JPS5927862A - (p-hydroxyphenyl)(perfluoroalkyl)acetonitrile derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (Rf is lower perfluoroalkyl; R is H or tertiary alkyl). EXAMPLE:4-(1'-Cyano-2',2',2'-trifluoroethyl)-2,6-di-t-butylphenol. USE:A synthetic intermediate of p-hydroxyphenyl-alpha-trifluoromethyl-acetic acid or its ester useful as a modifier of cephalosporin. PROCESS:The compound of formula I can be prepared by the catalytic hydrogenation of the quinone compound of formula II in the presence of a reduction catalyst (e.g. Pd/C). The reaction is preferably carried out in a solvent (e.g. acetonitrile) at 0-60 deg.C. A compound of formula I wherein R is tert-alkyl can be converted to another compound wherein R is H by reacting with aluminum chloride. The compound of formula II used as a starting material can be obtained by reacting a phenol, etc. with (perfluoroalkyl)aryl iodonium salt, and treating the reaction product with a base in the presence of acetocyanhydrin.

Description

DETAILED DESCRIPTION OF THE INVENTION The present defense provides a novel (p-hydroxyphenyl) compound represented by the general formula (where Itf is a lower perfluoroalkyl group and R is a hydrogen atom or a 6th-class alkyl group). It relates to (perfluoroalkyl)acetonitrile derivatives.

The (p-hydroxyphenyl)(perfluoroalkyl)acetonitrile derivative represented by the general formula (1) of the present invention can be used as a cephalosporin modifier.
It is an important intermediate for producing -hydroxyphenyl-α-trifluoromethylacetic acid or its ester (see US Pat. No. 3,879,385) (see reference side below).

Conventionally known methods for producing p-hydroxyphenyl-α-trifluoromethylacetic acid or its esters use expensive triphenylphosphine and chloromethyl methyl ether, which is carcinogenic. It is difficult to adopt it as an industrial manufacturing method such as point
U.S. Pat. No. 3,879,385 and J. Org.
(2) See em, , 32.2797 (1967)]
0 The inventor has conducted extensive studies to eliminate the drawbacks of the conventional technology.
c M As a result, we have discovered the compound of the present invention which can be converted into p-hydroxyphenyl-α-trifluoromethylacetic acid or its ester, and have come to form the present invention.

The compound of the present invention is produced according to the following reaction formula [Step B 几'OH 011] (In the formula, Rf is a lower perfluoroalkyl group, and le-R' is a hydrogen atom or a lower alkyl group. Yes, R
132I
・) [Process] This step involves hydrogenating the quinone compound represented by the above general formula (II) in the presence of a catalytic reduction catalyst to obtain (p-hydroxyphenyl) represented by the above general formula (I) (
This method produces perfluoroalkyl)acetonitrile derivatives. The above general formula (II) which is the raw material for this step
The quinone compound represented by
It can be easily produced by reacting di-t-amylphenol or other tho(perfluoroalkyl)aryliodonium salts and then treating with a base in the presence of acetone cyanohydrin (Chem, Lett, 1).
98 yu.

1666 and Reference Examples 1 and 2). As the catalytic reduction catalyst used in this step, metal catalysts commonly used in catalytic reduction, such as palladium-carbon, platinum, palladium, and Raney nickel, can be used.

In carrying out the reaction, it is preferable to use a solvent, examples of which include acetonitrile, dioxane, tetrahydrofuran, ether, ethanol, acetic acid, ethyl acetate, benzene, hexanes, and cyclohexane.

In the compound represented by the general formula (1) obtained in this step, a compound in which R has a tertiary alkyl group can be easily converted into a compound in which 11 is a hydrogen atom by reacting with aluminum chloride. In this dealkylation reaction, it is preferable to use a solvent, for example, an aromatic ring compound such as benzene, toluene, xylene, etc. can be used. In order to carry out this reaction smoothly, it is preferable to carry out the reaction by adding a nitro compound such as nitromethane in moles equivalent to 10 times the mole of aluminum chloride.

It is preferable to use an equivalent of 0.8 to 4 times. The dealkylation reaction proceeds between 0°C and 100°C, but from room temperature to 8°C.
00 is preferable because it improves the yield.

[B Process]

In this step, the (p-hydroxyphenyl)(perfluoroalkyl)acetonitrile derivative represented by the general formula (I) and the compound represented by the general formula (III) are treated with an acid to obtain the compound represented by the general formula ([V]). This method produces a (p-hydroxyphenyl)(perfluoroalkyl)acetic acid compound which is expressed as follows. The general formula ([r
Examples of the compound represented by [) include lower alcohols such as methanol and ethanol, and water.

Acids include sulfuric acid and chloride <A! i? The temperature is preferably 80°C to 150°C.

Reference Example 1 In a 25 ml eggplant flask, 82 2,6-di-t-7'ethylphenols (4 mmo+) and 162 pyridine were added.
m1 (2 mmol'), add 8 ml of acetonitrile and bring it to room temperature.
) and stirred at room temperature for 60 minutes. Remove the solvent under reduced pressure,
The mixture was applied to Nori gel chromatograph 2 and eluted with n-pentane. The solvent was distilled off under reduced pressure, and 550 m9 of 4-pentafluoroethyl-2,6-sheet t-7/tylphinol (
1.7 mmol) was obtained as colorless crystals. Yield: 85 cm.

m, p,: 48-49°C
F internal standard, ppm): 85.25 (s, 3F),
113.7 (s, 2F).

11(m21150,1200,1!+10(C
-F), 2980 (CH3), 3650 (OH).

+ Mass: 324 (M), 309 (M+-CH5
).

elemental analysis Increase resistance value: C; 59.25. H: 6.53%.

Actual measurements: C: 59.2B, H: 6.45chi.

Reference example 2 4-pentafluoroethyl in a 25 m eggplant flask
2,6-tert-Fuyorfue/-le'524m&
(1 mmol), 50% NaH126~(2,6 rrr
Add 10 ml of dry diethyl ether and add 120 J of acetone cyanohydrin (10 ml) with stirring at room temperature.
, 3 mmol) and stirred at room temperature for 14 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 to obtain Compound 276-(0.88 mmol) of the general formula (■) (几-t-J3u) as red crystals.

Yield 88%.

m, p, 254-55°C "f+' -NMR (CCl3F internal standard in deuterated chloroform, Ppm): 55.00 (s) I&m: 1140, 11B5, 1260.1275
(C-F), 1630, 1655 (C Eng C.

C=O), 2230 (CN), 2980 (C1(3).

Mass 2311 (M +), 296 (M+-
CH3).

Elemental analysis gt calculation value C; 65.58. H; 6.48. Ni4.
50I%.

Actual value: C165,60,f(;6.72.Ni4.
28% Example 1 The above general formula (II) (1-t
-Bu) compound 155! nII (0,5 mmo 1
), 5% Pd-C80η, acetonitrile 10m' (
The mixture was degassed, hydrogen gas was introduced, and the mixture was stirred at room temperature for 2 hours. Furthermore, 00 mg of 5% Pd-Cl 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 ethyl/n-pentane.

Reducing the solvent, 142 nl of (0.91 mmol) of 2,6-sheet t-7' methylphenol was obtained as colorless crystals.

Yield: 91 cm.

m, p,: 59-60゛c 19F-Nul+ (CC16B internal standard in deuterated chloroform, ppm) = 70.04 (s).

II: 1130, 1180.1250 (C-F).

2250 (cN), 2940.2970 (CH3).

3655 (OH).

Mass: 313 (M), 298 (M+-CH5)
.

+ Elemental analysis calculated value: C; 65.16, 1-1; 7.08. N;4.
41%.

Actual value: C; 65,29. H;7.26. N; 4.20
blood.

Example 2 4-(1-cyano-2°2.
Add 513 rng (1 mmol) of 2-trifluoroether)-2,6-di-t-butylphenol and 60 U++I (4,5 mmol) of acclimatized aluminum, and add Alcon [1/JL, 2 Biao of benzene, 6 nitromethane] under reduced pressure.
00 μQ (9.8 mmo 1 ) was added and stirred at 50° C. for 23 hours.

While cooling, 5 d of 4N-HCI was added, and the mixture was extracted with ether ILIOd, washed twice with water, and dried with f9804. After filtration, concentrate and apply silica gel column chromatography to 50% ether/
Eluted with pentane. The solvent was distilled off under reduced pressure and 4-(1-cyano-2,2,2-trifluoroether)phenol 19
/In9 (0.98 mmo 1 ) was obtained as colorless crystals. Yield: 98 cm.

m, p,: 58-59% 19F-NMR (CC13F internal standard in deuterated chloroform, ppm): 69.97 (d, 3F, J = 7.8) IVL)'H-NM
I ((TM8 internal standard in deuterated chloroform, ppm); 4
．． 43 (q, IH, J=7.8H1).

I&m': 1120-1280 (C-F), 153
0°1450, 1520, 1600,'1620
.

1900.2280 (CN), 3400 (OH).

Mass 2202 (M++1), 2 old (IVI”)
.

182 (M+-F), 132 (M+-CF3).

Reference Example 6 4-(1-Soarnow 2゜2゛,
91 m9 (0.29 mmol) of 2"-trifluoroether)-2,6-di-t-butylphenol and 2 m 1 of ethanol were added, and 1 ml of concentrated sulfuric acid was added to the mixture under stirring in ice water. After refluxing for 1 hour and a half, , cooled, added 1Tn1! of water, and extracted with ether.The extract was extracted with saturated carbonic acid l-IJ
It was washed with aqueous magnesium sulfate solution and dried with 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 4-(1-nitoxycarbonyl-2
,2,2-trifluorotechnicalfh)7x/-ru361V(
0.15 mmol) was obtained as a colorless oil. Yield 50
blood.

"F-NMR (3)j CCl3F internal standard in chloroform, pl)nl): 68, 60(s).

IRcIn': 111b, 1155.11B0, 122
0°1260 (C-F), 1740 (C-0).

3450 (OH).

Mass: 248 (M”).

elemental analysis Calculated value: C; 5125. H; 4.47chi.

Actual value: C; 5100. H: 4.44%.

Reference Example 4 581 ng (0.29 m
2.2 Same as Reference Example 6 except that mol) was used.
- ) trifluoroethyl) phenol was obtained.

Yield: 55 cm.

Reference Example 5 4-(1-cyano-2゜2.2
-trifluoroethyl)phenol 201η (1mmo
1), 1 m of 98% sulfuric acid/1 σ of water was added, and the mixture was stirred under heating under reflux for 5 hours and 45 minutes. The ether layer was made alkaline with saturated aqueous NaHCOs, the aqueous layer was made acidic with 1N-HCl, extracted with ether, washed twice with saturated brine, and dried over MgSO4. After filtration, the solvent was distilled off under reduced pressure to obtain 4-(1-carbonol 95~(0,4
3d) was obtained as colorless crystals. +■7 rate 45%.

m, p,: 169-171℃ ”F-NMR (CCl3F internal standard pp in heavy methanol
m): 68.13 (d, 5F, J=9.0H,)'H-
NM)L (heavy meta/-/l, medium TM8 internal standard ppm)
:4.56 (Q, IH, J=9.011mm).

6.77 (d, IH, J-8, 8H,).

7.25 (d, IH, J=8.8i1X).

I'm ”: 1120, 1150, 1180, 1250
,1520°1610 ,1750(-C(JOH),
5400(-Gl).

Mass: 221 (M”+1), 220 (M
”).

Elemental analysis: 6: C; 49.09, l-1; 5.18%
.

The center is Kawa 111↓:C;4):i,87.1-1;2. ν
8chi.

patent applicant

Claims (1)

[Scope of Claims] (p-hydroxyphenyl)(perfluoroalkyl)acetonitrile derivative represented by (1) (in the formula, f 1l
t (l is a perfluoroalkyl group, ■t is a hydrogen atom or a 6th-class alkyl group).