1-bromo-4-(bromomethyl)-2-chlorobenzene

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

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 1,2-dihydro-1-oxophthalazin-4-ylacetate (11.5 g.) and sodium hydride (2.7 g.; 50% w/w dispersion in mineral oil) in dimethylformamide (125 ml.) was stirred at 60° C. for 1 hour under nitrogen. The solution obtained was cooled to room temperature and then 4-bromo-3-chlorobenzyl bromide (15.0 g.) was added, and the mixture stirred at 60° C. for 2 hours. After cooling to 25° C. the reaction mixture was poured into water (500 ml.). The aqueous mixture obtained was extracted with ethyl acetate (400 ml.). The extracts were washed with water, dried (MgSO4), and evaporated to give a solid, which was crystallised from propan-2-ol to yield ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (7.3 g.), m.p. 142°-145° C. The solution obtained was cooled to room temperature the mixture stirred at 60° C. for 2 hours After cooling to 25° C. the reaction mixture The aqueous mixture obtained was extracted with ethyl acetate (400 ml.) The extracts were washed with water dried (MgSO4) evaporated to give a solid, which was crystallised from propan-2-ol

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 1,2-dihydro-1-oxophthalazin-4-ylacetate (11.5 g.) and sodium hydride (2.7 g.; 50% w/w dispersion in mineral oil) in dimethylformamide (125 ml.) was stirred at 60° C. for 1 hour under nitrogen. The solution obtained was cooled to room temperature and then 4-bromo-3-chlorobenzyl bromide (15.0 g.) was added, and the mixture stirred at 60° C. for 2 hours. After cooling to 25° C. the reaction mixture was poured into water (500 ml.). The aqueous mixture obtained was extracted with ethyl acetate (400 ml.). The extracts were washed with water, dried (MgSO4), and evaporated to give a solid, which was crystallised from propan-2-ol to yield ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (7.3 g.), m.p. 142°-145° C. The solution obtained was cooled to room temperature the mixture stirred at 60° C. for 2 hours After cooling to 25° C. the reaction mixture The aqueous mixture obtained was extracted with ethyl acetate (400 ml.) The extracts were washed with water dried (MgSO4) evaporated to give a solid, which was crystallised from propan-2-ol

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

Procedure: Add NBS (5.266 g, 23.9 mmol) and benzoyl peroxide (49 mg, 0.2 mmol) to a solution of 4-bromo-3-chlorotoluene (4.925 g, 23.9 mmol) in carbon tetrachloride (49 mL) and heat overnight at 90° C. Cool to 0° C. and filter the mixture. Concentrate the filtrate in vacuo to obtain the desired intermediate as a yellow oil (5.807 g, 85%). Cool to 0° C. filter the mixture Concentrate the filtrate in vacuo

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: 4-bromo-3-chlorotoluene [31.8 g, described by Cohen and Raper, J. Chem. Soc., 85, 1267 (1904)] was heated with N-bromosuccinimide (27.5 g) and benzoyl peroxide (3.6 g) in carbon tetrachloride (75 ml) at reflux for 10 hours. The cooled solution was filtered, washed with aqueous ferrous sulphate solution, dried over magnesium sulphate, filtered and evaporated to dryness. 4-Bromo-3-chlorobenzyl bromide (44 g) was obtained as a pale orange oil. at reflux for 10 hours The cooled solution was filtered washed with aqueous ferrous sulphate solution dried over magnesium sulphate filtered evaporated to dryness

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

Procedure: Add NBS (5.266 g, 23.9 mmol) and benzoyl peroxide (49 mg, 0.2 mmol) to a solution of 4-bromo-3-chlorotoluene (4.925 g, 23.9 mmol) in carbon tetrachloride (49 mL) and heat overnight at 90° C. Cool to 0° C. and filter the mixture. Concentrate the filtrate in vacuo to obtain the desired intermediate as a yellow oil (5.807 g, 85%). Cool to 0° C. filter the mixture Concentrate the filtrate in vacuo

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

Procedure: Benzoic peroxyanhydride (3.73 g, 15.41 mmol) was added to a degassed mixture of 1-bromo-2-chloro-4-methylbenzene (24.35 g, 118.50 mmol) and 1-bromopyrrolidine-2,5-dione (23.20 g, 130.35 mmol) in CCl4 (100 mL) at room temperature under nitrogen. The resulting mixture was stirred at reflux for 18 hrs. The reaction was cooled and washed with water (equal volume); satd sodium thiosulfite (equal volume) and water (equal volume). Mixture dried by passing through a phase seperating cartridge. Solvent removed to give crude 1-bromo-4-(bromomethyl)-2-chlorobenzene (31.7 g, 94%) as pale brown oil which was progressed without further purification. at reflux for 18 hrs The reaction was cooled washed with water (equal volume) Mixture dried seperating cartridge Solvent removed

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

Procedure: Sodium cyanide (10.91 g, 222.52 mmol) in water (10 mL) was added to a solution of chloroform (20 mL) of N-benzyl-N,N-diethylethanaminium chloride (25.3 g, 111.26 mmol). 1-Bromo-4-(bromomethyl)-2-chlorobenzene (31.64 g, 111.26 mmol) in chloroform (5 mL) was added dropwisely at room temperature. The mixture was stirred at room temperature for 1 h then heated to 45° C. for additional 2 h. The reaction mixture was cooled, separated into two layers and the organic layer was washed with 0.5 N NaOH then brine. The chloroform layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash Silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=330 g, flow rate=100 mL/min, elution gradient 0 to 100% EtOAc in isohexane over 40 minutes. Pure fractions were evaporated to dryness to afford 2-(4-bromo-3-chlorophenyl)acetonitrile (2.430 g, 9.48%) as a orange/yellow oil which solidified on standing. then heated to 45° C. for additional 2 h The reaction mixture was cooled separated into two layers the organic layer was washed with 0.5 N NaOH The chloroform layer was dried over sodium sulfate filtered concentrated The crude product was purified by flash Silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=330 g, flow rate=100 mL/min, elution gradient 0 to 100% EtOAc in isohexane over 40 minutes Pure fractions were evaporated to dryness

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

Procedure: Compound 39.3 was synthesized using the procedure described above for preparing 1.1 using 1-bromo-4-(bromomethyl)-2-chlorobenzene 39.1 (available from Metina AB) and methyl 3-(3-hydroxyphenyl)propanoate 39.2 (available from Aagile Labs Division of Tyger Scientific). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=2.0 Hz), 7.17-7.24 (2H, m), 6.78-6.85 (3H, m), 4.99 (2H, s), 3.68 (3H, s) 2.94 (2H, t, J=7.8 Hz), 2.64 (2H, t, J=7.8 Hz).