methyl 5-bromo-2-chlorobenzoate

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 solution of methyl 5-bromo-2-chlorobenzoate (9.23 g) in THF (50 ml) was added dropwise under ice-cooling to a suspension of lithium aluminum hydride (1.42 g) in THF (100 ml). After the completion of addition, the reaction mixture was stirred at room temperature for 45 minutes. Water (1.4 ml), 5N sodium hydroxide solution (1.4 ml) and water (4.2 ml) were sequentially added under ice-cooling to the reaction mixture. The precipitate was removed through Celite and the filtrate was concentrated under reduced pressure to obtain a title compound (7.56 g). After the completion of addition cooling to the reaction mixture The precipitate was removed through Celite the filtrate was concentrated under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(3-hydroxy-3-methylbut-1-ynyl)-3-methoxy-benzonitrile (62c) was prepared from aryl triflate 60d to give off-white crystals (19.1 g, 86%): mp 68-70° C. (hexanes/EtOAc); 1H NMR δ 7.54 (d, J=1.4 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.40 (dd, J=7.8 and 1.5 Hz, 1H), 5.55 (s, 1H), 3.87 (s, 3H), 1.46 s, 6H); HPLC (Method B) tR 4.09 min (100 area % at 230 nm). Anal. (C13H13NO2 0.4H2O) C, H. 3-(3-Hydroxy-3-methylbut-1-ynyl)benzonitrile (62d) was prepared from 3-bromobenzonitrile to give a light-brown oil (20.0 g, 100%): 1H NMR δ 7.85 (dd, J=1.5 and 1.5 Hz, 1H), 7.84 (ddd, J=7.8, 1.5 and 1.5 Hz, 1H), 7.72 (ddd, J=7.8, 1.5 and 1.5 Hz, 1H), 7.61 (dd, J=7.8, and 7.8 Hz, 1H), 5.57 (s, 1H), 1.47 (s, 6H); HPLC (method B) tR 3.99 min (100 area % at 254 nm). Anal. (C12H11NO) C, H, N. 4-Chloro-3-(3-hydroxy-3-methylbut-1-ynyl)benzonitrile (62e) was prepared from aryl iodide 60f to give off-white crystals (3.40 g, 82%): mp 80-82° C. (hexanes/EtOAc); 1H NMR δ 8.03 (dd, J=2.0 and 0.7 Hz, 1H), 7.86 (ddd, J=8.4, 2.0 and 0.7 Hz, 1H), 7.78 (dd, J=8.4 and 0.7 Hz, 1H), 5.63 (s, 1H), 1.49 (s, 6H); HPLC (method B) tR 4.86 min (100 area % at 254 nm). Anal. (C12H10ClNO) C, H, N, Cl. 3-(3-Hydroxy-3-methylbut-1-ynyl)-4-methoxy-benzonitrile (62f) was from 3-bromo-4-methoxybenzonitrile to give off-white crystals (30.5 g, 99%): mp 63-65° C. (hexanes/EtOAc); 1H NMR δ 7.82 (dd, J=8.7 and 2.1 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 5.51 (s, 1H), 3.90 (s, 3H), 1.46 (s, 6H); HPLC (method B) tR 3.83 min (100 area % at 254 nm). Anal. (C13H13NO2) C, H, N. 3-Methoxy-4-dibromomethylbenzonitrile (65). A mixture of 4-methyl-3-methoxybenzonitrile 64 (11.4 g, 77.6 mmol), NBS (34.5 g, 194 mmol), benzoyl peroxide (1.01 g, 4.17 mmol) in CCl4 was refluxed for 3 h. The reaction mixture was diluted with water and extracted with CH2Cl2. Column chromatography [hexane/EtOAc (19:1)] of the extracts afforded white crystals (18.3 g, 77%): mp 78-79° C.; 1H NMR δ 7.88 (d, J=8.0 Hz, 1H), 7.60 (d, J=1.4 Hz, 1H), 7.52 (dd, J=8.0 and 1.5 Hz, 1H), 7.34 (s, 1H), 3.96 (s, 3H); HPLC (Method B) tR 7.03 min (100 area % at 254 nm). Anal. (C9H7Br2NO) C, H, N, Br. 3-nitro-4-[(2-N,N-dimethylamino)ethenyl]benzonitrile (66). N,N-Dimethyl-formamide dimethyl acetal (12.1 g, 101 mmol) was added to a solution of nitrotoluene 63 (16.3 g, 101 mmol) in dry DMF (60 mL). The mixture was refluxed overnight under N2. The reaction mixture was poured into ice water to give a red solid (21.5 g, 99%): mp 122-126° C.; 1H NMR δ 8.22 (d, J=1.6 Hz, 1H), 7.84 (d, J=13.2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8 and 1.6 Hz, 1H), 5.67 (d, J=13.2 Hz, 1H), 2.98 (s, 6H). Anal. (C11H11N3O2) C, H, N. 2-Chloro-5-bromobenzoic acid methyl ester (72). A solution of benzoic acid 69 (30.0 g, 127 mmol) and H2SO4 (2 mL) in MeOH (2 L) was stirred at reflux for 3 d. The reaction mixture was concentrated to give white crystals (31.2 g, 98%): mp 43-44° C.; 1H NMR δ 7.99 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.6 and 2.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 3.87 (s, 3H); HPLC (Method B) tR 6.34 min (100 area % at 230 nm). 2-Chloro-5-cyanobenzoic acid methyl ester (73). DCC (11.4 g, 55.0 mmol) was added to a solution of benzoic acid 71, (9.08 g, 50.0 mmol), DMAP (0.60 g, 5.00 mmol) and MeOH (5 mL) in CH2Cl2 (100 mL) at 0° C. After 1 h the solution was warmed to 25° C. The reaction mixture was filtered and evaporated. The residue was purified by column chromatography (CH2Cl2) to give a light solid (9.21 g, 94%): mp 100-103° C.; 1H NMR δ 8.30 (d, J=2.2 Hz, 1H), 8.07 (dd, J=8.2 and 2.2 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 3.89 (s, 3H); HPLC (Method B) tR 4.57 min (100 area % at 254 nm). 4-Cyano-2-nitrobenzaldehyde (74a). NalO4 (65.0 g, 304 mmol) was added to a solution of intermediate 66 (21.0 g, 96.7 mmol) in THF and water (350 mL each). The mixture was stirred for 2.5 h, filtered, and extracted into EtOAc, and evaporated. Filtration of a suspension of the residue in CHCl3 through a plug of silica gel followed by recrystallization from toluene with activated carbon gave yellow crystals (13.1 g, 77%): mp 109-111° C.; 1H NMR δ 10.27 (s, 1H), 8.75 (d, J=1.5 Hz, 1H), 8.40 (dd, J=8.0 and 1.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H. Anal. (C8H4N2O3) C, H, N. 2-Chloro 4-cyanobenzaldehyde (74b). A solution of NaOEt was prepared from sodium (2.01 g, 87.4 mmol) and dry EtOH (150 mL). 2-Nitropropane (8 mL, 89 mmol) was added, followed after a few min by 3-chloro-4-bromomethylbenzonitrile (68, 13.5 g, 58.6 mmol). The mixture was stirred overnight, filtered, and evaporated. The residue was partitioned between water and EtOAc to give white solid (8.63 g, 89%). An analytical sample was recrystallized from aq. EtOH to give white needles: mp 117-119° C. (lit. 122-1230), see Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976); 1H NMR δ 10.34 (s, 1H), 8.29 (m, 1H), 8.00 (m, 2H). Anal. (C8H4ClNO) C, H, N, Cl. 5-Bromo-2-chlorobenzaldehyde (74c). A solution of pyrrolidine (4.00 g, 56.0 mmol) in MTBE (12 mL) was added dropwise over 20 min to a solution of Red-Al® (3.4 M solution in toluene, 16 ml, 54.4 mmol) in MTBE (33 mL) maintained at −20° C. The mixture was stirred for 1 h at 25° C. A solution of potassium tert-butoxide (0.60 g, 5.36 mmol) in THF (3 mL) was added. The resulting solution was added dropwise to a solution of 2-chloro-5-bromobenzoic acid methyl ester (72, 6.80 g, 27.3 mmol) in MTBE (15 mL) at 10° C. After 15 min the mixture was quenched with 2 N HCl (300 mL). Repeated recystallizations (hexanes) of the recovered material gave a crude solid (3.22 g, 54%, mp 43-46° C.), which was used without further purification in the next step. 2-Chloro-5-cyanobenzaldehyde (74e) was prepared from ester 73 as described above for 74c. See Dann, O., et al., Liebigs Ann. Chem., 3, 438-455 (1986). Column chromatography of crude material (7.60 g, 100%) [hexane/EtOAc (7:3)], followed by recrystallization from hexane/EtOAc (2:1) gave a solid (3.15 g, 41%): mp 191-193° C.; 1H NMR δ 10.28 (s, 1H), 8.28 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.2 and 2.2 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H); HPLC (Method B) tR 3.70 min (100 area % at 254 nm) Anal. (C8H4ClNO) C, H, N, Cl. An analytical sample was recrystallized from aq. EtOH to give white needles After 15 min the mixture was quenched with 2 N HCl (300 mL) Repeated recystallizations (hexanes) of the recovered material gave a crude solid (3.22 g, 54%, mp 43-46° C.), which was used without further purification in the next step Column chromatography of crude material (7.60 g, 100%) [hexane/EtOAc (7:3)], followed by recrystallization from hexane/EtOAc (2:1)

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

Procedure: 25.0 g of methyl 5-bromo-2-chlorobenzoate was dissolved in 130 ml of dichloromethane. To this solution, 230 ml of a 0.96 M DIBAL (diisobutylalminium hydride) hexane solution was added at −40° C. in a nitrogen atmosphere, followed by stirring at room temperature for 4 hours. To this reaction solution, 10% hydrochloric acid was carefully added while cooling, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with hexane to obtain 20.8 g of 5-bromo-2-chlorobenzyl alcohol as white crystals. while cooling followed by extraction with ethyl acetate drying over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained crude crystals were washed with hexane

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

Procedure: 25.0 g of methyl 5-bromo-2-chlorobenzoate was dissolved in 130 ml of dichloromethane. To this solution, 230 ml of a 0.96 M DIBAL (diisobutylalminium hydride) hexane solution was added at −40° C. in a nitrogen atmosphere, followed by stirring at room temperature for 4 hours. To this reaction solution, 10% hydrochloric acid was carefully added while cooling, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with hexane to obtain 20.8 g of 5-bromo-2-chlorobenzyl alcohol as white crystals. while cooling followed by extraction with ethyl acetate drying over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained crude crystals were washed with hexane

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

Procedure: A solution of methyl 5-bromo-2-chlorobenzoate (9.23 g) in THF (50 ml) was added dropwise under ice-cooling to a suspension of lithium aluminum hydride (1.42 g) in THF (100 ml). After the completion of addition, the reaction mixture was stirred at room temperature for 45 minutes. Water (1.4 ml), 5N sodium hydroxide solution (1.4 ml) and water (4.2 ml) were sequentially added under ice-cooling to the reaction mixture. The precipitate was removed through Celite and the filtrate was concentrated under reduced pressure to obtain a title compound (7.56 g). After the completion of addition cooling to the reaction mixture The precipitate was removed through Celite the filtrate was concentrated under reduced pressure

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

Procedure: A solution of methyl 5-bromo-2-chlorobenzoate (9.23 g) in THF (50 ml) was added dropwise under ice-cooling to a suspension of lithium aluminum hydride (1.42 g) in THF (100 ml). After the completion of addition, the reaction mixture was stirred at room temperature for 45 minutes. Water (1.4 ml), 5N sodium hydroxide solution (1.4 ml) and water (4.2 ml) were sequentially added under ice-cooling to the reaction mixture. The precipitate was removed through Celite and the filtrate was concentrated under reduced pressure to obtain a title compound (7.56 g). After the completion of addition cooling to the reaction mixture The precipitate was removed through Celite the filtrate was concentrated under reduced pressure

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

Procedure: Methyl 5-bromo-2-chlorobenzoate (2 g; 8.02 mmol; 1 eq.), zinc cyanide (564.79 mg; 4.81 mmol; 0.60 eq.), tris(dibenzylideneacetone)dipalladium(0) (58.73 mg; 0.06 mmol; 0.01 eq.), 1,1′-bis(diphenylphosphino)ferrocene (71.11 mg; 0.13 mmol; 0.02 eq.), zinc (20.97 mg; 0.32 mmol; 0.04 eq.) and zinc acetate (58.83 mg; 0.32 mmol; 0.04 eq.) were put in dry DMF (20 mL). The reaction mixture was purged with N2 and then heated to 90° C. for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with EtOAc. The organic phase was washed with water, brine, dried over MgSO4 and concentrated to afford a brown solid purified by flash chromatography eluting with cHex-EtOAc 8:2 affording the title compound as a yellow solid. It was washed with EtOH and dried under vacuum affording the title compound as a yellow solid (1.55 g, 98%). 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (m, 1H), 8.09-8.06 (m, 1H), 7.83-7.81 (m, 1H), 3.89 (s, 3H). LC/MS (Method B): 197.0 (M+H)+. HPLC (Method A) Rt 3.70 min (Purity: 83.7%) The reaction mixture was purged with N2 The reaction mixture was cooled to RT filtered over a pad of celite washed with EtOAc The organic phase was washed with water, brine dried over MgSO4 concentrated to afford a brown solid purified by flash chromatography eluting with cHex-EtOAc 8:2 affording the title compound as a yellow solid It was washed with EtOH dried under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-bromo-2-chlorobenzoic acid (E-Merck 8.14989.0101, 20 g; 84.94 mmol; 1 eq.) was dissolved in MeOH (400 mL). The solution was cooled down to 0° C. SOCl2 (18.49 mL; 254.82 mmol; 3 eq.) was added dropwise (addition took 30 min and IT increased to 9° C.). After addition, the reaction mixture was stirred at RT for 2 days. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (400 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), brine (100 mL), dried over MgSO4 and concentrated affording the title compound as a white solid (20.15 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.98-7.97 (d, J=2.40 Hz, 1H), 7.80-7.67 (dd, J=8.74 Hz, 2.40 Hz, 1H), 7.56-7.54 (d, J=8.23 Hz, 1H), 3.86 (s, 3H). HPLC (Method A) Rt 4.15 min (Purity: 99.9%). (addition took 30 min and IT increased to 9° C.) After addition The reaction mixture was concentrated the crude mixture was dissolved in EtOAc (400 mL) washed with a saturated aqueous solution of NaHCO3 (100 mL), brine (100 mL) dried over MgSO4 concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromo-2-chloro-benzoic acid methyl ester (5 g) in diethyl ether (200 mL) cooled to −70° C. is added 3 M methylmagnesium bromide in THF (20 mL) dropwisely. The solution is stirred at −78° C. for 2 h and allowed to warm to room temperature for 16 hours. The solution is cooled to 0° C. and 1 N HCl (100 mL) is added dropwisely. The mixture is extracted with EtOAc (2×150 mL). The combined organic layer is washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel eluting with 20% EtOAc in heptane to afford 2-(5 bromo-2-chloro-phenyl)-propan-2-ol (4.56 g). MS: 250 (M+H); 1H NMR (300 MHz, CDCl3) □7.8 (m, 1H); 7.5 (m, 1H); 7.2 (m, 1H); 4.4 (s, 1H); 1.6 (s, 6H). to warm to room temperature for 16 hours The solution is cooled to 0° C. The mixture is extracted with EtOAc (2×150 mL) The combined organic layer is washed with brine dried over sodium sulfate filtered evaporated in vacuo The residue is chromatographed on silica gel eluting with 20% EtOAc in heptane