JPH02196742A - Fluorine-containing compound and production thereof - Google Patents

Abstract

NEW MATERIAL:Fluorine-containing compounds expressed by formula I (R<1> is alkyl; R<2> is fluoroalkyl; Y is COOH, COCl, alkoxycarbonyl or CH2OH). EXAMPLE:(S)-(-)-2-Fluoro-2-(trifluoromethyl)hexanoic acid. USE:A raw material for functional materials, such as medicines, agricultural chemicals or liquid crystal compounds. PREPARATION:A compound expressed by formula II is hydrogenated to provide a compound expressed by formula III in the compounds expressed by formula I. The resultant compound expressed by formula III is then reacted with a chlorinating agent to afford a compound expressed by formula IV in the compounds expressed by formula I. The resultant compound expressed by formula IV is subsequently reacted with alcohols to provide a compound expressed by formula V (R is alkyl) in the compounds expressed by formula I. Further, the compounds expressed by formulas III to V are reacted with a metal hydride to afford a compound expressed by formula VI in the compounds expressed by formula I. The compounds expressed by formula I can be readily produced under mild conditions according to the aforementioned method and the optically active substances expressed by formula I can be extremely readily obtained by especially using the optically active substance expressed by formula III as a starting material.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for obtaining a fluorine-containing compound useful as a raw material for functional materials such as pharmaceuticals, agricultural chemicals, and liquid crystal compounds.

In general, many fluorine-containing compounds have unique physical properties and physiological activities, and there is much research into their synthesis [for example, Chemistry Review, "New Fluorine Chemistry," edited by the Chemical Society of Japan, Society Publishing Center (1980 )), L.

However, it is represented by the following general formula (I) (wherein R1 represents an alkyl group, R2 represents a fluoroalkyl group, and Y represents a carboxyl group, a chloroformyl group, an alkoxycarbonyl group or a hydroxymethyl group). The fluorine-containing compound that can be used is still unknown.

By the way, the present inventor has proposed the following general formula (■)R"
R2 X (wherein, R1 represents an alkyl group, and when X is F, R2
represents an alkyl group or a fluoroalkyl group, and when X is H, R8 represents a fluoroalkyl group), from the following general formula (II) R"-CH=CH-CH, -C-COOH(
II) (wherein, R1 represents an alkyl group, when X is F, R2 represents an alkyl group or a fluoroalkyl group, and when X is H, R2 represents a fluoroalkyl group), In particular, he proposed a method for producing optically active substances thereof (Japanese Patent Application No. 16881/1986).
4).

The present invention is a further development of research on the above-mentioned compounds, and is a novel fluorine-containing compound, particularly its optical An object of the present invention is to provide an active substance and a method for producing the same.

R”-(CH,)3-C-Y (1
) (wherein, R1 represents an alkyl group, R2 represents a fluoroalkyl group, and Y represents a carboxyl group, chloroformyl group, alkoxycarbonyl group, or hydroxymethyl group), a fluorine-containing compound represented by the general formula (n ) (In the formula, R1 represents an alkyl group and R2 represents a fluoroalkyl group). A method for producing a fluorine-containing carboxylic acid represented by the formula (wherein R2 represents a fluoroalkyl group), a general formula (TV )R'-(CH,), -C-COCI
(IV) (wherein R'' represents an alkyl group,
R2 represents a fluoroalkyl group), a general method comprising reacting a fluorine-containing carboxylic acid chloride represented by the above formula (IV) with an alcohol; A method for producing fluorine-containing carboxylic acid esters represented by formula (V) (wherein R1 and R represent an alkyl group and R2 represents a fluoroalkyl group), the above formulas (III) to (V)
The general formula % formula % () (in the formula, R1 represents an alkyl group and R2 represents a fluorine-containing carboxylic acid, an acid chloride, or an ester represented by the formula %) formed by reacting a metal hydride with a metal hydride (representing an alkyl group) and an optically active form of the fluorine-containing carboxylic acid represented by the above formula (III) as a starting material. This is a method for producing an optically active form of a fluorine-containing compound.

The compound of the above formula (I) is 2-fluoro-2-(trifluoromethyl)hexanoic acid, 2-fluoro-2-(trifluoromethyl)peptanoic acid, 2-fluoro-2-(trifluoromethyl)octanoic acid. , 2-fluoro-2-(
trifluoromethyl)nonanoic acid, 2-fluoro-2-(
trifluoromethyl)decane, 2-fluoro-2-(
trifluoromethyl)undecanoic acid, 2-fluoro-2
-(trifluoromethyl)dodecanoic acid, 2-fluoro-
2-(trifluoromethyl)hexanoyl chloride,
2-fluoro-2-(trifluoromethyl)peptanoyl chloride, 2-fluoro-2-(trifluoromethyl)octanoyl cochloride, 2-fluoro-2-(trifluoromethyl)nonanoyl chloride, 2-fluoro- 2-(trifluoromethyl)decanoyl chloride, 2-fluoro-2-(trifluoromethyl)undecanoyl chloride, 2-fluoro-2-(trifluoromethyl)dodecanoyl chloride, 2-fluoro-2-
Methyl (trifluoromethyl)hexanoate, ethyl 2-fluoro-2-(trifluoromethyl)hexanoate, 2
-Isopropyl fluoro-2-(trifluoromethyl)hexanoate, pentyl 2-fluoro-2-(trifluoromethyl)hexanoate, methyl 2-fluoro-2-(trifluoromethyl)peptanoate, 2-fluoro-2- (
Ethyl trifluoromethyl)beptanoate, isopropyl 2-fluoro-2-(trifluoromethyl)peptanoate, pentyl 2-fluoro-2-(trifluoromethyl)peptanoate, 2-fluoro-2-(trifluoromethyl)octane Methyl acid, ethyl 2-fluoro-2-(trifluoromethyl)octanoate, isopropyl 2-fluoro-2-(trifluoromethyl)octanoate, pentyl 2-fluoro-2-(trifluoromethyl)octanoate, 2-fluoro-2-(trifluoromethyl)octanoate Methyl -2-(trifluoromethyl)nonanoate, Ethyl 2-fluoro-2-(trifluoromethyl)nonanoate, Isopropyl 2-fluoro-2-(trifluoromethyl)nonanoate, 2-fluoro-2-(trifluoromethyl)nonanoate, Pentyl fluoromethyl)nonanoate, 2-fluoro-2
-Methyl (trifluoromethyl)decanoate, ethyl 2-fluoro-2-(trifluoromethyl)decanoate, 2-
Isopropyl fluoro-2-(trifluoromethyl)decanoate, Pentyl 2-fluoro-2-(trifluoromethyl)decanoate, Methyl 2-fluoro-2-(trifluoromethyl)undecanoate, 2-Fluoro-2-( Ethyl trifluoromethyl)undecanoate, 2-fluoro-
Isopropyl 2-(trifluoromethyl)undecanoate, Pentyl 2-fluoro-2-(trifluoromethyl)undecanoate, Methyl 2-fluoro-2-(trifluoromethyl)dodecanoate, 2-fluoro-2-(trifluoromethyl) ethyl)dodecanoate, 2-fluoro-2-(
isopropyl trifluoromethyl)dodecanoate, pentyl 2-fluoro-2-(trifluoromethyl)dodecanoate, 2-fluoro-2-(trifluoromethyl)-1-
Hexanol, 2-fluoro-2-(trifluoromethyl)-1-heptatool, 2-fluoro-2-(trifluoromethyl)-1-octatool, 2-fluoro-2
-(trifluoromethyl)-1-nonanol, 2-fluoro-2-(trifluoromethyl)-1-decanol,
Examples include 2-fluoro-2-(trifluoromethyl)-1-undecanol and 2-fluoro-2-(trifluoromethyl)-1-dodecanol.

In the above compound, the carbon at the 2-position is an asymmetric carbon, and the present invention also includes an optically active substance that is endowed with optical activity centered on this carbon. This optically active substance is particularly
It can be used as an intermediate raw material for pharmaceuticals and agricultural chemicals with excellent physiological activity, as well as ferroelectric liquid crystal compounds.

Next, the physical and chemical properties of typical compounds represented by the above general formula (1) will be described.

(S)-(-)-2-fluoro-2-(trifluoromethyl)hexanoic acid Boiling point 285-92°C 715 mmHg ■'HNMR (CDCI, ): 1.00 (3H, b
t), 1.1-1.7 (4H.

-), 1.8 to 2.6 (2H, m), 10.10 (O)
l, b) ■”F NMR (CDCI, external standard CF,
CO21 (): -0,25 (3F, d, 5.6Hz
), 96.0 (IF, m) ■13CNMR (CDCI
3): 13.3 (C6), 22.2 (C5), 24
゜0 (C4, d, JcF=2.0Hz), 30.5 (C
3, d, Jc, = 20.9 Hz), 94.1 (C2, d
q, JcF=119.4Hz.

31.2 FIz), 121-4 (CF 3 t d
q t J cl ” 28-7 HZ *284.3
Hz), 169.0 (C1, d, JeF: 26.5H
z)■(a): Knee 4.42° (C1,7-CHCl
3) (R)-(+)-2-fluoro-2-(trifluoromethyl)decanoic acid ■'HNMR (CDC1,): 0.90 (3)! ,
bt), 1.1-1.7 (12H, +a), 1.8-2
．． 6 (2tl, ++), 9.35 (OH, b) ■”F
NMR (CDCI, external standard CF, CO□H):
-0,40 (3F, d, 5.6Hz), ÷96 (I
F, m) ■ α♂: 100.111° (neat, Q
= 1.0) (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoyl chloride Boiling point: 40-60°C/150nnHg ■”HNMR (
CDCI, ): 0.95 (3) 1. t, 7.1Hz
), 1.1-1.8 (4H, a+), 2.0-2.7
(2H, m)■”F NMR (CDCI, external standard C
F, Co2H) : -1,17(3F,d,5.6H
z), 83.0 (IF, m) ■13CNMR (CDCI
, ): 13.6 (C6), 22.6 (C5), 24
゜3 (C4, d, J (7 = 2.6) 1z), 31.5 (
C3, d, JcF=21°0)1z), 97.5(C2
, dq, JcF=210.8Hz, 31.2Hz)12
1.4 (CFa, dq, JcF=29.3) 1z, 2
85.311z), 170.4 (CI, d, JcF=3
3.9Hz) ■ a: Knee 1.44° (neat,
Q = 1.0 am) (S)-(+)-2-fluoro-
2-(trifluoromethyl)decanoyl: chloride Boiling point = 62℃/3w+Hg ■'HNMR (CDCI, ): 0.90 (3H, 6
t), 1.1-1.8 (14H9 meals), 2.0-2
．． 7 (2H, m) ■”F NMR (CDCI, external standard CF, Co2H): -1,3 (3F, d, 5.6
)1z), ÷83(IF, m)■ a@knee 0.7
70” (neat, 12=1.0an) (S)
-(-)-2-fluoro-2-(trifluoromethyl)
Methyl hexanoate ■Boiling point = 100-140℃ (kugelol) ■"HNM
R (CDCI, ): 0.93 (3) 1. t, 7.0
Hz), 1.1-1.6 (4H, m), 1.9-2.3
(2H, m), 3.90 (3H, s) ■1″F NM
R (CDCI, , external standard CF, Co, H): -
0,25 (3F, d, 5.6Hz), 96 (IF, s)
■13CNMR (CDCI, ): 13,7 (C6)
, 22.4 (C5), 24°3 (C4, d, Jcr=2
．． 4Hz), 30.9 (C3, d, JcF=21°4H
z), 53.6 (OCR,), 94.3 (C2, dQ*
Jcr=201.6Hz, 31.6Hz), 122.0
(CF, , dq, Jc, = 28°6Hz, 286.
0Hz), 165.7 (CI, d, J, = 25.0) 1
z) ■[a]ff: -6,5' (co, 3.C)I
CI-)(S)-(÷)-2-fluoro-2-(trifluoromethyl)=1-hexanol ■ Boiling point = 150-155°C ■ "HNMR (CDC13): 0-94 (3H-
t-6,9Hz), 1.3 to 1.6 (4) 1. m), 1
．． 8-2.1 (28,+a), 2.69 (OH.

S), 3.88 (2H, d, 18.0) 1z) ■19
F NMR (CDCI, external standard CF, Co2H)
: 0.05 (3F, d, 5.6Hz), 97 (
IF, m)■”CNMR (CDCI,): 13.8
(C6), 23.1 (C5), 24°4 (C4, d,
Jcp=5.5Hz), 29.5(C3,d, Jcp=
21°1Hz), 61.5 (CI, d, Jcy=25
．． 5) 1z), 95.3 (C2, dq, JcF=185
．． 3Hz, 28.8Hz), 124.3(CF,.

dq, Jcr: 28.6Hz, 286.1Hz) ■
a unit: -0,050' (neat, Q
=1.0am)(R)-(-)-2-fluoro-2-(
Trifluoromethyl)-1-decanol ■ Boiling point: 88°C/3+nmHg ■18 NMR (CDCI, ): 0.90 (3) 1
．． bt), 1.3-2.3 (15H, m), 3.88 (
2f(,d, 18Hz)0”F NMR (CDCI,
, external standard mcF, Co2)1): +0.10(3
F, d, 5.6 Hz), +98 (IF, m) ■ a-base knee 1.94° (c5.7. C) IcI3) Above formula (I
The compound represented by ) can be synthesized using the fluorine-containing carboxylic acid represented by the above formula (II) as a starting material.

To explain further, the fluorine-containing carboxylic acid represented by the above formula (m) can be obtained by hydrogenating the compound represented by the above formula (II). By performing this hydrogenation reaction catalytically using a hydrogenation catalyst, hydrogenation can be carried out without racemization even when an optically active substance is used as a raw material, which is preferable, that is, the above formula (II) The compound represented by is dissolved in an organic solvent, palladium-supported activated carbon, platinum oxide, etc. are added as a catalyst, and the mixture is heated to zero under a hydrogen atmosphere.
Stirring is preferably carried out within the range from °C to the boiling point of the solvent. Ether is used as the reaction solvent.

Pentane, hexane, ethanol, ethyl acetate, etc. can be used, but due to ease of separation from the product, etc.
Ether is preferable, and the hydrogen pressure is preferably normal pressure to slightly pressurized in terms of reaction operation.

The fluorine-containing carboxylic acid chloride represented by the above formula (IV) is obtained by reacting the compound represented by the above formula (III) with a chlorinating agent such as phthalyl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, etc. Fractional distillation makes it possible to obtain an optically active substance without racemization even when the optically active substance is used as a raw material.

In this reaction, it is preferable to use 1 to 10 equivalents of the chlorinating agent, and the reaction temperature may be appropriately selected within the range of 20 to 110°C. As a reaction solvent, benzene, toluene,
Chloroform or the like can be used, but an excess of the chlorinating agent may also be used as a solvent. In particular, it is preferred to use phthalyl chloride as the chlorinating agent and solvent.

The fluorine-containing carboxylic acid compound represented by the above formula (V) can be obtained without racemization even when an optically active substance is used as a raw material. In this case, the reaction solvent is dichloromethane or chloroform.

Pyridine or the like can be used, but no solvent may be used.

The reaction temperature can be appropriately selected within the range of -10 to 50°C. Esters with lower alcohols are represented by the above formula (II
Although the compound represented by I) can be obtained by reacting with a large excess of alcohol in the presence of an acid catalyst, it becomes difficult to isolate the highly volatile product.

The fluorine-containing alcohol represented by the above formula (VI) can be any of the compounds represented by the above formulas (III) to (V),
Even when an optically active substance is used as a raw material by reducing with 1 to 20 equivalents of metal hydride.

Obtained without racemization. in this case.

Metal hydrides include lithium aluminum hydride,
Diisobutylaluminum hydride.

Sodium borohydride, etc. can be used, and ether, dimethoxyethane, tetrahydrofuran, toluene, etc. are preferably used as the reaction solvent. In particular, it is preferable to use lithium aluminum hydride as the reducing agent and conduct the reaction in an ether solvent. The temperature may be appropriately selected from a range of -10°C to the boiling point of the solvent.

ILfl (Example 1) (S)-(+)-2-fluoro-2-(trifluoromethyl)-4-hexenoic acid 19. Og ether room
Dissolve in Q, add 3g of 5% palladium-supported activated carbon,
The mixture was vigorously stirred at 0° C. for 5 hours and then at room temperature for 15 hours under a hydrogen atmosphere at atmospheric pressure. Filter through Celite, remove the solvent under reduced pressure, and (s)-(-)-2-fluoro-2-(
trifluoromethyl)hexanoic acid as the crude product 19
．． I got 0m. A portion of this product was distilled under reduced pressure, and its physical properties were measured. As a result, it had the physical and chemical properties shown above.

(Example 2) (S)-(-)-2-fluoro-2-(trifluoromethyl)hexanoic acid 8.0 g and phthalyl chloride 24.
After stirring at 80°C for 24 hours, distillation was carried out under reduced pressure to obtain (R)-(-)-2 having the above-mentioned physical and chemical properties.
8.2 g of -fluoro-2-(trifluoromethyl)hexanoyl cochloride was obtained.

(Reference example) (S)-(-)-1-phenylethylamine 0.05
g was dissolved in pyridine 2-a to obtain (R) in Example 2.
-(-)-2-fluoro-2-(trifluoromethyl)
Add 0.05g of hexanoyl cochloride and
The reaction mixture, which was stirred for 1 minute, was diluted with ether and washed sequentially with 1N hydrochloric acid, aqueous sodium bicarbonate solution, and brine. After drying with magnesium sulfate, it was concentrated and analyzed by liquid chromatography. As a result, the optical purity of the compound obtained in Example 2 was 93% ea.

(Example 3) 0.17 g of (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoyl cochloride was added to 0.5 ■ a of methanol, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was distilled using Kugelol at normal pressure to obtain 0.15 g of methyl (S)-(-)-2-fluoro-2-(trifluoromethino IX hexanoate) having the above-mentioned physicochemical properties.

(Example 4) 7.30 g of (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoylcochloride was dissolved in dry ether 801111, and lithium aluminum hydride (LiAIHJ 0 , 83 g gradually added.

The mixture was stirred for 30 minutes. Gradually add 1N hydrochloric acid while cooling with water.
Extracted with ether. The organic layer was dried over magnesium sulfate, the solvent was distilled off under normal pressure, and it was distilled to obtain (S)-(÷)-2-fluoro-2-(trifluoromethyl)-1 having the above-mentioned physical and chemical properties. - 4.6 g of hexanol was obtained.

(Example 5) 0.15 g of methyl (S)-(-)-2-fluoro-2-(trifluoromethyl)hexanoate was dissolved in 2 mΩ of ether, and 0.0 g of lithium aluminum hydride was dissolved under water cooling.
6 g was added. After stirring at room temperature for 40 minutes.

Dilute hydrochloric acid was added, and the organic layer was subjected to gas chromatography (SE
-30.2 m, 50°C). Comparison with the product obtained in Example 4 revealed that 2-fluoro-2-(trifluoromethyl)-1-hexanol was produced quantitatively.

(Example 6) (R)-2-fluoro-2-(trifluoromethyl)-
1.0 g (39 gaol) of 4-decene a was dissolved in ether 1201In, and 5% palladium-supported activated carbon 3
g and stirred vigorously for 96 hours under a hydrogen atmosphere at atmospheric pressure. After filtering through Celite, the solvent was distilled off under reduced pressure, and 8.5 g of (R)-(+)-2-fluoro-2-(trifluoromethyl)decanoic acid having the above-mentioned physical and chemical properties was obtained (yield: 85%). I got it.

(Example 7) 2.0 g (7.7 mn+ol) of (R)-(+)-2-fluoro-2-(trifluoromethyl)decanoic acid was cooled on ice, and 1.8 g (8.5 mmol) of phosphorus pentoxide was added. ), stirred under water cooling for 30 minutes and at room temperature for 8 hours, and then distilled under reduced pressure to obtain (R)-(-)-2-fluoro-2-(trifluoromethyl)decanoyl chloride having the above-mentioned physical and chemical properties. 1.4 g (yield 66%) was obtained.

(Example 8) (S)-(+)-2-fluoro-2-(trifluoromethyl)decanoyl:chloride 1.4 g (5.1 mmo
1) was dissolved in dry ether 10++i and lithium aluminum hydride (LiAlH4) 0,1 was added under water cooling.
4 g (3-5 aemol) was gradually added and stirred for 3 hours. 1N hydrochloric acid was gradually added while cooling with water, and the mixture was extracted with ether. This ether layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure, and (R)-(-)-2-fluoro-2-(
0.69 g (trifluoromethyl)-1-decanol (
A yield of 56% was obtained.

The novel compound of the present invention is useful as a raw material for medical products, agricultural chemicals, functional materials such as liquid crystal compounds, and the method of the present invention for producing this compound can be carried out under mild conditions. Moreover, it can be easily carried out, and in particular, it has the special effect of making it possible to obtain an optically active form of one of the compounds of the present invention very easily.

Claims (7)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents an alkyl group, R^2 represents a fluoroalkyl group, Y is a carboxyl group, a chloro A fluorine-containing compound represented by a formyl group, an alkoxycarbonyl group, or a hydroxymethyl group. (2) A fluorine-containing compound, wherein the compound represented by the general formula (I) according to claim (1) is an optically active compound. (3) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 represents an alkyl group and R^2 represents a fluoroalkyl group) Fluorine-containing carbon dioxide General formula (III) characterized by hydrogenation of acids ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R^1 represents an alkyl group, and R^2 represents a fluoroalkyl group. ) A method for producing fluorine-containing carboxylic acids. (4) General formula (IV) characterized by reacting a fluorine-containing carboxylic acid represented by general formula (III) according to claim (3) with a chlorinating agent ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(IV) A method for producing fluorine-containing carboxylic acid chlorides represented by the formula (wherein R^1 represents an alkyl group and R^2 represents a fluoroalkyl group). (5) General formula (V) characterized by reacting a fluorine-containing carboxylic acid chloride represented by general formula (IV) according to claim (4) with an alcohol ▲Mathematical formula, chemical formula, table, etc. ▼(V) (In the formula, R^1 represents an alkyl group and R^2 represents a fluoroalkyl group) A method for producing a fluorine-containing carboxylic acid ester. (6) General formula (VI) ▲Mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the formula, R^1 represents an alkyl group, R^2 represents a fluoroalkyl group, Y' represents a carboxyl group, (represents a chloroformyl group or an alkoxycarbonyl group)
General formula (VII) characterized by reacting a fluorine-containing compound represented by with a metal hydride ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VII) (In the formula, R^1 represents an alkyl group, R^2 represents a fluoroalkyl group) A method for producing a fluorine-containing alcohol. (7) The general formula ( I
) A method for producing an optically active form of a fluorine-containing compound.