methyl 4-amino-2-fluoro-5-methoxybenzoate

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:

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

Procedure: In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (150 mg, 0.259 mmol), was reacted with diisopropylethylamine (171 mg, 1.32 mmol), diphenylphosphinic chloride (155 mg, 0.656 mmol), then reacted with methyl 4-amino-2-fluoro-5-methoxybenzoate (Aldrich, 55 mg, 0.274 mmol,) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester (40 mg, 24%). MS (ES+) m/z [(M+H)+]: 646

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.0 g, 3.086 mmol), and methyl 4-amino-2-fluoro-5-methoxybenzoate (3.07 g, 15.43 mmol) was dissolved in dioxane (20 ml), and p-toluenesulfonic acid, monohydrate (2.99 g, 15.74 mmol) was added. The mixture was stirred at 95° C. for 24-48 h. The final compound was purified by reverse phase HPLC to give 400 mg product as white solid (40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4H) 1.93-1.98 (m, 4H) 3.29 (s, 3H) 3.51 (br. s., 2H) 3.61 (m, 3H), 3.86 (m, 3H) 3.94 (s, 3H) 4.88 (t, J=8.08 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1H) 7.41-7.57 (m, 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd for C24H27F2N5O4, 488. found 488. The final compound was purified by reverse phase HPLC

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.0 g, 3.086 mmol), and methyl 4-amino-2-fluoro-5-methoxybenzoate (3.07 g, 15.43 mmol) was dissolved in dioxane (20 ml), and p-toluenesulfonic acid, monohydrate (2.99 g, 15.74 mmol) was added. The mixture was stirred at 95° C. for 24-48 h. The final compound was purified by reverse phase HPLC to give 400 mg product as white solid (40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4H) 1.93-1.98 (m, 4H) 3.29 (s, 3H) 3.51 (br. s., 2H) 3.61 (m, 3H), 3.86 (m, 3H) 3.94 (s, 3H) 4.88 (t, J=8.08 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1H) 7.41-7.57 (m, 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd for C24H27F2N5O4, 488. found 488. The final compound was purified by reverse phase HPLC

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

Procedure: To an amount of 4-amino-2-fluoro-5-methoxybenzoic acid (4 g, 21.62 mmole) that was dissolved in DCM (40 ml) and MeOH (11 mL), was added TMS-diazomethane (16.2 mL, 32.43 mmole) slowly. The mixture was stirred at r.t for 30 mins. After the removal of solvent, the resulting tan solid (4.0 g, 93%) carried onto the next reaction without any purification. [M+H] calc'd for C9H10FNO3, 200. found 200. After the removal of solvent the resulting tan solid (4.0 g, 93%) carried onto the next reaction without any purification

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

Procedure: In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (150 mg, 0.259 mmol), was reacted with diisopropylethylamine (171 mg, 1.32 mmol), diphenylphosphinic chloride (155 mg, 0.656 mmol), then reacted with methyl 4-amino-2-fluoro-5-methoxybenzoate (Aldrich, 55 mg, 0.274 mmol,) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester (40 mg, 24%). MS (ES+) m/z [(M+H)+]: 646

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

Procedure: In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (150 mg, 0.259 mmol), was reacted with diisopropylethylamine (171 mg, 1.32 mmol), diphenylphosphinic chloride (155 mg, 0.656 mmol), then reacted with methyl 4-amino-2-fluoro-5-methoxybenzoate (Aldrich, 55 mg, 0.274 mmol,) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester (40 mg, 24%). MS (ES+) m/z [(M+H)+]: 646

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-amino-2-fluoro-5-methoxybenzoate (100 mg; 0.50 mmol; 1 eq.) was dissolved in MeOH (2 mL). NaOH (0.50 mL; 5 M; 2.51 mmol; 5 eq.) was added and the mixture was heated at 50° C. overnight. The solvents were evaporated. EtOAc was added and the resulting solution was washed with NH4Cl sat. The aqueous phase was extracted with EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording the title compound (92 mg; 99%). HPLC (Method A) Rt 1.92 min (Purity: 96.4%). The solvents were evaporated EtOAc was added the resulting solution was washed with NH4Cl sat. The aqueous phase was extracted with EtOAc Combined organic phases were dried over MgSO4 filtrated evaporated

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

Procedure: Methyl 2-fluoro-5-methoxy-4-nitrobenzoate (549 mg; 1.13 mmol; 1 eq.) was dissolved in MeOH (50 mL). The resulting solution was injected on a flow hydrogenation reactor (H-Cube), adapted with Pd/C cartridge (44 mm), a flow of 1 mL/min, a temperature of 60° C. and the full H2 option enabled. Solvents were evaporated, affording the title product as an off-white solid (220 mg; 97%). LC/MS (Method B): 200.0 (M+H)+. HPLC (Method A) Rt 3 min (Purity: 91.9%). The resulting solution was injected on a flow hydrogenation reactor a temperature of 60° C. Solvents were evaporated