ethyl 4-chloro-1-benzofuran-2-carboxylate

Conditions: temp:95.01; pressure:0.00; stir:

Procedure: tert-butyl piperazine-1-carboxylate (5.22 g, 28.04 mmol), ethyl 4-chlorobenzofuran-2-carboxylate (6.3 g, 28.04 mmol), 2-Dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (1.337 g, 2.80 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.284 g, 1.40 mmol) and CESIUM CARBONATE (11.88 g, 36.46 mmol) were heated under argon to 95 °C 14:51:42 overnight, LC showed no s.m. EN03969-25-001. The mixture was allowed to cool to rt, diluted with EtOAc (35 mL) and filtered through a pad of Celite, washed with EtOAc (total of 100 mL). The filterate was collected and the solvent was removed by rotary evaporation. The crude product was treated with diisopropylether under stirring at rt for 4 days, the mixture was filterered and washed with diisopropylether. The diisopropyletherphase was concentrated to give 3.6 g. The solid was treated with MeOH under stirring at rt for 4 h, filtrated, washed with MeOH, still not clear solution. The solid was vacuumdried at 40 °C over night to give 7.6 g. The MeOH-mixture was filterered through a process K200 filter, the formed solution was concentrated to give 1.4 g. No pure product in any of the solids, were combined (12.6 g) and dissolved in CH2Cl2 and put on silica (200 g) using 1. CH2Cl2 (500 mL), 2. EtOAc (400 mL) as eluent. Fr. 5-6 were combined and concentrated to give EN03969-25-002 (10.6 g, 28.3 mmol, 101 %). To the brownish solid was added ether (40 mL) and the slurry was stirred at 35 °C for 5-10 min. The now grey solid was filtered off, rinsed with 4x20 mL ether and dried under vacuum at 30 °C o.n, yielding EN03969-25-003 (6.7 g, 17.89 mmol, 63.8 %). 44 mg of EN03969-25-003 was sent to **** at Analytical Services and OA Support team **** for purity-assay (95 %), see report. EN03969-25-003 was delivered to CM in can: **32649089.**

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

Procedure: Ethyl 4-bromobenzofuran-2-carboxylate (prepared in analogy with ethyl 4-chlorobenzofuran-2-carboxylate, (Example 1b), starting from 2-bromo-6-hydroxy-benzaldehyde) (7.7 g, 29 mmol), tert-butyl piperazine-1-carboxylate (5.33 g, 28.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.31 g, 1.43 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (1.36 g, 2.86 mmol) and cesium carbonate (12.1 g, 37.2 mmol) in dioxane (40 mL) was heated under argon to +95° C. overnight. The mixture was allowed to cool, diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and eluted with 0-50% ethyl acetate in heptane. The collected fractions were combined and the solvent was removed to give the title compound, which was used in the subsequent step ii). Yield: 4.92 g, 46%. MS m/z 375.8 [M+H]+. to cool filtered through a pad of Celite The filtrate was collected the solvent was removed by rotary evaporation The crude product was added to a silica gel column eluted with 0-50% ethyl acetate in heptane the solvent was removed

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

Procedure: X-Phos (1.1 g, 2.2 mmol.), Pd2(dba)3 (1.0 g, 1.1 mmol) and cesium carbonate (14.5 g, 44 mmol) were added to a degassed solution of ethyl 4-chlorobenzofuran-2-carboxylate (Example 1b), 5.0 g, 22 mmol) and benzylpiperazine (5.8 ml, 33 mmol) in dioxane (100 mL). The reaction mixture was heated to +110° C. for 3 h, cooled to room temperature, filtered through a short pad of Celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by using hexane/ethyl acetate (3/1) as eluant to give the title compound. Yield: 7.0 g (86%). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (t, 3H) 2.69 (m, 4H) 3.28 (m, 4H) 4.46 (q, 2H) 6.68 (d, 1H) 7.20-7.43 (m, 7H) 7.59 (s, 1H). The reaction mixture was heated to +110° C. for 3 h filtered through a short pad of Celite the filtrate was concentrated under reduced pressure The crude residue was purified by silica gel column chromatography

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

Procedure: Ethyl chloroacetate (8.0 mL, 1.3 eq.) was added to a mixture of 2-chloro-6-hydroxy-benzaldehyde (Example 1a), 9.0 g, 57 mmol) and potassium carbonate (16.0 g, 114 mmol) in DMF (100 mL) at rt. The reaction mixture was heated at +120° C. for 1.5 h, cooled to room temperature and filtered through a short bed of Celite. The filtrate was acidified to pH 2 with 5 M HCl and the solution was extracted with dichloromethane (2×100 mL). The combined organic extracts was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by using hexane/ethyl acetate (9/1) as eluent to give the title compound. Yield: 10 g (77%). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (t, 3H) 4.56 (q, 2H) 7.29-7.32 (m, 1H) 7.35-7.40 (m, 1H) 7.49-7.52 (m, 1H) 7.60 (s, 1H). The reaction mixture was heated at +120° C. for 1.5 h filtered through a short bed of Celite the solution was extracted with dichloromethane (2×100 mL) The combined organic extracts was washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude residue was purified by silica gel column chromatography

Conditions: temp:95.01; pressure:0.00; stir: