dicarboxylic acid is identical with the ratio of the trans/trans body of the trans body of substituted cyclohexane carboxylic acid halides or bicyclohexane dicarboxylic acid carboxylic acid halides, becomes about 70～100% particularly.In addition,, compare, can access the higher substituted cyclohexane carboxylic acid or the bicyclohexane dicarboxylic acid of ratio of trans body with substituted cyclohexane carboxylic acid halides or bicyclohexane dicarboxylic acid carboxylic acid halides before the reaction by the partial crystallization condition after the adjustment hydrolysis.For example, when adding the contour polar water-miscible organic solvent of acetonitrile, methyl alcohol, ethanol, 2-propyl alcohol with water, the ratio of trans body further improves, thereby preferred.The preferred mixture ratio of water and above-mentioned organic solvent is according to the different of the kind of objectification compound and great changes have taken place.Generally, above-mentioned organic solvent is about 0.01～50 times with respect to the volume ratio of water, is preferably about 0.1～20 times.But, be not limited to this scope.
In addition, as required, also can so that to substituted cyclohexane carboxylic acid halides or the compound reaction that contains hydroxyl of bicyclohexane dicarboxylic acid carboxylic acid halides and aliphatics alcohols or phenols etc., thereby synthetic substituted cyclohexane carboxylicesters or bicyclohexane dicarboxylic diester.Equally, also can so that to substituted cyclohexane carboxylic acid halides or aromatic amines such as aliphatics amine such as bicyclohexane dicarboxylic acid carboxylic acid halides and Armeen or secondary aliphatic amine or aniline etc. contain compounds such as nitrogen-containing heterocycle compound such as amino compound or piperidines, morpholine, thiodiphenylamine and react, thereby synthetic substituted cyclohexane acid amides or bicyclohexane dicarboxylic acid diamide.According to method of the present invention, by for the time being via the operation that changes substituted cyclohexane carboxylic acid halides or bicyclohexane dicarboxylic acid carboxylic acid halides into, with starting raw material direct esterification or amidation are compared, can access high substituted cyclohexane carboxylicesters or bicyclohexane dicarboxylic diester or the substituted cyclohexane acid amides or the bicyclohexane dicarboxylic acid diamide of ratio of trans body.
Substituted cyclohexane carboxylic acid halides or bicyclohexane dicarboxylic acid carboxylic acid halides and aliphatics alcohols or phenols etc. contain hydroxyl compound reaction can with the common synthetic identical condition of the ester that has used carboxylic acid halides under carry out.For example, after the above-mentioned reaction that changes halo carbonyl from carboxyl into finishes, as required, wait the solvent remove in the system (being reaction reagent when the reaction reagent double as solvent) by distillation, then, the solution that has dissolved alcohols or phenols in organic solvent is added in the system, can carry out esterification thus.
In addition, the reaction that contains nitrogen-containing heterocycle compounds such as amino compound or piperidines, morpholine, thiodiphenylamine such as aromatic amines such as aliphatics amine such as substituted cyclohexane carboxylic acid halides or bicyclohexane dicarboxylic acid carboxylic acid halides and Armeen or secondary aliphatic amine or aniline can be carried out under the condition identical with the common amidate action that has used carboxylic acid halides.
In this esterification step and amidation operation, trans body can not be isomerizated into the cis body, perhaps trans/trans body can not be isomerizated into cis/cis body, cis/trans body, the ratio of the trans/trans body of the ratio of the substituted cyclohexane carboxylicesters that obtains or the trans body of substituted cyclohexane acid amides and the bicyclohexane dicarboxylic diester that obtains or bicyclohexane dicarboxylic acid diamide is identical with the ratio of the trans/trans body of the trans body of substituted cyclohexane carboxylic acid halides and bicyclohexane dicarboxylic acid carboxylic acid halides, becomes about 70～100% particularly.In addition, after esterification or amidate action finish, when making the substituted cyclohexane carboxylicesters of generation or bicyclohexane dicarboxylic diester or substituted cyclohexane acid amides or bicyclohexane dicarboxylic acid diamide crystallization, pass through selective solvent, the preceding higher substituted cyclohexane carboxylicesters or the substituted cyclohexane acid amides of substituted cyclohexane carboxylic acid halides of ratio reaction of trans body can be obtained, and the higher bicyclohexane dicarboxylic diester or the bicyclohexane dicarboxylic acid diamide of ratio bicyclohexane dicarboxylic acid carboxylic acid halides of trans/trans body can be obtained.For example, the solvent that uses during as crystallization, the solvent that the difference of the solubleness of the solubleness of trans body and cis body is increased can further improve the ratio of trans body, thereby preferred.
With the high substituted cyclohexane carboxylic-acid of the ratio of the trans body of method synthetic of the present invention (in this manual, with " substituted cyclohexane carboxylic acid ", " substituted cyclohexane carboxylic acid halides ", the meaning that " substituted cyclohexane carboxylicesters " and " substituted cyclohexane acid amides " all included is used), and the high bicyclohexane omega-dicarboxylic acids of the ratio of trans/trans body is (in this manual, with " bicyclohexane dicarboxylic acid ", " bicyclohexane dicarboxylic acid carboxylic acid halides ", the meaning that " bicyclohexane dicarboxylic diester " and " bicyclohexane dicarboxylic acid diamide " all included is used) can be used in various synthetic such as liquid crystal material and pharmaceuticals.For example, in [0020]～[0029] of TOHKEMY 2002-363343 communique, be useful in the illustrative compound that contains cyclohexane ring synthetic.
Embodiment
Followingly the present invention is described in further detail according to embodiment.The material of representing among the following embodiment, usage quantity, ratio, contents processing, treatment step etc. are only otherwise exceeding aim of the present invention just can suitably change.Therefore, scope of the present invention should not explained by embodiment shown below limitedly.
In addition, the ratio of cis body and trans body by
1The data of H-NMR are calculated.
[embodiment 1]
According to the synthetic 1-B of following proposal.
5.0g is contacted the 1-A (for the spatial relation of carboxyl and cyclohexyl, trans is 28%, and cis is 72%) that reduces and obtain to 4-(trans-4-ethyl cyclohexyl) phenylformic acid be dissolved in 10cm
3In the thionyl chloride, add 0.05cm
3Behind the vitriol oil, stirred 30 minutes down at 100 ℃.After heating up in a steamer thionyl chloride, add 100cm
3Acetonitrile and 100cm
3Water at room temperature stirred 30 minutes.The crystal that filtration is separated out is also dry, obtains 4.8g 1-B.By
1The mensuration of H-NMR as can be known, in the carboxyl of 1-B and the spatial relation of cyclohexyl, the ratio of trans body is 80%.
Below represent resulting 1-B's
1The H-NMR data.
1H-NMR(CDCl
3)δ：0.75～1.60(16H、m)、1.60～1.85(6H、m)、1.90～2.05(2H、m)、2.10～2.30(0.8H、m)、2.50～2.60(0.2H、m)。
[embodiment 2]
According to the synthetic 1-C of following proposal.
5.0g is contacted the 1-A (about the spatial relation of carboxyl and cyclohexyl, trans is 28%, and cis is 72%) that reduces and obtain to 4-(trans-4-ethyl cyclohexyl) phenylformic acid be dissolved in 10cm
3In the thionyl chloride, behind the vitriol oil of interpolation catalytic amount, stirred 30 minutes down at 100 ℃.After heating up in a steamer thionyl chloride, add 100cm
3Acetonitrile and 10cm
3Water at room temperature stirred 30 minutes.Crystal and drying by filtration is separated out obtain 2.7g 1-C.Measure 1-C's
1In the spatial relation of carboxyl and cyclohexyl, from the peak of cis body, 1-C is not 100% trans body as can be known for H-NMR, result.
Below represent resulting 1-C's
1The H-NMR data.
1H-NMR(CDCl
3)δ：0.75～1.25(14H、m)、1.30～1.50(2H、m)、1.60～1.85(6H、m)、2.10～2.30(1H、m)。
[embodiment 3]
According to following proposal Synthetic 2-C.
(2-B's is synthetic)
6.0g2-A (Tokyo changes into that industrial makes, transly is 26%, cis be 74%) is dissolved in 10cm
3In the thionyl chloride, add 1cm
3Behind the vitriol oil, stirred 1 hour down at 100 ℃.Heat up in a steamer thionyl chloride, obtain 7.3g2-B.
(2-C's is synthetic)
With 8.5g ethylphenol and 5.9cm
3Pyridine is dissolved in 80cm
3In the tetrahydrofuran (THF), under the temperature of reaction below 10 ℃, drip 2-B (7.3g) is dissolved in 20cm
3Tetrahydrofuran (THF) and the solution that obtains.At room temperature stirred then 5 hours.In reaction solution, add entry, filter crystal and the drying separated out, obtain 12.5g 2-C.By
1The mensuration of H-NMR as can be known, the ratio of the trans body of 2-C is 70%.
Below represent resulting 2-C's
1The H-NMR data.
1H-NMR(CDCl
3)δ：1.20～1.26(6H、m)、1.60～1.70(2.8H、m)、1.85～1.95(1.2H、m)、2.10～2.20(1.2H、m)、2.25～2.35(2.8H、m)、2.50～2.70(5.4H、m)、2.75～2.80(0.6H、m)、6.95～7.00(4H、m)、6.95～7.00(4H、m)、7.15～7.20(4H、m)。
[embodiment 4]
According to following proposal Synthetic 2-D.
(2-B's is synthetic)
At 1dm
3There-necked flask in add 25.8g 2-A (Tokyo changes into that industrial makes, transly is 26%, cis be 74%), 120cm
3Toluene and 1cm
3Sulfuric acid is warming up to 81 ℃.To wherein dripping 24.0cm
3Thionyl chloride is warming up to 93 ℃ and stirred 3 hours after drip finishing.
(2-D's is synthetic)
Cool the temperature to 81 ℃ then, drip the toluene 30cm of 4-ethylphenol 36.7g
3Solution after drip finishing remains in temperature 81 ℃ and stirred 2 hours.Be cooled to room temperature, add 480cm
3Methyl alcohol is separated out crystal, is cooled to below 5 ℃ with ice-water bath again.Use methanol wash behind the suction filtration, at room temperature dry resulting crystal one day obtains the 2-D of 28.5g as white crystal thus.Measure resulting 2-D's
1Not from the peak of cis body, 2-D is 100% trans body as can be known for H-NMR, result.
Below represent resulting 2-D's
1The H-NMR data.
1H-NMR(CDCl
3)δ：1.23(6H、t)、1.56～1.76(4H、m)、2.17～2.36(4H、m)、2.48～2.70(4H、d+2H、m)、6.98(4H、d)、7.20(4H、d)。
[embodiment 5]
According to the synthetic 3-B of following proposal.
To 4,4 '-diphenyl dicarboxylic acid contacts reduction and the 3-A that obtains (cis/cis body is 43%, the cis/trans body is 48%, trans/trans body be 9%) is dissolved in 30cm with 5.0g
3In the thionyl chloride, behind the vitriol oil of interpolation catalytic amount, stirred 8 hours down at 100 ℃.After heating up in a steamer thionyl chloride, add 10cm
3Tetrahydrofuran (THF) is added drop-wise to 30cm with it under ice-cooled
3Methyl alcohol and 8.5cm
3In the mixing solutions of triethylamine, at room temperature stirred 60 minutes.By reaction mixture is injected into 200cm
3In the dilute hydrochloric acid, filter, carry out recrystallization, obtain 1.4g 3-B with methyl alcohol.Measure 3-B's
1Not from the peak of cis/cis body, cis/trans body, 3-B is 100% trans/trans body as can be known for H-NMR, result.
Below represent resulting 3-B's
1The H-NMR data.
1H-NMR(CDCl
3)δ：0.90～1.20(6H、m)、1.32～1.50(4H、m)、1.75～1.85(4H、m)、1.95～2.05(4H、m)、2.10～2.30(2H、m)、3.65(6H、s)。
[embodiment 6]
According to following proposal Synthetic 2-E.
(2-B's is synthetic)
At 22cm
3Add 5.2g2-A (Tokyo changes into that industrial makes, transly is 26%, cis be 74%) and 0.2cm in the toluene
3The vitriol oil, being heated to internal temperature is 90 ℃ and stirring.To Dropwise 5 .6cm wherein
3Thionyl chloride, heating was stirred 4 hours simultaneously so that internal temperature reaches 97 ℃ then.Reaction solution is cooled to the toluene solution that obtains containing 2-B after the room temperature.
(2-E's is synthetic)
At 70cm
3Add 4-subcutin (with the pure medicine manufacturing of light) 6.3g and triethylamine 7.1g in the tetrahydrofuran (THF) (THF), being cooled to internal temperature with ice-water bath is below 10 ℃, to the toluene solution that wherein drips the above-mentioned 2-B of containing.Remove ice-water bath after the heat release calmness, stir after 4 hours under the room temperature and pour reaction solution into 5% salt sour water 300cm
3In.The solid that obtains is carried out filtration under diminished pressure, washing, drying, obtain 9.9g compound 2-E.By
1H-NMR obtains the stereoisomer ratio of resulting 2-E, and trans is 89%, and cis is 11%.
In addition, with the above-mentioned 2-E that obtains of methanol wash, obtain the pure trans body of 5.3g.
[embodiment 7]
According to following proposal Synthetic 2-F.
(2-F's is synthetic)
At 35cm
3Add 4-methyl piperidine 3.5g and triethylamine 3.6g among the THF, being cooled to internal temperature with ice-water bath is below 10 ℃.Input amount except reagent is 1/2 to wherein dripping, other and embodiment 5 fully similarly operate the toluene solution that contains 2-B that obtains.Remove ice-water bath after the heat release calmness, stir after 3 hours under the room temperature and pour reaction solution into 5% salt sour water 150cm
3In, use 200cm
3Ethyl acetate extraction, the washing ethyl acetate layer becomes neutrality up to water.After dried over mgso, to filter, decompression is heated up in a steamer and is desolvated, and obtains 3.2g 2-F.By
1H-NMR obtains the stereoisomer ratio of resulting 2-F, and trans is 80%, and cis is 20%.
Claims (8)
1, a kind of method of making the substituted cyclohexane carboxylic acid halides, wherein, in the presence of strong acid, with the ratio of trans body is that the carboxyl of the substituted cyclohexane carboxylic acid of a% changes halo carbonyl into, thereby the ratio of making trans body is the substituted cyclohexane carboxylic acid halides of b%, 0≤a wherein, a＜b.
2, a kind of manufacture method of substituted cyclohexane carboxylic acid is characterized in that, this manufacture method comprises following operation:
The 1st operation in this operation, in the presence of strong acid, is that the carboxyl of the substituted cyclohexane carboxylic acid of a% changes halo carbonyl into the ratio of trans body, wherein 0≤a and,
The 2nd operation, in this operation, with the halo carbonyl hydrolysis of the substituted cyclohexane carboxylic acid halides that obtains in the 1st operation, thereby the ratio that obtains trans body is the substituted cyclohexane carboxylic acid of c%, wherein a＜c.
3, the manufacture method of a kind of substituted cyclohexane carboxylicesters or substituted cyclohexane carboxylic acid amide is characterized in that, this manufacture method comprises following operation:
The 1st operation in this operation, in the presence of strong acid, is that the carboxyl of the substituted cyclohexane carboxylic acid of a% changes halo carbonyl into the ratio of trans body, thereby obtains the substituted cyclohexane carboxylic acid halides, wherein 0≤a and,
The 2nd operation, in this operation, make the substituted cyclohexane carboxylic acid halides that obtains in the 1st operation and contain the compound of hydroxyl or contain amino compound or the nitrogen-containing heterocycle compound reaction, thereby the ratio that obtains trans body is substituted cyclohexane carboxylicesters or substituted cyclohexane acid amides, the wherein a＜d of d%.
4, a kind of method of making bicyclohexane dicarboxylic acid carboxylic acid halides, wherein, in the presence of strong acid, with the ratio of trans/trans body in 1 on the bicyclohexane ring and 4 and 1 ' and 4 ' 's the spatial relation is that the carboxyl of the bicyclohexane dicarboxylic acid of e% changes halo carbonyl into, thereby the ratio of making trans/trans body is the bicyclohexane dicarboxylic acid carboxylic acid halides of f%, 0≤e wherein, e＜f.
5, a kind of manufacture method of bicyclohexane dicarboxylic acid is characterized in that, this manufacture method comprises following operation:
The 1st operation in this operation, in the presence of strong acid, is that the carboxyl of the bicyclohexane dicarboxylic acid of e% changes halo carbonyl into the ratio of trans/trans body in 1 on the bicyclohexane ring and 4 and 1 ' and 4 ' 's the spatial relation, wherein 0≤e and,
The 2nd operation, in this operation, with the halo carbonyl hydrolysis of the bicyclohexane dicarboxylic acid carboxylic acid halides that obtains in the 1st operation, thereby the ratio that obtains trans/trans body is the bicyclohexane dicarboxylic acid of g%, wherein e＜g.
6, the manufacture method of a kind of bicyclohexane dicarboxylic diester or bicyclohexane dicarboxylic acid diamide is characterized in that this manufacture method comprises following operation:
The 1st operation, in this operation, in the presence of strong acid, with the ratio of trans/trans body in 1 on the bicyclohexane ring and 4 and 1 ' and 4 ' 's the spatial relation is that the carboxyl of the bicyclohexane dicarboxylic acid of e% changes halo carbonyl into, thereby obtain bicyclohexane dicarboxylic acid carboxylic acid halides, wherein 0≤e and
The 2nd operation, in this operation, make the bicyclohexane dicarboxylic acid carboxylic acid halides that obtains in the 1st operation and contain the compound of hydroxyl or contain amino compound or nitrogen-containing heterocycle compound reaction, thereby the ratio that obtains trans/trans body is bicyclohexane dicarboxylic diester or bicyclohexane dicarboxylic acid diamide, the wherein e＜h of h%.
According to each described method in the claim 1～6, it is characterized in that 7, halo carbonyl is the chloro carbonyl.
According to each described method in the claim 1～7, it is characterized in that 8, described strong acid is sulfuric acid or sulfonic acid.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723825B (en) * | 2009-12-21 | 2012-08-22 | 浙江工业大学 | Method for separating mixed methyl cyclohexane diacid |
| CN104844450A (en) * | 2014-02-18 | 2015-08-19 | 东丽精细化工株式会社 | Method of preparing 1, 4-cyclohexane diformyl dichloro |
| CN101768074B (en) * | 2009-12-29 | 2017-09-26 | 大连九信精细化工有限公司 | A kind of new method for synthesizing 4 carboxymethyl cyclohexane-carboxylic acids |
| CN112272661A (en) * | 2018-06-11 | 2021-01-26 | 富士胶片株式会社 | Method for producing dicyclohexyldicarboxylic acid diester and method for producing dicyclohexyldicarboxylic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004256490A (en) * | 2003-02-27 | 2004-09-16 | Nagase Chemtex Corp | Method for producing trans-cyclohexane derivative |
-
2008
- 2008-12-19 CN CNA2008101780842A patent/CN101462939A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004256490A (en) * | 2003-02-27 | 2004-09-16 | Nagase Chemtex Corp | Method for producing trans-cyclohexane derivative |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723825B (en) * | 2009-12-21 | 2012-08-22 | 浙江工业大学 | Method for separating mixed methyl cyclohexane diacid |
| CN101768074B (en) * | 2009-12-29 | 2017-09-26 | 大连九信精细化工有限公司 | A kind of new method for synthesizing 4 carboxymethyl cyclohexane-carboxylic acids |
| CN104844450A (en) * | 2014-02-18 | 2015-08-19 | 东丽精细化工株式会社 | Method of preparing 1, 4-cyclohexane diformyl dichloro |
| CN104844450B (en) * | 2014-02-18 | 2019-03-08 | 东丽精细化工株式会社 | The manufacturing method of two formyl dichloro of 1,4- hexamethylene |
| CN112272661A (en) * | 2018-06-11 | 2021-01-26 | 富士胶片株式会社 | Method for producing dicyclohexyldicarboxylic acid diester and method for producing dicyclohexyldicarboxylic acid |
| CN112272661B (en) * | 2018-06-11 | 2023-08-08 | 富士胶片株式会社 | Process for producing dicyclohexyl dicarboxylic acid diester and process for producing dicyclohexyl dicarboxylic acid |
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