2-[3-(Trifluoromethyl)benzoyl]aminoacetic acid synthesis
- Product Name:2-[3-(Trifluoromethyl)benzoyl]aminoacetic acid
- CAS Number:17794-48-8
- Molecular formula:C10H8F3NO3
- Molecular Weight:247.17
2251-65-2
56-40-6
17794-48-8
GENERAL STEPS: In a 12 L four-necked round-bottomed flask equipped with a thermocouple controller, mechanical stirrer, heating jacket, condenser tube, and nitrogen inlet and outlet fittings, glycine (1, Alfa Aesar) (318 g, 4.19 mol), acetonitrile (1.2 L), and sodium hydroxide solution (5.31 L, 10.62 mol) were added. The mixture was cooled with stirring to 4°C. A solution of 3-(trifluoromethyl)benzoyl chloride (2, Alfa Aesar) (885.0 g, 4.12 mol) dissolved in acetonitrile (0.75 L) was added slowly and dropwise over a period of 2 h (1.39 L in total) while the internal temperature was controlled to be between 4-6°C. The mixture was then purified with a mixture of 2.5 g, 4.12 mol and 3-(trifluoromethyl)benzoyl chloride (2, Alfa Aesar). The resulting slightly orange-pink colored solution was continued to be stirred at 4°C for 30 min. The reaction mixture was acidified to pH=3 with concentrated hydrochloric acid (400 mL of 37% HCl solution was added over 30 min, keeping the temperature between 0-6°C) and stirred at 0°C for 1 h until a slightly pale yellow suspension was formed. The solid was collected by filtration, washed with cold (0°C) deionized water (300 mL x 2), dried in air for 2 h, and placed in a 60°C drying oven. Drying under room vacuum (120 mmHg) for 20 h gave pure 2-(3-(trifluoromethyl)benzoylamino)acetic acid (3) as an off-white solid. The filtrate was extracted with ethyl acetate (1 L x 2), and the combined organic phases were washed with brine (300 mL), concentrated to 66°C at room temperature, and then concentrated under high vacuum (20 mmHg) to give the crude product as an off-white waxy solid. The crude product was ground, sonicated with toluene (1 L) and stirred at 10°C for 1 hour. The solid was collected by filtration, washed with hexane (50 mL x 2) and dried in a vacuum oven at 50°C to give additional pure 2-(3-(trifluoromethyl)benzoylamino)acetic acid (3) as an off-white solid. The structure of product 3 was confirmed by 1H-NMR.
2251-65-2
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56-40-6
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17794-48-8
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Yield: 95%
Reaction Conditions:
Stage #1:3-(Trifluoromethyl)benzoyl chloride;glycine with sodium hydroxide in acetonitrile at 4 - 6; for 2.5 h;
Stage #2: with hydrogenchloride in water;acetonitrile; pH=3 at 0 - 6; for 1.5 h;
Steps:
71.A
A 12-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen in/outlet adapter was charged with gycine (1, Alfa Aesar) (318 g; 4.19 mol), acetonitrile (1.2 L), and a solution of sodium hydroxide (5.31 L; 10.62 mo) and the mixture was cooled to 4° C. with stirring. A solution of 3-(trifluoromethyl)benzoyl chloride (2, Alfa Aesar) (885.0 g; 4.12 mol) (640 mL) in acetonitrile (0.75 L) (total 1.39 L) was added dropwise over 2 h while the internal temperature was maintained between 4-6° C., and the slightly orange-pinkish solution was stirred at 4° C. for an additional 30 min. The reaction was acidified to pH=3 with conc. 37% HCl solution (400 mL added over 30 min) at 0-6° C., and stirred for 1 h at 0° C. (until a slightly yellowish suspension resulted). The solid was collected by filtration, washed with cold (0° C.) deionized ("D.I") H2O (300 mL*2), dried under air-suction for 2 h, and then placed in a drying oven at 60° C. under house vacuum (120 mmHg) for 20 h to afford pure 3 as an off-white solid. The filtrate was extracted with EtOAc (1 L*2), and the combined organic phases washed with brine (300 mL), and concentrated at 66° C. under house vacuum and then high vacuum (20 mmHg) to give crude product as an off-white waxy solid, which was triturated and sonicated with toluene (1 L) and stirred at 10° C. for 1 h. The resulting solid was collected by filtration, washed with hexanes (50 mL*2), dried in an vacuum oven at 50° C. under house vacuum to afford additional pure title compound, 3, as an off-white solid. The structure of 3 was confirmed with its 1H-NMR.
References:
Zhang, Xuqing;Hufnagel, Heather Rae;Hou, Cuifen;Johnson, Dana L.;Sui, Zhihua;Fegely, Barry;Breslin, David US2010/144695, 2010, A1 Location in patent:Page/Page column 61-62