6-bromoisoindolin-1-one

A solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 40 minutes at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in CH3) The compound obtained in step (2) (150 g, 0.49 mol) was dissolved in 600 ml of methanol.The system then added 25percent of ammonia to 4.5 liters of ammonia and the system reacted at 70°C for 5 hours.It was cooled and filtered to give 90 g of a pale yellow powder in a yield of 87percent.Step 2 Compound 1251 B (1.219g, 5.32 mmol) was dissolved in CCIPd2(dba)3 (350 mg, 0.38 mmol), XantPhos (540 mg, 0.93 mmol), cesium carbonate (9 g, 27.8 mmol, 2 eq), 6-bromo-isoindolin-1-one (XVII) (2.94 g, 14 mmol, 1 eq) and methyl 6-bromopicolinate (X) (3 g, 14 mmol, 1 eq) were combined in dioxane (100 mL). The mixture was degassed with nitrogen, sealed and heated at 80 C. for overnight. The reaction mixture was poured into water (100 mL). A precipitate formed was filtered and the filtrate was extracted with EtOAc (3*50 mL). The organic extracts were combined and concentrated. The resulting solid was triturated in IPA to give methyl 6-(6-bromo-1-oxoisoindolin-2-yl)picolinate (XVIII) as a solid (3.5 g, 73% yield). 1HNMR (400 MHz, DMSO-d6) delta 3.90 (s, 3H), 5.12 (m, 2H), 7.73 (m, 1H), 7.85 (m, 1H), 7.95 (m, 2H), 8.10 (m, 1H), 8.70 (m, 1H).Compound WX005-3 (1.00 g, 4.72 mmol, 1.00 eq), compound WXBB-1 (1.53 g, 14.15 mmol, 3.00 eq), cuprous iodide (89.82 mg, 471.61 mumol, 0.10 eq), potassium carbonate (1.96 g, 14.15 mmol, 3.00 eq), and tetramethylethylenediamine (54.81 mg, 471.61 mumol, 71.18 muL, 0.10 eq) were dissolved in toluene (10.00 mL). The mixture was purged with nitrogen three times, and then reacted at 130 C. for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was added with methanol (15 mL), and filtered, followed by concentrating of the filtrate. The crude product was separated and purified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 mum; mobile phase: [water (0.05% HCl)-ACN]; B %: 0-30 (10 min) %-30-55 (4 min) %, 14 min). Compound WX005-4 was obtained, 1H NMR (400 MHz, METHANOL-d4) delta ppm 8.07 (s, 1H), 7.89 (s, 1H), 7.80-7.83 (m, 1H), 7.72-7.74 (m, 1H), 7.384 (s, 1H), 4.53 (s, 2H), 1.90-1.95 (m, 1H), 0.89-0.93 (m, 2H), 0.76-0.78 (m, 2H). MS m/z: 239.9 [M+H]+.6-Bromoisoindolin-l-one (4 g, 18.9 mmol) was suspended in 70 ml of THF and cooled to 0-5C. Sodium hydride (60% in mineral oil) (1.5 g, 37.7 mmol, 2 equiv.) was added in portions at 0-5C and after 5 minutes (2RS)-2-bromo-2-phenyl-acetic acid (4.34 g, 20.2 mmol, 1.07 equiv.) were added and the mixture was stirred at 0-5 C for 2 hours. The reaction mixture was extracted with 1M HC1 solution and twice with ethyl acetate. The organic layers were dried over sodium sulfate and evaporated to dryness to obtain the desired (2RS)-2-(6-bromo-l-oxo-isoindolin-2-yl)-2- phenyl-acetic acid (5.78 g, 89 % yield) as a white solid, MS: m/e = 345.9/347.9 (M+H+).To a solution of 6-bromoisoindolin-l-one (2.418 g, 11.4 mmol) in DMF (57 mL) at 0 C. was added NaH (0.547 g, 13.68 mmol). The resulting dark suspension was allowed to stir for 60 min before addition of PMBC1 (1.86 mL, 13.68 mmol). The reaction was then allowed to stir at room temperature for 3 hours. The crude was diluted by EtOAc, washed with water and brine. The organic layers were dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel using 0->50% EtOAc in hexanes to afford 3.18 g yellow solid as compound 2 (84% yield). 1H NMR (400 MHz, Chloroform-d) delta8.04 (d, J=1.9 Hz, 1H), 7.65 (dd, J=8.0, 1.9 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 4.75 (s, 2H), 4.22 (s, 2H), 3.82 (s, 3H).

Molecular Weight:212.04
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:210.96328
Monoisotopic Mass:210.96328
Topological Polar Surface Area:29.1
Heavy Atom Count:11
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes