2,4-difluorobenzohydrazide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A suspension of 15.3 g (0.058 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 125 ml chloroform was treated with 58.1 ml 1N aqueous sodium hydoxide. 18 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 10.0 g (0.058 mol) 2,4-difluorobenzoic acid hydrazide in 110 ml chloroform over night at 50° C. The resulting precipitate was filtered off and dried. A yield of 8.50 g (42%) 2,4-difluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid. MS m/e (%): 354 (M+H+, 100). the mixture was extracted with chloroform dried with sodium sulfate the solvents were distilled off under reduced pressure The resulting precipitate was filtered off dried

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

Procedure: A suspension of 15.3 g (0.058 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 125 ml chloroform was treated with 58.1 ml 1N aqueous sodium hydoxide. 18 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 10.0 g (0.058 mol) 2,4-difluorobenzoic acid hydrazide in 110 ml chloroform over night at 50° C. The resulting precipitate was filtered off and dried. A yield of 8.50 g (42%) 2,4-difluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid. MS m/e (%): 354 (M+H+, 100). the mixture was extracted with chloroform dried with sodium sulfate the solvents were distilled off under reduced pressure The resulting precipitate was filtered off dried

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

Procedure: To a suspension of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.020 g, 0.070 mmol) in DCE (3 mL), under N2, was added EDCl (0.016 g, 0.081 mmol) and stirred at rt. After 5 min, 2,4-difluorobenzohydrazide (0.014 g, 0.081 mmol) was added and stirring was continued at rt. After 30 min, TsCl (0.016 g, 0.084 mmol) and P-BEMP (loading 2.2 mmol/g, 0.127 g, 0.28 mmol) were added and the mixture was heated at 100° C. for 20 min. The reaction was monitored by LC/MS. Subsequently, the mixture was heated at 120° C. for 30 min. Additional TsCl (0.020 g, 0.105 mmol) and P-BEMP (0.127 g, 0.28 mmol) were added and the mixture was heated at 120° C. another 20 min. Upon cooling, the resin was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.011 g, 38% yield): MS (ES) m/z 421 (M+1). stirring was continued at rt After 30 min the mixture was heated at 100° C. for 20 min Subsequently, the mixture was heated at 120° C. for 30 min the mixture was heated at 120° C. another 20 min Upon cooling the resin was filtered off washed with EtOAc The filtrate was concentrated in vacuo the residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient) The product was crystallized from CH2Cl2-hexanes

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

Procedure: To a suspension of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.020 g, 0.070 mmol) in DCE (3 mL), under N2, was added EDCl (0.016 g, 0.081 mmol) and stirred at rt. After 5 min, 2,4-difluorobenzohydrazide (0.014 g, 0.081 mmol) was added and stirring was continued at rt. After 30 min, TsCl (0.016 g, 0.084 mmol) and P-BEMP (loading 2.2 mmol/g, 0.127 g, 0.28 mmol) were added and the mixture was heated at 100° C. for 20 min. The reaction was monitored by LC/MS. Subsequently, the mixture was heated at 120° C. for 30 min. Additional TsCl (0.020 g, 0.105 mmol) and P-BEMP (0.127 g, 0.28 mmol) were added and the mixture was heated at 120° C. another 20 min. Upon cooling, the resin was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.011 g, 38% yield): MS (ES) m/z 421 (M+1). stirring was continued at rt After 30 min the mixture was heated at 100° C. for 20 min Subsequently, the mixture was heated at 120° C. for 30 min the mixture was heated at 120° C. another 20 min Upon cooling the resin was filtered off washed with EtOAc The filtrate was concentrated in vacuo the residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient) The product was crystallized from CH2Cl2-hexanes

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

Procedure: (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.0 g, 3.72 mmol) and 2,4-difluorobenzohydrazide (704 mg, 4.09 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (1.5 g, 96%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.6 (br s, 2H), 7.85-7.97 (m, 1H), 7.46 (d, J=8 Hz, 1H), 7.10-7.19 (m, 2H), 6.73 (d, J=8 Hz, 1H), 5.58 (d, J=7 Hz, 1H), 4.20-4.28 (m, 1H), 4.15-4.18 (m, 1H), 2.32 (s, 3H) and 1.38 (d, J=6 Hz, 3H).

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

Procedure: (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.0 g, 3.72 mmol) and 2,4-difluorobenzohydrazide (704 mg, 4.09 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (1.5 g, 96%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.6 (br s, 2H), 7.85-7.97 (m, 1H), 7.46 (d, J=8 Hz, 1H), 7.10-7.19 (m, 2H), 6.73 (d, J=8 Hz, 1H), 5.58 (d, J=7 Hz, 1H), 4.20-4.28 (m, 1H), 4.15-4.18 (m, 1H), 2.32 (s, 3H) and 1.38 (d, J=6 Hz, 3H).

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

Procedure: (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.0 g, 3.72 mmol) and 2,4-difluorobenzohydrazide (704 mg, 4.09 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (1.5 g, 96%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.6 (br s, 2H), 7.85-7.97 (m, 1H), 7.46 (d, J=8 Hz, 1H), 7.10-7.19 (m, 2H), 6.73 (d, J=8 Hz, 1H), 5.58 (d, J=7 Hz, 1H), 4.20-4.28 (m, 1H), 4.15-4.18 (m, 1H), 2.32 (s, 3H) and 1.38 (d, J=6 Hz, 3H).

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

Procedure: A suspension of 15.3 g (0.058 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 125 ml chloroform was treated with 58.1 ml 1N aqueous sodium hydoxide. 18 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting colorless oil was stirred together with 10.0 g (0.058 mol) 2,4-difluorobenzoic acid hydrazide in 110 ml chloroform over night at 50° C. The resulting precipitate was filtered off and dried. A yield of 8.50 g (42%) 2,4-difluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white solid. MS m/e (%): 354 (M+H+, 100). the mixture was extracted with chloroform dried with sodium sulfate the solvents were distilled off under reduced pressure The resulting precipitate was filtered off dried

Conditions: temp:0.00; pressure:0.00; stir: