JPH021820B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula The present invention relates to a novel trifluoromethyl-substituted quinone compound represented by the formula (wherein, R is a tertiary alkyl group and Z is a halogen atom or a cyano group) and a method for producing the same.

The trifluoromethyl-substituted quinone compound of the present invention represented by the above general formula () produces p-hydroxyphenyl-α-trifluoromethylacetic acid or its ester (see U.S. Pat. No. 3,879,385), which is important as a modifier for cephalosporin. (See Reference Examples 3 and 4).

Conventionally known p-hydroxyphenyl-α
-The manufacturing method of trifluoromethylacetic acid or its ester is difficult to adopt as an industrial manufacturing method because it uses expensive triphenylphosphine and chloromethyl methyl ether, which is carcinogenic. [U.S. Patent No.
3879385 and J.Org.Chem., 32 , 2797 (1967)].

As a result of intensive studies to eliminate the drawbacks of the conventional methods, the present inventors have found that p-hydroxyphenyl-
The present invention was completed by discovering the compound of the present invention which can be converted into α-trifluoromethylacetic acid or its ester.

The production method of the present invention can be represented by the following reaction formula.

(In the formula, R is a tertiary alkyl group, and X and Y are the same or different halogen atoms.) [Step A] This step involves treating the phenol compound represented by the above general formula () with a base. A trifluoromethyl-substituted haloquinone compound represented by the above general formula (-a) is produced by the following steps.

The phenol compound represented by the general formula (), which is the raw material of the present invention, is an industrially available 2,
6-di-t-butylphenol, 2,6-di-t
-It can be easily produced by reacting amylphenol etc. with (belhaloethyl)aryliodonium salt (Chem.Lett., 1981 ,
1663 and Reference Examples 1 and 2).

Bases used in this step include metal hydrides such as sodium hydride and potassium hydride, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and metal hydroxides such as sodium hydroxide and potassium hydroxide. , organic amines such as triethylamine, quaternary ammonium hydroxides such as benzyltrimethylammonium hydroxide (Triton B), and metal carbonates such as sodium carbonate and potassium carbonate. The amount of the base to be used is usually at least the equivalent molar amount to the phenol compound represented by the above general formula ().

Although a solvent is not necessarily required for carrying out the reaction, it is preferable to use a solvent in order for the reaction to proceed smoothly, such as methylene chloride, chloroform, carbon tetrachloride, halides such as dichloroethane, acetone, acetonitrile, dimethyl, etc. Polar solvents such as formamide (DMF), dimethyl sulfoxide (DMSO), nitromethane, ethyl acetate, and water, alcohols such as methanol, ethanol, and t-butanol, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and hydrocarbons such as benzene and toluene. Examples include solvents.

The reaction is carried out at -30°C to 120°C, preferably 0°C to 100°C.
When carried out, the reaction proceeds with good yield.

[B process]

In this step, the trifluoromethyl-substituted cyanoquinone compound represented by the general formula (-b) is produced by reacting the phenol compound represented by the general formula () with a cyano compound under basic conditions.

Examples of the cyano compound that can be used in this step include hydrogen cyanide, acetone cyanohydrin, sodium cyanide, and potassium cyanide. Basic conditions include, for example, sodium cyanide, potassium cyanide, etc., metal cyanides, metal hydrides such as sodium hydride, potassium hydride, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. A reaction system in which metal hydroxides, organic amines such as triethylamine, quaternary ammonium hydroxides such as benzyltrimethylammonium hydroxide (Triton B), and metal carbonates such as sodium carbonate and potassium carbonate are added to sodium hydroxide, potassium hydroxide, etc. This can be achieved by adding In addition, when using alkali metal cyanides such as sodium cyanide and potassium cyanide as raw materials,
Since these themselves exhibit basicity in the system,
There is no need to actively add a base. The amount of base used is usually 2 equivalents or more relative to the phenol compound.

Although a solvent is not necessarily required for carrying out the reaction, it is preferable to use a solvent in order for the reaction to proceed smoothly, such as methylene chloride, chloroform, carbon tetrachloride, halides such as dichloroethane, acetone, acetonitrile, dimethyl, etc. Examples include formamide (DMF), dimethyl sulfoxide (DMSO), nitromethane, ethyl acetate, polar solvents of hydrogen, alcohols such as t-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and hydrocarbon solvents such as benzene and toluene. be able to.

The reaction is carried out at -30°C to 120°C, preferably 0°C to 100°C.
When carried out, the reaction proceeds with good yield.

The trifluoromethyl-substituted cyanoquinone compound represented by the general formula (-b) is prepared by reacting the trifluoromethyl-substituted haloquinone compound represented by the general formula (-a) with the cyano compound under the same conditions as in reaction B. It can also be manufactured by

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

Reference example 1 824 mg (4 mmol) of 2,6-di-t-butylphenol and 162 ml of pyridine in a 25 ml eggplant flask.
(2 mmol) and 8 ml of acetonitrile were added thereto, and while stirring at room temperature, 840 mg (2 mmol) of pentafluoroethyl phenyl iodonium sulfate was added, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with n-pentane. The solvent was distilled off under reduced pressure, and 550 mg of 4-pentafluoroethyl-2,6-di-t-butylphenol was obtained.
(1.7 mmol) was obtained as colorless crystals. Yield 85%.

mp: 48-49℃. ¹⁹ F-NMR (CCl ₃ F internal standard in deuterated chloroform, ppm): 85.25 (s, 3F), 113.7 (s,
2F). I Rcm ^-1 : 1150, 1200, 1310 (C-F), 2980
(CH ₃ ), 3650 (OH). Mess: 324 (M ⁺ ), 309 (M ⁺ −CH ₃ ). Elemental analysis Calculated value: C; 59.25, H; 6.53%. Actual value: C: 59.28, H: 6.45%. Reference example 2 The reaction was carried out in the same manner and molar ratio as in Reference Example 1, except that 944 mg of pentafluoroethyl phenyl iodonium trifluoromethanesulfonate was used, and 450 mg of 2,6-di-t-butyl-4-pentafluoroethylphenol ( 69%) obtained.

Example 1 162 mg of 4-pentafluoroethyl-2,6-di-t-butylphenol in a 25 ml eggplant flask.
(0.5 mmol), 63 mg (1.3 mmol) of 50% NaH, and 5 ml of dry diethyl ether were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with 5% ether/n-pentane. The solvent was distilled off under reduced pressure, and 75 mg of the compound of the general formula () (Z=F, R=t-Bu) was obtained.
(0.25 mmol) was obtained as pale yellow crystals. Yield 49%
(GLC yield 96%).

mp: 67-69.5℃. ¹⁹ F-NMR (CCl ₃ F internal standard in deuterated chloroform, ppm): 64.13 (d, J = 8 Hz, 2F),
117.7 (q, j = 8Hz, 3F). I Rcm ^-1 : 1125, 1145, 1200, 1260, 1285
(C-F), 1640, 1650 (C=C, C=0),
2980 ( _CH3 ). Mess: 304 (M ⁺ ), 289 (M ⁺ −CH ₃ ). Elemental analysis Calculated value: C; 63.15, H; 6.62%. Actual value: C: 63.19, H: 6.72%. Example 2 20mg of 4-pentafluoroethyl-2,6-di-t-butylphenol in a 5ml eggplant flask
(0.06mmol), potassium hydroxide 56mg (1mmol),
0.5 ml of methylene chloride was added, and the mixture was refluxed for 30 minutes. After performing the same post-processing as in Example 1, the general formula ()
A compound (Z=F, R=t-Bu) was obtained (GLC yield 71%).

Example 3 4-(1′,1′-dichloro-2′,2′,2′-trifluoroethyl)-2,6-di-6-di-t-butylphenol 180 mg (0.5 mmol) was used. The compound of the general formula () (Z-C1, R=t-Bu) was prepared in the same manner as in Example 1, including reagents and solvents.
mg (40%) obtained as an oil.

¹⁹ F-NMR (CCl ₃ F internal standard in deuterated chloroform, ppm): 56.98 (bs, 3F). I Rcm ^-1 : 1140, 1180, 1250, 1270 (C-
F), 1630, 1645, (C=C, C=O),
2960 ( _CH3 ). Mess: 322 (M ⁺ +2), 320 (M ⁺ ), 305
(M ⁺ CH ₃ ). Elemental analysis Calculated value: C; 59.91, H; 6.28%. Actual value: C: 60.04, H: 6.39%. Example 4 In a 25 ml eggplant flask, apply the general formula () (Z=
F, R=t-Bu) compound 304 mg (1 mmol), 50
%NaH48mg (1.0mmol), dry diethyl ether
10 ml of the solution was added, and while stirring at room temperature, 92μ (1.0 mmol) of acetone cyanohydrin was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with 5% ether/n-pentane. The solvent was distilled off under reduced pressure, and 232 mg of the compound of the general formula () (Z=CN, R=t-Bu) was obtained.
(0.75 mmol) was obtained as red crystals. Yield 75%.

mp: 54-55°C ¹⁹ F-NMR (CCl ₃ F internal standard in deuterated chloroform, ppm): 55.00 (s). I Rcm ^-1 : 1140, 1185, 1260, 1275 (C-
F), 1630, 1655 (C=C, C=0), 2230
(CN), 2980 ( _CH3 ). Mess: 311 (M ⁺ ), 296 (M ⁺ −CH ₃ ). Elemental analysis Calculated values: C; 65.58, H; 6.48, N; 4.50%. Actual measurements: C: 65.60, H: 6.72, N: 4.28%. Example 5 324 mg of 4-pentafluoroethyl-2,6-di-tert-butylphenol in a 25 ml naph flask.
(1 mmol), 126 mg (2.6 mmol) of 50% NaH, and 10 ml of dry diethyl ether were added thereto, and while stirring at room temperature, 120 μ (1.3 mmol) of acetone cyanohydrin was added, and the mixture was stirred at room temperature for 14 hours. Remove the solvent under reduced pressure,
Subjected to silica gel column chromatography, 5
Eluted with % ether/n-pentane. The solvent was distilled off under reduced pressure, and the general formula () (Z=CN, R=t
-Bu) compound (273 mg (0.88 mmol)) was obtained as red crystals. Yield 88%.

Reference example 3 In a 25 ml eggplant flask, apply the general formula () (Z=
CN, R=t-Bu) compound 155 mg (0.5 mmol),
After adding 80 mg of 5% Pd-C and 10 ml of acetonitrile and degassing, hydrogen gas was introduced and the mixture was stirred at room temperature for 2 hours. Further, 100 mg of 5% Pd-C was added, and after degassing, hydrogen gas was introduced and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography and eluted with 40% ether/n-pentane. The solvent was distilled off under reduced pressure to obtain 4-(1'-cyano-2',
2',2'-trifluoroethyl)-2,6-di-t
-Butylphenol 142 mg (0.91 mmol) was obtained as colorless crystals. Yield 91% mp: 59-60℃ ¹⁹ F-NMR (CCl ₃ F internal standard in deuterated chloroform, ppm): 70.04 (s) I Rcm ^-1 : 1130, 1180, 1250 (C-F), 2250
(CN), 2940, 2970 (CH ₃ ), 3655 (OH). Mess: 313 (M ⁺ ), 298 (M ⁺ −CH ₃ ). Elemental analysis Calculated values: C; 65.16, H; 7.08, N; 4.41%. Actual values: C: 65.29, H: 7.29, N: 4.20%. Reference example 4 In a 25 ml eggplant flask, add 4-(1′-cyano-2′,
2',2'-trifluoroethyl)-2,6-di-t
- 91 mg (0.29 mmol) of butylphenol and 2 ml of ethanol were added, and 1 ml of concentrated sulfuric acid was added while stirring in ice water. After refluxing for 1.5 hours, the mixture was cooled, 1 ml of water was added, and the mixture was extracted with ether. The extract was washed with a saturated aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with 50% ether/n-pentane. The solvent was distilled off under reduced pressure, and p-hydroxyphenyl-α-trifluoromethylethyl acetate was obtained.
36 mg (0.15 mmol) was obtained as a colorless oil. Yield 50%.

¹⁹ F-NMR (CCl ₃ F internal standard in deuterated chloroform, ppm): 68.60 (s) I Rcm ^-1 : 1115, 1155, 1180, 1220, 1260
(C-F), 1740 (C=0), 3450 (OH). Mess: 248 (M ⁺ ). Elemental analysis Calculated value: C; 53.23, H; 4.47%. Actual value: C; 53.00, H; 4.44%.

Claims (1)

[Claims] 1. General formula A trifluoromethyl-substituted quinone compound represented by (wherein R is a tertiary alkyl group and Z is a halogen atom or a cyano group). 2 General formula The general formula consists of treating a phenolic compound represented by with a base. A method for producing a trifluoromethyl-substituted haloquinone compound represented by (wherein, R is a tertiary alkyl group, and X and Y are the same or different halogen atoms). 3 General formula The general formula consists of reacting a phenolic compound represented by with a cyano compound under basic conditions. A method for producing a trifluoromethyl-substituted cyanoquinone compound represented by (wherein R is a tertiary alkyl group, and X and Y are the same or different halogen atoms).