DE102009058573A1 - Preparing 1,4-substituted cyclohexane compounds with all-trans configuration comprises reacting the cyclohexane compounds corresponding 1,4-cis-cyclohexane compounds e.g. in presence of carbocation forming compound - Google Patents

Abstract

Preparing 1,4-substituted cyclohexane compounds (I) with all-trans configuration, comprises reacting (I) corresponding 1,4-cis-cyclohexane compounds in the presence of a carbocation forming compound and in the presence of an acid generating carbocation. Preparing 1,4-substituted cyclohexane compounds of formula (R1-(A1-(CH 2) n-) m-A2-R2) (I) with all-trans configuration, comprises reacting (I) corresponding 1,4-cis-cyclohexane compounds in the presence of a carbocation forming compound and in the presence of an acid generating carbocation. R1, R2 : unsubstituted, up to 9C-linear alkyl or -CH(CH 3) 2; m : 1 or 2; n : 0-4; and A1, A2 : trans-1,4-cyclohexyl.

Description

The present invention relates to a process for the preparation of all-trans-4,4'-disubstituted bicyclohexane derivatives and their analogs comprising an isomerization step that converts one or more cis-configured cyclohenxane rings into the trans configuration using a strong acid.

Functional chemicals are not only influenced by their existing functional groups, but also by their stereochemistry, ie their spatial structure. A not inconsiderable portion of stereochemistry is devoted to simple non-aromatic rings and the relative position of substituents on these rings.

A basic problem for stereochemistry is the cis-trans isomerism of substituents on cyclohexanes. Particular attention is paid to the isomerism of 1,4-substituted cyclohexane derivatives. Although numerous synthetic methods exist for terminating the stereochemistry of functionalized cyclohexanes (eg, cyclohexanecarboxylic acids, cyclohexylcarbaldehydes, cyclohexanols, or even phenylcyclohexanes), the stereochemistry of purely aliphatic, nonfunctionalized cyclohexanes is relatively difficult to control. The fact that no universally applicable solution exists for this purpose is astonishing insofar as compounds of this type have long been known for technical applications (cf. JP 59070624 A , 1984) and these are elaborately prepared via the functionalized cyclohexane compounds because of the cis / trans problem. One known reaction is the cis-trans isomerization of (4-alkylcyclohexyl) benzenes. The phenyl-substituted cyclohexane ring can be isomerized by suitable measures such that predominantly the 1,4-trans isomer is obtained from a cis-trans mixture ( JP 2004-256490 A ). In contrast to the subject matter of the present invention, the isomerization can be carried out in benzyl position. The benzylic position is comparatively easy to move to isomerization. Therefore, conventional synthetic routes for the preparation of trans-bicyclohexanes basically use cyclohexylbenzene intermediates, so that at least one of the cyclohexane rings can already be brought into the trans configuration. At 4,4 'dialkylated bicyclohexanes no successful isomerization has been described.

For isomerization processes in phenylcyclohexanes, strong bases such as potassium tert-butoxide have been hitherto used or, for functional cyclohexane derivatives, for example fluoride ions (US Pat. DE 102005034067 A1 ) used. However, these isomerization methods fail with unfunctionalized, ie purely aliphatic 4,4'-dialkylbicyclohexanes.

We have now found a generally applicable process for the preparation of 1,4-disubstituted cyclohexane compounds having all-trans configuration of general formula I, R ¹ - [A ¹ - (CH ₂ ) _n -] _m -A ² -R ² I wherein
R ¹ and R ² independently of one another represent an unsubstituted, straight-chain alkyl radical having up to 9 C atoms or -CH (CH ₃ ) ₂ ,
m 1 or 2,
n are each independently 0, 1, 2, 3 or 4,
preferably 0, 2 or 4 and
A ¹ , A ² trans-1,4-cyclohexyl,
mean,
the 1,4-cis-cyclohexane compounds corresponding to the reaction of compounds of the formula I in the presence of preferably catalytic amounts of a carbocation-forming compound (B) and in the presence of an acid which is generated from (B) carbocations and preferably also stabilizes. The acid is preferably a superacid.

As starting materials for the process according to the invention, the corresponding compounds of the formula I are used in which a cyclohexane ring or several cyclohexane rings are at least partially cis-configured. As a rule, cis / trans mixtures are used in the process, as they arise from the preceding syntheses. The last reaction step leading to the starting compound is usually a hydrogenation, z. B. the hydrogenation of 4,4'-dialkylbiphenyl, 1-alkyl-4- (4-alkyl-cyclohex-1-enyl) benzene or the hydrogenation of 1-acyl-4- (4-alkylcyclohexyl) benzene to cis / trans-mixture of the corresponding 4,4'-dialkylbicyclohexanes.

The carbocation-forming compound (catalyst) is a compound which produces small amounts of carbocationic compounds under the reaction conditions. These fulfill the role of a catalyst.

The carbocation-forming compound is referred to as a catalyst hereinafter. The catalyst is preferably used in substoichiometric amounts, i. H. in practice, a few mol% (0.05 to 15 mol%) based on the compound to be isomerized suffice.

Depending on the preparation of the starting material (vide infra), it may not be necessary to add the catalyst in some cases because sufficient impurities are already present to take over the role of the catalyst. This can be done in particular if the preparation of the starting material proceeds via the dehydration of an alcohol and subsequent hydrogenation or via a dehydrating hydrogenation and traces of alcohol are still left in the mixture to be isomerized. Preferably, however, the catalyst is added specifically.

The process is carried out in a preferred embodiment in the presence of a secondary or tertiary alkyl halide or sulfonate or a secondary or tertiary alcohol catalyst. As a catalyst, a tertiary halide, a halide on a bridgehead of a polycyclic system, such as. As adamantane, or a Neopentylhalogenid (primary halide) used. Preferred halides in this context are chlorine, bromine or iodine, in particular chlorine and bromine. The catalysts may also be geminal polyhalogenated compounds such as haloform or tetrahalomethane. Instead of a halide in the catalyst, a hydroxyl group is also possible in each case. Examples of good carbocationes are bridgehead substituted adamantane compounds (preferably, alcohol, halide, or alkyl ethers), e.g. 1-adamantanol or 1-haloadamantane, also norborneol and norbornyl chloride. Suitable catalysts are also the corresponding ethers of the abovementioned chlorides or alcohols with other simple alcohols such as methanol, eg. As methyl tert-butyl ether. Particularly economical due to the good availability and effectiveness is the use of tert-butyl chloride (2-chloro-2-methylpropane) or tert-butanol or 1-Methycyclohexanol as a catalyst. Another alternative are tert.-carboxylic acids / acid chlorides, such as. B. pivaloyl chloride (2,2-dimethylpropanoyl chloride), because after cleavage of a chloride with elimination of CO can form a tertiary carbocation.

Also suitable as catalyst are in principle those alkenes which can form a tertiary cation with addition of protons (for example 1-methylcyclohexene).

Suitable carbocating and stabilizing compounds are in the first place strong acids, preferably protic acids, for example those having a H ₀ value less than -11 (superacids), preferably perfluorinated alkylsulfonic acids, in particular trifluoromethanesulfonic acid, nonafluorobutanesulfonic acid, and derivatives thereof, such as tris (trifluorosulfonyl) methane (CF ₃ SO ₂ ) ₂ CH or (CF ₃ SO ₂ ) ₂ NH as examples, which examples are not meant to be limiting. Where necessary, the strength of the acid can be enhanced by combining it with a Lewis acid. This can be particularly advantageous when using alkenes as catalysts. Many other superacid systems in the liquid phase are known from the relevant literature (cf. Chapter 2 in GA Olah in "Superacid Chemistry", 2nd ed., Wiley, 2009 ), such as fluorosulfuric acid and mixtures with Lewis acids such as SbF ₅ etc ('magic acid'). Non-oxidizing systems are generally preferred, ie those which contain no sulfuric acid, persulfuric acid or sulfur trioxide. The term superacid and the H ₀ value are defined in the cited literature.

The catalyst, as well as, in general, the acid is used in catalytic amounts, in particular in an amount which is even lower than the molar amount of added strong acid. Preferred amounts of the catalyst are 0.01 to 2 mol% based on the product or 1 to 90 mol%, preferably 5 to 25% based on the acid. These quantities are not limiting. However, the addition of too large or even stoichiometric amounts of catalyst and / or acid may be disadvantageous to the process because by-products form.

The process is preferably carried out in a chlorinated or fluorinated solvent, such as. As in dichloromethane, polyfluorinated aromatics, eg. As benzotrifluoride, or chlorinated fluorocarbons performed. Suitable solvents are known from the chemistry of superacids (cf. GA Olah, various publications ).

The reaction temperature in the process is preferably from 20 to -180 ° C, more preferably from 0 ° C to -100 ° C, and most preferably from -30 ° C to -78 ° C. The low process temperature produces few by-products. Even sensitive starting materials can be used.

The desired product is usually obtained after a reaction time of 0.1 h to 4 h.

The process according to the invention is distinguished by a gentle procedure, by an extremely high trans content in the isomerization product and by few by-products. The separation of the added catalyst is straightforward.

The cyclohexanes used in the process according to the invention with a cis fraction to be isomerized are prepared by customary methods. Proven starting compounds are 4-substituted cyclohexanones, for example 4- (4-alkylcyclohexyl) cyclohexanones. From these educts, there are two synthetic routes to the cyclohexanes: By addition of Grignard or lithiated compounds to the carbonyl group followed by elimination and hydrogenation of the alkenes thus obtained on common catalysts or by Wittig reaction with alkylphosphonium salts and subsequent hydrogenation. The respective hydrogenations generally result in cis / trans mixtures with a trans content of less than 85%, usually significantly lower. A preferred method is therefore characterized in that the configuration of the reaction product on each 1,4-substituted cyclohexane ring corresponds to 94% or more of the trans configuration. Preferably, the configuration of the starting material on at least one 1,4-substituted cyclohexane ring corresponds to 90% or less of the trans configuration. Most preferably, the configuration of the reaction product at each 1,4-substituted cyclohexane ring corresponds to 97% and most preferably 99% or more of the trans configuration. The product therefore preferably has 97% or more of the all-trans configuration on the 1,4-cyclohexane radicals.

Another synthesis of the cyclohexane compounds to be isomerized is the hydrogenation of corresponding benzene compounds, for example substituted cyclohexylbenzenes. This class of compounds is easily obtained from basic chemical compounds. Suitable hydrogenation catalysts and the process parameters are familiar to the skilled worker.

A preferred process according to the invention is therefore characterized in that it comprises, as a further process step before the isomerization according to the invention with the acid, hydrogenation on a benzene ring, a cyclohexene ring or a cyclohexadiene ring, this ring being converted into a cyclohexane ring or being it a step prior to isomerization comprises hydrogenation of an alkylidene group attached directly to the cyclohexane ring. Preferably, exactly this ring is converted in the isomerization in the trans-configuration, as far as it emerges in the cis configuration of the hydrogenation. Preferably, the hydrogenation is directly preceded by isomerization.

The process according to the invention represents an efficient method for isomerizing the undesirable cis portion of the 1,4-cyclohexane derivatives. The method can be used to directly increase the trans content of cis / trans mixtures, even if the proportion of the trans isomer already 85% or more. The all-trans content after isomerization is preferably 94% and more, more preferably 97% and more, and most preferably 99% or more. Likewise, the process for the isomerization of residues with increased cis content from the enrichment of trans isomers, eg. As mother liquors from the crystallization can be used. Thus, unreachable residues of cis-configured material can be recycled by isomerization.

In a preferred embodiment of the invention, m = 1 and n = 0. (4,4'-disubstituted bicyclohexanes), R ¹ and R ² are preferably n-alkyl radicals having 2 to 7 carbon atoms or an isopropyl radical, again particularly preferred the total sum of all C atoms in R ₁ and R ₂ does not exceed eight. One of the two cyclohexane rings can already have the desired trans configuration before isomerization because it is retained during the isomerization.

In the event that the formula I has more than two cyclohexane rings, the inventive method is also suitable. In this case, even one or two of the cyclohexane rings may already have the desired trans configuration because this is retained. It is equally possible to carry out isomerizations on three rings simultaneously by the high trans selectivity of the isomerization process. The proportion of trans-trans or trans-trans-trans products (all-trans products) is usually high enough to make subsequent separation of cis derivatives superfluous. If a particularly high purity of the all-trans compounds is desired, a single crystallization step is generally sufficient to achieve Separate by-products, catalyst residues and the low cis content. Without an effective isomerization process, the separation of the cis isomers usually requires several crystallization stages, and the crystallization of the trans product is hampered by the presence of the cis isomer and the smectogenic character of the compounds.

The term "alkyl" preferably comprises unbranched or branched alkyl groups having 1 to 15 carbon atoms, in particular the unbranched groups methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl. Groups of 2 to 10 carbon atoms are generally preferred. As the branched alkyl group, the isopropyl group is preferable.

The process and the subsequent work-up of the reaction mixture can in principle be carried out as a batch reaction or in a continuous reaction mode. The continuous reaction includes z. As the reaction in a Ströhmungsrohr or in a microreaction apparatus. The reaction mixtures are optionally worked up, as required, by filtration over solid phases, chromatography, separation between immiscible phases (eg extraction), adsorption on solid supports, distilling off of solvents and / or azeotropic mixtures, selective distillation, sublimation, Crystallization, cocrystallization or by nanofiltration on membranes.

(mit Punkt) einen 1,4-trans-substituierten Cyclohexanring, und

einen 1,4-substituierten Cyclohexanring mit gemischter cis- und trans-Konfiguration oder überwiegend cis-Konfiguration.In the diagrams, the rings mean

(with dot) a 1,4-trans substituted cyclohexane ring, and

a 1,4-substituted cyclohexane ring with mixed cis and trans configuration or predominantly cis configuration.

Further preferred process variants can be taken from the examples whose details - also generalized according to general expert knowledge - are representative of preferred embodiments of the process according to the invention and its products.

Examples

General

The analysis of the withdrawn samples and the determination of the configuration of the final product is carried out by means of HPLC with acetonitrile as the solvent at a Purospher STAR ^® RP-18 column (Merck KGaA, Darmstadt). The intermediate samples are hydrolyzed with hydrochloric acid, neutralized with bicarbonate, extracted by evaporation and measured.

example 1

The starting material (26.5 g, 100 mmol, cis / trans = 38% / 60%) is introduced into 90 ml of anhydrous dichloromethane (for analysis) and cooled to -25 ° C. 0.660 ml of trifluoromethanesulfonic acid (about 7.5 mmol) are added. At -25 ° C., 456 mg of 1-adamantanol (3.0 mmol) in 10 ml of dichloromethane are added dropwise over 10 min. The batch is further stirred at -25 ° C, wherein every 15 minutes, a sample is taken to determine the degree of isomerization. After complete isomerization (0.2-3 h), the batch is worked up.

For workup, the mixture is stirred into a mixture of 100 ml of hydrochloric acid (25%) and 50 g of ice. The organic phase is separated off, washed with 50 ml of dilute NaHCO ₃ solution and 100 ml of water and concentrated on a rotary evaporator to the residue (22.9 g, 86.6% of theory). Table: Time course of the isomerization process Reaction time [min] 15 30 60 270 (*) trans, trans share [%] 89.68 93.93 96.42 99.64 (*) Isolated end product

Example 2

In 90 ml of anhydrous dichloromethane (for analysis), 26.45 g of starting material (100 mmol, cis / trans = 38% / 60%) are introduced and cooled to -25 ° C. To this is added 0.440 ml of trifluoromethanesulfonic acid and then 0.22 ml of 2-chloro-2-methylpropane. The mixture is stirred at -20 ° C. to -25 ° C. for 270 minutes, a sample being taken for determination of the degree of isomerization after 15, 30, 60, 120 and 180 minutes, respectively. It is worked up after 270 minutes as in Example 1. This gives 22.9 g of product (86.6% of theory). Table: Time course of the isomerization process Reaction time [min] 15 30 60 120 180 270 (*) all-trans share [%] 78 86 95 97.5 98.57 98.8 (*) Isolated end product

Further combinations of the embodiments and variants of the invention will become apparent from the claims.

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

• JP 59070624 A [0003]
• JP 2004-256490 A [0003]
• DE 102005034067 A1 [0004]

Cited non-patent literature

• Chapter 2 in GA Olah in "Superacid Chemistry", 2nd ed., Wiley, 2009 [0012]
• GA Olah, various publications [0014]

Claims (10)

Process for the preparation of 1,4-substituted cyclohexane compounds with all-trans configuration of general formula I. R ¹ - [A ¹ - (CH ₂ ) _n -] _m -A ² -R ² I wherein R ¹ and R ² are each independently an unsubstituted, straight-chain alkyl radical having up to 9 C atoms or -CH (CH ₃ ) ₂ , m 1 or 2, n are each independently 0, 1, 2, 3 or 4, and A ¹ , A ² trans-1,4-cyclohexyl, mean the reaction of compounds of formula I corresponding 1,4-cis-cyclohexane compounds in the presence of a carbocation forming compound (B) and in the presence of an (B) carbocation generating acid includes. A method according to claim 1, characterized in that it is carried out in the presence of a carbocation stabilizing acid or a superacid. A method according to claim 1 or 2, characterized in that it is carried out in the presence of a sulfonic acid or a bis (sulfonyl) imide. Method according to one or more of claims 1 to 3, characterized in that the reaction in the presence of one or more additives in the form of a tertiary or secondary alkyl halide or sulfonate of a tertiary or secondary alcohol or an alkyl ether or alkanoic acid ester of these compounds or on a primary halide , Sulfonate, alcohol or neopentyl-containing ether. Method according to one or more of claims 1 to 4, characterized in that the cation-forming compound is a bridgehead-substituted adamantane. Method according to one or more of claims 1 to 5, characterized in that trans / trans bicyclohexane compounds of the formula IA

wherein R ¹ and R ^{2 are} as defined in claim 1. Method according to one or more of claims 1 to 6, characterized in that the reaction is carried out at temperatures less than or equal to 20 ° C. Method according to one or more of claims 1 to 7, characterized in that the reaction is carried out in a chlorinated and / or fluorinated hydrocarbon as a solvent. Process according to one or more of claims 1 to 8, characterized in that the configuration of the reaction product on each 1,4-substituted cyclohexane ring corresponds to 94% or more of the trans configuration. Method according to one or more of claims 1 to 9, characterized in that it comprises, as a step before the isomerization going to the compounds of formula I hydrogenation on a benzene ring, a cyclohexene ring or a cyclohexadiene ring, said rings in a 1,4-substituted cyclohexane ring, or that it comprises hydrogenation of an alkylidene group bonded directly to the cyclohexane ring as a step prior to isomerization.