tert-butyl 1-[(3-amino-4-chlorophenyl)methyl]cyclopropane-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 398.5 mg (1.56 mmol) of (3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 4.7 ml of DMF and 1.6 ml of pyridine, and 647.8 mg (1.70 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight. A further 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate and 647.8 mg (1.70 mmol) of HATU were added, and the reaction mixture was stirred at 50° C. for another 4 h. After dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water). This gave 453 mg of the target product (55.9% of theory, diastereomer ratio >8:1). were added at RT the reaction mixture was stirred at 50° C. for another 4 h After dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 50.0 g (134.4 mmol) of tert-butyl 1-[3-(benzylamino)-4-chlorobenzyl]cyclopropanecarboxylate were dissolved in 1.5 liters of ethyl acetate, and 1.43 g (1.34 mmol) of palladium (10% on carbon) were added. The reaction mixture was stirred at RT under a hydrogen atmosphere at standard pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1). The resulting product was stirred in a methanol/water mixture (70:30) and the solid was isolated. 24.3 g (64.1% of theory) of the target compound were obtained. The reaction mixture was then filtered off with suction through kieselguhr the filtrate was concentrated The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1) The resulting product was stirred in a methanol/water mixture (70:30) the solid was isolated 24.3 g (64.1% of theory) of the target compound were obtained

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 200 mg (0.71 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate were dissolved in 6 ml of dioxane, the mixture was inertized with argon and 122 mg (1.42 mmol) of cyclopropylboronic acid, 256 mg (1.21 mmol) of potassium phosphate, 5 mg (0.02 mmol) of tricyclohexylphosphine and 6.5 mg (0.007 mmol) of tris(dibenzylideneacetone)dipalladium were added. The reaction mixture was then stirred in a microwave apparatus (Biotage) at a target temperature of 150° C. for 1 h. The reaction was checked by TLC (mobile phase cyclohexane/ethyl acetate 4:1), after which a further 10 mg of tricyclohexylphosphine and 13 mg of tris(dibenzylideneacetone)dipalladium were metered in, and the reaction mixture was stirred at 150° C. for another 2 h. The mixture was then filtered through kieselguhr, the residue was washed with dioxane and the combined filtrate was concentrated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 120 mg (59% of theory) of the target compound. were added was stirred at 150° C. for another 2 h The mixture was then filtered through kieselguhr the residue was washed with dioxane the combined filtrate was concentrated to dryness The residue obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 368 mg (1.38 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 15 ml of dichloromethane, 246 mg (1.84 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-1-amine were added and the mixture was then stirred at room temperature for 30 min. 279 μl (3.45 mmol) of pyridine and 324 mg (1.15 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)-cyclopropanecarboxylate were then added, and the reaction mixture was stirred at room temperature for another 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 540 mg of the target compound (88% of theory). the reaction mixture was stirred at room temperature for another 1 h The reaction mixture was then concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 50.0 g (134.4 mmol) of tert-butyl 1-[3-(benzylamino)-4-chlorobenzyl]cyclopropanecarboxylate were dissolved in 1.5 liters of ethyl acetate, and 1.43 g (1.34 mmol) of palladium (10% on carbon) were added. The reaction mixture was stirred at RT overnight under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was then filtered off with suction through kieselguhr and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1). The product obtained was triturated using a methanol/water mixture (70:30) and the solid was isolated. This gave 24.3 g (64.1% of theory) of the target compound. The reaction mixture was then filtered off with suction through kieselguhr the filtrate was concentrated The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1) The product obtained was triturated the solid was isolated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 398.5 mg (1.56 mmol) of (3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 4.7 ml of DMF and 1.6 ml of pyridine, and 647.8 mg (1.70 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight. A further 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate and 647.8 mg (1.70 mmol) of HATU were added, and the reaction mixture was stirred at 50° C. for another 4 h. After dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water). This gave 453 mg of the target product (55.9% of theory, diastereomer ratio >8:1). were added at RT the reaction mixture was stirred at 50° C. for another 4 h After dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 50.0 g (134.4 mmol) of tert-butyl 1-[3-(benzylamino)-4-chlorobenzyl]cyclopropanecarboxylate were dissolved in 1.5 liters of ethyl acetate, and 1.43 g (1.34 mmol) of palladium (10% on carbon) were added. The reaction mixture was stirred at RT under a hydrogen atmosphere at standard pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1). The resulting product was stirred in a methanol/water mixture (70:30) and the solid was isolated. 24.3 g (64.1% of theory) of the target compound were obtained. The reaction mixture was then filtered off with suction through kieselguhr the filtrate was concentrated The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1) The resulting product was stirred in a methanol/water mixture (70:30) the solid was isolated 24.3 g (64.1% of theory) of the target compound were obtained