* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium dihydrogenphosphate; tetra(n-butyl)ammonium hydrogensulfate In water Stage #2: With sodium hypochlorite In water for 0.5 h;
The 1- (p-trifluoromethylphenyl) -1-propanol solution prepared in step 1 was mixed with 3.9 kg of tetrabutylammonium hydrogen sulfate and 12.3 kg of sodium phosphate dihydrate monobasic, which were dissolved in 32 liters of purified water. After the mixture was washed by the addition of 10 liters of purified water, 318 kg of 12percent sodium hyperchlorite was added to the mixture, followed by EPO <DP n="19"/>washing by adding 35 liters of purified water. After the resulting solution was allowed to stand for 30 min, the formed organic layer was mixed with 358 liters of purified water and 18 kg of 38percent hydrochloric acid, and stirred for 5 min. The separated organic layer was washed with purified water, and 378 kg of p-trifluoromethyl propiophenone was obtained from the organic layer (yield: 97.2percent).
Reference：
[1] Synthetic Communications, 1989, vol. 19, # 9-10, p. 1735 - 1744
[2] Patent: WO2006/112565, 2006, A1, . Location in patent: Page/Page column 16-17
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 20, p. 3918 - 3932
[4] European Journal of Medicinal Chemistry, 1995, vol. 30, # 1, p. 85 - 94
[5] Journal of Organic Chemistry, 2003, vol. 68, # 4, p. 1594 - 1596
[6] Patent: US5478826, 1995, A,
[7] Catalysis Science and Technology, 2016, vol. 6, # 9, p. 3208 - 3213
[8] Helvetica Chimica Acta, 2017, vol. 100, # 3,
[9] Green Chemistry, 2017, vol. 19, # 2, p. 474 - 480
2
[ 149946-79-2 ]
[ 711-33-1 ]
Reference：
[1] Organic Letters, 2015, vol. 17, # 24, p. 6102 - 6105
[2] Green Chemistry, 2010, vol. 12, # 9, p. 1628 - 1633
3
[ 402-43-7 ]
[ 104863-65-2 ]
[ 711-33-1 ]
Reference：
[1] Angewandte Chemie, International Edition, 2009, vol. 48, p. 4543 - 4545[2] Angewandte Chemie, 2009, vol. 121, p. 4613 - 4615
4
[ 392-83-6 ]
[ 123-62-6 ]
[ 711-33-1 ]
Yield
Reaction Conditions
Operation in experiment
34.5 %Chromat.
Stage #1: With ethylmagnesium bromide; magnesium; lithium chloride In tetrahydrofuran; ethyl bromide at 45 - 50℃; for 5 h; Inert atmosphere Stage #2: at 20 - 30℃; for 2 h; Inert atmosphere
General procedure: To a 200 ml-four-necked flask with a thermometer,75.0 g of tetrahydroffiran (1.04 mol; manufactured by Nacalai Tesque, Inc.), 5.1 g of magnesium powder (0.208 mol; manufactured by Chuo-kosan), 1.7 g of LiC1 (0.04 mol; manufactured by Nacalai Tesque, Inc.) were placed and the mixture was stirred while the inside of the system was substituted with a nitrogen gas. To this, 0.5 g of 1 mol/L ethylmagnesium bromide THF solution (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and water in the system was removed. Subsequently, 0.44 g of ethyl bromide (0.004 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred for a while; and the generation of heat was confirmed. Subsequently, 36.1 g of o-chlorobenzotrifluoride (0.2 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was gradually added dropwise, while the temperature of the reaction solution was kept at 45 to 50° C. After the completion of the dropwise addition, the mixture was allowed to mature while stirred at 45° C. for five hours, thereby obtaining a Grignard reagent solution.10043] Next, to a 200 ml-four-necked flask with a thermometer, 30.6 g of acetic anhydride (0.3 mol; manufactured by Wako Pure Chemical Industries, Ltd.), 10.8 g of toluene (0.3 fold by weight/o-chlorobenzotrifluoride: manufactured by Wako Pure Chemical Industries, Ltd.) were placed and the mixture was stirred in a water bath while the inside of the system was substituted with a nitrogen gas. To this, the above Grignard reagent solution was added dropwise while the temperature of the reaction solution was controlled so as to be 20 to 30° C. The entire volume of the Grignard reagent solution was added dropwise and then the mixture was stirred at 25° C. for two hours. After the completion of the stirring, the temperature of the reaction solution was decreased to room temperature; and 39.2 g of 3percent hydrogen chloride aqueous solution was gradually added dropwise thereto in a water bath. Afier the dropwise addition, the hydrolysis was completed by stirring for one hour. After the hydrolysis, the stirring was stopped; and the resultant was lefi to stand for separation, thereby obtaining an oil phase containing o-trifluoromethyl acetophenone. The obtained oil phase was analyzed by a gas chromatography method (GC) and as a result, the yield of 2’-trifluoromethyl acetophenone reaction was 82.7percent (based on the raw material, o-chlorobenzotrifluoride). A reaction was carried out in the same manner as described in Example 1 except that 36.1 g (0.2 mol) of o-chlorobenzotrifluoride was altered to 45.0 g (0.2 mol) of o-bromobenzotrifluoride in Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 2’-tri- fluoromethyl acetophenone reaction was 85.5percent (based on the raw material, o-bromobenzotrifluoride). [0054] A reaction was carried out in the same manner as described in Comparative Example 1 except that 45.0 g (0.2 mol) of m-bromobenzotrifluoride was altered to 45.0 g (0.2 mol) of p-bromobenzotrifluoride in Comparative Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 4’-trifluoromethyl acetophenone reaction was 40.0percent (based on the raw material, p-bromobenzotrifluoride). [0055] A reaction was carried out in the same manner as described in Comparative Example 2 except that 30.6 g (0.3 mol) of acetic anhydride was altered to 39.0 g (0.3 mol) of propionic anhydride in Comparative Example 2. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 4’-trifluoromethyl propiophenone was 34.5percent (based on the raw material,p-bromobenzotrifluoride).
The 1- (p-trifluoromethylphenyl) -1-propanol solution prepared in step 1 was mixed with 3.9 kg of tetrabutylammonium hydrogen sulfate and 12.3 kg of sodium phosphate dihydrate monobasic, which were dissolved in 32 liters of purified water. After the mixture was washed by the addition of 10 liters of purified water, 318 kg of 12percent sodium hyperchlorite was added to the mixture, followed by EPO <DP n="19"/>washing by adding 35 liters of purified water. After the resulting solution was allowed to stand for 30 min, the formed organic layer was mixed with 358 liters of purified water and 18 kg of 38percent hydrochloric acid, and stirred for 5 min. The separated organic layer was washed with purified water, and 378 kg of p-trifluoromethyl propiophenone was obtained from the organic layer (yield: 97.2percent).
With pyridinium chlorochromate; In diethyl ether; dichloromethane;
REFERENCE EXAMPLE 12 4-Trifluoromethylpropiophenone STR25 A solution of the compound obtained in reference example 11 (23 g, 0.11 mol) in CH2 Cl2 (60 mL) was added dropwise to a suspension of PCC (36.6 g, 0.17 mol, 1.5 eq) and celite (35 g) in CH2 Cl2 (260 mL) at room temperature. The mixture was stirred for 1 h and then diethyl ether (500 mL) was added. The resulting mixture was filtered through celite, washed with aqueous NaOH solution, dried and concentrated to a dark brown oil (20.7 g, 95percent mass balance) that was used in the next step without further purification. 1 H NMR (80 MHz, CDCl3) delta (TMS): 8.05 (d, J=8.2 Hz, 2H, arom), 7.71 (d, J=8.2 Hz, 2H, arom), 3.04 (q, J=7.1 Hz, 2H, CH2), 1.24 (t, J=7.1 Hz, 3H, Me).
(4,6-Dimethyl-pyrimidin-5-yl)-(4-methyl-4-{(S)-3-methyl-4-[(S)-1-(4-trifluoromethyl-phenyl)-propyl]-piperazin-1-yl}-piperidin-1-yl)-methanone[ No CAS ]
(2R*,3R*)-2-<4-(trifluoromethyl)phenyl>-3-<N-<(benzyloxycarbonyl)methyl>-N-<4-(trifluoromethyl)benzoyl>amino>-1-(1H-1,2,4-triazol-1-yl)-2-butanol[ No CAS ]
88A) 1-(1-Methylenepropyl)-4-(trifluoromethyl)-benzene To a stirred suspension of methyltriphenylphosphonium bromide (3.53 g, 9.89 mmol) in THF (30 ml) was added potassium tert-butoxide (1.11 g, 9.89 mmol) in THF (10 ml) dropwise at 0° C. and the mixture was stirred at ambient temperature for 2 hours. Then, to this mixture was added 4-(trifluoromethyl)propiophenone (Aldrich, 1.00 g, 4.95 mmol) in THF (10 ml) at 0° C. and stirred at ambient temperature for 2 hours. The reaction was quenched with small amount of water and evaporated to remove the solvent. The crude mixture was diluted with hexane. The formed precipitates were filtered and the organic layer was separated. After evaporation of solvent, residue was applied to a silica gel chromatography column and eluted with hexane to afford 1.12 g (crude 100percent) of the title compound as a red oil. 1H NMR (270 MHz, CDCl3) delta ppm 1.11 (3H, t, J=7.2 Hz), 2.53 (2H, q, J=7.2 Hz), 5.17 (1H, s), 5.34 (1H, s), 7.51 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz).
With sodium chloride; iodine; magnesium; In thionyl chloride; diethyl ether; benzene;
EXAMPLE 8 2-Bromo-4'-trifluoromethylpropiophenone 43.5 g (0.229 mol) of 4-trifluoromethylbenzoic acid are introduced in portions into a 500 ml three-necked flask equipped with a magnetic stirrer and containing 150 ml of thionyl chloride, and the mixture is then heated gradually to about 70° C. After 6 hours at this temperature, the mixture is left to stand for 20 hours and the excess thionyl chloride is then driven off in vacuo. The oily residue is then distilled under a pressure of 130 to 650 Pa. A colourless fraction consisting of 42.1 g of 4-trifluoromethylbenzoyl chloride is collected at between 36° and 40° C. A crystal of iodine is added to a suspension of 9.6 g of magnesium turnings, previously ground in a mortar, in 120 ml of dry diethyl ether, and a solution of 43.6 g (0.4 mol) of ethyl bromide in 80 ml of dry diethyl ether is then added slowly, the mixture being cooled at the same time in order to limit the reflux of the solvent. The mixture is then heated under reflux for half an hour and cooled to 5° C. and 36.7 g of cadmium chloride, dried beforehand, are added in portions. The resulting reaction is very exothermic; the temperature of the mixture is kept below 10° C. A further 100 ml of diethyl ether are added in order to make the mixture more fluid. The mixture is heated under reflux for 40 minutes and left to stand overnight at ambient temperature. The diethyl ether is then evaporated off in vacuo, the pasty residue is taken up in 140 ml of dry benzene, the mixture obtained is cooled to between 5° and 10° C. and a solution of 41.7 g (0.2 mol) of the previously prepared 4-trifluoromethylbenzoyl chloride in 60 ml of dry benzene is added slowly so as to keep the temperature below 10° C. After this addition, the mixture is allowed to return to ambient temperature, stirring being continued for one hour in order to homogenize it, and then heated for two hours under reflux. The mixture is cooled in an ice bath to 10° C. and then poured into an ice saturated solution of sodium chloride, with stirring. The precipitate which forms is filtered off and washed with diethyl ether. The phases of the filtrate are separated by decantation and the milky aqueous phase is extracted with diethyl ether. The organic phases are combined, extracted with dilute sodium hydroxide solution, washed, dried over sodium sulphate and concentrated in vacuo. After distillation under a vacuum of about 6.5 Pa at between 50° and 56° C. and recrystallization from petroleum ether, 14.4 g of white crystals of 4'-trifluoromethylpropiophenone melting at 36°-37° C. are obtained.
(a) Preparation of alpha-chloro-4-trifluoromethylpropiophenone 4-trifluoromethylpropiophenone (26.3 g.) was dissolved in carbon tetrachloride (25 cm3) and stirred at the ambient temperature. Sulphuryl chloride (19.3g 1.1 eq) in carbon tetrachloride (5 cm3) was added. The mixture was heated to 90° C. for 4 hours then allowed to cool. The mixture was concentrated by evaporation of the solvent to give a colourless oil 30.5 g. (99percent) This material was 93percent pure by n.m.r., minor amounts of starting material and dichlorinated material being present.
1-(4-Trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1-propanone hydrochloride To a mixture of 2.50 g of <strong>[711-33-1]1-(4-trifluoromethylphenyl)-1-propanone</strong>, 1.11 g of paraformaldehyde, 1.60 g of pyrrolidine hydrochloride and 20 ml of isopropanol was added 0.1 ml of concentrated hydrochloride acid, and the resulting solution was heated under reflux for 16 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure to give the residue. To the resulting residue was added with water and washed with ethyl acetate. The aqueous layer was alkalized with aqeous ammonia, and then was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium salfate, and then was evaporated under reduced pressure to give 1.58 g (44.8percent) of 1-(4-trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1-propanone as an oil. Mass m/z (relative intensity): 285 (2.21, M+), 214 (100), 173 (100), 145 (100), 95 (29.7), 84 (100)
(R,S)-2-methyl-3-pyrrolidino-1-(4-trifluoromethylphenyl)-propan-1-one hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.58 g (44.8%)
With paraformaldehyde; In isopropyl alcohol;
1-(4-Trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1-propanone hydrochloride To a mixture of 2.50 g of <strong>[711-33-1]1-(4-trifluoromethylphenyl)-1-propanone</strong>, 1.11 g of paraformaldehyde, 1.60 g of pyrrolidine hydrochloride and 20 ml of isopropanol was added 0.1 ml of concentrated hydrochloride acid, and the resulting solution was heated under reflux for 16 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure to give the residue. To the resulting residue was added with water and washed with ethyl acetate. The aqueous layer was alkalized with aqeous ammonia, and then was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sa lfate, and then was evaporated under reduced pressure to give 1.58 g (44.8percent) of 1-(4-trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1-propanone as an oil. This oil was dissolved in ethyl ether and gaseous hydrogen chloride introduced into the solution to give the corresponding hydrochloride salt.
EXAMPLE 2 1-(4-Trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1-propanone (Compd. No. 4-1) hydrochloride. A mixture of <strong>[711-33-1]1-(4-trifluoromethylphenyl)-1-propanone</strong> (2.50g), paraformaldehyde (1.10g), pyrrolidine hydrochloride (1.60g), and hydrochloric acid (0.1 ml) was refluxed for 16 hours. The mixture was evaporated in vacuo to give the residue. The residue was partitioned into water and ethyl acetate. The aqueous layer was neutralized with ammonia water and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated in vaccuo to give 1-(4-trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1propanone (1.58g; yield: 44.8percent) as an oil. IR numaxneat: 1690 cm-1 STR321 Mass m/z (relative intensity): 285 (2.21, M+), 214 (100); 173 (100), 145 (100), 95 (29.7), 84 (100).
REFERENCE EXAMPLE 2 4-Trifluoromethylpropiophenone A solution of the compound obtained in reference example 1 (23 g, 0.11 mol) in dichloromethane (60 mL) was added dropwise to a suspension of pyridiniumchlorochromate (PCC) (36.6 g, 0.17 mol) and celite (35 g) in dichloromethane (260 mL) at room temperature. The mixture was stirred for 1 h and then diethyl ether (500 mL) was added. The resulting mixture was filtered through celite, washed with aqueous NaOH solution, dried and concentrated. The title compound of the example was obtained as a dark brown oil (20.7 g). 1H RMN (80 MHz, CDCl3) delta (TMS): 8.05 (d, J= 8.2 Hz, 2H, arom), 7.71 (d, J= 8.2 Hz, 2H, arom), 3.04 (q, J=7.1 Hz, 2H, CH2), 1.24 (t, J=7.1 Hz, 3H, Me).
With hydrogenchloride; In ethanol; water; for 0.5h;Heating / reflux;
The p-trifluoromethyl propiophenone solution of 378 kg, prepared in step 2, was supplemented with 90 kg of ethanol, 17.8 kg of 95percent paraformaldehyde, 3.6 kg of 38percent hydrochloric acid, and 50.6 kg of pyrrolidine, and was stirred for 30 min under reflux. Then, 184 liters of purified water and 14.6 kg of 38percent hydrochloric acid were added to the solution, and an organic layer was separated and washed with 184 liters of purified water. The separated aqueous layer was mixed with 2.2 kg of activated charcoal, filtered, and washed with 32 liters of purified water. 42.4 kg of edible salt was added to the filtrate and dissolved therein. Then, the filtrate was supplemented with 67.9 kg of 25percent aqueous ammonia, and stirred for 30 min to separate an organic layer. The organic layer was washed with 300 kg of 10percent saline, and concentrated under pressure, thereby obtaining 117.5 kg of 2-methyl-3- (1-pyrrolidinyl) -4 '- trifluoromethylpropiophenone in oil phase (yield: 88.3percent).
3-(3-Oxopiperazin-1-ylmethyl)-2-(4-trifluoromethylphenyl)quinoline-4-carboxylic Acid ((S)-1-cyclohexylethyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 45 3-(3-Oxopiperazin-1-ylmethyl)-2-(4-trifluoromethylphenyl)quinoline-4-carboxylic Acid ((S)-1-cyclohexylethyl)-amide The compound was prepared following the procedure of Example 26 starting from 1-(4-trifluoromethylphenyl)-propan-1-one (CAS [711-33-1]) and isatin (CAS [91-56-5]) according to Description 23-25).
With methanol; sodium tetrahydroborate; at 20℃; for 3h;
To 4-trifluoromethylpropiophenone (1.0 g, 5.0 mmol) in MeOH (25 mL, 0.20 M), was added NaBH4 (187 mg, 5,0 mmol). After 3 hours at RT, the reaction was concentrated in vacuo, partitioned between H2O and CH2Cl2, dried, filtered and concentrated to give the title compound as a white solid (0.97 g, 96percent). 1H NMR (300 MHz, CHLOROFORM-D) delta ppm 0.93 (t, J=7.54 Hz, 3 H) 1.71-1.85 (m, 2 H) 1.85-1.92 (m, 1 H) 4.69 (td, J=6.41, 3.39 Hz, 1 H) 7.44-7.50 (m, 2 H) 7.61 (d, J=8.29 Hz, 2 H).
96%
c) l-(4-Trifluoromethyl-phenyl)-propan-l-olTo 4-trifluoromethylpropiophenone (1.0 g, 5.0 mmol) in MeOH (25 mL, 0.20 M), was added NaBH4 (187 mg, 5,0 mmol). After 3 hours at RT, the reaction was concentrated in vacuo, partitioned between H2O and CH2Cl2, dried, filtered and concentrated to give the title compound as a white solid (0.97 g, 96percent). 1H NMR (300 MHz, CHLOROFORM-D) delta ppm 0.93 (t, J=7.54 Hz, 3 H) 1.71 - 1.85 (m, 2 H) 1.85 - 1.92 (m, 1 H) 4.69 (td, J=6.41, 3.39 Hz, 1 H) 7.44 - 7.50 (m, 2 H) 7.61 (d, J=8.29 Hz, 2 H).
INTERMEDIATE PREPARATION 6; methyl 3-methyl-6-(methylsulfonyl)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate6-bromo-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid5-Bromoisatin (198 g, 788 mmol) was dissolved in ethanol (1.2 L) in a 6L conical jacketed lab reactor equipped with a mechanical stirrer and an internal temperature probe. A solution of KOH (265 g, 4730 mmol) in water (0.480 L) was added slowly via addition funnel over ca. 1 hour, such that the vessel temperature was maintained at 20 °C. 1-[3- (Trifluoromethyl)phenyl]-1-propanone (159 g, 788 mmol) was added in one portion and the reactor was heated to reflux for 1 h. The reaction mixture was cooled to 20 °C and acidified to pH ~ 2 by addition of 450 mL of concentrated HCI. An additional 1.5 L of 50percent EtOH/H20 was added to facilitate filtration. The slurry was filtered and the filter cake was rinsed twice with 1 L portions of 50percent EtOH/water. The solid was dried in vacuo to give 6-bromo-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (281.7 g, 87 percent yield) as a fine off-white solid. MS (m/z) 412.7 (M+H+).
With silver (II) carbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; lithium acetate; palladium diacetate; tricyclohexylphosphine; In 1,2-dimethoxyethane; at 100℃; for 24h;Schlenk technique; Inert atmosphere;
General procedure: In a glove box, a 25 mL of Schlenk tube equipped with a stir bar was charged with Pd(OAc)2 (0.03 mmol, 0.1 equiv), PCy3 (0.03 or 0.06 mmol, 0.1 or 0.2 equiv), LiOAc (0.45 mmol, 1.5 equiv) (or NaOAc), TEMPO (0.12 mmol, 0.4 equiv), Ag2CO3 (0.9 mmol, 3 equiv). The tube was fitted with a rubber septum and removed out of the glove box. DME (2 mL), propiophenone (0.9 mmol, 3.0 equiv) and thiophene (0.3 mmol, 1.0 equiv) were added in turn to the Schlenk tube through the rubber septum using syringes, and then the septum was replaced with a Teflon screwcap under nitrogen flow (if the thiophene or the substituted propiophenone was solid, it was added to the tube in the glove box). The reaction mixture was stirred at 100 oC or 120 oC for 24 h. After cooling down, the reaction mixture was diluted with 10 mL of ethyl ether, filtered through a pad of silica gel, followed by washing the pad of the silica gel with the same solvent (20 mL), concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel with 2-15 percent ethyl ether in petroleum ether as eluent to provide the corresponding product.
General procedure: A mixture of the lithium salt of the corresponding ethyl 3-methyl-2,4-dioxo-4-phenylbutanoate (13.8mmol) and substituted phenylhydrazine (15.6mmol) were suspended in 50mL of EtOH and H2SO4 was added dropwise in an ice bath. The mixture was heated to reflux and stirred until the starting material was completely consumed. The resulting solution was cooled to room temperature and the excess of ethanol was removed in vacuo. 20mL of water was added and the suspension was neutralized with NaHCO3 and then extracted with CHCl3 (3×20mL). The organic layer was successively dried over Na2SO4, filtered and concentrated in vacuo. The residue containing the ester product was then dissolved in 20mL of EtOH and KOH (23mmol) was added. The mixture was allowed to react 12h at 50°C. The resulting suspension was concentrated in vacuo and dissolved in 30mL of water and later washed with hexane (3×15mL). The aqueous layer was acidified with concentrated HCl until the pure carboxylic acids precipitated.
General procedure: A mixture of the lithium salt of the corresponding ethyl 3-methyl-2,4-dioxo-4-phenylbutanoate (13.8mmol) and substituted phenylhydrazine (15.6mmol) were suspended in 50mL of EtOH and H2SO4 was added dropwise in an ice bath. The mixture was heated to reflux and stirred until the starting material was completely consumed. The resulting solution was cooled to room temperature and the excess of ethanol was removed in vacuo. 20mL of water was added and the suspension was neutralized with NaHCO3 and then extracted with CHCl3 (3×20mL). The organic layer was successively dried over Na2SO4, filtered and concentrated in vacuo. The residue containing the ester product was then dissolved in 20mL of EtOH and KOH (23mmol) was added. The mixture was allowed to react 12h at 50°C. The resulting suspension was concentrated in vacuo and dissolved in 30mL of water and later washed with hexane (3×15mL). The aqueous layer was acidified with concentrated HCl until the pure carboxylic acids precipitated.
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