2-[(2-methylpropan-2-yl)oxy]ethyl methanesulfonate

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

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

Procedure: To a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (2.50 g, 7.80 mmol) in anhydrous DMF (20 mL) cooled to 0° C. in an ice bath was added a 60% dispersion of sodium hydride in mineral oil (0.47 g, 11.7 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. 2-tert-Butoxyethyl methanesulfonate (2.3 g, 11.7 mmol) was added and the mixture was stirred at 0° C. in an ice bath, then allowed to slowly warm to ambient temperature and stirred for 18 hours. The mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated and washed with aqueous 1N HCl, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40M; 20% ethyl acetate/hexane) to afford (S)-benzyl 3-(tert-butoxycarbonyl(2-tert-butoxyethyl)amino)pyrrolidine-1-carboxylate (2.87 g, 88%). the mixture was stirred at 0° C. in an ice bath to slowly warm to ambient temperature stirred for 18 hours The mixture was partitioned between water (50 mL) and ethyl acetate (100 mL) The layers were separated washed with aqueous 1N HCl, water and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage, 40M; 20% ethyl acetate/hexane)

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

Procedure: Combine 2-t-butoxyethanol (3.37 g, 28.5 mmol), triethylamine (6 mL, 43 mmol), and dichloromethane (150 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (2.9 mL, 37.5 mmol). After 3 days, dilute the reaction mixture with dichloromethane and extract with a saturated solution of sodium bicarbonate and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 2-(t-butoxy)ethyl mesylate: Rf=0.75 (silica gel, 50% ethyl acetate/hexane). Cool in an ice bath extract with a saturated solution of sodium bicarbonate Dry the organic layer over Na2SO4 filter evaporate in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity. Cool the reaction mixture to room temperature Wash with water (1× 30 mL) and brine (1× 30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity. Cool the reaction mixture to room temperature Wash with water (1× 30 mL) and brine (1× 30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

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

Procedure: At 0° C. add triethylamine (35.4 mL, 254 mmol) to a stirring solution of 2-tert-butoxyethanol (10.0 g, 84.6 mmol) and methanesulfonic chloride (13.1 mL, 169 mmol) in dichloromethane (169 mL). Allow the reaction mixture to warm to room temperature overnight. Dilute the reaction mixture with dichloromethane (200 mL) and wash it with water (1×100 mL), 1.0 N HCl (1× 100 mL) and 1.0 N NaOH (1× 100 mL). Dry the organic layer over MgSO4, filter and concentrate to give the title compound: 1H NMR (CHCl3-d6) 4.33 (t, 2H), 3.62 (t, 2H), 3.06 (s, 3H), 1.21 (s, 9H) GC/MS, tR 13.7 min, % of total 92.9%. wash it with water (1×100 mL), 1.0 N HCl (1× 100 mL) and 1.0 N NaOH (1× 100 mL) Dry the organic layer over MgSO4 filter concentrate

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

Procedure: To a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (2.50 g, 7.80 mmol) in anhydrous DMF (20 mL) cooled to 0° C. in an ice bath was added a 60% dispersion of sodium hydride in mineral oil (0.47 g, 11.7 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. 2-tert-Butoxyethyl methanesulfonate (2.3 g, 11.7 mmol) was added and the mixture was stirred at 0° C. in an ice bath, then allowed to slowly warm to ambient temperature and stirred for 18 hours. The mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated and washed with aqueous 1N HCl, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40M; 20% ethyl acetate/hexane) to afford (S)-benzyl 3-(tert-butoxycarbonyl(2-tert-butoxyethyl)amino)pyrrolidine-1-carboxylate (2.87 g, 88%). the mixture was stirred at 0° C. in an ice bath to slowly warm to ambient temperature stirred for 18 hours The mixture was partitioned between water (50 mL) and ethyl acetate (100 mL) The layers were separated washed with aqueous 1N HCl, water and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by column chromatography (Biotage, 40M; 20% ethyl acetate/hexane)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity. Cool the reaction mixture to room temperature Wash with water (1×30 mL) and brine (1×30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

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

Procedure: At 0° C. add triethylamine (35.4 mL, 254 mmol) to a stirring solution of 2-tert-butoxyethanol (10.0 g, 84.6 mmol) and methanesulfonic chloride (13.1 mL, 169 mmol) in dichloromethane (169 mL). Allow the reaction mixture to warm to room temperature over night. Dilute the reaction mixture with dichloromethane (200 mL) and wash it with water (1×100 mL), 1.0 N HCl (1×100 mL) and 1.0 N NaOH (1×100 mL). Dry the organic layer over MgSO4, filter and concentrate to give the title compound: 1H NMR (CHCl3-d6) 4.33 (t, 2H), 3.62 (t, 2H), 3.06 (s, 3H), 1.21 (s, 9H) GC/MS, tR 13.7 min, % of total 92.9%. wash it with water (1×100 mL), 1.0 N HCl (1×100 mL) and 1.0 N NaOH (1×100 mL) Dry the organic layer over MgSO4 filter concentrate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity. Cool the reaction mixture to room temperature Wash with water (1×30 mL) and brine (1×30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

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

Procedure: At 0° C. add triethylamine (35.4 mL, 254 mmol) to a stirring solution of 2-tert-butoxyethanol (10.0 g, 84.6 mmol) and methanesulfonic chloride (13.1 mL, 169 mmol) in dichloromethane (169 mL). Allow the reaction mixture to warm to room temperature over night. Dilute the reaction mixture with dichloromethane (200 mL) and wash it with water (1×100 mL), 1.0 N HCl (1×100 mL) and 1.0 N NaOH (1×100 mL). Dry the organic layer over MgSO4, filter and concentrate to give the title compound: 1H NMR (CHCl3-d6) 4.33 (t, 2H), 3.62 (t, 2H), 3.06 (s, 3H), 1.21 (s, 9H); GC/MS, tR 13.7 min % of total 92.9%. wash it with water (1×100 mL), 1.0 N HCl (1×100 mL) and 1.0 N NaOH (1×100 mL) Dry the organic layer over MgSO4 filter concentrate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity. Cool the reaction mixture to room temperature Wash with water (1×30 mL) and brine (1×30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate