JP2008189629A - Method for producing 4-substituted cyclohexanecarbaldehyde compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a cyclohexanecarbaldehyde compound having a substituent at the 4-position and useful as a liquid crystal intermediate and a pharmaceutical intermediate, in which a readily available cyclohexanemethanol compound is used and subjected to an oxidation reaction without requiring a special reactor without problems such as malodor. <P>SOLUTION: The cyclohexanemethanol compound having the substituent at the 4-position corresponding to the cyclohexanecarbaldehyde compound represented by formula (II) (wherein, R represents a substituent) is reacted with an oxidizing agent to afford the aldehyde compound. In the process, the oxidation is carried out in the presence of nitroxide radicals to produce the cyclohexanecarbaldehyde compound represented by formula (II). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing an aldehyde compound useful as an intermediate in organic synthesis, and more particularly to a method for producing a novel cyclohexanecarbaldehyde compound useful as a liquid crystal intermediate or a pharmaceutical intermediate.

Aldehyde compounds are used not only as raw materials for alcohol and carboxylic acid synthesis, but also for organic synthesis of a wide range of compounds by aldol reaction, reductive alkylation reaction, hydrazone formation reaction, oxirane formation reaction, carbon extension reaction using Wittig reagent, etc. Used for
Cyclohexanecarbaldehyde is useful as a building block for liquid crystal intermediates and pharmaceutical intermediates, among other applications. For example, the use of cyclohexanecarbaldehyde as a pharmaceutical intermediate is described in International Publication No. WO2005 / 113511 and International Publication No. WO2005 / 118547. International Publication No. WO97 / 20791, European Patent No. 470590. Describes use as a liquid crystal intermediate.

As described above, the cyclohexanecarbaldehyde compound is a useful synthetic intermediate. However, with regard to the steric configuration, trans is more useful than the cis in the relative configuration at the 1 and 4 positions, mainly in the liquid crystal field. . The 4-substituted cyclohexanemethanols used as raw materials in this case are often produced by hydrogenating the benzene ring, and in this case, it is generally obtained as a mixture of a cis isomer and a trans isomer.
As for cyclohexanecarbaldehyde having a substituted methyl group at the 4-position, as described in Non-Patent Document 1, an aldehyde is obtained by so-called Swern oxidation of cyclohexanemethanol derivatives using dimethyl sulfoxide and oxalyl chloride. However, there is no description about the ratio of the cis isomer and the trans isomer of aldehyde which is a product from an alcohol composed of a mixture of cis isomer and trans isomer at positions 1 and 4. Moreover, since the low temperature is requested | required as reaction temperature regarding the swarn acidification used here, the problem that a special manufacturing equipment is required or the dimethyl sulfide produced | generated by reaction is bad smell is pointed out.

Bulletin of Chemical Society of Japan, 71: 7, 1639 (1998), Macromolecules, 1992, 25:13, 3362

  An object of the present invention is to prepare a raw material of a mixture of a cis isomer and a trans isomer (cyclohexane methanol) which is easily available in producing a cyclohexane carbaldehyde compound having a substituent at the 4-position, which is useful as a liquid crystal intermediate or a pharmaceutical intermediate. The present invention provides a method for producing a cyclohexanecarbaldehyde compound that does not require a special reaction apparatus, undergoes an oxidation reaction without problems such as offensive odor, and produces a trans isomer predominantly with respect to the cis isomer in terms of configuration. It is.

The above problems have been achieved by the following means.
In the production of an aldehyde, an oxidant is allowed to act on the primary alcohol of the cis- and trans-isomer mixture represented by the general formula (I), and oxidation is performed in the presence of a nitroxide radical. A process for producing an aldehyde compound represented by II).

In the formula, R represents a substituent.
In the present invention, a trans isomer is predominantly produced over a cis isomer of the aldehyde compound represented by the general formula (II) as a product. Here, “predominantly produced” means that the molar ratio of the trans isomer to the cis isomer in the aldehyde compound represented by the general formula (II) is preferably 55/45 or more, more preferably 67/33 or more. .

  By the method of the present invention, a mixture of cis-isomer and trans-isomer is used as a raw alcohol, and a corresponding aldehyde compound is obtained as a product in which the proportion of the trans-isomer in the product is superior to the proportion in the raw alcohol. . Moreover, the subject of the low cooling temperature and the malodor which were the subjects at the time of using swarn oxidation can be solved.

Hereinafter, the present invention will be described in more detail.
In the general formulas (I) and (II), R represents a substituent, and as this example, a substituent that does not contain a carbon atom or has 1 to 30 carbon atoms is preferable, and has 1 to 20 carbon atoms. Substituents are more preferred. Specific examples include an alkyl group, an alkoxycarbonyl group, a cyano group, a carbamoyl group, a halogen atom, an acyl group, an aryl group, and the like. A particularly preferred example is a substituted methyl group (- CH2X). Here, X is particularly preferably a halogen atom (fluorine, chlorine, bromine, iodine), a sulfonyloxy group, or a carbonyloxy group.
Examples of when X is a sulfonyloxy group include a methylsulfonyloxy group, an ethylsulfonyloxy group, a butylsulfonyloxy group, a phenylsulfonyloxy group, a biphenylsulfonyloxy group, a decylsulfonyloxy group, a diethylaminosulfonyloxy group, and the like. These groups may further have a substituent. Examples of the substituent include an alkyl group, an aryl group, a halogen atom, an alkoxy group, an aryloxy group, a sulfanyl group, a sulfonyl group, an acyl group, and an acyloxy group. , An acylamino group, a carbamoyl group, a sulfamoyl group, a cyano group, a carboxyl group, a nitro group, a sulfonylamino group and the like. The total carbon number is preferably 1-30, more preferably 1-20, and most preferably 1-12. .
Examples of when X is a carbonyloxy group include an acetoxy group, a propionyloxy group, a butanoyloxy group, a benzoyloxy group, a naphthoyloxy group, a biphenylcarbonyloxy group, an ethoxycarbonyloxy group, and a dimethylaminocarbonyloxy group. These groups may further have a substituent, and examples of the substituent include the above-mentioned substituents. 1-30 are preferable, as for total carbon number, 2-20 are more preferable, and 2-12 are the most preferable.

  The cis-isomer / trans-isomer mixing ratio of the raw material alcohol used in the present invention can be any, but the cis-isomer content is preferably 10 to 95 mol%, more preferably 25 to 90 mol. %.

The nitroxide radical used in the present invention is preferably a nitroxide radical having 6 to 25 carbon atoms, more preferably 8 to 15 carbon atoms, and may be a chain form, but a cyclic nitroxide radical is preferred. Specifically, 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6, 6-tetramethylpiperidine-1-oxyl, 3-carbamoylproxyl, 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 3-carboxy-2,2,5,5-tetramethyl Pyrrolidine-1-oxyl, di-t-butyl nitroxide, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxylbenzoate, 4-methoxy-2,2,6,6-tetramethylpiperidine Examples include -1-oxyl, and 2,2,6,6-tetramethylpiperidine-1-oxyl free radical is most preferably used.
The amount of the nitroxide radical used in the present invention is preferably used in the range of 0.001 to 1 equivalent, more preferably 0.01 to 0.2 equivalent, relative to the starting alcohol compound. A range of 0.05 to 0.1 equivalent is most preferred.

  In addition to hypochlorites (such as sodium hypochlorite), the oxidizing agent used in the present invention is hydrogen peroxide, iodine, N-chlorosuccinimide, N-bromosuccinimide, persulfates (sodium persulfate). ), Chloramine B, chloramine T, peracids, N, N-dibromobenzenesulfonamide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, dichloramine B, Dichloramine T, sodium dichloroisocyanurate, t-butyl hypochlorite, iodosobenzenes, oxone, trichloroisocyanuric acid, and the like include hypochlorites, hydrogen peroxide, iodine, N-chlorosuccinimide, N -Bromosuccinimide is more preferred, and hypochlorites are most preferably used.

The reaction conditions in the present invention will be described. The order of addition of the reaction reagents may be any order as long as the temperature can be controlled. For example, preferably, the starting alcohol compound is dissolved in a solvent, and the nitroxide radical and bromide salt are added. A method of adding an oxidizing agent under temperature control is used. The amount of the oxidizing agent used is preferably 80 to 300 mol%, more preferably 100 to 130 mol%, based on 1 mol of the alcohol compound represented by the general formula (I) of the raw material.
Regarding the bromide salt, sodium bromide, potassium bromide and the like are preferable, and the addition amount is preferably 0.01 to 1 equivalent, more preferably 0.05 to 0.3 equivalent to the raw material alcohol compound, added as an aqueous solution. It is preferable to do.
Although the reaction temperature depends on the raw material alcohol compound to be used, it is usually preferably −10 to 40 ° C., more preferably 0 to 35 ° C.
The reaction solvent system is most preferably a two-phase system of water and an organic solvent, and halogen solvents (dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc.) are preferably used as the organic solvent. , Toluene, chlorobenzene, ethyl acetate, butyl acetate, propionitrile, butyronitrile and the like.
In the present invention, it is also preferable to add various salts in order to control the pH during the reaction. These salts preferably have a buffering action and can be used as long as they have a buffering action. In addition to sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate potassium carbonate, borate salts, phosphate salts and the like Preferably, these can also be mixed and used as appropriate.

  EXAMPLES Next, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.

Example 1
Synthesis of 4- (benzenesulfonyloxymethyl) cyclohexanecarbaldehyde (1-1) Synthesis of benzenesulfonic acid 4- (vinyloxymethyl) cyclohexylmethyl ester 170.3 g of 4- (hydroxymethyl) cyclohexylmethyl (vinyl) ether ( Wako Pure Chemical Industries, Ltd. (320-22695) (cis / trans mixture) was dissolved in 1 L of toluene, and 134 mL of benzenesulfonyl chloride was added and stirred. 88 mL of pyridine was slowly added dropwise to this mixture and left overnight.
Thereafter, 500 mL of water was added, liquid separation was performed, and the organic phase was concentrated to obtain crude benzenesulfonic acid 4- (vinyloxymethyl) cyclohexylmethyl ester.

(1-2) Benzenesulfonic acid 4- (hydroxymethyl) cyclohexylmethyl ester 1 L of tetrahydrofuran, 100 mL of water, and 20 g of p-toluenesulfonic acid monohydrate were added to the total amount of the compound synthesized in the previous section, and the mixture was allowed to stand overnight.
Tetrahydrofuran was distilled off under reduced pressure, and then ethyl acetate was added for liquid separation extraction. The organic phase was concentrated and then purified by silica gel column chromatography to obtain 202 g of benzenesulfonic acid 4- (hydroxymethyl) cyclohexylmethyl ester. Yield 70.3%. This obtained benzenesulfonic acid 4- (hydroxymethyl) cyclohexylmethyl ester was 58/42 in terms of the cis isomer / trans isomer with respect to the 1,4 positions.

(1-3) Synthesis of 4- (benzenesulfonyloxymethyl) cyclohexanecarbaldehyde 199 g of benzenesulfonic acid 4- (hydroxymethyl) cyclohexylmethyl ester was dissolved in 800 mL of methylene chloride, and TEMPO (2,2,6,6-tetra 2 g of methylpiperidine-N-oxide radical) and 200 mL of 3% aqueous sodium bromide solution were added and stirred at room temperature. To this, sodium hypochlorite (effective chlorine 5%) containing 2% sodium hydrogen carbonate was added dropwise at 25-30 ° C. After confirming the disappearance of the raw materials, the organic phase was separated, washed with water and washed with an aqueous sodium thiosulfate solution, concentrated to about 50%, and purified by silica gel column chromatography. The target product was obtained as a viscous oil at room temperature. Yield 151.5 g, yield 76.7%.
Nmr spectral data (CDCl ₃ ) of 4- (benzenesulfonyloxymethyl) cyclohexanecarbaldehyde (cis, trans mixture): 9.65 (0.25H, s), 9.60 (0.75H, d, J = 1) .5 Hz), 7.94-7.87 (2H, m), 7.70-7.63 (1H, m), 7.60-7.52 (2H, m), 3.88 (1.5H) , D, J = 6.3 Hz), 3.81 (0.5 H, d, J = 6.8 Hz), 2.43 (0.25 H, m), 2.16 (0.75 H, m), 2 .07-1.50 (5H, m), 1.32-1.17 (2H, m), 1.10-0.95 (2H, m)
From the nmr spectrum, the cis isomer / trans isomer was in excess of trans at a molar ratio of 25/75.

Example 2
Synthesis of 4- (chloromethyl) cyclohexanecarbaldehyde (2-1) Synthesis of 4- (chloromethyl) cyclohexanemethanol 500 g of 1,4-cyclohexanedimethanol (manufactured by Wako Pure Chemical Industries, Ltd .: 03-315405) ( Cis / trans mixture) and 500 g of concentrated hydrochloric acid were mixed and reacted at 100 ° C. for 10 hours. After cooling, 1 L of water was added, neutralized with sodium bicarbonate, and then extracted with ethyl acetate. The organic phase was washed with water and concentrated, and then purified by silica gel column chromatography to obtain 220 g of 4- (chloromethyl) cyclohexanemethanol as an oil at room temperature. Yield 39.0%. The obtained 4- (chloromethyl) cyclohexanemethanol was found to have a cis / trans isomer at a molar ratio of 48/52 with respect to positions 1 and 4.

(2-2) Synthesis of 4- (chloromethyl) cyclohexanecarbaldehyde 162.7 g of 4- (chloromethyl) cyclohexanemethanol (mixture of cis-isomer / trans-isomer from nmr) was dissolved in 800 mL of methylene chloride, and TEMPO (2 2,6,6-tetramethylpiperidine-N-oxide radical) and 200 mL of 3% aqueous sodium bromide solution were added and stirred at room temperature. To this, sodium hypochlorite (effective chlorine 5%) containing 2% sodium hydrogen carbonate was added dropwise at 25-30 ° C. After confirming the disappearance of the raw materials, the organic phase was separated, washed with water and washed with an aqueous sodium thiosulfate solution, concentrated to about 50%, and purified by silica gel column chromatography. The target product was obtained as an oil. Yield 140.1 g, Yield 87.2%
A part of the obtained compound was taken and carefully separated and purified by silica gel chromatography. The molar ratio of the cis form and the trans form was about 1: 3, and the trans form was in excess.
Nmr (CDCl ₃ ) of the trans isomer: 9.632 (1H, d, J = 1.32 Hz), 3.423 (2H, d, J = 1.18), 2.203 (1H, m), 2. 029 (4H, m), 1.642 (1H, m), 1.319 (2H, m), 1.124 (2H, m)
Cis isomer nmr (CDCl ₃ ): 9.700 (1H, s), 3.360 (2H, d, J = 4.92), 2.452 (1H, m), 2.157 (2H, m) 2.041 (1H, m), 1.764 (2H, m), 1.615 (2H, m), 1.130 (2H, m)

Example 3
Synthesis of 4- (acetoxymethyl) cyclohexanecarbaldehyde (3-1) Synthesis of acetic acid 4- (hydroxymethyl) cyclohexylmethyl ester 3 g of dimethylaminopyridine was added to a mixture of 350 mL of acetic anhydride and 300 mL of pyridine at room temperature. Stir. While cooling this with ice water, 480 g of 4- (hydroxymethyl) cyclohexylmethyl (vinyl) ether (manufactured by Wako Pure Chemical Industries, Ltd .: 320-22695) (cis / trans mixture) was added dropwise. Then, after gradually reaching room temperature, it was left overnight. After confirming the completion of the reaction, the reaction solution was poured into 2 L of water and extracted with ethyl acetate. The organic phase was washed with dilute hydrochloric acid and concentrated under reduced pressure, and the residue was dissolved in 2 L of THF. 200 mL of water and 50 mL of trifluoroacetic acid were added and reacted at 40 ° C. for 2 nights. After that, the reaction solution was concentrated and extracted by adding water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography. Yield 403 g, Yield 76.8% (mixture with a cis / trans molar ratio of 52/48 from nmr)

(3-2) Synthesis of 4- (acetoxymethyl) cyclohexanecarbaldehyde 373 g of acetic acid 4- (hydroxymethyl) cyclohexylmethyl ester was dissolved in 1500 mL of methylene chloride, and TEMPO (2,2,6,6-tetramethylpiperidine-N -Oxide radical) 6 g and 3% aqueous sodium bromide solution 400 mL were added and stirred at room temperature. To this, sodium hypochlorite (effective chlorine 5%) containing 2% sodium hydrogen carbonate was added dropwise at 25-30 ° C. After confirming the disappearance of the raw materials, the organic phase was separated, washed with water and washed with an aqueous sodium thiosulfate solution, concentrated to about 50%, and purified by silica gel column chromatography. The target product was obtained as an oil at room temperature. Yield 330.1 g, Yield 89.6%.
Nmr spectral data (CDCl ₃ ) of 4- (acetoxymethyl) cyclohexanecarbaldehyde (cis, trans mixture): 9.70 (0.23H, s), 9.63 (0.77H, d, J = 1.5 Hz) ), 3.92 (1.54H, d, J = 6.6 Hz), 3.88 (0.46H, d, J = 6.6 Hz), 2.44 (0.23H, m), 2.20 (0.77H, m), 2.06 (3H, s), 2.06-2.02 (1H, m), 1.91 (2H, m), 1.63 (2H, m), 1. 29 (2H, m), 1.07 (2H, m)
From the nmr spectrum, the cis / trans isomer had a molar ratio of 23/77.

Example 4
Synthesis of 4- (bromomethyl) cyclohexanecarbaldehyde (4-1) Synthesis of 4- (bromomethyl) cyclohexanemethanol 500 g of 1,4-cyclohexanedimethanol (manufactured by Wako Pure Chemical Industries, Ltd .: 03-315405) (cis / Trans mixture) and 1000 g of 47% hydrobromic acid were mixed, and the reaction was carried out for 15 hours with the external temperature set at 95 ° C. After cooling, 1 L of water was added, neutralized with sodium bicarbonate, and then extracted with ethyl acetate. After the organic phase was washed with water and concentrated, 100 mL of hexane was added and stirred, and then the hexane soluble part was discarded. After performing this operation three times, the residue was purified by silica gel column chromatography to obtain 225 g of 4- (bromomethyl) cyclohexanemethanol as an oil. Yield 31.3%. The resulting 4- (bromomethyl) cyclohexanemethanol had a cis / trans isomer molar ratio of 43/57 with respect to the 1 and 4 positions.

(4-2) Synthesis of 4- (bromomethyl) cyclohexanecarbaldehyde 207 g of 4- (bromomethyl) cyclohexanemethanol (cis / trans mixture from nmr) was dissolved in 1000 mL of methylene chloride, and TEMPO (2, 2, 6, 6 -Tetramethylpiperidine-N-oxide radical) 3 g and 3% aqueous sodium bromide solution 200 mL were added and stirred at room temperature. To this, sodium hypochlorite (effective chlorine 5%) containing 2% sodium hydrogen carbonate was added dropwise at 25-30 ° C. After confirming the disappearance of the raw materials, the organic phase was separated, washed with water and washed with an aqueous sodium thiosulfate solution, concentrated to about 50%, and purified by silica gel column chromatography. The target product was obtained as an oil. Yield 186 g, yield 90.7%.
From the nmr spectrum of the obtained compound, the cis / trans ratio was about 20/80 in molar ratio, and the trans isomer was excessive.
Nmr spectral data (CDCl ₃ ) of cis / trans mixture: 9.70 (0.20H, s), 9.63 (0.80H, d, J = 1.2 Hz), 3.31 (1.6H, d, J = 6.0 Hz), 3.25 (0.4 H, d, J = 6.4 Hz), 2.44 (0.20 H, m), 2.20 (0.80 H, m), 2. 08-1.99 (3H, m), 1.90-1.55 (2H, m), 1.40-1.22 (2H, m), 1.20-1.08 (2H, m)

Claims (2)

In the presence of a nitroxide radical, an oxidant is allowed to act on a primary alcohol compound composed of a mixture of cis- and trans-positions at positions 1 and 4 of the compound represented by formula (I) to obtain the corresponding aldehyde compound. A process for producing a cyclohexanecarbaldehyde compound represented by the general formula (II), characterized in that oxidation is carried out.

In the formula, R represents a substituent.   The method for producing an aldehyde according to claim 1, wherein R is a substituted methyl group.