tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL dichloromethane was added tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut MP-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+ 470.2, obs'd 470.1 to stir for 1 hour at room temperature stirred overnight at room temperature The mixture was then filtered concentrated Added dichloromethane (1 mL) and stirred treated with trifluoroacetic acid (1 mL) The reaction mixture was concentrated after 2 hours of stirring at room temperature the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL dichloromethane was added tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut MP-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+ 470.2, obs'd 470.1 to stir for 1 hour at room temperature stirred overnight at room temperature The mixture was then filtered concentrated Added dichloromethane (1 mL) and stirred treated with trifluoroacetic acid (1 mL) The reaction mixture was concentrated after 2 hours of stirring at room temperature the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was synthesized from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate following the procedure described in EXAMPLE 120. Mass spectrum (ESI) 529.2 (M+1).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL dichloromethane was added tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut MP-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+470.2, obs'd 470.1 to stir for 1 hour at room temperature stirred overnight at room temperature The mixture was then filtered concentrated Added dichloromethane (1 mL) and stirred treated with trifluoroacetic acid (1 mL) The reaction mixture was concentrated after 2 hours of stirring at room temperature the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available furan-2,4(3H,5H)-dione (0.433 g, 4.33 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (commercially available from multiple vendors, acetic acid salt, 0.65 g, 2.2 mmol) in 20 mL i-PrOH was heated in a sealed tube at 110° C. overnight. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in 30 mL DCM and 5 mL TFA and stirred at rt for 1 h. The mixture was concentrated, and the residue was purified by preparative TLC (10%2N NH3 in methanol-DCM). LC/MS: [(M+1)]+=223 The solid was filtered off the filtrate was concentrated under vacuum The residue was dissolved in 30 mL DCM The mixture was concentrated the residue was purified by preparative TLC (10%2N NH3 in methanol-DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL dichloromethane was added tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut MP-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+ 470.2, obs'd 470.1 to stir for 1 hour at room temperature stirred overnight at room temperature The mixture was then filtered concentrated Added dichloromethane (1 mL) and stirred treated with trifluoroacetic acid (1 mL) The reaction mixture was concentrated after 2 hours of stirring at room temperature the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The reaction was performed under an N2 atmosphere. tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (869 mg, 3.62 mmol), 4-chloropyridine hydrochloride (1.08 g, 7.20 mmol) and TEA (2.5 ml, 18 mmol) were suspended in isopropanol (10 ml). The mixture was heated to 80° C. and stirred overnight at 80° C. Then the solvent was removed in a rotary evaporator. The residue was taken up in DCM and concentrated to small volume again. This process was repeated twice more. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2). The product obtained still contained impurities and was used in the next stage in that condition. 2. The reaction was performed under an N2 atmosphere. The carbamate (1.034 g, max. 3.26 mmol) was dissolved in MeOH (5 ml) and mixed with 4 M HCl in dioxane (5 ml). The reaction batch was stirred for 2 h at RT. Then the solvent was removed. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2→95:5→9:1). Yield: 455 mg, 58% over 2 stages. Then the solvent was removed in a rotary evaporator concentrated to small volume again The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2) The product obtained still contained impurities The reaction batch was stirred for 2 h at RT Then the solvent was removed The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2→95:5→9:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available furan-2,4(3H,5H)-dione (0.433 g, 4.33 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (commercially available from multiple vendors, acetic acid salt, 0.65 g, 2.2 mmol) in 20 mL i-PrOH was heated in a sealed tube at 110° C. overnight. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in 30 mL DCM and 5 mL TFA and stirred at rt for 1 h. The mixture was concentrated, and the residue was purified by preparative TLC (10% 2N NH3 in methanol-DCM). LCMS: [(M+1)]+=223 The solid was filtered off the filtrate was concentrated under vacuum The residue was dissolved in 30 mL DCM The mixture was concentrated the residue was purified by preparative TLC (10% 2N NH3 in methanol-DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: BINAP (293 mg, 0.47 mmol) and Pd(OAc)2 (317 mg, 1.4 mmol) was added to a mixture of 2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5.66 g, 23.6 mmol), 4-bromopyridine HCl (4.58 g; 23.6 mmol) and sodium tert-butylate (6.8 g, 70.8 mmol) in toluene and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. The mixture was then diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 53% the reaction mixture was degassed under argon for 20 minutes heated under reflux for 4 h The mixture was then diluted with ethyl acetate filtered over Celite The organic phase was washed with water and sat. NaCl solution dried over sodium sulfate concentrated under reduced pressure The crude product was purified by column chromatography