Trifluoroacetic acid → 1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid

To a solution of (4-chloro-3-fluoro-phenyl)-propynoic acid ethyl ester (57.08 g, 252 mmol) in dichloromethane (240 mL) was added trifluoroacetic acid (1.9 mL, 25.2 mmol). The reaction mixture was cooled with a water bath at ambient temperature and a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (93.43 g, 378 mmol) in dichloromethane (185 mL) was added dropwise over a period of 3 h. After stirring for 20 h at ambient temperature further N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (15.6 g, 63.0 mmol) in dichloromethane (30 mL) was added and stirring was continued for another 4 h. The solvent was removed and the residue was dissolved in dioxane (540 mL). After addition of water (270 mL) and aqueous sodium hydroxide (32%, 64.8 ml, 700 mmol), it was stirred for 44 h at ambient temperature. After concentration the resulting residue was diluted with water (225 mL) and extracted with tert-butylmethylether (225 mL). The organic layer was washed with water (225 mL) and the aqueous layer was cooled to 5° C. and set to pH=1.5 with aqueous hydrogen chloride (25%, 112 mL). After stirring for 1 h at 5° C., the resulting solid was filtered and washed with water (795 mL) and ethanol (225 mL). Drying gave a light yellow solid which was stirred with ethanol (4 L) for 1 h at 85° C. The resulting suspension was filtered and the filtrate was concentrated. Trituration with tert-butylmethylether (2 L) afforded the title compound (62.34 g, 67%) as an off-white solid. MS m/e: 330.1 [M−H]−.

1. additionwas added
2. customThe solvent was removed
3. dissolutionthe residue was dissolved in dioxane (540 mL)
4. stirringwas stirred for 44 h at ambient temperature
5. concentrationAfter concentration the resulting residue
6. additionwas diluted with water (225 mL)
7. extractionextracted with tert-butylmethylether (225 mL)
8. washThe organic layer was washed with water (225 mL)
9. temperaturethe aqueous layer was cooled to 5° C.
10. stirringAfter stirring for 1 h at 5° C.
11. filtrationthe resulting solid was filtered
12. washwashed with water (795 mL) and ethanol (225 mL)
13. customDrying
14. customgave a light yellow solid which
15. filtrationThe resulting suspension was filtered
16. concentrationthe filtrate was concentrated

ORD record

ord-c57d8fef3d504cbab704487c04bd19a2

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346786B2