4-FLUORO-N-ISOPROPYLANILINE

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: A process according to claim 1, wherein the N-alkyl-arylamine (I) is of the formula ##STR31## 4-fluoro-nitrobenzene is employed as the nitroarene and acetone as the carbonyl compound, the reaction mixture consisting of the stated catalyst and the reactants, wherein the acetone is employed in excess and constitutes the sole diluent for the reaction, the 4-fluoro-N-isopropyl-aniline of the above formula (3) being produced in a yield of at least 90% of theory. for the reaction

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

Procedure: To a stirring solution of 17 mL (180 mmol) of 4-fluoroaniline in 550 mL of THF at RT is added 26.7 mL (180 mmol, 1.0 equiv) of acetone, 10.3 mL (180 mmol, 1.0 equiv) acetic acid, and 57.22 g (270 mmol, 1.5 equiv) of sodium triacetoxyborohydride. The solution is stirred at RT for 15 h, cooled to 0° C., and then quenched by addition of H2O. The reaction mixture warmed to RT and is poured into EtOAc, the organic layer is separated, washed with brine (1×200 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane 1:1 as eluent afforded 14.9 g (54%) of (4-Fluoro-phenyl)-isopropyl amine. A solution of 6.68 g (43.6 mmol) of (this material in 50 mL of DCM is cooled to 0° C. and 6 mL (43.6 mmol, 1.0 equiv) triethyl amine is added, followed by dropwise addition of 2.27 mL (43.6 mmol, 1.0 equiv) of bromoacetyl bromide. The solution is stirred at RT for 15 h and then poured into DCM (200 mL). The organic layer is separated, washed with saturated aq NaHCO3 (4×50 mL), 1N HCl (6×50 mL), brine (1×50 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane (3:17) as eluent afforded 5.32 g of 2-Bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide: 1HNMR (CDCl3, 300 MHz) δ7.26-7.09 (m, 4H), 4.85 (m,1H), 3.51 (s, 2H), 1.05 (d, 6H, J=6.9); low resolution MS(FAB) m/e 274 (MH+). cooled to 0° C. quenched by addition of H2O The reaction mixture warmed to RT is poured into EtOAc the organic layer is separated washed with brine (1×200 mL) dried (MgSO4) the solvents removed in vacuo Purification of the material by silica gel flash column chromatography

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

Procedure: Following the procedure described for Preparation 1(A); (4-fluoro-phenyl)-isopropyl-amine (13.70 g, 89.54 mmol) was alkylated with bromoacetyl bromide (7.78 mL, 89.54 mmol) to provide 15.02 g of 2-bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide as an oil. 1H NMR (CD2Cl2) δ 7.14-7.23 (m, 4H), 4.90 (m, 1H), 3.53 (s, 2H), 1.05 (d, 6H).

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

Procedure: Following the procedure described for Preparation 1(A), (4-fluoro-phenyl)-isopropyl-amine (13.70 g, 89.54 mmol) was alkylated with bromoacetyl bromide (7.78 mL, 89.54 mmol) to provide 15.02 g of 2-bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide as an oil. 1H NMR (CD2Cl2) δ 7.14-7.23 (m, 4H), 4.90 (m, 1H), 3.53 (s, 2H), 1.05 (d, 6H).

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

Procedure: When the product of Step A and 4-bromobenzaldehyde were substituted for sarcosine hydrochloride salt and 4-(5-(((4-fluorophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde, respectively, in Example 22, Step C, the similar process afforded the title compound in 93% yield, as a pale paste. 1H-NMR (CDCl3) 7.39 (d, 2H, J=8.18 Hz); 7.14 (d, 2H, J=8.08 Hz); 6.91-6.81 (m, 2H); 6.62-6.57 (m, 2H); 4.26 (s, 2H); 4.11-4.04 (m, 1H); 1.18 (d, 2H, J=5.34 Hz).

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

Procedure: When the product of Step A and 4-bromobenzaldehyde were substituted for sarcosine hydrochloride salt and 4-(5-(((4-fluorophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde, respectively, in Example 22, Step C, the similar process afforded the title compound in 93% yield, as a pale paste. 1H-NMR (CDCl3) 7.39 (d, 2H, J=8.18 Hz); 7.14 (d, 2H, J=8.08 Hz); 6.91-6.81 (m, 2H); 6.62-6.57 (m, 2H); 4.26 (s, 2H); 4.11-4.04 (m, 1H); 1.18 (d, 2H, J=5.34 Hz).

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

Procedure: A mixture of 4-fluoro-aniline (1.12 g; 10 mmol), 2-bromopropane (1.13 ml) and K2CO3 (1.38 g, 10 mmol) in anhydrous DMF (6 ml) was stirred for 5 h at reflux. The mixture was cooled to room temperature, diluted to 100 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O (2×20 ml) and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC(SiO2, hexane/EtOAc) to give the title compound (0.65 g; 43%), as light yellow oil. 1H-NMR (CDCl3) 6.89-6.82 (m, 2H); 6.53-6.47 (m, 2H); 3.58-3.49 (m, 1H); 1.18 (d, 6H, J=6.25 Hz). at reflux extracted with EtOAc (50 ml) The organic layer was washed with H2O (2×20 ml) dried over MgSO4 filtered The filtrate was evaporated to dryness the residue was purified by FCC(SiO2, hexane/EtOAc)

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

Procedure: To a stirred solution of the product of Step A (0.436 g, 2 mmol) in anhydrous CH2Cl2 (10 ml) and Et3N (0.3 ml) mesyl chloride (0.4 ml) was added at 0° C. and stirring was continued for 1 h. The solvents were evaporated to dryness under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to give the crude product (0.63 g) as pale paste, which was taken up in anhydrous toluene and 4-fluoro-N-isopropylaniline (0.5 ml) was added to it. The mixture was stirred overnight at reflux and the solvent was evaporated. The residue was purified by FCC(SiO2, hexane/EtOAc) to give the title compound (0.14 g, 20%), as light creamy paste. 1H-NMR (CDCl3) 9.98 (s, 1H,); 7.82 (d, 2H, J=8.31 Hz); 7.66 (d, 2H, J=8.31 Hz); 7.28 (d, 1H, J=3.69 Hz); 6.93-6.86 (m, 3H); 6.81-6.76 (m, 2H); 4.79 (s, 2H); 4.08-3.99 (m, 1H); 1.22 (d, 6H, J=6.6 Hz). The solvents were evaporated to dryness under reduced pressure the residue was diluted to 50 ml with EtOAc washed with H2O The organic layer was separated dried over MgSO4 filtered The filtrate was evaporated to give the crude product (0.63 g) as pale paste, which The mixture was stirred overnight at reflux the solvent was evaporated The residue was purified by FCC(SiO2, hexane/EtOAc)

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

Procedure: A process according to claim 1, wherein the N-alkyl-arylamine (I) is of the formula ##STR31## 4-fluoro-nitrobenzene is employed as the nitroarene and acetone as the carbonyl compound, the reaction mixture consisting of the stated catalyst and the reactants, wherein the acetone is employed in excess and constitutes the sole diluent for the reaction, the 4-fluoro-N-isopropyl-aniline of the above formula (3) being produced in a yield of at least 90% of theory. for the reaction