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This material was dissolved in 200 ml isopropanol, and hydrogen chloride gas was passed into the solution resulting in a weight gain of 8 g. The solution was stirred at 50 C. for 30 minutes, then evaporated to dryness. The residue was treated with ether, and the solids collected by filtration and dried in vacuo, providing 2.7 g (79% yield) 2-(trifluoromethyl)phenylhydrazine hydrochloride as a white powder, mp 241-242 C.
With potassium carbonate; In water; ethyl acetate; 2,6-difluorobenzoylchloride;
EXAMPLE 35 The 2,6-difluoro-N'-(alpha,alpha,alpha-trifluoro-o-tolyl)-benzhydrazide required as the starting material in Examples 10 and 26 can be produced as follows: 59.8 g (0.28 mol) of <strong>[3107-34-4]o-trifluoromethyl-phenylhydrazine hydrochloride</strong> are placed in a two-phase system of 280 ml of ethyl acetate and 85 ml of water and the mixture is treated portionwise with 84.9 g (0.62 mol) of potassium carbonate while stirring well at 10-20 C. After a clear solution has formed (15 minutes) there are added dropwise in the next 30 minutes 49.4 g (0.28 mol) of 2,6-difluorobenzoyl chloride so that the temperature is held at a maximum of 25 C. After a further 30 minutes the mixture is diluted with 300 ml of water and the organic phase is separated, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in 30 ml of hot acetone and the 2,6-difluoro-N'-(alpha,alpha,alpha-trifluoro-o-tolyl)-benzhydrazide is precipitated by adding 500 ml of n-hexane. M.p. 123-125 C.; IR spectrum: 3405, 1694 cm-1.
With calcium hydroxide; potassium carbonate; In water; ethyl acetate;
EXAMPLE 36 The 2,6-difluoro-N'-(alpha,alpha,alpha-trifluoro-o-tolyl)-benzhydrazide can also be produced as follows: 13.6 g (98 mmol) of potassium carbonate in 70 ml of water are added at 10 C. while stirring to a suspension of 10.4 g (49 mmol) of alpha,alpha,alpha-trifluoro-o-tolylhydrazine hydrochloride in 50 ml of ethyl acetate. 7.8 g (49 mmol) of 2,6-difluorobenzoyl fluoride are subsequently added dropwise to the clear solution while cooling so that the internal temperature is maintained at 3 C. The mixture is stirred at 5 C. for 60 minutes and thereafter at 25 C. for 4 hours, and the organic phase is separated. The aqueous phase is back-extracted with 50 ml of ethyl acetate and subsequently treated with 1.85 g (25 mmol) of calcium hydroxide in order to precipitate the calcium fluoride. The combined organic phases are washed in each case once with dilute hydrochloric acid and sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After recrystallization from acetone and n-hexane there is obtained 2,6-difluoro-N' -(alpha,alpha,alpha-trifluoro-o-tolyl)-benzhydrazide as a white crystallizate, m.p. 129-130 C.; mass spectrum m/e: M+ 316(26), 141(100).
3-(2-chloro-4-fluorophenyl)-5-methyl-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In toluene;
EXAMPLE 39 A mixture of 6.1 g (22 mmol) of ethyl N-acetyl-2-chloro-4-fluorobenzimidate and 6.7 g (25 mmol) of o-trifluoromethylphenylhydrazine hydrochloride in 100 ml of toluene is treated with 3.9 ml (28 mmol) of triethylamine and the whole is heated at reflux temperature for 18 hours. Thereafter, the reaction mixture is washed once with water and extracted twice with 50 ml of concentrated hydrochloric acid. The acidic aqueous phases are neutralized with ice-cold sodium hydroxide solution and extracted twice with diethyl ether, and the combined extracts are dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is subjected to a bulb-tube distillation, the fractions with b.p. 200 C./0.01 mmHg (9.33 Pa) being collected and finally crystallized from diisopropyl ether/n-hexane. In this manner there is obtained 3-(2-chloro-4-fluorophenyl)-5-methyl-1-(alpha,alpha,alpha-trifluoro-o-tolyl)-1H-1,2,4-triazole, m.p. 116 C.; 1 H--NMR (CDCl3, 60 MHz): 2.37 (s,CH3); mass spectrum: 335 (48), 314(43), 159(100).
EXAMPLE 11A 5-Amino-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonitrile In analogy to the preparation of Example 10A, 5.02 g (76.9% of theory) of the desired product are obtained starting from 4.8 g (25.9 mmol) of <strong>[3107-34-4]2-trifluoromethylphenylhydrazine hydrochloride</strong>, 3.16 g (25.9 mmol) of ethoxymethylenemalononitrile and 7.2 ml (51.7 mmol) of triethylamine. m.p.: 190 C. MS (ESI pos): m/z=253 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=6.6 (s, 2H), 7.5 (d, 1H), 7.7-8.0 (m, 4H) ppm.
6-(Trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole To 4-piperidone.HCl (1.36 g, 10.0 mmol) and 2-trifluoromethylphenylhydrazine.HCl (2.13 g, 10.0 mmol) in acetic acid (50 mL) was added the 1.0 M borontrifluoride etherate (2.46 mL, 20.0 mmol) and the reaction stirred at 90 C. for 8 hours and then allowed to cool. The mixture was concentrated in vacuo and ethanol (ca 20 mL) added and then cooled to 0 C., the solid was filtered off and the mother liquor was concentrated in vacuo and water (adjusted to pH 14 with 2M NaOH) added to the residue. The solid was filtered off and washed with water and dried under high vacuum. MS (+ve ESI): 240 (M+H)+ 1H NMR (400.132 MHz, DMSO) delta 3.07 (2H, t), 3.47 (2H, t), 4.33 (2H, s), 7.19 (1H, t), 7.45 (1H, d), 7.79 (1H, d), 11.52 (1H, s)
General procedure: To a mixture of substituted phenyl amine (0.06 mol) and 15% HCl (60 mL), NaNO2 (5 g, 0.072 mol) in H2O (200 mL) was added drop-wise at 0 C. After the completion of addition, the reaction mixture was stirred at this temperature for 30 min. and then was dropped into the mixture of saturated solution of sodium hydrogen sulfite (22.5 g, 0.216 mol), keeping the reaction below 20 C. Upon completing the addition, the reaction was heated under refluxed for 3 h and cooled to room temperature. The solid is filtered and washed with ethyl acetate and the cake was dried to give white solid 9a-h yielded 90%.
General procedure: To a mixture of substituted phenyl amine (0.06 mol) and 15%HCl (60 mL), NaNO2 (5 g, 0.072 mol) in H2O (200 mL) was addeddrop-wise at 0 C. After the completion of addition, the reaction mixture was stirred at this temperature for 30 min. and then wasdropped into the mixture of saturated solution of sodium hydrogen sulfite (22.5 g, 0.216 mol), keeping the reaction below 20 C. Upon completing the addition, the reaction was heated under refluxed for 3 h and cooled to room temperature. The solid is filtered and washed with ethyl acetate and the cake was dried to give white solid 9a-h yielded 90%.
(4Z)-4-(((3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)amino)methylene)-3-methyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5(4H)-one[ No CAS ]
(4Z)-4-(((3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)amino)methylene)-3-methyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5(4H)-one[ No CAS ]
(4Z)-4-(((3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)amino)methylene)-3-methyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5(4H)-one[ No CAS ]
3-methyl1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.5%
With acetic acid;Reflux;
General procedure: To a solution of an appropriate intermediate 9a-h (0.028 mol) and ethyl acetoacetate (0.034 mol) dissolved in acetic acid (10 mL), the reaction mixture was heated under refluxed with stirring until the starting materials could no longer be detected by TLC. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and saturated sodium bicarbonate solution, the mixture was washed with saturated sodium bicarbonate solution (20 mL 3), brine (20 mL 3) in sequence, and the organic phase was separated, dried, and evaporated. The crude product was crystallized from THF and Hexane to afford brown solids 10a-h. Yield 74.5%. mp 122-123 C. ESI-MS m/z: 243.20 [M + H]+.
74.5%
With acetic acid;Reflux;
General procedure: To a solution of an appropriate intermediate 9a-h (0.028 mol)and ethyl acetoacetate (0.034 mol) dissolved in acetic acid(10 mL), the reaction mixture was heated under refluxed with stirringuntil the starting materials could no longer be detected by TLC. The solvent was evaporated under reduced pressure and the residuewas dissolved in ethyl acetate and saturated sodium bicarbonatesolution, the mixture was washed with saturated sodiumbicarbonate solution (20 mL 3), brine (20 mL 3) in sequence, and the organic phase was separated, dried, and evaporated. Thecrude product was crystallized from THF and Hexane to affordbrown solids 10a-h.
ethyl 5-hydroxy-1-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
at 85℃; for 12h;
4.1.1. 5-methyl-1-(4-((N-methylsulfiiamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylic acid (12a)
General procedure: Step 2. To a solution of 8a (118 mg, 1 mmol) and 4-hydrazino-N-methylbenzenemethanesulfonamide hydrochloride (9, 252 mg, 1 mmol) in anhydrous ethanol (10 mL) was stirred at 85 °C overnight. The reaction was allowed to cool to room temperature and concentrated. The crude material was purified by Isolera Biotage LPLC (PE/EA = 30%) to give a mixture of methyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (10a) and ethyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (11a) as a white solid.
39%
at 85℃; for 12h;
4.1.1. 5-methyl-1-(4-((N-methylsulfiiamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylic acid (12a)
General procedure: Step 2. To a solution of 8a (118 mg, 1 mmol) and 4-hydrazino-N-methylbenzenemethanesulfonamide hydrochloride (9, 252 mg, 1 mmol) in anhydrous ethanol (10 mL) was stirred at 85 °C overnight. The reaction was allowed to cool to room temperature and concentrated. The crude material was purified by Isolera Biotage LPLC (PE/EA = 30%) to give a mixture of methyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (10a) and ethyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (11a) as a white solid.
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