JP2008189630A - 4-(substituted methyl)cyclohexanecarbaldehyde - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new cyclohexanecarbaldehyde useful as a building block of a liquid crystal intermediate or a pharmaceutical intermediate. <P>SOLUTION: The cyclohexanecarbaldehyde is represented by general formula (I) [wherein, X represents a halogen atom (a fluorine, a chlorine or an iodine), an alkylsulfonyloxy group or an arylsulfonyloxy group]. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

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

Compounds with aldehyde functional groups are not only used as raw materials for alcohols and carboxylic acids, but also a wide range of organic compounds such as aldol reactions, reductive alkylation reactions, hydrazone formation reactions, oxirane formation reactions, and carbon extension reactions using Wittig reagents. It is one of the most important compounds used for synthesis.
Cyclohexanecarbaldehyde is useful as a building block for liquid crystal intermediates and pharmaceutical intermediates, among other applications. For example, Patent Documents 1 and 2 describe use of cyclohexanecarbaldehyde as a pharmaceutical intermediate, and Patent Documents 3 and 4 describe use as a liquid crystal intermediate.

  Thus, cyclohexane carbaldehydes are useful synthetic intermediates, but have a halomethyl group or a sulfonyloxymethyl group at the 4-position except that Patent Document 5 describes 4- (bromomethyl) cyclohexanecarbaldehyde. Cyclohexanecarbaldehyde was not known.

International Publication No. WO2005 / 113511 Pamphlet International Publication No. WO2005 / 118547 Pamphlet International Publication No. WO097 / 20791 Pamphlet European Patent No. 470590 Japanese Patent Laid-Open No. 9-278698

  An object of the present invention is to provide a novel cyclohexanecarbaldehyde useful as a building block for liquid crystal intermediates and pharmaceutical intermediates.

The above object was achieved by the following.
(1) Cyclohexanecarbaldehyde represented by the following general formula (I).

式中、Ｘはハロゲン原子（フッ素、塩素またはヨウ素）、アルキルスルホニルオキシ基またはアリールスルホニルオキシ基を表す。
（２）Ｘがアルキルスルホニルオキシ基またはアリールスルホニルオキシ基である（１）記載のシクロヘキサンカルボンアルデヒド。

In the formula, X represents a halogen atom (fluorine, chlorine or iodine), an alkylsulfonyloxy group or an arylsulfonyloxy group.
(2) The cyclohexanecarbonaldehyde according to (1), wherein X is an alkylsulfonyloxy group or an arylsulfonyloxy group.

  In the formula, X represents a halogen atom (fluorine, chlorine or iodine), an alkylsulfonyloxy group or an arylsulfonyloxy group. When X is an alkylsulfonyloxy group, the alkyl group preferably has 1 to 8 carbon atoms, more preferably 1 to 6 lower alkyl groups, a halogen atom (fluorine, chlorine, bromine or iodine), an alkoxy group (methoxy) Group, ethoxy group, etc.), carbonyloxy group (formyloxy group, acetoxy group, methoxycarbonyloxy group etc.), carbonylamino group (acetylamino group etc.), sulfanyl group (methylsulfanyl group, phenylsulfanyl group etc.), acyl group (Acetyl group, benzoyl group, etc.), sulfonyl group (methanesulfonyl group, phenylsulfonyl group, etc.), cyano group, nitro group may be substituted. When X is an arylsulfonyloxy group, the total number of carbon atoms in X is preferably 6-10, more preferably 6-8, a halogen atom (fluorine, chlorine, bromine or iodine), an alkoxy group (methoxy group, ethoxy group, etc.), Carbonylamino group (acetylamino group etc.), carbonyloxy group (formyloxy group, acetoxy group, methoxycarbonyloxy group etc.), sulfanyl group (methylsulfanyl group etc.), acyl group (acetyl group etc.), sulfonyl group (methanesulfonyl) Group), a cyano group, and a nitro group.

  The compound of the present invention is a novel compound useful as an intermediate for liquid crystal production or a pharmaceutical synthesis intermediate.

  Next, specific examples of the compound represented by formula (I) are shown.

Several synthetic routes to the compound represented by the general formula (I) of the present invention are conceivable, but synthesis is possible using 1,4-cyclohexanedimethanol or its monovinyl ether, which is readily available.
An outline of a synthetic route of the compound represented by the general formula (I) of the present invention is shown in the following scheme. In the following scheme, X has the same meaning as described above, and R represents an aryl group or an alkyl group. The final oxidation step in Schemes A and B consists of Swern oxidation (dimethyl sulfoxide / oxalyl chloride method) as an oxidizing agent, hypochlorite and TEMPO (2,2,6,6-tetramethylpiperidine- in the presence of bromide ions). N-oxide radicals) can be used.

EXAMPLES Next, although this invention is demonstrated further in detail based on an Example, this invention is not restrict | limited by the following description.
Example 1 Synthesis of 4- (benzenesulfonyloxymethyl) cyclohexanecarbaldehyde (CA-11) (1-1) Synthesis of benzenesulfonic acid 4- (vinyloxymethyl) cyclohexylmethyl ester 170.3 g of 4- (hydroxymethyl) ) Cyclohexylmethyl (vinyl) ether (manufactured by Wako Pure Chemical Industries, Ltd .: 320-22695) 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%

(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 (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)

Example 2 Synthesis of 4- (fluoromethyl) cyclohexanecarbaldehyde (CA-3) 10 g of 4- (benzenesulfonyloxymethyl) cyclohexanecarbaldehyde (cis, trans mixture) was dissolved in 20 mL of N-methylpyrrolidone and 50 mL After adding tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution), tetrahydrofuran was distilled off under reduced pressure. The concentrate was reacted at 120 ° C. for 3 hours, extracted by adding water and ethyl acetate, the organic phase was concentrated, and the residue was carefully purified by silica gel chromatography. The eluate was hexane / ethyl acetate = 19/1, and the cis isomer eluted earlier. Yield: 0.2 g of cis isomer and 0.5 g of trans isomer Both oily (room temperature).
Cis isomer nmr (CDCl ₃ ): 9.706 (1H, s), 4.21 (2H, dd, J = 6.32 Hz, 47.5 Hz), 2.458 (1H, m), 2.155 ( 2H, m), 1.781 (1H, m), 1.70-1.65 (4H, m), 1.60 (2H, m), 1.128 (2H, m)
Transformer nmr (CDCl ₃ ): 9.633 (1H, d, J = 1.32 Hz), 4.260 (2H, dd, J = 5.88 Hz, 47.5 Hz), 2.206 (1H, m ), 2.062 (2H, m), 1.914 (2H, m), 1.675 (1H, m), 1.303 (2H, m), 1.114 (2H, m)

Example 3 Synthesis of 4- (iodomethyl) cyclohexanecarbaldehyde (CA-2) 20 g of 4- (benzenesulfonyloxymethyl) cyclohexanecarbaldehyde (cis, trans mixture) was dissolved in 100 mL of acetone and 30 g of sodium iodide. And heated under reflux for 3 hours. After cooling, water and ethyl acetate were added for liquid separation, the organic phase was concentrated, and the residue was carefully purified by silica gel chromatography. The eluate was hexane / ethyl acetate = 19/1, and the cis isomer eluted earlier. Yield: 0.5 g of cis isomer, 2.2 g of trans isomer Both oily (room temperature).
Cis isomer nmr (CDCl ₃ ): 9.697 (1H, s), 3.069 (2H, d, J = 6.69 Hz), 2.402 (1H, m), 2.144 (2H, m) 1.980 (1H, m), 1.802 (2H, m), 1.591 (2H, m), 1.086 (2H, m)
Transformer nmr (CDCl ₃ ): 9.62 (1H, d, J = 1.3), 3.14 (2H, d, J = 6.2 Hz), 2.22 (1H, m), 2. 00 (4H, m), 1.6-1.2 (3H, m), 1.07 (2H, m)

Example 4 Synthesis of 4- (chloromethyl) cyclohexanecarbaldehyde (CA-1) (4-1) Synthesis of 4- (chloromethyl) cyclohexanemethanol 500 g of 1,4-cyclohexanedimethanol (Wako Pure Chemical Industries, Ltd.) ): 03-315405) 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 (room temperature). Yield 39.0%

(4-2) Synthesis of 4- (chloromethyl) cyclohexanecarbaldehyde 162.7 g of 4- (chloromethyl) cyclohexanemethanol was dissolved in 800 mL of methylene chloride, and TEMPO (2,2,6,6-tetramethylpiperidine was dissolved. -N-oxide radical) 2 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 140.1 g, Yield 87.2%
The obtained compound was further carefully purified by silica gel chromatography. The eluate was hexane / ethyl acetate = 19/1, and the cis isomer eluted earlier.
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)

Claims (1)

Cyclohexanecarbaldehyde represented by the following general formula (I).

In the formula, X represents a halogen atom (fluorine, chlorine or iodine), an alkylsulfonyloxy group or an arylsulfonyloxy group.