DE102015000119A1 - A process for the preparation of bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester - Google Patents

Abstract

The invention relates to a process for the preparation of bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid esters, as well as intermediates for its preparation and their derivatizations.

Description

The invention relates to a process for the preparation of bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid esters, as well as intermediates for its preparation and their derivatizations.

The liquid crystalline compound bis- [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester and its use in a dichroic host-guest polarizer is disclosed in U.S. Pat WO 2005/045485 A1 disclosed. According to the general synthetic strategy disclosed, bis [4- (6-acryloyloxy-hexyl) -phenyl] -cyclohexane-1,4-dicarboxylic acid ester can be prepared starting from 6- (tetrahydropyran-2-yloxy) -1-bromohexane and 4- (tetrahydropyrane). 2-yloxy) -phenylmagnesium bromide can be obtained in a five-step synthesis. Disadvantages of this synthesis strategy are the relatively expensive Ausgansstoffe and the extent of the necessary synthetic steps associated with yield losses.

One of the objects of the present invention is to provide a low-cost and efficient process for producing bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester, which is particularly suitable for industrial scale, as well as To provide intermediates which have technically useful properties or can serve as starting compounds for the efficient synthesis of further derivatives.

The invention therefore comprises a process for preparing bis [4- (6-acryloyloxy-hexyl) -phenyl] -cyclohexane-1,4-dicarboxylic acid ester comprising a process step which comprises a condensation reaction of trans-1,4-cyclohexanedicarboxylic acid with 6- ( 4-hydroxy-phenyl) -hexyl-chloropropionic acid ester.

• • ein Verfahren zur Herstellung von Bis-[4-(6-acryloyloxy-hexyl)-phenyl]cyclohexan-1,4-dicarbonsäureester, umfassend einen weiteren Verfahrensschritt der eine Veresterung von 6-(4-Hydroxy-phenyl)-1-hexanol mit 3-Chlorpropionsäure zum 6-(4-Hydroxy-phenyl)-hexyl-chlorpropion-säureester umfasst,
• • ein Verfahren zur Herstellung von Bis-[4-(6-acryloyloxy-hexyl)-phenyl]cyclohexan-1,4-dicarbonsäureester, umfassend einen weiteren Verfahrensschritt der eine Hydrierung von 1-(4-Benzyloxy-phenyl)-6-hydroxy-hexan-1-on zum 6-(4-Hydroxy-phenyl)-1-hexanol umfasst, sowie
• • ein Verfahren zur Herstellung von Bis-[4-(6-acryloyloxy-hexyl)-phenyl]cyclohexan-1,4-dicarbonsäureester, umfassend einen weiteren Verfahrensschritt der eine Grignard-Reaktion eines Weinreb-Amids, erhalten aus der Reaktion von ε–Caprolacton und N,O-Dimethyl-hydroxylamin-Hydrochlorid, mit 4-Benzyloxy-phenyl-magnesiumbromid zum 1-(4-Benzyloxy-phenyl)-6-hydroxy-hexan-1-on umfasst.

Further objects of the present invention are:

• A process for the preparation of bis [4- (6-acryloyloxy-hexyl) phenyl] cyclohexane-1,4-dicarboxylic acid ester comprising a further process step of esterifying 6- (4-hydroxy-phenyl) -1-hexanol with 3-chloropropionic acid to 6- (4-hydroxy-phenyl) -hexyl-chloropropionic acid ester,
• A process for the preparation of bis [4- (6-acryloyloxyhexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester comprising a further process step of hydrogenating 1- (4-benzyloxyphenyl) -6-hydroxy -hexan-1-one to 6- (4-hydroxy-phenyl) -1-hexanol, as well as
• A process for the preparation of bis [4- (6-acryloyloxyhexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester, comprising a further process step of a Grignard reaction of a Weinreb amide obtained from the reaction of ε- Caprolactone and N, O-dimethylhydroxylamine hydrochloride, with 4-benzyloxy-phenyl-magnesium bromide to give 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one.

An overview of the overall process is summarized in Scheme 1 below.

Schema 1: Verfahren zur Herstellung von Bis-[4-(6-acryloyloxy-hexyl)-phenyl]cyclohexan-1,4-dicarbonsäureester

Scheme 1: Process for the preparation of bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester

The bis- (4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid according to the invention finds use in liquid-crystalline media due to its mesogenic properties.

In a first process step, ε-caprolactone is converted with the aid of N, O-dimethylhydroxylamine hydrochloride into a Weinreb amide, which is used in situ with the Grignard reagent of 4-benzyloxy-1-bromo-benzene for 1- ( 4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one is reacted.

Preference is given to using an excess of ε-caprolactone based on 4-benzyloxy-phenyl-magnesium bromide. More preferably 1.1 to 1.5 moles of ε-caprolactone per 1 mole of 4-benzyloxy-phenyl-magnesium bromide, in particular 1.2 to 1.3 moles of ε-caprolactone per 1 mole of 4-benzyloxy-phenyl-magnesium bromide.

The process is preferably carried out in suitable anhydrous, aprotic solvents or in corresponding solvent mixtures. Suitable solvents are known in the art and preferably include cyclic and acyclic ethers, cyclic or acyclic hydrocarbons or halogenated solvents.

Preferably, the cyclic and acyclic ethers are selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether and dimethoxyethane. Suitable hydrocarbons are z. As toluene, cyclohexane, hexane and heptane. Suitable halogenated solvents in this context are chloroform or dichloromethane, preferably dichloromethane.

Particular preference may also be given to using tetrahydrofuran / dichloromethane mixtures.

It is preferable to use 40 to 900 parts by weight, in particular 60 to 800 parts by weight, of solvent per 100 parts by weight of ε-caprolactone. The process is preferably carried out under a protective gas atmosphere. Suitable protective gases or inert gases are known in the art and include, for example, argon or nitrogen, preferably nitrogen.

Preferably, magnesium organyls are added to the reaction. Suitable magnesium organyls include, for example, solutions of isopropylmagnesium halides in THF, preferably isopropylmagnesium chloride or isopropylmagnesium bromide in THF. Preferably used 1 to 3 mol, in particular 2 to 3 moles of a magnesium organyl per 1 mole of 4-benzyloxy-phenyl-magnesium bromide Suitable reaction temperatures are, for. For example, those in the range of -30 to + 15 ° C, preferably -10 to + 10 ° C, more preferably -5 to + 5 ° C.

The reaction time is, as known in the art, inter alia, depending on the mixing and the batch size. Typically, the reaction time is 2 to 100 hours, preferably 3 to 40 hours.

The prepared 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one can be isolated in various ways, preferably by extraction or crystallization from a suitable solvent, such as. As toluene but also other solvents known in the art or mixtures thereof can be used according to the invention. Suitable work-up conditions are dependent upon the choice of purification method of the intermediate and can be readily adapted by one skilled in the art. Suitable purification methods preferably include column chromatographic purification, crystallization and extraction.

The intermediate 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one can be converted by catalytic hydrogenation in one step almost quantitatively to the desired 6- (4-hydroxy-phenyl) -1-hexanol.

Suitable reaction conditions are known to those skilled in the art from manuals and related encyclopaedias.

In a preferred embodiment, for the hydrogenation of 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one in addition to the preferred heterogeneous catalysis is also a homogeneous catalysis. In homogeneous catalysis, the hydrogenation catalyst is completely dissolved in the solvent. This is achieved by the use of suitable ligands on the metal. Heterogeneous catalysis involves an insoluble mixture of hydrogenation catalyst and solvent with the compound to be hydrogenated. The process is preferably carried out with the aid of heterogeneous catalysis.

When using salts as hydrogenation catalysts, the salt is generally first reduced and the finely divided element forms the active hydrogenation catalyst.

Suitable hydrogenation catalysts are those catalysts which allow the addition (addition) of hydrogen. Preferably, platinum metals such as palladium and platinum are used in the hydrogenation. Furthermore, it is also possible to use rhodium, ruthenium, cobalt, iron, nickel, copper chromite and zinc chromite as hydrogenation catalysts.

The catalysts are usually applied to a support. Suitable carriers are, for example, activated carbon, silicon dioxide, calcium carbonate, barium sulfate or aluminum oxide.

The hydrogenation catalysts are particularly preferably selected from the group comprising platinum black, Adams catalyst (platinum (IV) oxide), palladium on activated carbon, colloidal palladium, palladium (II) oxide, palladium on barium sulfate, palladium (II) hydroxide on barium sulfate , Lindlar catalyst (palladium on calcium carbonate and poisoned with lead (II) acetate), palladium on calcium carbonate, or palladium black, particularly preferred is palladium on charcoal.

In addition to the support material, a preferred catalyst process typically contains from 1 to 20% by weight, preferably from 5 to 10% by weight, of palladium, based on the total dry catalyst.

For the process according to the invention, the catalyst can be used in the dry or moist state (up to 60% water), but the use of dry catalyst is preferred.

For the process according to the invention, the weight ratio of the catalyst used to give 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one is 0.0001 to 0.1 to 1, preferably 0.005 to 0.05 to 1.

Preferably, the reaction is carried out in suitable polar solvents or solvent mixtures. Suitable polar solvents are known to the person skilled in the art and include, for example, alcohols, cyclic ethers and / or esters, preferably dioxane, glacial acetic acid, ethyl acetate, methanol, ethanol, isopropanol, particularly preferably ethyl acetate.

Preferably used 40 to 900 parts by weight, in particular 60 to 800 parts by weight, solvent per 100 parts by weight of 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one.

Preferably, the reaction is carried out under a hydrogen atmosphere at elevated pressure. Suitable pressures are known to those skilled in the art and include ranges from 1 to 20 bar, preferably 2 to 10 bar, more preferably 3 to 7 bar.

In a further embodiment, the catalytic hydrogenation is carried out with hydrazine, cyclohexadienes or formic acid as the source of hydrogen.

Suitable reaction temperatures are for. For example, those in the range of +10 to + 80 ° C, preferably +20 to + 60 ° C, more preferably +30 to + 50 ° C.

The reaction time is 2 to 100 hours, preferably 5 to 40 hours.

In a preferred embodiment, the catalyst is filtered off for workup and the solvent is evaporated to dryness. Alternatively, however, the produced 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one can also be isolated after filtration of the reaction solution by extraction or crystallization. Suitable work-up conditions are dependent upon the choice of purification method of the intermediate and can be readily adapted by one skilled in the art. Suitable purification methods preferably include column chromatographic purification, crystallization and extraction.

In a next step in the synthesis, 6- (4-hydroxy-phenyl) -1-hexanol is reacted with 3-chloropropionic acid to give the corresponding 6- (4-hydroxy-phenyl) -hexyl-chloropropionic acid ester.

Preference is given to using an excess of 3-chloropropionic acid based on 6- (4-hydroxyphenyl) -1-hexanol. Particularly preferred 1.1-1.5 moles of 3-chloropropionic acid per mole of 6- (4-hydroxy-phenyl) -1-hexanol, in particular 1.1 to 1.3 moles of 3-chloropropionic acid per mole of 6- (4-hydroxy-phenyl) -1-hexanol ,

Preferably, the process is carried out in suitable hydrophobic, aprotic solvents or corresponding solvent mixtures. Suitable solvents are known in the art and include, for example, cyclic and acyclic ethers, cyclic or acyclic hydrocarbons or halogenated hydrocarbons.

Suitable ethers are, for. For example, 2-methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether and dimethoxyethane, suitable hydrocarbons are, for. For example, toluene, cyclohexane, hexane and heptane and suitable halogenated hydrocarbons in this context are chloroform or dichloromethane, preferably dichloromethane.

It is preferred to use from 10 to 100 parts by weight, in particular from 10 to 50 parts by weight, particularly preferably from 10 to 25 parts by weight, of solvent per part by weight of 6- (4-hydroxyphenyl) -1-hexanol

Preferably, an acidic catalyst is added, preferably p-toluenesulfonic acid or sulfuric acid, more preferably p-toluenesulfonic acid. Its advantage over sulfuric acid is that it does not oxidize. Preference is given to using from 0.1 to 0.5 mol, in particular from 0.1 to 0.3 mol, particularly preferably from 0.15 to 0.25 mol, of p-toluenesulfonic acid per mole of 6- (4-hydroxyphenyl) -1-hexanol Preferably, the reaction is carried out in the boiling heat of the solvent. In the preferred use of dichloromethane, suitable reaction temperatures are typically those in the range of + 15 ° C to + 40 ° C, preferably + 20 ° C to + 40 ° C, more preferably + 35 to + 40 ° C.

The reaction time is, as known in the art, inter alia, depending on the mixing and the batch size. Typically, the reaction time is 10 to 200 hours, preferably 25 to 100 hours.

The prepared 6- (4-hydroxy-phenyl) -hexyl-chloropropionic can be isolated in a variety of ways known in the art, preferably by extraction or crystallization from a suitable solvent. Suitable work-up conditions are dependent upon the choice of purification method of the intermediate and can be readily adapted by one skilled in the art. Suitable purification methods preferably include column chromatographic purification, crystallization and extraction.

According to the invention, the 6- (4-hydroxy-phenyl) -hexyl-chloropropionic acid ester is then reacted with trans-1,4-cyclohexanedicarboxylic acid in a condensation reaction in the bis [4- (6-acryloyloxy-hexyl) -phenyl] -cyclohexane. Converted 1,4-dicarboxylic acid ester.

Preferably, the process is carried out in suitable anhydrous, hydrophobic, aprotic solvents or corresponding solvent mixtures. Suitable solvents are known to the person skilled in the art and include, for example, cyclic or acyclic ethers, cyclic or acyclic hydrocarbons or halogenated hydrocarbons.

Preferred ethers are, for. For example, 2-methyltetrahydrofuran, diethyl ether, tert-butyl methyl ether and dimethoxyethane, preferred hydrocarbons are, for. Toluene, cyclohexane, hexane and heptane and preferred halogenated hydrocarbons include chloroform or dichloromethane, most preferably dichloromethane.

Preference is given to using 5 to 10 parts by weight, in particular 6 to 8 parts by weight of solvent per 1 part by weight of trans-1,4-cyclohexane-dicarboxylic acid, which is initially introduced and suspended in the corresponding solvent.

To the resulting suspension is added trifluoroacetic anhydride. Preference is given to using an excess of trifluoroacetic anhydride based on trans-1,4-cyclohexanedicarboxylic acid. Particularly preferably 2.1-2.5 mol, in particular 2.1 to 2.3 mol trifluoroacetic anhydride per 1 mol of trans-1,4-cyclohexane-dicarboxylic acid.

An excess of 6- (4-hydroxy-phenyl) -hexyl-chloropropionic acid ester based on trans-1,4-cyclohexanedicarboxylic acid is used according to the invention. Preference is given to 2.1-2.5 moles, in particular 2.1 to 2.3 moles, of 6- (4-hydroxyphenyl) -hexyl-chloropropionic acid ester per mole of trans-1,4-cyclohexanedicarboxylic acid.

Preferably, the process is carried out under a protective gas atmosphere. Suitable shielding gases are known in the art and include, for example, argon or nitrogen, preferably nitrogen.

Preferably, the reaction is carried out in the boiling heat of the solvent. When using dichloromethane, suitable reaction temperatures are typically those in the range of + 15 ° C to + 40 ° C, preferably + 20 ° C to + 40 ° C, more preferably + 35 to + 40 ° C.

The reaction time is, as known in the art, depending on the mixing and the batch size. Typically, the reaction time is 10 to 200 hours, preferably 25 to 100 hours.

The bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester prepared can be isolated in a variety of ways known to those skilled in the art, e.g. Example, by extraction or crystallization from a suitable solvent, preferably the product is extracted from the reaction solution. Suitable work-up conditions can be readily adapted by the skilled person. Suitable purification methods preferably include column chromatographic purification, crystallization and extraction.

Above and below, percentages are by weight. All temperatures are in degrees Celsius.

The accompanying examples further illustrate the present invention without limiting it in any way.

Examples

The starting compounds, reagents and solvents used in the exemplary syntheses were either commercially available or prepared by literature methods. The exemplary syntheses were usually carried out in dry apparatus with exclusion of moisture and - if the relevant implementation so required - even under a protective gas atmosphere to exclude air. The course of reactions was generally monitored by thin layer chromatography or gas chromatography. The reaction products can be worked up and purified by customary methods, for example by column chromatography or crystallization. Their structural identity was confirmed by mass spectrometry and ¹ H NMR spectroscopy. Yields are not optimized.

1. Synthesis of 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one

ε-Caprolactone (13.7 g, 120 mmol) and N, O-dimethyl-hydroxylamine hydrochloride (11.7 g, 120 mmol) are placed under nitrogen and treated with 450 ml of dichloromethane. A 2 M solution of isopropylmagnesium chloride in THF (123 g, 250 mmol) is added dropwise to the solution at about -5 ° C. After completion of the addition, the clear solution is stirred at -5 ° C to + 3.5 ° C for a further 30 minutes. Subsequently, a 1 M solution of 4-benzyloxy-phenyl-magnesium bromide in THF (105 g, 100 mmol) is added dropwise at -3 ° C to + 1 ° C. The reaction mixture is stirred for 3 hours at 0 ° C and then hydrolyzed by the addition of 2 N hydrochloric acid. The phases are separated and the organic phase is washed with aqueous sodium bicarbonate solution and water. The organic phase is concentrated by adding toluene. The residue is crystallized from toluene. The product is filtered off, washed with cold toluene, dried in vacuo and characterized by MS and ¹ H-NMR.
Yield: 81%

2. Synthesis of 6- (4-hydroxy-phenyl) -1-hexanol

1- (4-Benzyloxyphenyl) -6-hydroxy-hexan-1-one (24.5 g, 81.5 mmol) is hydrogenated in ethyl acetate with 5% Pd / C at 5 bar hydrogen pressure and at 40 °. After filtering off the catalyst, the product solution is concentrated to dryness to the solid residue. The product is characterized by MS and ¹ H-NMR.
Yield: 93%

3. Synthesis of 6- (4-hydroxy-phenyl) -hexyl-chloropropionic acid ester

6- (4-Hydroxy-phenyl) -1-hexanol (27.0 g, 139 mmol) is initially charged in a Dean-Stark apparatus in 400 ml of dichloromethane and washed successively with p-toluenesulfonic acid (5.3 g, 28 mmol), and 3-chloropropionic acid (16.1 g, 149 mmol). The mixture is then heated to boiling and stirred for 96 h. The reaction solution is cooled and water is added. The phases are separated and the organic phase is washed with water until pH 5 is reached. After phase separation, the organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The product obtained is fractionally filtered through silica gel and then concentrated to dryness. The product is characterized by MS and ¹ H-NMR. Yield: 63%

4. Synthesis of bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester

Trans-1,4-cyclohexanedicarboxylic acid (8.77 g, 51 mmol) is suspended in 100 ml of anhydrous dichloromethane. Then trifluoroacetic anhydride (15.6 ml, 112 mmol) is added and stirred at 30 ° C for 1 h. To the resulting clear solution now 6- (4-hydroxy-phenyl) -hexyl-chloropropionic acid ester (32 g, 112 mmol) in 50 ml of anhydrous dichloromethane are added and stirred for 12 h.

Subsequently, 100 ml of water are added to the reaction mixture and the phases are separated. The aqueous phase is extracted twice with 20 ml of dichloromethane and the combined organic phases are dried over sodium sulfate. Subsequently, the solvent is removed under reduced pressure. The crude product is taken up in dichloromethane again, mixed with 40 ml of triethylamine and stirred at 40 ° C for 12 h. After cooling and adding the reaction solution with dilute hydrochloric acid and further dichloromethane, the phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and the solvent removed after addition of BHT under reduced pressure. The crude product is filtered through silica gel (eluent: dichloromethane / ethyl acetate, 99: 1) fractionated. The organic product phases are combined and the solvent removed after addition of BHT under reduced pressure. The product is characterized by MS and ¹ H-NMR. Yield: 95%.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2005/045485 A1 [0002]

Claims (5)

A process for preparing bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester comprising a process step which comprises a condensation reaction of trans-1,4-cyclohexanedicarboxylic acid with 6- (4-hydroxy-phenyl ) -hexyl-chloropropionic acid ester. A process for the preparation of bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester according to claim 1, comprising a further process step of esterifying 6- (4-hydroxyphenyl) -1- hexanol with 3-chloropropionic acid to 6- (4-hydroxy-phenyl) -hexyl-chloropropionic acid ester. A process for preparing bis [4- (6-acryloyloxy-hexyl) -phenyl] -cyclohexane-1,4-dicarboxylic acid ester as claimed in claims 1 and 2, comprising a further process step of hydrogenating 1- (4-benzyloxy-phenyl) - 6-hydroxy-hexan-1-one to 6- (4-hydroxy-phenyl) -1-hexanol. A process for producing bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester according to claim 1 to 3, comprising a further step of a Grignard reaction of a Weinreb amide obtained from the reaction of ε-caprolactone and N, O-dimethylhydroxylamine hydrochloride, with 4-benzyloxy-phenyl-magnesium bromide to give 1- (4-benzyloxy-phenyl) -6-hydroxy-hexan-1-one. Use of a bis [4- (6-acryloyloxy-hexyl) -phenyl] cyclohexane-1,4-dicarboxylic acid ester prepared as claimed in claim 1 as a constituent of a liquid-crystalline medium.