JPH10287596A - Production of fluorine-containing compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply obtain a fluorine-containing compound by reacting an α- perfluoroalkylated alcohol with a Broensted acid in an aprotic solvent. SOLUTION: A perfluoroalkylsulfonic acid ester or perfluoroarylsulfonic acid ester of an α-perfluoroalkylated alcohol of the formula R<1> R<2> Rf<1> C-OSO2 Rf<2> [R<1> and R<2> are each H, an alkyl, an aromatic, an aralkyl, an alkenyl or an alkynyl or R<1> and R<2> together may form a ring; Rf<1> and Rf<2> are each a perfluoroalkyl or a perfluoro aromatic] is reacted with a Broensted acid of the formula M<x+> m Q<y-> n [M<x+> is a metal ion or polyatomic cation; Q<y-> is a conjugated base of the Broensted acid QHy ; (x), (y), (m) and (n) are each an integer satisfying the formula xm=yn] in a solvent such as DMF at -100 to 200 deg.C to provide the objective fluorine-containing compound of the formula (R<1> R<2> Rf<1> C-)y Q (Q is a Broensted acid residue). The compound can be utilized as a synthetic intermediate for medicines and agrochemicals such as aticancer agents and enzyme inhibitors and functional materials such as ferroelectric liquid crystals.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a fluorine-containing compound, which is useful as a pharmaceutical or agricultural chemical such as an anticancer agent or an enzyme inhibitor, or a synthetic intermediate for a functional material such as a ferroelectric liquid crystal.

[0002]

2. Description of the Related Art Many compounds having a fluorine-containing atomic group such as a perfluoroalkyl group in a molecule are known to exhibit specific physiological activities and physical properties. Has attracted attention as a functional material such as a liquid crystal. Many methods have been reported for introducing a perfluoroalkyl group such as a trifluoromethyl group into an organic compound. Above all, a method of reacting a perfluoroalkyl anion equivalent such as a perfluoroalkylsilane with a carbonyl compound to obtain an alcohol derivative having a perfluoroalkyl group at the α-position uses a relatively inexpensive reagent under mild conditions. Since the reaction proceeds in good yield, it can be said that this is one of the excellent perfluoroalkyl group introduction methods (Kenji Uneyama,
Coupling, 49, 7, 612 (1991): R. Krishnamurti et al., J.
Org. Chem., 56, 984 (1991): JP-A-7-118188). Recently, an optically active fluorinated epoxide has been expected as a building block of an optically active fluorinated compound, which can be led to an optically active α-perfluoroalkylated alcohol derivative by opening the ring (Japanese Patent Laid-Open Publication No. -174735: C. Bussche-Hunnefeld et al., Chem.
Ber., 125, 2795 (1992): JP-A-7-165750).

[0003] However, it is known that α-perfluoroalkylated alcohol derivatives obtained by these methods are different from ordinary alcohols in that conversion of hydroxyl functional groups hardly proceeds due to the strong electron-withdrawing property of perfluoroalkyl groups. ing. For example, in the case of ordinary alcohols, the hydroxyl group is converted into a sulfonic ester such as p-toluenesulfonic acid having a high elimination ability, and then reacted with various nucleophiles to convert the hydroxyl group into a functional group or to form a carbon-carbon bond. Can be produced, which is a very common technique in synthetic organic chemistry (Ed. By DN Jones, Comprehensive Orga
nic Chemistry, Vol. 3, p341, Pergamon Press (1979)
: T. Sato, J. Otera, Synlett, 336 (1995): T. Sat
o, J. Otera, J. Org. Chem., 60, 2627 (1995)). However, sulfonic acid esters of α-perfluoroalkylated alcohols are very unlikely to undergo nucleophilic attack, and it has been difficult to obtain fluorine-containing compounds in which the sulfonyloxy group has been substituted with another atomic group. A slightly known example is the reaction of p-toluenesulfonic acid ester of α-trifluoromethylated alcohol with the sodium salt of thiophenol generated in the system to form the α-position of the trifluoromethyl group. Has been reported to introduce a phenylthio group (J.-
M. Vatele, Tetrahedron Lett., 42, 4443 (1986)), p.
-Toluenesulfonic acid esters are known to react only with sulfur nucleophiles and selenium nucleophiles (Tomoya Kitazume et al., Fluorine Chemistry, p128, Kodansha Scientific
(1993)), a method applicable to various nucleophiles other than sulfur nucleophiles and selenium nucleophiles was not known. In addition, an example has been reported in which p-toluenesulfonic acid ester and trifluoromethanesulfonic acid ester of α-trifluoromethylated alcohol are converted to esters or ethers by solvolysis in a protic solvent. (AD Allen et al., J. Am. Chem. Soc., 10
5, 2343 (1983): AD Allen et al., J. Am. Chem. Soc.,
115, 10091 (1993): AD Allen et al., J. Am. Chem. So
c., 117, 8974 (1995)), this reaction was limited to a protic solvent, and a highly versatile substitution reaction in an aprotic solvent was not known. As described above, the α-perfluoroalkylated alcohol derivative is a compound whose functional group conversion is very difficult, which significantly limits the applicable range of the above-mentioned perfluoroalkyl group introduction reaction, and poses a great obstacle to the development of this field. Had become. The present inventors have conducted studies to remove this obstacle, and as a result, by coexisting a basic substance such as a fluoride salt, α-
We have found that the nucleophilic substitution of perfluoroalkylated alcohol sulfonates proceeds stereoselectively (Toshiki Hagiwara, Katsumi Tanaka, Takamasa Fuchigami, Proceedings of the 70th Annual Meeting of the Chemical Society of Japan, 4H336). However, this is an excellent method that can be applied to various sulfonic acid esters, but some nucleophiles include low-boiling liquids and gases, those with pungent odors and odors, and the basic substance used is moisture absorption. Since there are many operational difficulties such as those having high properties, it has been desired to develop a more convenient functional group conversion reaction of an α-perfluoroalkylated alcohol derivative.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a highly versatile method for inexpensively, simply and safely achieving a functional group conversion reaction of an α-perfluoroalkylated alcohol derivative, which has been considered difficult. Is to do.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned disadvantages of the prior art, and as a result, have found that α-perfluoroalkylated alcohols can be converted to perfluoroalkylsulfonic acid esters or perfluoroarylsulfonic acid. It has been found that the conversion of α-perfluoroalkylated alcohol derivatives into functional groups can be achieved at low cost, simply and safely by conducting the reaction in an aprotic solvent using an ester and a salt of Bronsted acid as a nucleophile. Thus, the present invention has been completed.

That is, the present invention relates to a compound represented by the general formula: R ¹ R ² R _f ¹ C-OSO ₂ R _f ² (I) wherein R ¹ and R ² each independently have a hydrogen atom or a substituent. Represents an alkyl group, an aromatic group, an aralkyl group, an alkenyl group or an alkynyl group which may be substituted.
Further, R ¹ and R ² may form a ring together with the carbon atom to which they are bonded.
Further, each represents R _f ¹ and R _f ² are independently perfluoroalkyl group or a perfluoro aromatic group. And a perfluoroalkylsulfonic acid ester or a perfluoroarylsulfonic acid ester of an α-perfluoroalkylated alcohol represented by the general formula: M ^{x +} _m Q ^y- _n (II) (where M ^{x +} is a metal ion or a polyatomic cation) Q ^y- represents a conjugate base of Bronsted acid QH _y .
x, y, m, and n are any positive integers that satisfy the relational expression xm = yn. ) And a salt of a Bronsted acid,
A general formula (R ¹ R ² R _f ¹ C-) _y Q (III), wherein R ¹ , R ² , R _f ¹ and y are as defined above. Is the same.
Q is the above Brönsted acid residue. ),
The present invention relates to a method for producing a fluorine-containing compound.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The above general formula (I) in the present invention
And the alkyl group for R ¹ and R ² in formula (III) is an optionally branched alkyl group or cycloalkyl group having 1 to 20 carbon atoms which may have a substituent. The aromatic group represents an aromatic hydrocarbon group and a heterocyclic aromatic group, and may include a phenyl group, a naphthyl group, an anthryl group, an anthryl group, a pyridyl group, a furyl group, a thienyl group, which may have a substituent. Can be illustrated. Examples of the aralkyl group include a benzyl group, a naphthylmethyl group, a furfuryl group, and an α-phenethyl group which may have a substituent. As the alkenyl group, a vinyl group which may have a substituent, β-styryl group, 1-propenyl group, 1-butenyl group, 1-hexenyl group, 1-octenyl group, 1-decenyl group, 1-cyclohexenyl Groups, allyl group, methallyl group, cinnamyl group, 2-butenyl group, 2-hexenyl group, 2-octenyl group, 2-decenyl group, 2-cyclohexenyl group and the like. Examples of the alkynyl group include an optionally substituted ethynyl group, a phenylethynyl group, a 2-propynyl group, and the like. When R ¹ and R ² are combined with the atom to which they are bonded to form a ring, a tetramethylene group, a pentamethylene group, a hexamethylene group, an o-xylylene group and the like can be exemplified. . In any of the above groups, the substituent may be a branched or branched alkyl group having 1 to 10 carbon atoms, an aromatic group, a halogen atom, a hydroxyl group, an alkoxy group, an amino group, a nitro group, an azide group, an acyl group. Group, formyl group, carboxyl group, cyano group, thiol group, alkylthio group, phosphino group, silyl group and the like.

The general formula (I) and the general formula (III)
R _f ¹ and R _f ² in the number of 1 to 20 carbon, it may even have branched perfluoroalkyl group, a perfluorocycloalkyl group or a perfluoro aromatic group, such as trifluoromethyl group, pentafluoroethyl Groups, heptafluoropropyl group, nonafluorobutyl group, heptadecafluorooctyl group, heptafluoroisopropyl group, undecafluorocyclohexyl group, pentafluorophenyl group and the like.

M ^{x +} in the general formula (II) is a metal ion or a polyatomic cation, for example, lithium, sodium, potassium, cesium, magnesium, calcium, barium, scandium, titanium (III), titanium
(IV), vanadium, chromium, manganese, iron (II), iron (II
I), cobalt, nickel, copper (I), copper (II), silver, zinc,
Cadmium, mercury (I), mercury (II), boron, aluminum, silicon, germanium, tin (II), tin (IV), lead,
Antimony, bismuth, ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, benzyltrimethylammonium, tetramethylphosphonium, tetraethylphosphonium, tetrabutylphosphonium, benzyltriphenylphosphonium, triethyloxonium, trimethylsulfonium, diphenyliodonium ions, etc. Can be exemplified.

In the general formula (II), Q ^y- is a conjugate base of Bronsted acid QH _y and includes, for example, fluoride, chloride, bromide, iodide, hydride, oxide, sulfide,
Nitride, azide, hydroxide, hydrosulfide, amide, cyanide, cyanic acid, isocyanic acid, thiocyanic acid, isothiocyanic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, hydrogen sulfate, carbonic acid, hydrogen carbonate, chloric acid , Perchloric acid, bromic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, boric acid, methoxide, ethoxide, t-butoxide, phenoxide, thiomethoxide, thioethoxide, thiophenoxide, formic acid,
Acetic acid, propionic acid, butyric acid, stearic acid, oxalic acid,
Hydrogen oxalate, malonic acid, hydrogen malonate, succinic acid, hydrogen succinate, adipic acid, hydrogen adipate, acrylic acid, methacrylic acid, oleic acid, maleic acid, hydrogen maleate, chloroformic acid, chloroacetic acid, trifluoroacetic acid ,
Cyclohexanecarboxylic acid, pivalic acid, benzoic acid, toluic acid, naphthoic acid, phthalic acid, hydrogen phthalate, cinnamic acid, nicotinic acid, thiophenecarboxylic acid, S-thioacetic acid,
Dithioacetic acid, S-thiobenzoic acid, dithiobenzoic acid, thiocarbonic acid, trithiocarbonic acid, xanthogenic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, phenylphosphonic acid, phthalimide, diphenylphosphinic acid, triphenylmethanide , Bis (ethoxycarbonyl) methanide, acetyl (ethoxycarbonyl) methanide, diacetylmethanide, acetylcyanomethanide, dicyanomethanide, (ethoxycarbonyl) (diethoxyphosphoryl) methanide, acetylmethanide, benzoylmethanide, 2-oxocyclohexanide And 2-oxocyclopentanide, acetylide, 2-phenylethinide, nitromethanide, cyclopentadienide, methylsulfinylmethanide, and the like.

In the present invention, it is essential that the reaction is carried out in an aprotic solvent. As aprotic solvents, hexane, benzene, toluene, xylene, acetone, methyl ethyl ketone, ethyl acetate, diethyl carbonate, dichloromethane, chloroform, carbon tetrachloride, ether, tetrahydrofuran (THF), acetonitrile, propionitrile, N, N- Dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidinone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), dimethylacetamide
(DMAc), hexamethyltriamide phosphate (HMPA), tetramethylurea (TMU), tetraethylurea, N, N'-dimethylpropyleneurea (DMPU) and the like. Also,
The solvent may be a single kind of aprotic solvent or a mixture of two or more kinds of aprotic solvents in any ratio.

A method for synthesizing a perfluoroalkylsulfonic acid ester or a perfluoroarylsulfonic acid ester of an α-perfluoroalkylated alcohol represented by the aforementioned general formula (I) is known (RK Crossland, KL).
Servis, J. Org. Chem., 35, 3195 (1970))
It can be easily synthesized by the same method as that of a conventionally known perfluoroalkylsulfonic acid ester of a hydrocarbon alcohol or a perfluoroarylsulfonic acid ester. That is, an α-perfluoroalkylated alcohol is reacted with a corresponding perfluoroalkylsulfonic acid or an acid chloride or acid anhydride of perfluoroarylsulfonic acid in the presence of a base such as pyridinetriethylamine with dichloromethane, carbon tetrachloride, ether or the like. The reaction may be performed in a solvent that does not participate in the reaction.

In the method of the present invention, for the synthesis of an optically active substance, an optically active substance can be used as a perfluoroalkylsulfonic acid ester or a perfluoroarylsulfonic acid ester as a substrate. In this case, the reaction proceeds stereospecifically, and a product having an inverted configuration can be obtained without substantially impairing the optical purity of the substrate.

Various salts of the Brönsted acid represented by the above general formula (II) are known, and these can be purchased from commercial products and synthesized by well-known methods. . Alternatively, they may be synthesized in a reaction system by a well-known method and used directly in the reaction without isolation. The amount of the salt to be used is arbitrary, but is preferably at least 1 equivalent to the substrate perfluoroalkylsulfonic acid ester or perfluoroarylsulfonic acid ester from the viewpoint of yield.

The reaction temperature can be appropriately selected from the range of -100 ° C. to 200 ° C.
A range of 50 ° C. is preferred.

[0016]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Embodiment 1

[0018]

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In a test tube with a cap, add potassium chloride (0.048
g, 0.64 mmol) and replace with argon.
After adding F (1.0 ml), the temperature was raised to 80 ° C. 1- (trifluoromethyl) heptyl trifluoromethanesulfonate
(0.158 g, 0.50 mmol) and added under an argon atmosphere.
The reaction was performed at a temperature of 5 ° C. for 5 hours. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured.
It was revealed that the desired 2-chloro-1,1,1-trifluorooctane had been produced at a conversion rate of 00% and a conversion yield of 43.1%. The ether solution was dried over anhydrous sodium sulfate, and the solvent was distilled off by heating under reduced pressure to obtain a crude product. From this, the target product was isolated by preparative gas chromatography and subjected to various instrumental analysis. 2-chloro-1,1,1-trifluorooctane ¹ H-NMR (CDCl ₃ , TMS): δ = 0.86-0.93 (m, 3H), 1.26-1.5
2 (m, 7H), 1.56-2.09 (m, 3H), 4.06 (dqd, J = 10.2 Hz, 6.
7 F, 3.4 Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -75.29 (d, J = 6.7 Hz). MS (EI): m / e = 204 (M ⁺ ), 202 (M ⁺ ).

Embodiment 2

[0021]

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Cesium chloride (0.102) was placed in a test tube with a cap.
g, 0.60 mmol) and replace with argon.
After adding F (1.0 ml), the temperature was raised to 80 ° C. 1- (trifluoromethyl) heptyl trifluoromethanesulfonate
(0.158 g, 0.50 mmol) and added under an argon atmosphere.
The reaction was performed at a temperature of 5 ° C. for 5 hours. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured.
It became clear that the desired 2-chloro-1,1,1-trifluorooctane was produced at a conversion rate of 00% and a conversion yield of 51.0%.

Embodiment 3

[0024]

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Potassium bromide (0.080
g, 0.67 mmol) and replace with argon.
After adding F (1.0 ml), the temperature was raised to 80 ° C. 1- (trifluoromethyl) heptyl trifluoromethanesulfonate
(0.158 g, 0.50 mmol) and added under an argon atmosphere.
The reaction was performed at a temperature of 5 ° C. for 5 hours. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured.
It was clear that the desired 2-bromo-1,1,1-trifluorooctane had been produced at a conversion rate of 00% and a conversion yield of 73.6%. The ether solution was dried over anhydrous sodium sulfate, and the solvent was distilled off by heating under reduced pressure to obtain a crude product. From this, the target product was isolated by preparative gas chromatography and subjected to various instrumental analysis. 2-bromo-1,1,1-trifluorooctane ¹ H-NMR (CDCl ₃ , TMS): δ = 0.86-0.93 (m, 3H), 1.17-1.4
9 (m, 7H), 1.54-1.73 (m, 1H), 1.76-2.15 (m, 2H), 4.07
(dqd, J = 10.5 Hz, 7.1 Hz, 3.5 Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -72.79 (d, J = 7.1 Hz) .MS (EI): m / e = 248 (M ⁺ ), 246 (M ⁺ ).

Embodiment 4

[0027]

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A test tube with a cap was charged with potassium thiocyanate (0.118 g, 1.22 mmol) and purged with argon. DMF (2.0 ml) was added as a solvent, and the temperature was raised to 80 ° C. 1- (trifluoromethyl) trifluoromethanesulfonic acid
Heptyl (0.316 g, 1.00 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. The target thiocyanic acid was obtained at a conversion of 100% and a conversion yield of 47.0%.
It became clear that 1- (trifluoromethyl) heptyl was formed. Preparative thin-layer chromatography (silica gel, ethyl acetate: hexane = 1:
The target product was isolated by 5) and subjected to various instrumental analysis. 1- (trifluoromethyl) heptyl thiocyanate ¹ H-NMR (CDCl ₃ , TMS): δ = 0.89-0.92 (m, 3H), 1.28-1.5
3 (m, 7H), 1.63-1.74 (m, 1H), 1.81 (dddd, J = 14.7 Hz, 1
0.7 Hz, 9.7 Hz, 4.6 Hz, 1H), 2.08 (dddd, J = 14.7 Hz,
10.1 Hz, 6.2 Hz, 3.9 Hz, 1H), 3.43 (dqd, J = 10.7 H
. z, 7.4 Hz, 3.9 Hz , 1H) 13 C-NMR (CDCl 3, TMS): δ = 13.90 (CH 3), 22.40 (CH 2), 2
_{6.13 (CH 2), 27.64 (} CH 2), 28.30 (CH 2), 31.26 (CH 2), 50.0
8 (q, ² J _CF = 23.0 Hz, CH), 108.17 (-SCN), 124.84 (q, ¹ J
_{.. CF = 208.1 Hz, CF} 3) 19 F-NMR (CDCl 3, CFCl 3): δ = -71.69 (d, J = 7.4 Hz) IR (neat): 3420, 2960, 2940, 2860, 2160 (- (SCN), 146
0, 1260, 1170, 1130, 1110, 685 cm ^-1 . Anal .: Calcd. For C ₉ H ₁₄ F ₃ NS: C, 47.98; H, 6.26; N, 6.
22%. Found: C, 47.93; H, 6.38; N, 6.04%.

Embodiment 5

[0030]

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Sodium azide in test tube with cap
(0.078 g, 1.20 mmol), and the atmosphere was replaced with argon. DMF (2.0 ml) was added as a solvent, and the temperature was raised to 80 ° C. To this was added 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.314 g, 0.99 mmol), and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added as an internal standard substance to the ether layer, and ¹⁹ F-NMR was measured. As a result, the desired 2-azido-1 was obtained at a conversion of 100% and a conversion yield of 80.7%. , 1,
It became clear that 1-trifluorooctane was formed. The ether solution was dried over anhydrous sodium sulfate, and the solvent was distilled off by heating under reduced pressure to obtain a crude product. From this, the target product was isolated by preparative gas chromatography and subjected to various instrumental analysis. 2-azido-1,1,1-trifluorooctane ¹ H-NMR (CDCl ₃ , TMS): δ = 0.87-0.93 (m, 3H), 1.22-1.4
. 8 (m, 8H), 1.68-1.87 (m, 2H), 3.58-3.74 (m, 1H) 19 F-NMR (CDCl 3, CFCl 3): δ = -75.82 (d, J = 6.9 Hz). Anal .: Calcd. For C ₈ H ₁₄ F ₃ N ₃ : C, 45.92; H, 6.75; N, 2
0.09%. Found: C, 46.11; H, 6.77; N, 20.07%.

Embodiment 6-13

[0033]

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A variety of acetates (0.60 mmol for monovalent metal salts, 0.30 mmol for divalent metal salts) are placed in a test tube with a cap.
Was replaced with argon, DMF (1.0 ml) was added as a solvent, and the temperature was adjusted to 80 ° C. To this, 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.158 g, 0.5
0 mmol) and reacted at 80 ° C. for 5 hours under an argon atmosphere. The resulting reaction mixture was extracted with ether / water, it was measured GLC analysis and ^{1 9} F-NMR of the ether layer,
It became clear that the desired 1- (trifluoromethyl) heptyl acetate was formed. The product identification is 1,1,1-
The spectra were compared with those of a sample synthesized from trifluoro-2-octanol and acetyl chloride by an ordinary method. Table 1 shows the results of reactions performed on various acetates. Product yield was determined by GLC analysis using tridecane as an internal standard. Acid 1- (trifluoromethyl) heptyl _{^{1 H-NMR (CDCl 3,}} TMS): δ = 0.85-0.92 (m, 3H), 1.28-1.3
0 (m, 8H), 1.74-1.92 (m, 2H), 2.15 (s, 3H), 5.21-5.37
(m, 1H). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -77.76 (d, J = 6.8 Hz).

[0035]

[Table 1] Example Acetate (CH ₃ COOM) Conversion rate (%) Conversion yield (%) ────────────────────────── 6 CH ₃ COOLi 100 48.7 7 CH ₃ COONa 100 50.6 8 CH ₃ COOK 100 56.1 9 CH ₃ COOCs 100 57.0 10 (CH ₃ COO) ₂ Mg 66.6 42.9 11 (CH ₃ COO) ₂ Zn 47.8 29.8 12 CH ₃ COONH ₄ 100 32.6 13 CH ₃ COONBu ₄ 100 46.6 ──────────────── ──────────

Embodiment 14-16

[0037]

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Sodium benzoate in a test tube with a cap
(0.086 g, 0.60 mmol) and the atmosphere was replaced with argon, and the solvent (1.
0 ml) and the temperature was raised to 80 ° C. 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.15
8 g, 0.50 mmol) at 80 ° C under an argon atmosphere.
A time reaction was performed. The reaction mixture was extracted with ether / water, and GLC analysis and ¹⁹ F-NMR measurement of the ether layer revealed that the desired 1- (trifluoromethyl) heptyl benzoate had been formed. . Table 2 shows the results of the reaction using various solvents. Product yield was determined by GLC analysis using tridecane as an internal standard. 1- (trifluoromethyl) heptyl benzoate ¹ H-NMR (CDCl ₃ , TMS): δ = 0.86 (m, 3H), 1.26-1.43 (m,
8H), 1.83-1.94 (m, 2H), 5.56 (q, J = 6.7 Hz, 1H), 7.43-
7.66 (m, 3H), 8.06-8.12 (m, 2H) ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -77.52 (d, J = 6.7 Hz)

[0039]

[Table 2] 例 Example Solvent conversion (%) Conversion yield (%) ──── ──────────────────────── 14 N, N-dimethylformamide (DMF) 100 44.4 15 N-methylhydroxylicinone (NMP) 100 56.5 16 N, N -Cimethylimidasoricinone (DMI) 100 50.8-

Comparative Example 1

Sodium benzoate was placed in a test tube with a cap.
(0.086 g, 0.60 mmol), and the atmosphere was replaced with argon. DMF (1.0 ml) was added as a solvent, and the temperature was raised to 80 ° C. 1- (trifluoromethyl) heptyl methanesulfonate (0.131
g, 0.50 mmol) and reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured.
No formation of (trifluoromethyl) heptyl was observed

Comparative Example 2

In a test tube with a cap, benzoic acid (0.073 g,
0.60 mmol) was added and replaced with argon, and DMF (1.
0 ml) and the temperature was raised to 80 ° C. 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.15
8 g, 0.50 mmol) at 80 ° C under an argon atmosphere.
A time reaction was performed. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured.
No formation of (trifluoromethyl) heptyl was observed

Embodiment 17

[0045]

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A test tube with a cap was charged with sodium methoxide (0.034 g, 0.62 mmol) and the atmosphere was replaced with argon. DMF (1.0 ml) was added as a solvent, and the temperature was raised to 80 ° C. 1- (trifluoromethyl) trifluoromethanesulfonic acid
Heptyl (0.158 g, 0.50 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. As a result, the target 1,1,1 was obtained at a conversion of 100% and a conversion yield of 38.6%. It became clear that -trifluoro-2-methoxyoctane was formed. The product identification can be found in the reference (AE Greene
J. Am. Chem. Soc., 102, 7583 (1980)), a standard synthesized separately by reacting 1,1,1-trifluoro-2-octanol with methyl iodide in the presence of silver oxide. It was performed by comparing the spectrum with the product. 1,1,1-trifluoro-2-methoxyoctane ¹ H-NMR (CDCl ₃ , TMS): δ = 0.86-0.92 (m, 3H), 1.26-1.4
4 (m, 8H), 1.54-1.67 (m, 2H), 3.38-3.50 (m, 1H), 3.55
(s, 3H). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -77.36 (d, J = 6.6 Hz).

Embodiment 18

[0048]

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Into a test tube with a cap, potassium phthalimide (0.111 g, 0.60 mmol) was added, the atmosphere was replaced with argon, DMF (1.0 ml) was added as a solvent, and the temperature was raised to 80 ° C. 1- (trifluoromethyl) trifluoromethanesulfonic acid
Heptyl (0.158 g, 0.50 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. As a result, the target N-1001- was obtained at a conversion of 100% and a conversion yield of 47.0%. It became clear that (trifluoromethyl) heptyl diphthalimide was formed. N- ｛1- (trifluoromethyl) heptyl｝ phthalimide ¹ H-NMR (CDCl ₃ , TMS): δ = 0.85 (m, 3H), 1.15-1.39 (m,
8H), 1.86-2.02 (m, 1H), 2.52-2.61 (m, 1H), 4.73 (m, 1
H), 7.73-7.94 (m, 4H) ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -72.90 (d, J = 8.1 Hz) MS: m / z (rel. Int.) = 313 (M ⁺ , 100), 209 (49), 160 (4
1), 148 (69), 130 (64), 105 (47), 104 (27), 76 (23), 41
(twenty four)

Embodiment 19

[0051]

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Potassium thioacetate was placed in a test tube with a cap.
(0.069 g, 0.60 mmol), and the atmosphere was replaced with argon. After DMF (1.0 ml) was added as a solvent, the temperature was raised to 80 ° C. To this was added 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.158 g, 0.50 mmol), and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. The conversion ratio was 100% and the conversion yield was 95.7%. -
It became clear that (trifluoromethyl) heptyl was formed. The ether solution was dried over anhydrous sodium sulfate, and the solvent was distilled off by heating under reduced pressure to obtain a crude product.
From this, the target product was isolated by preparative thin-layer chromatography (silica gel, ethyl acetate: hexane = 1: 20).
It was subjected to various instrumental analysis. Thioacetic acid S-1- (trifluoromethyl) heptyl ¹ H-NMR (CDCl ₃ , TMS): δ = 0.85-0.91 (m, 3H), 1.17-1.4
3 (m, 8H), 1.51-1.70 (m, 1H), 1.84-1.98 (m, 1H), 2.41
(s, 3H), 4.09 (dqd, J = 10.1 Hz, 8.9 Hz, 3.9 Hz, 1
H). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -70.87 (d, J = 8.9 Hz) .IR (neat): 2940, 1715 (C = O), 1260, 1170, 1125, 1100,
620 cm ^-1 .

Embodiment 20

[0054]

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In a test tube with a cap, add sodium hydride (6
0% in paraffin, 0.024 g, 0.60 mmol) was added, and the atmosphere was replaced with argon.After DMF (1.0 ml) was added as a solvent, diethyl malonate (0.099 ml, 0.65 mmol) was added with stirring at room temperature.
Is reacted while generating gas, and diethyl sodiomalonate is formed to form a homogeneous solution. The mixture was stirred at room temperature for 1 hour. After the temperature was raised to 80 ° C., 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.158 g, 0.50 mmol) was added, and the mixture was heated under an argon atmosphere.
The reaction was performed at a temperature of 5 ° C. for 5 hours. The reaction mixture was treated with ether /
After extraction with water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. As a result, the desired {1- (trifluoromethyl) heptyl} was obtained at a conversion of 91.8% and a conversion yield of 30.6%. It became clear that diethyl malonate was formed. The ether solution was dried over anhydrous sodium sulfate, and the solvent was distilled off by heating under reduced pressure to obtain a crude product. From this, the target product was isolated by preparative thin-layer chromatography (silica gel, ethyl acetate: hexane = 1: 5) and subjected to various instrumental analysis. ｛1- (trifluoromethyl) heptyl｝ malonate diethyl ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -68.84 (d, J = 9.1 Hz). GC-MS (CI, isobutane): m / e = 327 [(M + H) ⁺ ]

Comparative Example 3

The reaction was attempted in methanol, which is a protic solvent. Metallic sodium (0.0
14 g, 0.60 mmol) and purge with argon.
(1.0 ml), gas was generated and sodium was dissolved to form a uniform sodium methoxide solution.To this, diethyl malonate (0.099 ml, 0.6
5 mmol) and stirred at room temperature for 1 hour to produce diethyl sodiomalonate. After the temperature was raised to 80 ° C., 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.158 g, 0.50 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard, and ¹⁹ F-NMR was measured. The formation of the desired diethyl {1- (trifluoromethyl) heptyl} malonate was confirmed. I was not able to admit.

Embodiment 21

[0059]

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In a test tube with a cap, add sodium benzoate
(0.144 g, 1.00 mmol), and the atmosphere was replaced with argon. After DMF (2.0 ml) was added as a solvent, optically active 1- (trifluoromethyl) heptyl (R) -trifluoromethanesulfonic acid (0.158 g) was added thereto. , 0.50 mmol), and reacted at room temperature for 16 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, and tridecane was added to the ether layer as an internal standard substance. GLC analysis was carried out. As a result, the target 1- (trifluoromethyl) heptyl benzoate had a conversion of 68.
It was found that the product was formed at a conversion yield of 83.4% and a conversion yield of 63.4%. After isolating the product by preparative thin-layer chromatography (silica gel, ethyl acetate: hexane = 1: 5), a high-performance liquid using an optically active column (Daicel CHIRALPAK AD, 2-propanol: hexane = 1: 400) The optical purity was measured by chromatography, and it was found that 1,1,1-trifluoro-2-octyl (S) -benzoate having an inverted configuration was produced at an enantiomeric excess of 96% or more. It was ok. The absolute configuration of the product is (R) -1,1,1
Determined by comparison with 1- (trifluoromethyl) heptyl (R) -benzoate synthesized from -trifluoro-2-octanol and benzoyl chloride by conventional methods.

Embodiment 22

[0062]

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In a test tube with a cap replaced with argon,
2,2-trifluoro-1-phenylethanol (0.088 g, 0.5
0 mmol), carbon tetrachloride (1.0 ml) and triethylamine
(0.101 g, 1.00 mmol) was added to 0 ° C., and trifluoromethanesulfonic anhydride (0.169 g, 0.
60 mmol) was slowly added dropwise. The red oily trifluoromethanesulfonic acid amine salt separated into the upper layer with the dropwise addition, and the mixture was stirred at 0 ° C. for 1 hour, and then the lower carbon tetrachloride layer was separated. To this was added DMF (1.0 ml), carbon tetrachloride was distilled off under reduced pressure, and 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate was added.
A DMF solution was prepared. In another test tube with a cap, potassium thioacetate (0.069 g, 0.60 mmol) was added, the atmosphere was replaced with argon, DMF (1.0 ml) was added as a solvent, and the trifluoromethanesulfonic acid 2,2,2- Trifluoro-1-
Add a phenylethyl DMF solution, and add
The reaction was performed at 0 ° C. for 5 hours. The reaction mixture was treated with ether /
After extraction with water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured.The conversion ratio was 100% and the conversion yield was 31.2% .The desired thioacetic acid S-2,2,2- It became clear that trifluoro-1-phenylethyl was formed. Thioacetic acid S-2,2,2-trifluoro-1-phenylethyl ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -68.84 (d, J = 9.2 Hz).

Embodiment 23

[0065]

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In a test tube with a cap, potassium thiocyanate (0.058 g, 0.60 mmol) and 2,2,2-trifluoro-1-phenylethyl pentafluorobenzenesulfonate (0.2
03 g, 0.50 mmol) and replace with argon.
DMF (1.0 ml) was added, and the reaction was carried out at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture is extracted with ether / water,
Benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured.The conversion ratio was 97.2% and the conversion yield was 27.0% .The desired thiocyanic acid 2,2,2-trifluoro-1 was obtained.
-It became clear that phenylethyl was formed. 2,2,2-trifluoro-1-phenylethyl thiocyanate ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -68.73 (d, J = 7.8 Hz).

Embodiment 24

[0068]

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Potassium thioacetate was placed in a test tube with a cap.
(0.137 g, 1.20 mmol), and the atmosphere was replaced with argon. DMF (2.0 ml) was added as a solvent, and the temperature was raised to 80 ° C. To this was added 2-phenyl-1- (trifluoromethyl) ethyl trifluoromethanesulfonate (0.322 g, 1.00 mmol), and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. The target thioacetic acid was obtained at a conversion of 100% and a conversion yield of 45.5%.
It became clear that S-2-phenyl-1- (trifluoromethyl) ethyl was formed. S-2-phenyl-1- (trifluoromethyl) ethyl thioacetate ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -70.60 (d, J = 8.5 Hz).

Embodiment 25

[0071]

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In a test tube with a cap, sodium benzoate was added.
(0.086 g, 0.60 mmol), and the atmosphere was replaced with argon. DMF (1.0 ml) was added as a solvent, and the temperature was raised to 80 ° C. To this, trifluoromethanesulfonic acid 2,2,3,3,3-pentafluoro-1-
Methylpropyl (0.148 g, 0.50 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. The target benzoic acid was obtained at a conversion of 100% and a conversion yield of 62.2%.
It became clear that 2,2,3,3,3-pentafluoro-1-methylpropyl was formed. Benzoic acid 2,2,3,3,3-pentafluoro-1-methylpropyl ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -129.45 (dd, J = 280 Hz, 1
6 Hz, 1F), -122.25 (ddd, J = 280 Hz, 7.9 Hz, 2.3 Hz,
1F), -82.51 (s, 3F).

Embodiment 26

[0074]

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In a test tube with a cap, add metallic potassium (0.024
g, 0.60 mmol) and replace with argon, diethyl carbonate (1.0 ml) was added as a solvent, and diethyl malonate (0.99 ml, 0.65 mmol) was added dropwise with stirring at room temperature. Then, diethylpotassiomalonate was produced, and the mixture was stirred at room temperature for 1 hour. 1- (trifluoromethyl) trifluoromethanesulfonic acid
Heptyl (0.158 g, 0.50 mmol) was added, and the mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. As a result, it was found that the conversion rate was 49.5% and the conversion yield was 72.6%. It was found that diethyl (fluoromethyl) heptyl permalonate was formed.

Examples 27-33

In a test tube with a cap, add sodium hydride (6
After adding 0% in paraffin, 0.024 g, 0.60 mmol) and replacing with argon, and adding diethyl carbonate (1.0 ml) as a solvent, diethyl malonate (0.99 ml, 0.
When 65 mmol) was added dropwise, the reaction was carried out while generating gas, and diethyl sodiomalonate was formed. Therefore, the mixture was stirred at room temperature for 1 hour. To this, an additional solvent and further 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.15
8 g, 0.50 mmol), and added at 80 ° C under argon atmosphere.
A time reaction was performed. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard, the conversion was determined by ¹⁹ F-NMR, and
The conversion yield of-(trifluoromethyl) heptyldimalonate was determined. Table 3 shows the results of the reaction performed using various additive solvents.

Table 3 ─────────────────────────── Example Additive solvent Addition amount (ml) Conversion rate (%) Conversion yield ( %) ─────────────────────────── 27 DMF 0.047 52.2 73.0 28 DMSO 0.043 60.0 74.7 29 DMI 0.066 44.3 65.5 30 HMPA 0.105 73.3 71.1 31 TMU 0.072 54.3 78.0 32 Tetraethyl urea 0.114 62.2 83.8 33 DMPU 0.073 67.7 78.5 ───────────────────────────

Example 34-36

In a test tube with a cap, add sodium hydride (6
0% in paraffin, 0.048 g, 1.20 mmol) was added, and the atmosphere was replaced with argon.After adding diethyl carbonate (1.0 ml) as a solvent, diethyl malonate (0.197 ml,
When 1.30 mmol) is added dropwise, it reacts while generating a gas to produce diethyl sodiomalonate.
Stirred for hours. To this, an additional solvent and further 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.
158 g, 0.50 mmol) at 80 ° C under an argon atmosphere.
A time reaction was performed. The reaction mixture was extracted with ether / water, and benzotrifluoride was added to the ether layer as an internal standard substance. The conversion and the conversion of the target diethyl {1- (trifluoromethyl) heptyl} malonate were determined by ¹⁹ F-NMR. The rate was determined. Table 4 shows the results of the reaction using various additive solvents.

Table 4 ─────────────────────────── Example Additive solvent Addition amount (ml) Conversion rate (%) Conversion yield ( %) ─────────────────────────── 34 HMPA 0.105 93.8 82.6 35 Tetraethyl urea 0.114 85.8 86.7 36 DMPU 0.073 93.8 88.7 ───── ──────────────────────

Embodiment 37

[0083]

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In a test tube with a cap, sodium hydride (6
After 0% in paraffin, 0.048 g, 1.20 mmol) was added and the atmosphere was replaced with argon, diethyl carbonate (1.0 ml) was added as a solvent, and ethyl cyanoacetate (0.138 ml,
When 1.30 mmol) is added dropwise, it reacts while generating gas, and ethyl cyanosodiacetate is formed.
Stirred for hours. To this, DMPU (0.073 ml) and further 1- (trifluoromethyl) heptyl trifluoromethanesulfonate (0.158 g, 0.50 mmol) were added, and under an argon atmosphere,
The reaction was performed at 80 ° C. for 24 hours. The reaction mixture was extracted with ether / water, benzotrifluoride was added to the ether layer as an internal standard substance, and ¹⁹ F-NMR was measured. As a result, the desired cyano 1-(-) was obtained at a conversion of 86.2% and a conversion yield of 43.4%. It became clear that trifluoromethyl) heptyl｝ ethyl acetate was formed. Cyano {1- (trifluoromethyl) heptyl} ethyl acetate ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): δ = -70.58 (d, J = 8.8 Hz).

[0085]

The present invention provides a simple method for producing a fluorine-containing compound, which is useful as a pharmaceutical or agricultural chemical such as an anticancer agent or an enzyme inhibitor, or a synthetic intermediate for a functional material such as a ferroelectric liquid crystal. .

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/26 A61K 31/26 31/40 31/40 C07C 17/093 C07C 17/093 19/14 19/14 41/16 41 / 16 43/12 43/12 67/11 67/11 69/62 69/62 247/04 247/04 253/30 253/30 255/19 255/19 327/40 327/40 331/04 331/04 C07D 209/48 C07D 209/48 Z

Claims (1)

[Claims] 1. A compound represented by the general formula: R ¹ R ² R _f ¹ C-OSO ₂ R _f ^{2 wherein} R ¹ and R ² are each independently a hydrogen atom or an alkyl group which may have a substituent, Represents an aromatic group, an aralkyl group, an alkenyl group, or an alkynyl group.
Further, R ¹ and R ² may form a ring together with the carbon atom to which they are bonded.
Further, each represents R _f ¹ and R _f ² are independently perfluoroalkyl group or a perfluoro aromatic group. ) And a perfluoroalkylsulfonic acid ester or a perfluoroarylsulfonic acid ester of an α-perfluoroalkylated alcohol represented by the general formula M ^{x +} _m Q ^y- _n (wherein, M ^{x +} represents a metal ion or a polyatomic cation). Q ^y- represents a conjugate base of Bronsted acid QH _y .
x, y, m, and n are any positive integers that satisfy the relational expression xm = yn. ) And a salt of a Bronsted acid,
A general formula (R ¹ R ² R _f ¹ C-) _y Q, wherein R ¹ , R ² , R _f ¹ and y are the same as described above, wherein the reaction is carried out in an aprotic solvent. .
Q is the above Brönsted acid residue. ),
A method for producing a fluorine-containing compound.