3-(4-fluorophenyl)propan-1-amine

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 ketone 25 (2.3 g, 9.3 mmol) in 2-propanol (30 mL) was added 4 Å molecular sieves and 3-(4-fluorophenyl)-1-propylamine (1.76 g, 9.3 mmol). The reaction mixture was stirred for 4 hours. Sodium borohydride (0.49 g, 13.03 mmol) was added, and the reaction mixture was stirred overnight, quenched with MeOH, and concentrated under reduced pressure. Purification by flash chromatography (silica, 9.5:5:1 CH2Cl2:MeOH:NH4OH) gave 6-{trans-4-[3-(4-fluorophenyl)propylamino]cyclohexyl}-3H-benzthiazol-2-one (0.24 g, 7%): 1H NMR (500 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.25-7.06 (m, 6H), 3.01 (m, 1H), 2.86 (t, J=8 Hz, 2H), 2.61 (t, J=8 Hz, 2H), 2.37 (m, 1H), 2.01 (m, 2H), 1.92-1.81 (m, 4H), 1.49-1.36 (m, 4H). the reaction mixture was stirred overnight quenched with MeOH concentrated under reduced pressure Purification by flash chromatography (silica, 9.5:5:1 CH2Cl2:MeOH:NH4OH)

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

Procedure: By the method of part A of Example 3 N-(tert-butyloxycarbonyl)-N-methyl-D-alanine (2.03 g.) was condensed with 3-(4-fluorophenyl)propylamine (prepared by condensing 4-fluorobenzaldehyde with cyanoacetic acid in refluxing pyridine using piperidine as catalyst and hydrogenating the resulting β-4-fluorophenyl)acrylonitrile in ethanolic ammonia under high pressure using Raney nickel catalyst, m.r. of methanesulfonate salt 129°-131° C.; 2.49 g.), affording N2 -(tert-butyloxycarbonyl)-N2 -methyl-N-[3-(4-fluorophenyl)propyl]-D-alaninamide as a syrup (2.77g.).

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

Procedure: By the method of part A of Example 3 N-(tert-butyloxycarbonyl)-N-methyl-D-alanine (2.03 g.) was condensed with 3-(4-fluorophenyl)propylamine (prepared by condensing 4-fluorobenzaldehyde with cyanoacetic acid in refluxing pyridine using piperidine as catalyst and hydrogenating the resulting β-4-fluorophenyl)acrylonitrile in ethanolic ammonia under high pressure using Raney nickel catalyst, m.r. of methanesulfonate salt 129°-131° C.; 2.49 g.), affording N2 -(tert-butyloxycarbonyl)-N2 -methyl-N-[3-(4-fluorophenyl)propyl]-D-alaninamide as a syrup (2.77g.).

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(4-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(4-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (432 mg, 80%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (100), 146 (76), 119 (43), 109 (30) and 91 (39). was heated

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

Procedure: The product from step c (823 mg, 4.39 mMol) and 3-(4-fluorophenyl)propylamine (674 mg, 4.39 mMol) were dissolved in anhydrous acetonitrile (10 ml). To this solution, lithium trifluoromethanesulfonate (1.44 g, 9.23 mMol) was added, and the solution was stirred overnight. The mixture was concentrated in-vacuo, then the residue was dissolved in EtOAc (60 ml), washed with saturated sodium bicarbonate (2×20 ml), followed by water (20 ml). The organic phase was dried over sodium sulfate and concentrated to a yellow oil. Purified via flash chromatography, eluting with EtOAc, 2.5% 7N NH4 in MeOH/EtOAc, 5% 7N NH4 in MeOH/EtOAc to yield 1.2 g of a colorless oil as product. ESI+MS detects 341 (M+H). The mixture was concentrated in-vacuo the residue was dissolved in EtOAc (60 ml) washed with saturated sodium bicarbonate (2×20 ml) The organic phase was dried over sodium sulfate concentrated to a yellow oil Purified via flash chromatography eluting with EtOAc, 2.5% 7N NH4 in MeOH/EtOAc, 5% 7N NH4 in MeOH/EtOAc

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

Procedure: 1-(para-fluorophenyl)-3-aminopropane (1.00 g, 6.53 mmol, 1 eq.) and triethylamine (0.91 mL, 6.53 mmol, 1 eq.) were dissoved in THF (10 mL) at 25° C. under N2. Then a THF solution (5 mL) of acetyl chloride (0.46 mL, 6.53 mmol, 1 eq.) was added dropwise via an addition funnel over 10 minutes. Worked up after 20 minutes by filtering off the solids then stripping the filtrate to obtain an amber oil. The oil was purified over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 EtOAc/MeOH. Obtained 1.10 g of an amber oil as product. MS (ESI) detects (M+H)+=196. by filtering off the solids to obtain an amber oil The oil was purified over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 EtOAc/MeOH

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

Procedure: The product from step e (0.79 g, 6.4 mmol) was dissolved in 100 mL of MeOH and added carefully to 0.20 g of 10% Pd/C under N2. The mixture was hydrogenated in a Parr shaker at 50 PSI overnight. Filtration through fiberglass filter paper under N2 and under vacuum yielded 0.56 g of a clear colorless oil. was hydrogenated in a Parr shaker at 50 PSI overnight Filtration through fiberglass filter paper under N2

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

Procedure: To a solution of ketone 25 (2.3 g, 9.3 mmol) in 2-propanol (30 mL) was added 4 Å molecular sieves and 3-(4-fluorophenyl)-1-propylamine (1.76 g, 9.3 mmol). The reaction mixture was stirred for 4 hours. Sodium borohydride (0.49 g, 13.03 mmol) was added, and the reaction mixture was stirred overnight, quenched with MeOH, and concentrated under reduced pressure. Purification by flash chromatography (silica, 9.5:5:1 CH2Cl2:MeOH:NH4OH) gave 6-{trans-4-[3-(4-fluorophenyl)propylamino]cyclohexyl}-3H-benzthiazol-2-one (0.24 g, 7%): 1H NMR (500 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.25-7.06 (m, 6H), 3.01 (m, 1H), 2.86 (t, J=8 Hz, 2H), 2.61 (t, J=8 Hz, 2H), 2.37 (m, 1H), 2.01 (m, 2H), 1.92-1.81 (m, 4H), 1.49-1.36 (m, 4H). the reaction mixture was stirred overnight quenched with MeOH concentrated under reduced pressure Purification by flash chromatography (silica, 9.5:5:1 CH2Cl2:MeOH:NH4OH)

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

Procedure: By the method of part A of Example 3 N-(tert-butyloxycarbonyl)-N-methyl-D-alanine (2.03 g.) was condensed with 3-(4-fluorophenyl)propylamine (prepared by condensing 4-fluorobenzaldehyde with cyanoacetic acid in refluxing pyridine using piperidine as catalyst and hydrogenating the resulting β-4-fluorophenyl)acrylonitrile in ethanolic ammonia under high pressure using Raney nickel catalyst, m.r. of methanesulfonate salt 129°-131° C.; 2.49 g.), affording N2 -(tert-butyloxycarbonyl)-N2 -methyl-N-[3-(4-fluorophenyl)propyl]-D-alaninamide as a syrup (2.77g.).