4-bromo-N,N-diethylbenzamide

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:250.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.7 g (2.3 mmol) of N-acetyl-m-anisidine, 10.6 g (41.4 mmol) of 4-bromo-N,N-diethylbenzamide and 0.42 g of CuI were heated to 1000° C.; 3 g (22.3 mmol) of K2CO3 were added and the resulting mixture was heated to 250° C. for 2 hours. The residue was dissolved in CH2Cl2 and washed with H2O, the organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The resulting residue was dissolved in 20 ml of absolute EtOH and refluxed for 2 h. The solvent was removed in vacuo, the residue was taken up in H2O and the aqueous layer extracted with AcOEt. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The resulting residue was purified by flash chromatography (AcOEt/Hexane 6:4), yielding 3 g of the title compound. washed with H2O the organic layer was dried over Na2SO4 the solvent was removed in vacuo The resulting residue was dissolved in 20 ml of absolute EtOH refluxed for 2 h The solvent was removed in vacuo the aqueous layer extracted with AcOEt The organic layer was dried over Na2SO4 the solvent removed in vacuo The resulting residue was purified by flash chromatography (AcOEt/Hexane 6:4)

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: To a solution of N,N-diethyl-4-bromo-benzamide (128 mg, 0.5 mmol) (see structural formula at entry 3 of Table 1) and Cp2ZrCl2(207 mg, 0.7 mmol, 1.4 eq.) in THF (3 mL) at RT was rapidly added a 1 M tetrahydrofuran (THF) solution of LiAlH(Ot-Bu)3 (0.7 mL, 0.7 mmol, 1.4 eq.). After addition, thin layer chromatography (TLC) using EtOAc/Hexanes showed the substrate had been consumed completely. The reaction was quenched by distilled H2O immediately. Dilute acid (0.5 N HCl in distilled water) was added until the pH was less than 5. Then EtOAc was added (3×10 mL) and the mixture was extracted. Combined organic layers were washed with brine, dried over MgSO4 and concentrated via evaporation under reduced pressure. Initial purification of the crude product was performed by passing the solution through a filter of silica gel (silica gel 60, 230-400 mesh). Purity was then checked by TLC. If further purification was needed, it was performed by flash column chromatography (silica gel 60, 230-400 mesh) using EtOAc/hexanes as eluent. 4-Bromobenzaldehyde (89 mg, 96% yield) was obtained as a colorless solid. Its melting point was determined to be 55-56° C. (hexanes). After addition, thin layer chromatography (TLC) had been consumed completely The reaction was quenched by distilled H2O immediately Dilute acid (0.5 N HCl in distilled water) was added until the pH was less than 5 Then EtOAc was added (3×10 mL) the mixture was extracted Combined organic layers were washed with brine dried over MgSO4 concentrated via evaporation under reduced pressure Initial purification of the crude product a filter of silica gel (silica gel 60, 230-400 mesh) If further purification

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

Procedure: A solution of 3.5 g (14.1 mmol) of N-(3-methoxyphenyl)-1-propyl-4-piperidinamine, 3.61 g (14.1 mmol) of N,N-diethyl-4-bromobenzamide, 129 mg (0.141 mmol) tris(dibenzylideneacetone)-dipalladium(0) (Pd2dba3), 263 mg (0.423 mmol) of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (+BINAP) and 1.89 g (19.7 mmol) of sodium t-butoxide in 25 mL of dry toluene was heated at 110° C. under Ar in a pressure vessel for 16 h. The mixture was cooled and partitioned between CH2Cl2 and H2O. The organic layer was washed with brine, dried (K2CO3) and the solvent was evaporated. The residue was chromatographed on a Biotage Flash 75 unit using CH2Cl2:MeOH:NH4OH, 92:8:0.8 as eluent. There was obtained 3.2 g (53% yield) of N,N-diethyl-4-[3-methoxyphenyl(1-propylpiperidin-4yl)amino]benzamide as a solid. A fumarate salt was prepared out of 2-PrOH: mp 168-169° C. MS m/z=424 (M++H). 300 MHz 1H NMR (DMSO-d6) δ7.3 (t, 1H); 7.2 (d, 2H); 6.8 (d, 1H); 6.6 (m, 4H); 6.5 (s, 2H); 4.0 (m, 1H); 3.75 (s, 3H); 3.3 (q, 4H); 3.1 (d, 2H); 2.4 (m, 4H); 1.9 (d, 2H); 1.4 (m, 4H); 1.1 (t, 6H); 0.8 (t, 3H). Anal calcd. for C26H37N3O2.C4H4O4: C, 66.77; H, 7.65; N, 7.78. Found: C, 66.69; H, 7.76; N 7.68. The mixture was cooled partitioned between CH2Cl2 and H2O The organic layer was washed with brine dried (K2CO3) the solvent was evaporated The residue was chromatographed on a Biotage Flash 75 unit

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

Procedure: A solution of 3.5 g (14.1 mmol) of N-(3-methoxyphenyl)-1-propyl-4-piperidinamine, 3.61 g (14.1 mmol) of N,N-diethyl-4-bromobenzamide, 129 mg (0.141 mmol) tris(dibenzylideneacetone)-dipalladium(0) (Pd2dba3), 263 mg (0.423 mmol) of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (+BINAP) and 1.89 g (19.7 mmol) of sodium t-butoxide in 25 mL of dry toluene was heated at 110° C. under Ar in a pressure vessel for 16 h. The mixture was cooled and partitioned between CH2Cl2 and H2O. The organic layer was washed with brine, dried (K2CO3) and the solvent was evaporated. The residue was chromatographed on a Biotage Flash 75 unit using CH2Cl2:MeOH:NH4OH, 92:8:0.8 as eluent. There was obtained 3.2 g (53% yield) of N,N-diethyl-4-[3-methoxyphenyl(1-propylpiperidin-4yl)amino]benzamide as a solid. A fumarate salt was prepared out of 2-PrOH: mp 168-169° C. MS m/z=424 (M++H). 300 MHz 1H NMR (DMSO-d6) δ7.3 (t, 1H); 7.2 (d, 2H); 6.8 (d, 1H); 6.6 (m, 4H); 6.5 (s, 2H); 4.0 (m, 1H); 3.75 (s, 3H); 3.3 (q, 4H); 3.1 (d, 2H); 2.4 (m, 4H); 1.9 (d, 2H); 1.4 (m, 4H); 1.1 (t, 6H); 0.8 (t, 3H). Anal calcd. for C26H37N3O2.C4H4O4: C, 66.77; H, 7.65; N, 7.78. Found: C, 66.69; H, 7.76; N 7.68. The mixture was cooled partitioned between CH2Cl2 and H2O The organic layer was washed with brine dried (K2CO3) the solvent was evaporated The residue was chromatographed on a Biotage Flash 75 unit

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

Procedure: A solution of N-benzyl-1-propyl-4-piperidinamine (3.47 g, 14.9 mmol), N, N-diethyl-4-bromobenzamide (3.82 g, 14.9 mmol), Pd2 dba3 (0.14 g, 0.149 mmol), (+)-BINAP (0.28 g, 0.448 mmol) and sodium t-butoxide (2.00 g, 20.9 mmol) in 18.5 mL of dry toluene was heated at 120° C. under Argon in a pressure vessel for 46 h. The mixture was cooled, and dichloromethane (75 mL) and water (75 mL) were added to the reaction flask. The layers were separated, and the aqueous layer was extracted twice with dichloromethane (75 mL). The organic layers were combined and washed with brine (75 mL) and dried (Na2SO4). Evaporation of the solvent afforded a dark brown oil with some solid particles evident. This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform) to provide 3.75 g (62% yield) of N,N-diethyl-4-[benzyl(1-propylpiperidin-4-yl)amino]benzamide as a golden-brown oil. This material was dissolved in acetonitrile, and oxalic acid (0.82 g) was added. Upon addition of diethyl ether, a cream-colored precipitate came out of solution. Recrystallization from acetonitrile and diethyl ether afforded 2.41 g (32% yield) of a cream-colored solid, mp 92-99° C. MS (ES), m/z 408 (MH+). 300 MHz 1H NMR (DMSO-d6) δ0.89 (t, J=7.3 Hz, 3H), 1.08 (t, J=7.0 Hz, 6H), 1.56-1.73 (m, 2H), 1.82-2.10 (m, 4H), 2.94 (brt, J=7.8 Hz, 2H), 3.08 (br t, 2H), 3.31 (dd, J=6.9 Hz, 2H), 3.46 (br d, J=11.5 Hz, 2H), 4.18-4.35 (br m, 1H), 4.49 (br s, 2H), 6.74 (d, J=8.7 Hz, 2H), 7.20-7.35 (m, 7H). Elemental analysis: Calculated for C26H37N3O.C2H2O4.0.6H2O: C, 66.14; H, 7.97; N, 8.26. Found C, 65.90; H, 7.78; N, 8.01. The mixture was cooled The layers were separated the aqueous layer was extracted twice with dichloromethane (75 mL) washed with brine (75 mL) dried (Na2SO4) Evaporation of the solvent afforded a dark brown oil with some solid particles evident This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dry flask containing 1-benzyl-piperidin-4-ylamine 6 (5.0 mL; 1.2 eq) in dry toluene (75 mL) was added N,N-diethyl-4-bromobenzamide (5.24 g; 1.0 eq), BINAP (383 mg; 0.03 eq), palladium acetate (92 mg; 0.02 eq) and sodium tert-butoxide (2.75 g; 1.4 eq). The reaction was heated to 80° C. under nitrogen. After 2 hours the reaction was cooled, diluted with ethyl acetate and washed with two portions water. The organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 5% to 10% methanol in dichloromethane. The residue obtained was boiled in ethyl acetate, cooled and collected by filtration. A pale yellow solid was obtained (5.724 g; 77% yield). After 2 hours the reaction was cooled washed with two portions water The organics were dried over anhydrous magnesium sulfate filtered concentrated The residue was purified by flash chromatography eluting with 5% to 10% methanol in dichloromethane The residue obtained cooled collected by filtration A pale yellow solid was obtained (5.724 g; 77% yield)