Patent Application
20190256477
The invention discloses a method for the preparation of 3-(trifluoromethyl)pyrazine-2-carboxylic acid esters starting from alkyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoates by reaction with ethylenediamine.
3-(Trifluoromethyl)pyrazine-2-carboxylic acid esters as well as the corresponding acid are important intermediates for the preparation of biologically active compounds, such as drugs or agrochemicals.
One specific example of an important, biologically active compound requiring such esters as synthetic intermediates is the fungicide pyraziflumid (CAS 942515-63-1).
A number of different preparation methods of such esters have been disclosed, but all of them require more than three synthetic steps, are based on expensive starting materials, or require the use of expensive or dangerous reagents. For instance, WO 2010/122794 A1 discloses the conversion of 4,4,4-trifluoro-3-oxo-2-halobutanoates into such esters by treatment with sodium azide, followed by reaction with ethylenediamine and dehydrogenation with a noble metal catalyst. Sodium azide is a hazardous reagent, and requires costly safety precautions when handled on a large scale. Noble metal catalysts are expensive, and traces of noble metals are sometimes difficult to remove from the products of noble-metal-catalyzed reactions.
U.S. Pat. No. 5,374,615 A1 discloses the nitrosation of 4,4,4-trifluoro-3-oxobutanoates with sodium nitrite in acetic acid, as specific example the preparation of 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoic acid, ethyl ester, is described in example 21 A.
There was a need for a method for preparation of such esters that does not require more than three synthetic steps, that is not based on expensive starting materials, and that does not require the use of expensive or dangerous, such as toxic or explosive reagents, such as noble metal catalysts or sodium azide.
A preparation method for such esters was found that is short, that is based on readily available starting materials, that does not require toxic or explosive reagents or intermediates, and that is well suited for the large scale preparation of such esters. The method can be done as a one-pot method without mandatorily requiring any isolation of an intermediates, the method can be done without change of a solvent.
Subject of the invention is a method for the preparation of compound of formula (I);
the method comprises two steps, a step ST1 and a step ST2;
ST1 comprises a reaction REAC1, wherein compound of formula (II)
R30 is H or C1-6 alkyl, the C1-6 alkyl is unsubstituted or substituted with phenyl.
BF3OEt2 is boron trifluoride diethyletherate.
In another preferred embodiment,
Preferably, R30 is H or C3-6 alkyl, the C3-6 alkyl is unsubstituted or substituted with phenyl; more preferably, R30 is H, C4-6 alkyl hydroperoxide or cumene hydroperoxide; even more preferably, R30 is is H, C4 alkyl hydroperoxide or cumene hydroperoxide. especially, R30 is is H.
Preferably, REAC0 is done in the absence of water.
Internal standard for 1H NMR: Triisobutyl phosphate, if not otherwise stated
To a mixture of acetic acid (30 ml, 0.5 mol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (9.21 g, 50.0 mmol) at 15° C. a solution of sodium nitrite (4.52 g, 65.5 mmol) in water (7.0 ml) was added dropwise within 10 min. After stirring at room temperature for 1.5 h the mixture was diluted with ethyl acetate (100 ml) and, while stirring and cooling to maintain the temperature below 30° C., a solution of sodium hydroxide (16 g, 0.4 mol) in water (200 ml) was added. Phases were separated, and NaHCO3 (1 g) was added to the aqueous phase. The aqueous phase was then extracted with ethyl acetate (two times 50 ml), and the combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The product was obtained as an oil (9.60 g, 91% pure by 1H NMR; yield: 82%), which slowly and partially solidified. According to the NMR spectra this oil consisted of an equimolar mixture of the hydrated and the non-hydrated form.
To ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (0.11 g, approx 0.5 mmol, prepared according to Example 1) were added at room temperature in the following order acetic acid (0.09 ml, 1.5 mmol), pyridine (0.80 ml, 10 mmol), ethylenediamine (0.05 ml, 0.75 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol). The mixture was stirred at room temperature for 6 h, cooled to 15° C., and bromine (0.128 ml, 2.5 mmol) was added dropwise while stirring. The mixture was stirred at room temperature for 16 h. Analysis of a sample by 19F NMR indicated that the title pyrazine had been formed in approximately 50% yield. The product ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was isolated by addition of aqueous 1N HCl (10 ml), saturation with NaCl, and extraction with ethyl acetate (3 ml). Addition of iBu3PO4 (0.05 ml), concentration of a sample of the ethyl acetate extract, and analysis by 1H NMR indicated, that the title pyrazine ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate had been formed in 44% yield.
To ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (0.176 g, approx 0.75 mmol, prepared according to Example 1) were added at 0° C. in the following order acetic acid (0.18 ml, 3.0 mmol), pyridine (1.2 ml, 15 mmol), ethylenediamine (0.065 ml, 0.98 mmol), and triethyl phosphite (0.193 ml, 1.13 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 16 h. Tetrabutylammonium iodide (54 mg, 0.15 mmol) and tert-butylhydroperoxide (70 wt-% in water, 0.416 ml, 3.0 mmol) were then added, and stirring at room temperature was continued for 7 h. The mixture was then diluted with 1 N aqueous hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate (3 ml). To the extract was added triisobutylphosphate (0.05 ml, 0.182 mmol) as internal standard. Analysis by 1H NMR indicated, that ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate had been formed in 37% yield.
To ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (0.176 g, approx 0.75 mmol, prepared according to Example 1) were added at 0° C. in the following order acetic acid (0.18 ml, 3.0 mmol), pyridine (1.2 ml, 15 mmol), ethylenediamine (0.065 ml, 0.98 mmol), and triethyl phosphite (0.193 ml, 1.13 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to −30° C., and sodium tungstate hydrate (Na2WO4—H2O, 50 mg, 0.15 mmol) and tert-butylhydroperoxide (70 wt-% in water, 0.416 ml, 3.0 mmol) were then added, and the mixture was stirred at room temperature for 9 h. The mixture was then diluted with 1 N aqueous hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate (3 ml). To the extract was added triisobutylphosphate (0.05 ml, 0.182 mmol) as internal standard. Analysis by 1H NMR indicated, that ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate had been formed in 32% yield.
To ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (0.176 g, approx 0.75 mmol, prepared according to Example 1) were added at 0° C. in the following order acetic acid (0.18 ml, 3.0 mmol), pyridine (1.2 ml, 15 mmol), ethylenediamine (0.065 ml, 0.98 mmol), and triethyl phosphite (0.193 ml, 1.13 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 16 h. The mixture was then cooled to 0° C., hydrogen peroxide (50 wt-% in water, 0.17 ml, 3.0 mmol) was added, and the mixture was stirred at 0° C. for 1 h and at room temperature for 5.5 h. The mixture was then diluted with 1 N aqueous hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate (3 ml). To the extract was added triisobutylphosphate (0.05 ml, 0.182 mmol) as internal standard. Analysis by 1H NMR indicated, that ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate had been formed in 23% yield.
To a mixture of acetic acid (4.8 ml, 80 mmol) and ethyl 4,4,4-trifluoro-3-oxobutanoate (2.92 ml, 20.0 mmol) at 5 to 15° C. was added dropwise a solution of sodium nitrite (1.79 g, 25.9 mmol) in water (2.32 ml) within 10 min. The mixture was stirred at 0° C. for 1 h, and nitrous gases were removed by bubbling nitrogen through the mixture for five minutes. Pyridine (30 ml, 0.37 mol) was added, and the mixture was cooled to 0° C. Ethylenediamine (1.736 ml, 26.0 mmol) was added dropwise, followed by the addition of triethyl phosphite (5.14 ml, 30.0 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 15 h. The mixture was cooled to 0° C. and bromine (3.09 ml, 60.3 mmol) was added dropwise within 15 min. The mixture was stirred at 0° C. for 15 min, then at room temperature for 5 h. The mixture was diluted with brine (150 ml) and water (50 ml), and acidified by addition of aqueous concentrated hydrochloric acid (approximately 32 ml). The product was extracted with ethyl acetate (four times 50 ml), the combined extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to yield a mixture of triethyl phosphate and the title compound. Analysis by NMR indicated that the yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 46%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), 2-methylpentanoic acid (0.251 ml, 2.0 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.121 ml, 0.70 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 14 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 30 min and then at room temperature for 2.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-trifluoromethyl)pyrazine-2-carboxylate was 51%.
To a stirred mixture of pyridine (0.812 ml, 10 mmol), methanesulfonic acid (0.033 ml, 0.5 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.121 ml, 0.70 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 14 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 30 min, and then at room temperature for 2.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 32%.
To a stirred mixture of pyridine (0.812 ml, 10 mmol), N-hydroxysuccinimide (231 mg, 2.0 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.121 ml, 0.70 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 14 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 30 min, and then at room temperature for 2.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 25%.
To a stirred mixture of pyridine (0.812 ml, 10 mmol), pyridine hydrochloride (116 mg, 1.0 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.121 ml, 0.70 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 30 min, and then at room temperature for 5.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 15%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), benzoic acid (215 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 15.5 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 30 min, and then at room temperature for 5.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 65%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), 4-toluenesulfonic acid hydrate (95 mg, 0.5 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 15.5 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 30 min, and then at room temperature for 5.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 43%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), propionic acid (0.158 ml, 2.12 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 3 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 46%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), dichloroacetic acid (0.145 ml, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 3 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 39%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), formic acid (0.066 ml, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 3 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 24%.
To a stirred mixture of pyridine (0.812 ml, 10 mmol), benzoic acid (215 mg, 1.76 mmol), dichloromethane (0.812 ml), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 3 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 51%.
To a stirred mixture of pyridine (1.624 ml, 20 mmol), 2-chlorobenzoic acid (275 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 0.5 h, and then at room temperature for 14.5 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 2 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 55%.
To a stirred mixture of pyridine (1.624 ml, 20 mmol), nicotinic acid (216 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 0.5 h, and then at room temperature for 14.5 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 2 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 20%.
To a stirred mixture of pyridine (1.624 ml, 20 mmol), nicotinic acid N-oxide (244 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 0.5 h, and then at room temperature for 14.5 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 2 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 21%.
To a stirred mixture of pyridine (1.624 ml, 20 mmol), salicylic acid (243 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and triethyl phosphite (0.129 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 0.5 h, and then at room temperature for 14.5 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 2 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 58%.
To a stirred mixture of pyridine (3.24 ml, 40 mmol), pivalic acid (0.402 ml, 3.5 mmol), ethylenediamine (0.087 ml, 1.3 mmol), and trimethyl phosphite (0.177 ml, 1.5 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (195 mg, 0.84 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to 0° C., and bromine (0.154 ml, 3.0 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 2.5 h the mixture was diluted with 1N aqueous hydrochloric acid (12 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 48%.
To a mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (0.146 ml, 1.0 mmol) and n-butyl nitrite (0.129 ml, 1.1 mmol) at 0° C. was added acetyl chloride (0.079 ml, 1.1 mmol), and the mixture was stirred at 0° C. for 1 h and then at room temperature for 23 h. Benzoic acid (0.427 g, 3.5 mmol) was added, followed by the addition of pyridine (3.24 ml, 40 mmol) and ethylenediamine (0.087 ml, 1.3 mmol). The mixture was cooled to 0° C., and trimethyl phosphite (0.177 ml, 1.5 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h, and then at room temperature for 22 h. The mixture was then cooled to 0° C., and bromine (0.154 ml, 3.0 mmol) was added dropwise. After stirring at 0° C. for 1 h, and then at room temperature for 2.5 h the mixture was diluted with 1N aqueous hydrochloric acid (12 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 55%.
To a mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (1.46 ml, 10.0 mmol) and n-butyl nitrite (1.29 ml, 11.0 mmol) at 0° C. was added acetyl chloride (0.785 ml, 11.0 mmol), and the mixture was stirred at 0° C. for 6 h. More n-butyl nitrite (0.60 ml, 5.13 mmol) was added, and the mixture was stirred at room temperature for 15 h. Vacuum (40 mbar) was applied to remove volatiles. Analysis of the mixture (3.78 g) by 1H and 19F NMR indicated, that it mostly consisted of ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate and butyl acetate. The density was 1.06 g/ml.
To a mixture of 3-methylpyridine (1.46 ml, 15.0 mmol), benzoic acid (213 mg, 1.75 mmol), ethylenediamine (0.043 ml, 0.65 mmol), and trimethyl phosphite (0.082 ml, 0.70 mmol) at 0° C. was added this mixture (0.197 ml containing 0.50 mmol oxime). The resulting mixture was stirred at 0° C. for 0.5 h and then at room temperature for 21 h. The mixture was then cooled to 0° C. and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 1 h and at room temperature for 2 h the mixture was diluted with 1N HCl (10 ml), saturated with NaCl, and extracted with ethyl acetate (3 ml). Triisobutyl phosphate (0.060 ml, 0.219 mmol) was added as internal standard, and a concentrated sample was analyzed by 1H and 19F NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 67%.
To a stirred mixture of pyridine (1.20 ml, 15 mmol), benzoic acid (215 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and trimethyl phosphite (0.089 ml, 0.75 mmol) at 0° C. was added dropwise a solution of ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1), in pyridine (0.40 ml, 5.0 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 16 h. The mixture was then cooled to 0° C., and tetrabutylammonium iodide (20 mg, 0.05 mmol) and N,N′,N″-trichloroisocyanuric acid (152 mg, 0.65 mmol) were added. After stirring at 0° C. for 0.5 h, and then at room temperature for 24 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 48%. o 25
To a stirred mixture of pyridine (1.20 ml, 15 mmol), benzoic acid (215 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and trimethyl phosphite (0.089 ml, 0.75 mmol) at 0° C. was added dropwise a solution of ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1), in pyridine (0.40 ml, 5.0 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 16 h. The mixture was then cooled to 0° C., and tetrabutylammonium iodide (20 mg, 0.05 mmol) and hydrogen peroxide (50% in water, 0.114 ml, 2.0 mmol) were added. After stirring at 0° C. for 0.5 h, and then at room temperature for 24 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 28%. As byproduct, an N-oxide of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was formed in 26% yield.
To a stirred mixture of pyridine (1.20 ml, 15 mmol), benzoic acid (184 mg, 1.51 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and trimethyl phosphite (0.089 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 0.5 h, and then at room temperature for 15 h. The mixture was then cooled to 0° C., and iodine (386 mg, 1.5 mmol) was added. After stirring at 0° C. for 1 h, and then at room temperature for 5.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 66%. o 27
To a stirred mixture of pyridine (1.60 ml, 19.8 mmol), benzoic acid (215 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and trimethyl phosphite (0.089 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (115 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 0.5 h, and then at room temperature for 15 h. The mixture was then cooled to 0° C., and sodium tungstate dihydrate (Na2WO4×2 H2O; 15 mg, 0.045 mmol) and hydrogen peroxide (50% in water, 0.114 ml, 2.0 mmol) were added. After stirring at 0° C. for 1 h, and then at room temperature for 5.5 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3(trifluoromethyl)pyrazine-2-carboxylate was 28%. As byproduct, an N-oxide of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was formed in 40% yield.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), 1-hydroxybenzotriazole hydrate (269 mg, 1.76 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and trimethyl phosphite (0.089 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (116 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1.5, and then at room temperature for 20 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 0.5 h, and then at room temperature for 2 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 49%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), trifluoroacetic acid (0.026 ml, 0.35 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and trimethyl phosphite (0.089 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (116 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1.5, and then at room temperature for 20 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 0.5 h, and then at room temperature for 2 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 39%.
To a stirred mixture of pyridine (1.62 ml, 20 mmol), boron trifluoride diethyletherate (0.050 ml, 0.41 mmol), ethylenediamine (0.044 ml, 0.65 mmol), and trimethyl phosphite (0.089 ml, 0.75 mmol) at 0° C. was added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (116 mg, 0.5 mmol, prepared according to Example 1). The mixture was stirred at 0° C. for 1.5, and then at room temperature for 20 h. The mixture was then cooled to 0° C., and bromine (0.077 ml, 1.5 mmol) was added dropwise. After stirring at 0° C. for 0.5 h, and then at room temperature for 2 h the mixture was diluted with 1N aqueous hydrochloric acid (10 ml), saturated with sodium chloride, and extracted with ethyl acetate (3 ml). An internal standard (triisobutyl phosphate) was added, and the extract was analyzed by NMR. The yield of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was 29%.
The product of Example 1 (prepared according to Example 1, 2.07 g, approx 9.3 mmol) was mixed with dichloromethane (100 ml) and anhydrous calcium chloride (7.2 g, 64.9 mmol). The mixture was stirred at room temperature for 15 h.
Analysis of a sample by 1H NMR in CDCl3 indicated, that the dehydratization was complete. Filtration of the mixture over Celite and concentration under reduced pressure yielded 1.58 g of a turbid oil, which solidified completely after some days at room temperature. NMR confirmed that it was dehydrated ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate. 1H NMR (CDCl3, 400 MHz) delta=4.43 (quart, J=7 Hz, 2H), 1.38 (t, J=7 Hz, 3H). 19F NMR (CDCl3, 376.5 MHz) delta=−72.8 (s).
To ethyl 4,4,4-trifluoro-3-oxobutanoate (1, 3.70 g, 20.1 mmol) at 0° C. were added n-butyl nitrite (2.81 ml, 24.0 mmol) and benzoic acid (366 mg, 3.00 mmol), and the mixture was stirred at 0° C. for 2 h and then at room temperature for 24 h. Vacuum (10 mbar, 40° C.) was applied for 0.5 h, to remove the excess butyl nitrite. The residue was the crude oxime. In a separate flask a mixture of benzoic acid (8.18 g, 67.0 mmol), 3-picoline (38 ml, 0.39 mol), and ethylenediamine (1.74 ml, 26.1 mmol) was prepared. Upon addition of the amine, a precipitate formed. After cooling to 0° C. trimethyl phosphite (3.31 ml, 28.0 mmol) was added, followed by the dropwise addition of the crude oxime. The oxime container was rinsed with 3-picoline (3.0 ml, 31 mmol), and this rinsing solution was also added to the reaction mixture. After stirring at 0° C. for 0.5 h and at room temperature for 3.5 h, the mixture was heated to 70° C. for 0.5 h and then cooled to 0° C. Bromine (2.56 ml, 50.0 mmol) was then added dropwise within 5 min. The mixture was stirred at 0° C. for 0.5 h, and then at room temperature for 1.5 h.
The mixture was cooled to 0° C. and added to an ice-cold mixture of concentrated aqueous hydrochloric acid (67 ml, 0.70 mol) and water (200 ml). After adding sodium bisulfite (3.12 g, 30.0 mmol), the product was extracted with butyl acetate (3 times with 50 ml), and the combined extracts were washed with brine (100 ml), with a solution of potassium carbonate (15 g, 0.11 mol) in water (100 ml), with brine (100 ml), were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography over silica gel (30 g; gradient elution with heptane/ethyl acetate from 100/0 to 8/2). Ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate was obtained as an oil (1.81 g, 40% yield, 99% pure by 1H NMR with triisobutyl phosphate as internal standard).
To pyridine (1.2 ml, 15 mmol) was added benzoic acid (214 mg, 1.75 mmol) and ethylene diamine (0.040 ml, 0.60 mmol), and the mixture was cooled to 0° C. To this mixture were added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (107 mg, 0.50 mmol) and then trimethyl phosphite (0.130 ml, 1.10 mmol). The resulting mixture was stirred at room temperature for 3.5 h, cooled to 0° C., and bromine (0.090 ml, 1.75 mmol) was added dropwise. After stirring at room temperature for 2 h the mixture was diluted with brine (15 ml), extracted (3 ml AcOEt), and triisobutyl phosphate (0.140 ml, 0.50 mmol) was added as internal standard to the organic phase. Analysis by 1H NMR of a sample of the organic phase, after concentration by removal of parts of ethylacetate by evaporation, indicated, that ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate had been formed in 71% yield.
To pyridine (1.2 ml, 15 mmol) was added benzoic acid (214 mg, 1.75 mmol) and ethylene diamine (0.040 ml, 0.60 mmol), and the mixture was cooled to 0° C. To this mixture were added ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate (107 mg, 0.50 mmol) and then trimethyl phosphite (0.106 ml, 0.90 mmol). The resulting mixture was stirred at room temperature for 3.5 h, cooled to 0° C., and bromine (0.090 ml, 1.75 mmol) was added dropwise. After stirring at room temperature for 2 h the mixture was diluted with brine (15 ml), extracted (3 ml AcOEt), and triisobutyl phosphate (0.140 ml, 0.50 mmol) was added as internal standard to the organic phase. Analysis by 1H NMR of a sample of the organic phase, after concentration by removal of parts of ethylacetate by evaporation, indicated, that ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate had been formed in 64% yield.
| Number | Date | Country | Kind |
|---|---|---|---|
| 16186871.6 | Sep 2016 | EP | regional |
| 16203697.4 | Dec 2016 | EP | regional |
| 17157057.5 | Feb 2017 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2017/071690 | 8/30/2017 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62382446 | Sep 2016 | US |
