1-tert-butylpiperidin-4-one

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

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

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 7-[(1-tert-butylpiperidin-4-yl)amino]-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (COMPOUND CCC4, STEP A) and the 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) by a procedure analogous to that described in EXAMPLE CCC18, STEP A. Mass spectrum (ESI) 677.2 (M+1).

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

Procedure: To a 0° C. solution of 1.0 g of 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) in 2 mL of THF was added 6.4 mL of a 1M solution of lithium aluminum hydride in THF dropwise. The mixture was stirred 10 min at rt, then quenched by careful addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.6 mL of water. The mixture was stirred vigorously for 30 min, then filtered and concentrated to yield the title compound. quenched by careful addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.6 mL of water The mixture was stirred vigorously for 30 min filtered concentrated

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

Procedure: To a solution of (bromomethyl)triphenylphosphonium bromide (1.52 g, 3.48 mmol) in dry THF (15 mL) at −78° C. was added potassium tert-butoxide (3.5 mL, 1.0M) slowly. After stirring 20 minutes, 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) (595 mg, 3.83 mmol) in THF (2 mL) was added, and the reaction mixture was warmed up to rt slowly over 2 h. The reaction mixture was quenched with brine, and it was extracted with CH2Cl2. The combined extracts were dried over Na2SO4 then concentrated in vacuo. The crude material was purified by flash chromatography eluting first with hexane then gradually increasing to 5% acetone/hexane to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 5.85 (s, 1H); 2.56 (m, 4H); 2.43 (t, J=5.6 Hz, 2H); 2.28 (t, J=5.6 Hz, 2H); 1.08 (s, 9H). The reaction mixture was quenched with brine, and it was extracted with CH2Cl2 The combined extracts were dried over Na2SO4 then concentrated in vacuo The crude material was purified by flash chromatography eluting first with hexane then gradually increasing to 5% acetone/hexane

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

Procedure: A dichloromethane solution (3 mL) containing 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) (120 mg, 0.77 mmol), benzyl amine (0.17 mL, 1.56 mmol), acetic acid (0.05 mL) and sodium triacetoxy borohydride (246 mg, 1.16 mmol) was stirred for several days. The solution was concentrated and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH/NH4OH (87/12/1) as eluent to give N-benzyl-1-tert-butylpiperidin-4-amine. Mass spectrum (ESI) 247 (M+1). 1H NMR (500 MHz, CD3OD): δ 1.09(s, 9H); 1.38-1.48(m, 2H); 1.91-1.97(m, 2H); 2.11-2.18(m, 2H); 2.40-2.48(m, 1H); 3.02-3.08(m, 2H); 3.76(s, 2H); 4.87(s, 1H); 7.21-7.26(m, 1H); 7.29-7.36(m, 4H). The solution was concentrated the residue partitioned between aqueous potassium carbonate and ethyl acetate The organic phase was dried over sodium sulfate filtered concentrated The residue was purified by silica gel chromatography

Conditions: temp:78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 137 mL (1.3 moles) of tert-butylamine in 700 mL of toluene was added solution of 70 g (0.260 moles) of 1-ethyl-1-methyl-4-oxopiperidinium iodide and 2.18 g (0.026 moles) of NaHCO3 in 100 mL of water. The mixture was stirred at 78° C. for 6 h. After it had cooled to rt, the layers were separated and the aq layer was washed with three 200 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to an oil that purified by distillation under reduced pressure. Fractions distilling at 72° C. at 3 mm were collected to afford the title compound as a colorless liquid. 1H NM(CDCl3, 500 MHz): δ 1.15 (s, 9H), 2.45 (t, 4H, J=6.1 Hz), 2.86 (t, 4H, J=6.1H); Mass spectrum (ESI) 156 (M+1). After it had cooled to rt the layers were separated the aq layer was washed with three 200 mL portions of ethyl acetate The combined organic layers were washed with brine dried (MgSO4) concentrated to an oil that purified by distillation under reduced pressure Fractions distilling at 72° C. at 3 mm were collected

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

Procedure: 1-t-Butyl-4-piperidone (1.3 g, 8.4 mmol, 1.0 equiv), NaCN (0.61 g, 12.6 mmol, 1.5 equiv), and NH4Cl (0.67 g, 12.6 mmol, 1.5 equiv) were combined in 34 mL of 2 M NH3 in MeOH. The mixture was refluxed for 2 h at which time an additional 34 mL of 2 M NH3 in MeOH was added followed by another 2 h at reflux. The mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was triturated with CH2Cl2 and filtered again. The solution was concentrated to a thick red oil which was used without further purification; MS, m/z 182=M+1. was added at reflux The mixture was cooled filtered The filtrate was concentrated in vacuo the residue was triturated with CH2Cl2 filtered again The solution was concentrated to a thick red oil which was used without further purification

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(t-Butyl-amino)-N-methoxy-N-methyl-propanamide (5 g, 26.6 mmol, 1.0 equiv) was dissolved in dry THF (50 mL) under Ar. The solution was cooled to −78° C. and a 1 M solution of vinylmagnesium bromide (66.5 mL, 66.5 mmol, 2.5 equiv) was added dropwise over a 20 min period. The reaction was then stirred at −78° C. for 30 min and at 0° C. for 30 min at which time the reaction solution was transferred via a double-ended cannula into ice-cold saturated sodium bicarbonate solution under Ar. The mixture was stirred for 10 min and the crude product was extracted 2×150 mL EtOAc. The organic extracts were combined and concentrated in vacuo to a red oil. Purification was done by flash chromatography on silica using 100% CH2Cl2 through 4, 8, and 16% MeOH in CH2Cl2. The product was isolated as an orange oil (1.3 g, 32%); MS, m/z 156=M+1. The mixture was stirred for 10 min the crude product was extracted 2×150 mL EtOAc concentrated in vacuo to a red oil Purification

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