JPH01165566A - Production of benzenesulfonate derivative - Google Patents

Abstract

PURPOSE:To obtain a 2-cyclohexyl-2-oxoethylbenzeoesulfonate industrially and advantageously, by reacting a 1-cyclohexyl-1-ethanone with a benzenesulfonic acid in the presence of p-toluenesulfonylazide. CONSTITUTION:A compound shown by formula I (R2 is H or alkyl with the proviso that when R2 is alkyl, two substituent groups on cyclohexane ring are mutually trans) is reacted with a compound shown by formula II (R1 is alkyl or alkoxy; l is 0-3 integer) in the presence of p-toluenesulfonylazide, preferably further a base (preferably sodium methoxide or potassium 6-butoxide) and/or an acylating agent (1-2C fatty acid lower alkyl ester, preferably methyl formate or dimethyl oxalate) to give the aimed compound shown by formula III having antilipemic action from the compound shown by formula I by one process in high yield, simply and inexpensively.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (wherein R1 represents an alkyl group or an alkoxy group) having an antilipemic effect disclosed in JP-A-58-135850.
2 represents a hydrogen atom or an alkyl group. ρ represents an integer of 0 to 3. However, when R2 is an alkyl group, the two substituents on the cyclohexane ring are trans to each other.

) The present invention relates to a method for producing a 2-cyclohexyl-2-oxoethylbenzenesulfonate derivative represented by:

Prior art and its problems The compound represented by the above general formula (II) disclosed in JP-A-58-135850 is synthesized by the following methods A and B. However, these methods involve a large number of steps, and method A uses explosive diazomethane, so there are problems in making it a practical industrial production method.

Means for Solving the Problems In view of this situation, the present inventors have developed the general formula (II)
As a result of intensive studies on an excellent industrial method for producing the compound represented by We have discovered the method of the present invention, which is useful as a commercial production method.

The present invention relates to 1-cyclohexyl represented by the general formula (wherein R2 is the same as above. However, when R2 is an alkyl group, the two substituents on the cyclohexane ring are trans to each other.) -1-ethanone derivative in the presence of p-toluenesulfonyl azide, formula (wherein R1 and Ω are the same as above).

) (where R1, R2 and Q are the same as above. However, when R2 is an alkyl group, the two substituents on the cyclohexane ring are , and each other are trans).

The above-mentioned alkyl groups represented by R1 and R2 include straight-chain or branched alkyl groups having 1 to 6 carbon atoms;
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl,
Examples include pentyl and hexyl groups. Examples of the alkoxy group represented by R1 include lower alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, propyloxy, isopropyloxy, and butyloxy groups. Each substituent represented by R1 above can be present at any position on the benzene ring, and there is no need for one substituent, and two to three substituents may be present. Further, the substituent represented by R2 can be present at any position of the cyclohexyl group, and its steric configuration is trans-configuration.

The reaction of the present invention is usually carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but generally ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, and aprotic solvents such as acetonitrile, chloroform, dichloromethane, and benzene are used. It will be done. Preferably, benzene, ether and tetrahydrofuran are suitable.

The reaction of the present invention is carried out in the presence of p-toluenesulfonyl azide. The appropriate amount to be used is 1 to 3.0 mol, preferably 1.5 mol, per 1 mol of compound (I). Furthermore, the presence of a base and/or an acylating agent allows the reaction to proceed more advantageously. As a base,
Although not particularly limited, organic bases such as triethylamine, pyridine, lutidine, sodium hydride, sodium methoxide, potassium t-butoxide, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide are generally used. It will be done. Preferably, sodium methoxide and potassium t-butoxide are suitable. The appropriate amount of the base to be used is 1 to 3.0 mol, preferably 1.5 mol, per 1 mol of compound (I).

As the acylating agent, lower alkyl esters of fatty acids having 1 to 2 carbon atoms, such as methyl formate, ethyl formate, dimethyl oxalate, and diethyl oxalate, are used. Preferably,
Methyl formate and dimethyl oxalate are suitable. The appropriate amount of the acylating agent to be used is 1 to 3.0 mol, preferably 1.5 mol, per 1 mol of compound 6 (■).

The appropriate amount of the various benzenesulfonic acids represented by general formula (m) to be used is 1 to 6.0 mol, preferably 3.0 mol, per 1 mol of compound (1).

The reaction temperature of the present invention is not particularly limited, but it proceeds advantageously at -50 to +50°C, preferably 0 to +20°C, and the reaction time is also not particularly limited, but
Usually completed within 5-6 hours.

The target compound (II) obtained by the above method can be isolated and purified by commonly known separation and purification means such as recrystallization and column chromatography.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Preparation of 2-trans(4-isobutylcyclohexyl)-2-oxoethyl benzenesulfonate 5.46 g (0.03 mol) of trans-1-acetyl-4-inbutylcyclohexane was dissolved in 20% of tetrahydrofuran, and under water cooling, sodium methoxide 2.4
3g (0,045 mol) and 2.7g methyl formate (
0,045 mol) was added thereto and stirred for 2 hours. Then p
-Toluenesulfonyl azide 8.87g (0,045
After stirring for 1 hour, 14% of benzenesulfonic acid was added.
22g (0.09 mol) was added and stirred for 2 hours. Further, 50 mQ of benzene and 50 mQ of water were added, the organic layer was separated, washed with water, and the solvent was distilled off. After cooling the residue to -20°C,
Petroleum ether was added to crystallize and collect. The obtained crystals were recrystallized from ethanol to obtain 7.0 g (yield: 69.0%) of 2-trans(4-isobutylcyclohexyl)-2-oxoethyl benzenesulfonate. The melting point was 50-51°C.

IH nuclear magnetic resonance spectrum (TMS internal standard, CDCR
3) δppm; 7, 42-8. 10 (5H, m), 4.64 (2
H,s), 2.48 (IH,t t, J=4°12Hz), 0.64-2.00 (12H,m), 0.84 (6
H, d) Example 22-) Lance (4-ethylcyclohexyl)-
Production of 2-oxoethyl benzenesulfonate trans-1-acetyl-4-ethylcyclohexane 4
．． 62 g (0.03 mol) was dissolved in 20 mQ of ether and 2.43 g (0.03 mol) of sodium methoxide was dissolved at room temperature.
045 mol) and dimethyl oxalate 5.31 g (0,
045 mol) was added and stirred for 3 hours. Next, 8.87 g (0,045 mol) of p-toluenesulfonyl azide was added, and after stirring for 1 hour, 14.22 g of benzenesulfonic acid was added.
g (0.09 mol) and stirred for 2 hours. Subsequent operations were carried out as in Example 1, yielding 5.69 g (61.2% yield) of 2-trans(4-ethylcyclohexyl)-2-oxoethyl benzenesulfonate. Melting point 5
The temperature was 8-59°C.

1H nuclear magnetic resonance spectrum (TMS internal standard, CDCΩ
3) δppm; 7.80-8.10 (2H, m), 7.40-7.80 (3H, m), 4.65 (2H, s), 2, 64 (IH, broad), 1 .00~2.00 (11H, m), 0.84 (3
H, t) Example 3 Preparation of 2-trans(4-isopropylcyclohexyl)-2-oxoethyl 4-ethoxybenzenesulfonate 5.04 g (0.03 mol) of trans-1-acetyl-4-isopropylcyclohexane was added to benzene 2011
Dissolved in 1Q and cooled with water, potassium t-butoxide 5.0
4g (0,045 mol) and diethyl oxalate 6.5
7 g (0,045 mol) was added and stirred for 1 hour. Next, 8.87 g of p-toluenesulfonyl azide (0
,045 mol) and stirred for 1 hour, 18.18 g (0.09 mol) of 4-ethoxybenzenesulfonic acid was added and stirred for 2 hours. Subsequent operations were carried out as in Example 1, with 2-trans(4-isopropylcyclohexyl)-
6.07 g (yield 55%) of 2-oxoethyl 4-ethoxybenzenesulfonate was obtained. Melting point 80-81℃
Met.

1H nuclear magnetic resonance spectrum (TMS internal standard, CDC
A) δppm near, 85 (2H, d), 6.99 (2H, d), 4.58 (2H, s), 4.11 (2H, q), 2.48 (IH, t t, J-4゜12Hz), 0.95-2.00 (IOH, m), 1.45 (3
H,t), 0.86 (6H,d) Examples 4 to 8 Compound (II) shown in Table 1 below was reacted under the same conditions as in Example 1, and the results as shown in Table 1 were obtained. Obtained.

Table 1 (that's all)

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_2 represents a hydrogen atom or an alkyl group. However, if R_2 is an alkyl group, the two substituents on the cyclohexane ring are p-cyclohexyl-1-ethanone derivative represented by
In the presence of toluenesulfonyl azide, benzenesulfonic acid represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 represents an alkyl group or an alkoxy group. l represents an integer from 0 to 3) There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by the reaction of
When _2 is an alkyl group, 2 on the cyclohexane ring
The two substituents are trans to each other. ) A method for producing a 2-cyclohexyl-2-oxoethylbenzenesulfonate derivative represented by: (2) 2- as set forth in claim 1, wherein the reaction is carried out in the presence of a base and/or an acylating agent;
A method for producing a cyclohexyl-2-oxoethylbenzenesulfonate derivative.