JPS6213941B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a fluoroalkyl malonic acid ester. Some compounds having a trifluoromethyl group among fluoroalkyl groups are known to exhibit biological activity. For example, trifluoromethyl malonic acid ester is believed to be useful as an intermediate in the synthesis of trifluoromethyl group-containing biologically active substances. Methods for synthesizing this ester include (1) a method in which octafluoroisobutene-methanol adduct (hereinafter referred to as OFIB-MeOH adduct) is converted into hexafluoroisobutyric acid ester with sulfuric acid, and then methanolysis is performed; (2) A known method is to convert heptafluoroisobutenyl methyl ether obtained by dehydrofluorination of an OFIB-MeOH adduct into a quaternary amino enolate using triethylamine, and then perform methanolysis. However, the above method (1) requires the reaction to be carried out in two stages and is complicated to operate.
Furthermore, although the method (2) above is easy to operate, it is known that the yield of the target product is low. The present inventors have discovered a method for easily and efficiently synthesizing fluoroalkylmalonic acid esters such as dimethyl trifluoromethylmalonate in one step by improving the method (2) above, and have invented the present invention. has been reached. That is, the method according to the invention has the general formula: (However, Rf represents a fluoroalkyl group and R represents an alkyl group.) By reacting the fluorine-containing aliphatic compound-alcohol adduct represented by the formula with a tertiary amine in a predetermined amount of an aprotic polar solvent. A quaternary ammonium enolate is produced, and then an alcohol is gradually applied to the quaternary ammonium enolate to perform alcoholysis to produce a monoester derived from the alcohol adduct, and then this ester is further converted to an alcohol. It is characterized in that a fluoroalkylmalonic acid ester represented by the general formula: RfCH(COOR) ₂ (where Rf and R are the same as those described above) is obtained by reacting and then treating with a mineral acid. What should be noted in the method of the present invention is that an aprotic polar solvent is used when the alcohol acts on the quaternary ammonium enolate, and that the alcohol is not added all at once as in method (2) above. Instead, it should be added gradually over time (particularly by dropping). This makes it possible to sufficiently generate the intermediate product to be converted into the target malonic acid ester, thereby making it possible to significantly improve the yield of the target product. This method according to the present invention can be expressed, for example, by the following reaction formula when the above-mentioned OFIB-MeOH adduct is used as a starting material. This reaction may be carried out, for example, under the following conditions. First, the OFIB-MeOH adduct is treated with 2 equivalents of triethylamine in an aprotic polar solvent such as dimethylformamide, and the quaternary ammonium enolate ( 2 ) is added via heptafluoroisobutyl methyl ether ( 1 ) above.
generated in situ (without removing the solvent) and then slowly added dropwise with methanol in an ice bath. After the dropwise addition, a small amount of the monoester (as described above) is stirred at room temperature for one hour.
A ketene acetal containing 4 ) ( 3 ) above is produced. When this ketene acetal is stirred in methanol for a longer period of time, it becomes an orthoester. At this stage, it is poured into water to separate the oil layer, and when this oil layer is treated with concentrated sulfuric acid, the monoester ( 3 and 4 above) is simultaneously hydrated. It is decomposed and converted into the target dimethyl trifluoromethylmalonate ( 5 above) in high yield. In the present invention, the alcohol adduct that can be used as a starting material includes the above OFIB-MeOH
This adduct is particularly desirable because of the excellent biological activity of the trifluoromethyl group, but this OFIB-MeOH
General formulas including adducts: Any formula represented by [Formula] can be used. Rf
as CF ₃ (CF ₂ ) n- or (CF ₃ ) ₂ CF
Perfluoroalkyl group _represented by ( _CF2 )n-, such as _CF3- , _CF3CF2- , _CF3 ( _CF2 ) _2- ,
CF ₃ (CF ₂ ) ₃ −, CF ₃ (CF ₂ ) ₄ −, CF ₃ (CF ₂ ) ₅
−, (CF ₃ ) ₂ CF−, (CF ₃ ) ₂ CFCF ₂ −, (CF ₃ ) ₂ CF
(CF ₂ ) ₂ −, (CF ₃ ) ₂ CF(CF ₂ ) ₃ − may be selected. Furthermore, aromatic group _{- substituted} fluoroalkyl groups, such as _C6H5CF2- , _C6H5 ( _{CF2 ) 2-} , may also be selected. In addition to CH ₃ −, the above R may also be
C ₂ H ₅ −, CH ₃ (CH ₂ ) ₂ −, (CH ₃ ) ₂ CH−, CH ₃
It may be an alkyl group having 5 or less carbon atoms, such as (CH ₂ ) ₃ -, CH ₃ (CH ₂ ) ₄ -, and the like. Further, the above-mentioned tertiary amines that can be used in the present invention are those necessary for dehydrofluorination and the production of quaternary ammonium enolate as starting materials, and include, for example, trimethylamine, trimethylamine, etc. in addition to triethylamine.
Those having 12 or less carbon atoms are preferred, such as triisopropylamine, pyridine, and N.N-dimethylaniline. This number of carbon atoms defines the tertiary amine.
When expressed as R ₃ N (R is an alkyl group), each R is preferably 4 or less. It has been confirmed that when a lower amine is used in place of a tertiary amine, the reaction does not proceed at all. Furthermore, an aprotic polar solvent is used to generate the coordination compound (quaternary ammonium enolate) using the tertiary amine. Preference is given to using, for example, dimethylformamide, acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoamide. This polar solvent has a large solvation energy for cations and has the effect of increasing the reaction rate of anionic reagents. In addition to the above-mentioned methanol, examples of the alcohol used to alcoholyze the quaternary ammonium enolate include aliphatic alcohols such as ethanol, propanol, isopropanol, butanol, and pentanol. In addition, mineral acids to be used to dealcoholize the intermediate product in order to obtain the target fluorine-containing aliphatic malonic acid ester include H ₂ SO ₄ , HCl, HNO ₃ ,
H ₃ PO ₄ etc. can be used. As described above, according to the method of the present invention, the tertiary amine is reacted in an aprotic polar solvent and the alcohol is gradually reacted in the alcoholysis stage, so that it is converted into the target product. The desired intermediate product can be efficiently produced, and therefore, fluoroalkyl malonic acid ester can be synthesized in higher yield and more easily than in known methods. As a result of the inventor's study of this synthesized malonic acid ester, it was found that alkylation is difficult because β-fluorine is easily eliminated along with its α-hydrogen, but if a specific base is used during alkylation, It turned out that alkylation is possible. That is, for example, in the above ester 5 , the highly acidic α-hydrogen is easily eliminated by a base to form the carbanion 6 , as shown in the following formula, but this carbanion removes fluoride ions from the _CF3 group. It is eliminated to form terminal difluoromethylene malonic acid ester 7 . In this case, in a nucleophilic solvent (methanol, water, etc.), addition of the solvent and desorption of fluoride ions are repeated, and the CF ₃ group disappears. On the other hand, when a non-nucleophilic solvent or base (e.g. NaH/dimethylformamide) is used, the carbanion 6 and the terminal difluoromethylene malonic acid ester 7 undergo Michael addition, and the fluoride ion is eliminated. The following condensate 8 is produced. Therefore, from this, in order to alkylate the fluorine-containing aliphatic malonic ester 5 , it is necessary that an equilibrium between the carbanion 6 and the terminal difluoromethylene malonic ester 7 exists on the side of the carbanion 6 . Become. After repeated studies, the inventor of the present invention found that by using an excess of cesium fluoride, which is a base and a good source of fluoride ions, the above equilibrium is shifted to the anion side, making it possible to alkylate it. I discovered that. This reaction can be expressed as follows. The RX used here needs to be a highly reactive alkyl halide (examples shown in the table below); if a low-reactive alkyl halide is used, almost no alkylated product will be obtained, and the above-mentioned Only condensate 8 is obtained. Note that diglyme is diethylene glycol dimethyl ether. In the above alkylation reaction, the use of CsF shifts the equilibrium toward the carbanion 6 , making it easier for R to attack the anion, and it is thought that the alkylated product 9 is easily produced. [Table] In addition, in the above alkylation reaction, alkylation can be carried out in the same way by using KF instead of CsF, and RX used may be other alkyl halides having 5 or less carbon atoms (for example, C ₂ H ₅ I) is acceptable. Next, embodiments of the present invention will be described in detail, but the following embodiments do not limit the present invention, and various modifications can be made based on the technical idea thereof. Example 1 OFIB-MeOH adduct in the three-necked flask of 1
Add 116 g (500 mmol) and 100 c.c. of acetonitrile, and add 101.2 g (1 mol) of triethylamine for 10 to 20 minutes.
It was added dropwise at ℃. After stirring for about 40 minutes and 1 hour at room temperature, and confirming the formation of quaternary aminoenolate by ¹⁹ F NMR, 100 c.c. of methanol was added dropwise in an ice bath while being careful not to generate heat (about 40 minutes). The mixture was stirred at around 10°C for 1 hour and 10 minutes. Formation of 3 and 4 was observed by ¹⁹ F NMR, so the mixture was poured into water, the oil layer was separated, and the aqueous layer was extracted with diethyl ether. The oil and ether layers were combined, washed twice with water, and dried over magnesium sulfate. After distilling off the ether under reduced pressure, 10 c.c. of concentrated sulfuric acid was added, stirred overnight, and poured onto ice. After separating the oil layer and extracting the aqueous layer with ether, water,
It was washed with saturated brine and dried over magnesium sulfate. After distilling off the ether under reduced pressure, vacuum distillation was performed to yield 67.52 g of dimethyl trifluoromethylmalonate CF ₃ CH (COOCH ₃ ) ₂ with a boiling point of 65-66°C/10 mmHg.
Got it at 68%. This product was confirmed by the following spectral analyses. IR: 1755cm ^-1 (C=O) ¹⁹ F NMR: -11.1ppm (d, J = 8.0Hz) ¹ H NMR (CCl ₄ ): 4.11ppm (q, CF ₃ -C H
-), 3.83ppm (S, -OMe) Example 2 Cesium fluoride 9.11 in a 100ml eggplant flask
g (60 mmol) and dried under reduced pressure at 200°C for 2 hours. After returning to room temperature, quickly add 40c.c.
was added, powdered the hardened cesium fluoride with a glass rod, and dimethyl trifluoromethylmalonate 4
g (20 mmol) and 3.12 g (22 mmol) of methyl iodide
mol) was added. After stirring overnight at room temperature, the mixture was poured into water and extracted with ether three times. Wash with water 4 or 5 times until the diglyme disappears from the ether layer,
Dry with magnesium sulfate. After ether distillation under reduced pressure, vacuum distillation is performed to obtain a boiling point of 63-65℃/10mm.
Hg methyl-trifluoromethylmalonate dimethyl _CF3 ( _CH3 )C( _COOCH3 ) ₂ 2.56g yield 60
Obtained in %. This product was confirmed by the following spectral analyses. IR: 1750 cm ^-1 (C=O) ¹⁹ F NMR: -7.5 ppm (S) ¹ H NMR (CCl ₄ ): 1.66 ppm (S, CH ₃ -),
3.81ppm (S, -OMe) Example 3 9.11g of cesium fluoride in a 50c.c. three-necked flask
(60 mmol) was added and dried at 200°C for 2 hours under reduced pressure. After returning to room temperature, 16 c.c. of diglyme was quickly added, the solidified cesium fluoride was pulverized with a glass rod, and 3.76 g (22 mmol) of benzyl bromide was added.
Place the three-necked flask in an oil bath and add 4 g (20 mmol) of dimethyl trifluoromethylmalonate at 70-75°C.
and a solution of 20 c.c. of diglyme was slowly added dropwise. After dropping for 1 hour and 10 minutes, the mixture was stirred for 1 hour, poured into water, and treated in the same manner as described above. Perform vacuum distillation to determine the boiling point
2.77 g (yield: 48%) of dimethyl benzyl-trifluoromethylmalonate [formula] having a temperature of 115-120°C/2 mmHg was obtained. This product was confirmed by the following spectral analysis. IR: 1745 cm ^-1 (C=O) ¹⁹ F NMR: -12.2 ppm (S) ¹ H NMR (CCl ₄ ): 7.29 ppm (S, aromatic 5H), 3.50 ppm (S, Ph-C H ₂ -) , 3.73ppm (S, -OMe)

Claims (1)

[Claims] 1. General formula: (However, Rf is a fluoroalkyl group, and R is an alkyl group.) By reacting the fluoroalkyl compound-alcohol adduct represented by the formula with a predetermined amount of tertiary amine in an aprotic polar solvent, quaternary ammonium An enolate is produced, and then this quaternary ammonium enolate is gradually treated with an alcohol to perform alcoholysis to produce a monoester derived from the alcohol adduct, and then this ester is further reacted with an alcohol. A fluoroalkylmalonic acid characterized in that a fluoroalkylmalonic acid ester represented by the general formula: RfCH(COOR) ₂ (wherein Rf and R are the same as above) is obtained by treating with a mineral acid. Method for producing esters. 2. The method according to claim 1, wherein Rf consists of _CF3 . 3. The method according to claim 1 or 2, wherein R is an alkyl group having 5 or less carbon atoms. 4. The method according to any one of claims 1 to 3, wherein two equivalents of a tertiary amine having 12 or less carbon atoms are applied. 5. Any one of claims 1 to 4, in which dimethylformamide, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoamide is allowed to act as the aprotic polar solvent. The method described in Section 1.