1-(4-bromophenyl)sulfonylazetidine

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: The title compound is analogously synthesized as described for 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 1.28 g of 4-bromo-benzenesulfonyl chloride, 643 mg of commercially available o-toluidine in 20 ml of dichloromethane and 10 ml of K2CO3 solution. Purification by chromatography on flash silica gel (eluent: neat dichloromethane) affords 830 mg of the title compound as colorless, amorphous solid of m.p. 114° C. GC-MS: 327.0 (MH+). TLC: Rf=0.58 (neat dichloromethane). Purification by chromatography on flash silica gel (eluent: neat dichloromethane)

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

Procedure: The title compound is analogously synthesized as described for 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 767 mg of 4-bromo-benzenesulfonyl chloride, 451 mg of commercially available 2-fluoro-4-methyl-aniline in 12.0 ml of dichloromethane and 6.0 ml of K2CO3 solution to yield 727 mg of the title compound as colorless, amorphous solid of m.p. 111° C. ESI-MS: 361.2/363.3 (MNH4+, 100%:87%). TLC: Rf=0.57 (neat dichloromethane).

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

Procedure: 4.09 g of azetidine are dissolved in a two-phase solvent system of 200 ml of dichloromethane and 130 ml of an aqueous potassium carbonate solution (strength 4.0 M). Subsequently, a solution of 15.25 g of commercially available 4-bromo-benzenesulfonyl chloride in 70 ml of dichloromethane is slowly added to the reaction mixture. Thereafter, the mixture is vigorously stirred for 17 hours at room temperature. For extraction, 200 ml of dichloromethane and 100 ml of water are added. The organic layer is dried using Na2SO4, filtered with suction, and concentrated in vacuo to yield 15.22 g of the title compound as a colorless, amorphous solid of m.p. 145° C. ESI-MS: 276.1/278.0 (MH+, 100%:95%). TLC: Rf=0.59 (dichloromethane/ethanol 10:1 parts by volume). For extraction, 200 ml of dichloromethane and 100 ml of water are added The organic layer is dried filtered with suction concentrated in vacuo

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 378 mg of 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) are dissolved in 10 ml of oxygen-free dioxane under an atmosphere of dry nitrogen. Subsequently, 383 mg of bis(pinacolato)diboron, 30 mg of Pd(Cl)2(dppf).CH2Cl2, 23 mg of DPPF (1,1′-bis(diphenylphosphino)-ferrocene), and 403 mg of potassium acetate are added. The reaction mixture is heated at 110° C. for 16 hours during which time the former yellowish suspension becomes black (LC-MS monitoring for boronic ester intermediate). Thereafter, 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1), 2.70 ml of aqueous sodium carbonate solution (strength 2.0 M), and 66 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) are added and the reaction mixture is heated at 110° C. for 72 hours. Subsequently, the mixture is diluted with 50 ml of water and extracted three times each with 100 ml of dichloromethane. The organic layer is separated, dried using Na2SO4 (solid) and concentrated in vacuo. The resulting crude material is purified by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) to yield 187 mg of the title compound as an oil. ESI-MS: 454.2 (MH+). TLC: Rf=0.29 (dichloromethane/ethanol 10:1 parts by volume). the reaction mixture is heated at 110° C. for 72 hours extracted three times each with 100 ml of dichloromethane The organic layer is separated dried concentrated in vacuo The resulting crude material is purified by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol)

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

Procedure: The title compound was prepared by the method of example 144 step (i) using the product from example 151 step (iv), 1-[(4-bromophenyl)sulfonyl]azetidine and THF as solvent. Yield 0.028 g.