* 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.
With triethylamine In dimethyl sulfoxide at 80℃; for 14 - 16 h;
Example 139 Synthesis of 5- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-7-trifluoromethyl-2, 3,4, 5- tetrahydro-benzo [b] azepine-1-carboxylic acid tert-butyl ester. Step 1. Preparation of Methyl-3-trifluoromethyl-2-aminobenzoate Add palladium (II) acetate (1.89 g, 8.4 mmol), 1,1- bis (diphenylphosphino) ferrocene (6.83 g, 12.3 mmol), and triethyl amine (32 mL, 44.0 mmol) to a solution of 2-bromo-4-trifluoromethylanaline (10.0 g, 42.0 mmol) in dimethylsulfoxide (283 mL) and methanol (187 mL). At 100 psi of carbon monoxide, heat the mixture to 80 °C. After heating for 14-16 h cool the reaction to room temperature and filter. Dilute the organics with ethyl acetate (500 mL), wash with water (3x200 mL) and brine (200 mL). Dry the organics over sodium sulfate and filter. Remove solvent under vacuum and chromatograph the crude product using ethyl acetate/hexane (10 percent) to elute. This provides the title compound (8.0 g, 88percent) as an off white solid: H NMR (CDC13,400 MHz) 8 3.93 (s, 3H), 6.11 (bs, 2H), 6.73 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 2.0, 8.4 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H).
Step 3 Methyl 2-amino-5-(trifluoromethyl)benzoate To a solution of 2-amino-5-(trifluoromethyl)benzoic acid (400 mg, 1.95 mmol) in MeOH (10 mL) at RT was added cone. H2SO4 (1 mL). The reaction was heated at reflux for 18 h, cooled to RT then diluted with EA (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over Na2S04 and concentrated to give methyl 2-amino-5-(trifluoromethyl)benzoate (400 mg, 94.0percent yield) as a yellow oil. Used without further purification.
51%
at 125℃; for 2 h; Microwave irradiation
A solution of 2-amino-5-(trifluoromethyl)benzoic acid (1.07 g, 5.2 mmoles) in methanol (20 ml) was treated with concentrated sulphuric acid (0.5 ml) and heated under microwave conditions at 125° C. for 2 h. The mixture was evaporated to dryness and treated with water (100 ml) then basified to saturation with potassium carbonate and extracted with ethyl acetate (2*40 ml). The combined extracts were dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 1 as a colorless oil (0.59 g, 51percent). 1H-NMR (CDCl3, 300 MHz) δ 8.15 (s, 1H, ArH), 7.47 (dd, J=2 and 9 Hz, 1H, ArH), 6.72 (d, J=9 Hz, 1H, ArH), 5.62-5.95 (brs, 2H, NH2), 3.92 (s, 3H, CH3).
methyl 5-trifluoromethyl-2-[(trifluoromethyl)sulfonylamino]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With triethylamine; In dichloromethane; at -78 - 20℃;
To a solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (0.25 g, 1.141 mmol) and triethylamine (0.115 g, 0.16 ml, 1.14 mmol) in 3 ml of dry dichloromethane was added trifluoromethane sulfonic anhydride (0.64 g, 2.28 mmol) at -78 C. The mixture was maintained below -40 C. for 3 h and stirred at RT for over night. Water was added and extracted with dichloromethane. The organic layer was dried and concentrated. The product was purified by flash chromatography to give 0.3 g (75%) of methyl 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoate as white solid. MS found: (M+H)+=352.
75%
With triethylamine; In dichloromethane; at -78 - 20℃;
Preparation B6, Step 3: To a solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (0.25 g, 1.141 mmol) and triethylamine (0.115 g, 0.16 ml, 1.14 mmol) in 3 ml of dry dichloromethane was added trifluoromethane sulfonic anhydride (0.64 g, 2.28 mmol) at -78 C. The mixture was maintained below -40 C. for 3 h and stirred at RT for over night. Water was added and extracted with dichloromethane. The organic layer was dried and concentrated. The product was purified by flash chromatography to give 0.3 g (75%) of methyl 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoate as white solid. MS found: (M+H)+=352.
To a solution of N-(4-(trifluoromethyl)phenyl)pivalamide (1 g, 4.08 mmol) in 20 ml of dry THF under nitrogen was added n-butyllithium (0.65 g, 4.1 ml) at 0 C. The reaction mixture was maintained at 0 C. for 3 h and added onto dry ice and stirred at RT over night. The reaction mixture was concentrated and the solid product obtained was dissolved in 25 ml of dry methanol and purged HCl gas for 30 min at 0 C. The mixture was stirred at RT for 2 h and heated at 55 C. over night. The reaction mixture was concentrated, basified with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. The crude product was purified by flash chromatography to give methyl 2-amino-5-(trifluoromethyl)benzoate (0.55 g) as white solid.
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In dimethyl sulfoxide; at 80℃; under 5171.62 Torr; for 14 - 16h;
Example 139 Synthesis of 5- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-7-trifluoromethyl-2, 3,4, 5- tetrahydro-benzo [b] azepine-1-carboxylic acid tert-butyl ester. Step 1. Preparation of Methyl-3-trifluoromethyl-2-aminobenzoate Add palladium (II) acetate (1.89 g, 8.4 mmol), 1,1- bis (diphenylphosphino) ferrocene (6.83 g, 12.3 mmol), and triethyl amine (32 mL, 44.0 mmol) to a solution of 2-bromo-4-trifluoromethylanaline (10.0 g, 42.0 mmol) in dimethylsulfoxide (283 mL) and methanol (187 mL). At 100 psi of carbon monoxide, heat the mixture to 80 C. After heating for 14-16 h cool the reaction to room temperature and filter. Dilute the organics with ethyl acetate (500 mL), wash with water (3x200 mL) and brine (200 mL). Dry the organics over sodium sulfate and filter. Remove solvent under vacuum and chromatograph the crude product using ethyl acetate/hexane (10 %) to elute. This provides the title compound (8.0 g, 88%) as an off white solid: H NMR (CDC13,400 MHz) 8 3.93 (s, 3H), 6.11 (bs, 2H), 6.73 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 2.0, 8.4 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H).
With triethylamine; In dichloromethane; at 20℃; for 72h;
Step 2. Preparation of Methyl-3-trifluoromethyl-2-t-butoxycarbonylaminobenzoate. Add di-t-butyl dicarbonate (2.0 g, 9.1 mmol) to a solution of methyl-3- trifluoromethyl-2-aminobenzoate (2.0 g, 9.1 mmol) in dichloromethane (20 mL). To this mixture, add triethylamine (9.1 mmol) and stir at room temperature under an atmosphere of nitrogen for 72 h. Dilute the reaction with dichloromethane (100 mL) and wash with water (100 mL x 2). Dry the separated organic phase over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product on silica gel using hexane/ethyl acetate (gradient, 2-10 % ethyl acetate/hexane) to elute. This provides the title compound as a colorless solid (1.43 g, 49%) : H NMR (CDCl3, 400 MHz) 8 1.54 (s, 9H), 3.99 (s, 3H), 7.75 (dd, J = 2.0, 9.2 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 9.2 Hz), 10.48 (s, 1H).
REFERENCE EXAMPLE 28 Methyl 2-Amino-5-trifluoromethylbenzoate To a solution of methyl 2-t-butoxycarbonylamino-5-trifluoromethylbenzoate (3.80 g; prepared in Reference Example 27.) in methylene chloride (30 ml), trifluoroacetic acid (6 ml) was added. The mixture was stirred for 8 hours at room temperature. The solvent was distilled off azeotropically with toluene three times. To the reaction mixture, an aqueous sodium hydrogencarbonate solution was added to neutralize. The mixture was extracted with ethyl acetate, washed, dried, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt 5:1) to give the title compound (2.35 g) having the following physical data. TLC: Rf 0.20 (hexane:AcOEt=5:1).
2-(N-pivaloyl)-5-trifluoromethylbenzoic acid[ No CAS ]
[ 117324-58-0 ]
Yield
Reaction Conditions
Operation in experiment
4.0 g (71%)
In methanol; chloroform;
PREPARATION 39 Methyl 2-Amino-5-trifluoromethylbenzoate A solution of 7.46 g (0.026 mol) of 2-(N-pivaloyl)-5-trifluoromethylbenzoic acid in 300 ml of methanol was cooled to 5 C. and saturated with gaseous hydrochloric acid. The reaction mixture was then heated at reflux for 20 hours, and evaporated to a solid. The crude solid was dissolved in chloroform and washed with saturated aqueous sodium bicarbonate. The organic layer was dried and evaporated to a viscous oil, which was purified by silica gel chromatography (9:1 hexane:ethylacetate). The title compound was isolated as a white solid, m.p. 51-52 C.; yield 4.0 g (71%).
With triethylamine;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 50℃; for 120h;
Step 1 Synthesis of [2-iodo-5-(trifluoromethyl)phenyl]methanol 2-Iodo-4-(trifluoromethyl)aniline (8.0 g, 27.9 mmol), methanol (5 ml) and triethylamine (10 ml) were dissolved in dimethylformamide (50 ml) and, under a carbon monoxide atmosphere, tetrakis(triphenylphosphine)palladium (1.6 g, 1.4 mmol) was added and the mixture was stirred at 50C for 5 days. The solvent was evaporated and work-up according to a conventional method gave a crude product of methyl 2-amino-5-(trifluoromethyl)benzoate.
With triethylamine; In dichloromethane; at 0 - 20℃;
Step 1 Synthesis of methyl {2-(cyclopropylcarbonyl)amino-5-trifluoromethyl}benzoate Methyl 2-amino-5-(trifluoromethyl)benzoate (0.20 g, 0.91 mmol) obtained as an intermediate for Step 1 of Example 7 was dissolved in methylene chloride (10 ml), triethylamine (0.25 ml, 1.82 mmol) and cyclopropanecarbonyl chloride (0.11 g, 1.1 mmol) were added at 0C, and the mixture was stirred overnight at room temperature. After work-up according to a conventional method, the mixture was purified by silica gel column chromatography (10% to 30% mixed solvent of ethyl acetate/hexane) to give the title compound (0.10 g, 0.35 mmol).
The obtained crude product was dissolved in tetrahydrofuran (20 ml), lithium aluminum hydride (1.0 g, 26.3 mmol) was added under cooling, and the mixture was stirred for 2 hr. Water (1 ml), 30% aqueous sodium hydroxide solution (1 ml) and water (3 ml) were sequentially added, the precipitate was filtered off, and the filtrate was concentrated to give a crude product of [2-amino-5-(trifluoromethyl)phenyl]methanol.
Preparation B6, Step 2: To a solution of N-(4-(trifluoromethyl)phenyl)pivalamide (1 g, 4.08 mmol) in 20 ml of dry THF under nitrogen was added n-butyllithium (0.65 g, 4.1 ml) at 0° C. The reaction mixture was maintained at 0° C. for 3 h and added onto dry ice and stirred at RT over night. The reaction mixture was concentrated and the solid product obtained was dissolved in 25 ml of dry methanol and purged HCl gas for 30 min at 0° C. The mixture was stirred at RT for 2 h and heated at 55° C. over night. The reaction mixture was concentrated, basified with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. The crude product was purified by flash chromatography to give methyl 2-amino-5-(trifluoromethyl)benzoate (0.55 g) as white solid.
With sulfuric acid; for 18h;Reflux; Inert atmosphere;
Step 3 Methyl 2-amino-5-(trifluoromethyl)benzoate To a solution of 2-amino-5-(trifluoromethyl)benzoic acid (400 mg, 1.95 mmol) in MeOH (10 mL) at RT was added cone. H2SO4 (1 mL). The reaction was heated at reflux for 18 h, cooled to RT then diluted with EA (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over Na2S04 and concentrated to give methyl 2-amino-5-(trifluoromethyl)benzoate (400 mg, 94.0% yield) as a yellow oil. Used without further purification.
51%
With sulfuric acid; at 125℃; for 2h;Microwave irradiation;
A solution of 2-amino-5-(trifluoromethyl)benzoic acid (1.07 g, 5.2 mmoles) in methanol (20 ml) was treated with concentrated sulphuric acid (0.5 ml) and heated under microwave conditions at 125 C. for 2 h. The mixture was evaporated to dryness and treated with water (100 ml) then basified to saturation with potassium carbonate and extracted with ethyl acetate (2*40 ml). The combined extracts were dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 1 as a colorless oil (0.59 g, 51%). 1H-NMR (CDCl3, 300 MHz) delta 8.15 (s, 1H, ArH), 7.47 (dd, J=2 and 9 Hz, 1H, ArH), 6.72 (d, J=9 Hz, 1H, ArH), 5.62-5.95 (brs, 2H, NH2), 3.92 (s, 3H, CH3).
methyl 2-amino-3-iodo-5-(trifluoromethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N-iodo-succinimide; trifluoroacetic acid; at 20℃; for 18h;
A solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (0.59 g, 2.7 mmoles) in trifluoroacetic acid (5 ml) was treated with N-iodosuccinimide (0.68 g, 3.0 mmoles) and stirred at ambient temperature for 18 h. The mixture was evaporated to dryness and the residue treated with water (25 ml) and basified with potassium carbonate then extracted with dichloromethane (25 ml). The organic phase was then washed with 10% sodium metabisulphite solution (25 ml), separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 2 as a white solid (0.633 g, 68%). 1H-NMR (CDCl3, 300 MHz) delta 8.18 (d, J=3 Hz, 1H, ArH), 8.01 (d, J=3 Hz, 1H, ArH), 6.55-7.05 (brs, 2H, NH2), 3.92 (s, 3H, CH3).
methyl 2-(3-(3-(tert-butyldimethylsilyloxy)propyl)ureido)-5-(trifluoromethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.3%
Step 4 Methyl 2-(3-(3-(tert-butyldimethylsilyloxy)propyl)ureido)-5-(trifluoromethyl)benzoate To a solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (400 mg, 1.70 mmol) and TEA (2.4 mL, 1.7 mmol) in DCM (5 mL) at 0C was added triphosgene (200 mg, 0.68 mmol) portionwise. The reaction was warmed to RT, stirred for 1 h then 3-(tert-butyldimethylsilyloxy)propan-l- amine (480 mg, 2.36 mmol) was added. The reaction mixture was stirred at RT for 1 h, poured into water-ice (30 mL) and extracted with EA (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4 and concentrated to give methyl 2-(3-(3-(tert- butyldimethylsilyloxy)propyl)ureido)-5-(trifluoromethyl)benzoate (600 mg, 78.3% yield) as a yellow oil. Used without further purification.
With dmap; In tetrahydrofuran; at 26 - 32℃; for 4h;Inert atmosphere;
To a solution of compound 13a (0.92 g, 4.2 mmol) and Boc 2O (3.17 g, 14.7 mmol) in THF (15 mL) was added DMAP (256 mg, 2.1 mmol) at 26-32C. The reaction was stirred at 26-32C for 4 h. The reaction solution was concentrated in vacuum to give the crude residue, which was purified by column chromatography on silica gel (0-10%EtOAc in petroleum ether) to afford the desired product compound 13b (1.43 g, 81.2% yield) as an off-white solid. LCMS: Rt = 1.078 min in 5-95AB_220&254. lcm chromatography (MERCK RP-18e 25-2mm), MS (ESI) m/z= 442.1 [M+23] +. 1H NMR (400MHz, CDCl 3) delta 8.28 (d, J=1.6 Hz, 1H), 7.95 (dd, J=2.0, 8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.93 (s, 3 H), 1.36 (s, 18 H).
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenylamino)-1,3,5-triazin-2-ylamino)-4-methoxyphenyl)acrylamide[ No CAS ]
methyl 2-((4-(methylsulfonyl)phenyl)sulfonamido)-5-(trifluoromethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With indium; In acetonitrile; at 110℃; for 18h;
To a solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (0.261 g, 1.19 mmol) and 4-(methylsulfonyl)benzenesulfonyl chloride (0.300 g, 1.18 mmol) in 5 mL acetonitrile was added powdered indium metal (0.027 g, 0.24 mmol). The mixture was stirred at 110 C. for 18 hours. The reaction was then concentrated to a residue. The crude product was purified by silica flash chromatography to afford methyl 2-((4-(methylsulfonyl)phenyl)sulfonamido)-5-(trifluoromethyl)benzoate as a solid. LCMS-ESI- (m/z): [M-H]- calcd 436.01; found 436.18
methyl 2-(thiomorpholine-4-sulfonamido)-5-(trifluoromethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a mixture of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (512 mg, 2.3 mmol) in dichloromethane (11 mL) of was added chlorosulfonic acid (170 muL, 2.6 mmol) followed by phosphorus pentoxide (535 mg, 2.6 mmol). The mixture was heated at 75 C. block overnight. After cooling, the reaction mixture was added to a solution of triethylamine (0.81 mL, 5.8 mmol) in dichloromethane (5 mL) that was cooled in an ice-water bath. A mixture of N,N-diisopropylethylamine (0.81 mL, 4.7 mmol) and thiomorpholine (244 muL, 2.6 mmol) in dichloromethane (5 mL) was added to the mixture, which was then stirred at 0 C. for 45 minutes. The cooling bath was removed, and the mixture was allowed to warm to room temperature. Ethyl acetate and saturated aqueous sodium chloride solution were added, and the layers were separated. The organic phase was washed once each with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to a residue, which was then purified by flash chromatography (silica gel) to provide the desired intermediate. LCMS-ESI- (m/z): [M-H]- calcd 383.04; found 383.18
(S)-methyl 2-(2-acetoxypropionylamino)-5-trifluoromethyl benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
In diethyl ether; at -10 - 20℃; for 3h;
To a stirred suspension of S-<strong>[117324-58-0]methyl 2-amino-5-trifluoromethylbenzoate</strong> (4.2 g, 19.2 mmol) in diethyl ether (300 mL), compound 3(11.56 g, 76.8 mmol) was added dropwise at - 10-0C. The reaction mixture was stirred at room temperature for 3h. After the completion of reaction (monitored by TLC), mixture was washed with hydrochloric acid, water, NaHCO3 solution,and aqueous saturated sodium chloride then dried over Na2SO4. The dried extract was filtered and concentrated under reduced pressure to give S-methyl 2-(2-acetoxypropionyl amino)-5-trifluoromethyl benzoate compound 4 (5.87 g, 92.0%).
methyl 2-(N-(methylsulfonyl)methylsulfonamido)-5-(trifluoromethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In dichloromethane; at 20℃; for 672h;
A solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (1.5 g, 6.9 mmol) in dichloromethane (20 mL) was treated successively with pyridine (5.6 mL, 69 mmol) and methanesulfonyl chloride (5.4 mL, 69 mmol). The mixture was alternately stirred magnetically and allowed to stand for four weeks at room temperature. The reaction mixture was treated with 10% hydrochloric acid (approximately 30 mL), stirred for 15 minutes, and then diluted with ethyl acetate. The entire mixture was filtered through a fritted pad of Celite diatomaceous earth. Next, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution (admixed with some 10% hydrochloric acid), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a mixture of the desired intermediate and bis-sulfonylated product (methyl 2-(N-(methylsulfonyl)methylsulfonamido)-5-(trifluoromethyl)benzoate), which was carried forward to hydrolysis without further purification.
A solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (1.5 g, 6.9 mmol) in dichloromethane (20 mL) was treated successively with pyridine (5.6 mL, 69 mmol) and methanesulfonyl chloride (5.4 mL, 69 mmol). The mixture was alternately stirred magnetically and allowed to stand for four weeks at room temperature. The reaction mixture was treated with 10% hydrochloric acid (approximately 30 mL), stirred for 15 minutes, and then diluted with ethyl acetate. The entire mixture was filtered through a fritted pad of Celite diatomaceous earth. Next, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution (admixed with some 10% hydrochloric acid), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a mixture of the desired intermediate and bis-sulfonylated product (methyl 2-(N-(methylsulfonyl)methylsulfonamido)-5-(trifluoromethyl)benzoate), which was carried forward to hydrolysis without further purification. Step 2: Preparation of 2-(methylsulfonamido)-5-(trifluoromethyl)benzoic acid (0473) A mixture containing both methyl 2-(N-(methylsulfonyl)methylsulfonamido)-5-(trifluoromethyl)benzoate and methyl 2-(methylsulfonamido)-5-(trifluoromethyl)benzoate (unknown ratio, assumed 6.9 mmol combined) was taken up as a suspension in tetrahydrofuran (30 mL) and treated with water and methanol (10 mL each) and then sodium hydroxide (1.7 g, 42 mmol) was added. Mixture was allowed to stand overnight and room temperature, and then on the following day, it was heated at 65 C. with stirring. Upon completion of the hydrolysis, the mixture was acidified with 10% hydrochloric acid and extracted three times with ethyl acetate (3×30 mL). The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The desired material was crystallized from methanol/water and dried under vacuum to provide the desired intermediate. LCMS-ESI- (m/z): [M-H]- calcd 282.01; found 282.02.
methyl 2-((1-(4-methoxyphenyl)pyrrolidin-2-ylidene)amino)-5-(trifluoromethyI)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
A solution of 1 -(4-methoxyphenyl)pyrrolidin-2-one (2.00 g, 10.5 mmol) in methylene chloride (20 ml_) was treated with phosphorous oxychloride (1.46 ml_, 15.7 mmol) and stirred under a nitrogen atmosphere at ambient temperature for 7 h. The mixture was treated with a solution of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (3.21 g, 14.6 mmol) in methylene chloride (20 ml_) and heated at 45 C for 2 d. After this time, the reaction mixture was allowed to cool to ambient temperature, quenched with saturated aqueous sodium bicarbonate (40 ml_), and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 12-100% ethyl acetate/heptane) to provide methyl 2-((1-(4-methoxyphenyl)pyrrolidin-2-ylidene)amino)-5-(trifluoromethyl)benzoate (2.19 g, 53%) as a clear gum: 1 H NMR (500 MHz, CDCIs) d 8.10 (s, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.56 (dd, J = 8.5, 1.5 Hz, 1H), 6.90 (d, J = 8.5 Hz, 3H), 3.88-3.85 (m, 5H), 3.79 (s, 3H), 2.47 (t, J = 7.5 Hz, 2H), 2.1 1-2.05 (m, 2H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
