methyl 2-bromo-5-chlorobenzoate

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

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromo-5-chlorobenzoate (1.15 g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (100 mg, 0.086 mmol) and the reaction is stirred at 90° C. over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate). The reaction was partitioned between ethyl acetate and water The organic was concentrated in vacuo purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of methyl 2-bromo-5-chlorobenzoate from the previous step (11.5 g, 46 mmol) in degassed DMF (50 mL) was added zinc cyanide (2.82 g, 24.0 mmol) and palladium tetrakis-triphenylphosphine (1.0 g, 0.86 mmol) and the mixture was heated to 90° C. for 18 h. The reaction was partitioned between EtOAc (200 mL) and water (100 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography eluting with a gradient of 10%, 15%, 20% ethyl acetate in hexane yielding methyl 5-chloro-2-cyanobenzoate as a white solid (8.0 g, 88% yield). TLC Rf=0.4 (15% EtOAc-hexanes); HPLC RT=3.13 min, method A; 1H NMR (CDCl3, 400 MHz) 8.13 ppm (d, 1H, J=1.83 Hz); 8.09 ppm (d, 1H, J=8.24 Hz); 7.29 ppm (dd, I H, J=8.34, 2.10 Hz); 4.02 ppm (s, 3H). The reaction was partitioned between EtOAc (200 mL) and water (100 mL) The organic phase was concentrated in vacuo the residue was purified by flash chromatography eluting with a gradient of 10%, 15%, 20% ethyl acetate in hexane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of methyl 2-bromo-5-chlorobenzoate from the previous step (11.5 g, 46 mmol) in degassed DMF (50 mL) was added zinc cyanide (2.82 g, 24.0 mmol) and palladium tetrakis-triphenylphosphine (1.0 g, 0.86 mmol) and the mixture was heated to 90° C. for 18 h. The reaction was partitioned between EtOAc (200 mL) and water (100 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography eluting with a gradient of 10%, 15%, 20% ethyl acetate in hexane yielding methyl 5-chloro-2-cyanobenzoate as a white solid (8.0 g, 88% yield). TLC Rf=0.4 (15% EtOAc-hexanes); HPLC RT=3.13 min, method A; 1H NMR (CDCl3, 400 MHz) 8.13 ppm (d, 1H, J=1.83 Hz); 8.09 ppm (d, 1H, J=8.24 Hz); 7.29 ppm (dd, I H, J=8.34, 2.10 Hz); 4.02 ppm (s, 3H). The reaction was partitioned between EtOAc (200 mL) and water (100 mL) The organic phase was concentrated in vacuo the residue was purified by flash chromatography eluting with a gradient of 10%, 15%, 20% ethyl acetate in hexane

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

Procedure: Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0° C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92% yield). TLC Rf=0.6 (5% EtOAc-hexanes); HPLC RT=3.48 min, method A; 1H NMR (CDCl3, 400MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz); 7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H). The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography

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

Procedure: A solution of methyl 2-bromo-5-chlorobenzoate (4.9 g, 19.64 mmol) in THF (50 mL) was cooled to 0° C. and treated with the dropwise addition of LAH (1.0M in THF) (20.62 mL, 20.62 mmol), causing a mild exotherm and gas evolution. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched using the Steinhardt procedure (see Fieser & Fieser, Reagents for Organic Synthesis, p. 584). The resulting precipitate was removed by filtration and washed with ethyl acetate. The combined filtrates were concentrated in-vacuo to yield a colorless oil which solidified upon standing. The residue was purified over a 330 g silica gel column via ISCO, eluting with a 10-100% EtOAc/Hexanes gradient over 30 minutes, to yield the title compound (2.04 g, 47% yield) as a colorless powder. The reaction was quenched the Steinhardt procedure (see Fieser & Fieser, Reagents for Organic Synthesis, p. 584) The resulting precipitate was removed by filtration washed with ethyl acetate The combined filtrates were concentrated in-vacuo to yield a colorless oil which The residue was purified over a 330 g silica gel column via ISCO eluting with a 10-100% EtOAc/Hexanes gradient over 30 minutes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 2-bromo-5-chlorobenzoate (1.0 g, 4 mmol), lithium chloride (490 mg, 11.58 mmol), tetraethyltin (0.81 mL, 4.1 mmol) and bis(triphenylphosphine)-palladium(II)chloride (100 mg, 0.13 mmol) were combined in DMF (20 mL) and heated at 100° C. for 5 h. Solvent was removed at reduced pressure and the residue was diluted with water and EtOAc. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 10% EtOAc/hexane) provided the title compound (435 mg, 55%). Solvent was removed at reduced pressure the residue was diluted with water and EtOAc The organic layer was separated washed with water dried over sodium sulfate concentrated

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an N,N-dimethylformamide solution (100 mL) of methyl 2-bromo-5-chlorobenzoate (25, 100 mmol) was added palladium(II) acetate (480 mg, 2.1 mmol) tri(o-tolyl)phosphine (1.2 g, 3.9 mmol), acrylonitrile (6 g, 113 mmol), and anhydrous sodium acetate (10 g, 122 mmol). The mixture was heated at 120° C. Additional palladium(II) acetate (224 mg, 1 mmol) and tri(o-tolyl)phosphine (600 mg, 2 mmol) were added, after 36 hours. The mixture was heated at 120° C. for 24 hours. N,N-Dimethylformamide was removed in vacuo and the remaining mixture was quenched with 1 N HCl(aq) and extracted with ethyl acetate. The ethyl acetate extracts were concentrated and the residue was dissolved in 1:1 dichloromethane:methanol (50 mL). (Trimethylsilyl)diazomethane (30 mL, 2 N in diethyl ether, 60 mmol) was added dropwise. After stirring overnight, the mixture was quenched with acetic acid, concentrated under reduced pressure and purified by silica gel column chromatography eluting with 2:1 hexanes:ethyl acetate to afford the title compound (2:1 E/Z isomers). 1H NMR (E isomer, Example 45A, 300 MHz, DMSO-d6) δ ppm 8.08 (d, J=16.2 Hz, 1H), 7.91 (d, J=2.1 HZ, 1H), 7.84 (d, J=8.7 HZ, 1H), 7.78 (dd, J=2.1, 8.4 Hz, 1H), 6.45 (d, J=16.5 Hz, 1H), and 3.88 (s, 3H). The mixture was heated at 120° C. for 24 hours N,N-Dimethylformamide was removed in vacuo the remaining mixture was quenched with 1 N HCl(aq) extracted with ethyl acetate The ethyl acetate extracts were concentrated the residue was dissolved in 1:1 dichloromethane the mixture was quenched with acetic acid concentrated under reduced pressure purified by silica gel column chromatography eluting with 2:1 hexanes

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromo-5-chlorobenzoate (1.15 g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (100 mg, 0.086 mmol) and the reaction is stirred at 90° C. over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate). The reaction was partitioned between ethyl acetate and water The organic was concentrated in vacuo purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromo-5-chlorobenzoate (1.15 g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (100 mg, 0.086 mmol) and the reaction is stirred at 90° C. over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate). The reaction was partitioned between ethyl acetate and water The organic was concentrated in vacuo purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A re-sealable vial containing methyl 2-bromo-5-chlorobenzoate (0.205 g, 0.822 mmol), Pd(Ph3P)4 (0.042 g, 0.036 mmol), and anhydrous potassium phosphate, tribasic (0.275 g, 1.296 mmol) was evacuated and purged with N2 (g) (3×). To the solids was added a solution of tert-butyl 1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate (0.236 g, 0.648 mmol) in MeOH (2×1 mL, 2 mL total) and 1,4-Dioxane (2×1 mL, 2 mL total). The suspension was evacuated and purged with N2 (g) (3×), the vial was sealed, and the contents heated to 80° C. LC-MS analysis indicated complete conversion to desired product with in 4 h. After 4 h, the reaction mixture was cooled to room temperature and filtered over Celite. The filter cake was washed with MeOH (3×) and the filtrate was concentrated to give a brown oil. The oil was purified on Biotage system (5% EtOAc:95% Hexanes to 30% EtOAc:70% Hexanes, then isocratic 30% EtOAc:70% Hexanes). The product methyl 2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate (0.226 g, 0.555 mmol, 86% yield) was isolated as a clear oil. LC/MS m/z 407 [M+H]+. was evacuated purged with N2 (g) (3×) The suspension was evacuated purged with N2 (g) (3×) the vial was sealed with in 4 h the reaction mixture was cooled to room temperature filtered over Celite The filter cake was washed with MeOH (3×) the filtrate was concentrated to give a brown oil The oil was purified on Biotage system (5% EtOAc