4-morpholin-4-ylbutan-1-amine

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

Conditions: temp:-55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 14.8 g lithium aluminium hydride were weighed under N2 atmosphere into a round-bottomed flask. The substance was cooled down to −55° C. and 150 ml ether was added dropwise. The suspension was allowed to stir; then 30 g 4-Morpholin-4-yl-butyronitrile were dissolved in 200 ml ether and the solution was added dropwise to the reaction mixture. Again 200 ml ether were added to the mixture and the reaction was stirred at room temperature overnight. At the next day the mixture was cooled down to less than 10° C. and 35 ml H2O were added carefully. After five hours the mixture was fritted and the residue was washed with 300 ml ether. The filtrate was dried, concentrated and finally distilled under vacuum. The product fractions were collected at 74-78° C. and 2.1-1.6 Torr. The purity of the colourless oil was judged by gas chromatography, GC-MS and 1H-NMR. the solution was added dropwise to the reaction mixture the reaction was stirred at room temperature overnight At the next day the mixture was cooled down to less than 10° C. the residue was washed with 300 ml ether The filtrate was dried concentrated finally distilled under vacuum The product fractions were collected at 74-78° C.

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

Procedure: A solution of N-acetyl-colchicinol (0.357 g; 1 mmol), 4-nitrophenyl chloroformate (0.262 g; 1.3 mmol) and triethylamine (182 μl; 1.3 mmol) in dichloromethane (10 ml) was stirred, under argon atmosphere, at ambient temperature for 90 minutes. 4-(4-Aminobutyl)morpholine (0.237 g; 1.5 mmol) was then added and the mixture was further stirred for 4 hours. After evaporation to dryness the residue was purified by flash chromatography eluting with a gradient of 0–12% ethanol/dichloromethane to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl N-(4-morpholinobutyl)carbamate as a white foam. After evaporation to dryness the residue was purified by flash chromatography eluting with a gradient of 0–12% ethanol/dichloromethane

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

Procedure: A suspension of 4-morpholinobutan-1-amine (0.63 g, 4.00 mmol), 1,2-difluoro-4-nitrobenzene (0.64 g, 4.00 mmol) and K2CO3 (1.10 g, 8.00 mmol) in acetonitrile (20 mL) was stirred at rt for 19 h under N2, then filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification. filtered The filtrate was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To anhydrous THF (70 mL) was added LiAlH4 (5.37 g, 142 mmol) in one portion. The mixture was stirred at 0° C. for 20 min, and a solution of 4-morpholinobutanenitrile (7.26 g, 47 mmol) in anhydrous THF (40 mL) was added dropwise. Upon the end of addition the mixture was refluxed for 4 h, then cooled to 0° C., diluted with water (20 mL) and filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification. Upon the end of addition the mixture was refluxed for 4 h cooled to 0° C. filtered The filtrate was concentrated in vacuo

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

Procedure: Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 4-morpholinylbutylphthalimide (231 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1. the resulting solution was refluxed Reaction times and process as per Example 1

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

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

Procedure: A suspension of 4-morpholinobutan-1-amine (0.63 g, 4.00 mmol), 1,2-difluoro-4-nitrobenzene (0.64 g, 4.00 mmol) and K2CO3 (1.10 g, 8.00 mmol) in acetonitrile (20 mL) was stirred at rt for 19 h under N2, then filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification. filtered The filtrate was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To anhydrous THF (70 mL) was added LiAlH4 (5.37 g, 142 mmol) in one portion. The mixture was stirred at 0° C. for 20 min, and a solution of 4-morpholinobutanenitrile (7.26 g, 47 mmol) in anhydrous THF (40 mL) was added dropwise. Upon the end of addition the mixture was refluxed for 4 h, then cooled to 0° C., diluted with water (20 mL) and filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification. Upon the end of addition the mixture was refluxed for 4 h cooled to 0° C. filtered The filtrate was concentrated in vacuo

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

Procedure: Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 4-morpholinylbutylphthalimide (231 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1. the resulting solution was refluxed Reaction times and process as per Example 1

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of phthalimide 307 (9.42 g, 32.7 mmol) and N2H4—H2O (3.2 mL, 65.3 mmol) in EtOH (140 mL) was stirred at reflux temperature for 2 h. The mixture was cooled to 0° C., filtered, the filtrate cooled at 0° C. for 3 h, and filtered. The filtrate was evaporated and the residue dissolved in 1 M HCl. The solution was washed with ether (2×50 mL) and the pH adjusted to 10 with aqueous NH3 solution. The resulting mixture was extracted with CHCl3 (4×50 mL), the combined organic fraction dried and the solvent evaporated to give diamine 308 (Thompson, A. M.; et. al., J. Med. Chem., 1997, 40, 3915-3925) (2.0 g, 39%) as a colourless oil: 1H NMR δ 3.72 (br t, J=4.7 Hz, 4H, 2×CH2O), 2.71 (br dd, J=6.9, 6.7 Hz, 2H, CH2N), 2.44 (br t, J=4.6 Hz, 4H, 2×CH2N), 2.34 (br dd, J=7.8, 7.0 Hz, 2H, CH2N), 1.62 (br s, 2H, NH2), 1.42-1.59 (m, 4H, 2×CH2)— at reflux temperature for 2 h filtered the filtrate cooled at 0° C. for 3 h filtered The filtrate was evaporated the residue dissolved in 1 M HCl The solution was washed with ether (2×50 mL) The resulting mixture was extracted with CHCl3 (4×50 mL) the combined organic fraction dried the solvent evaporated

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

Procedure: 4-(4-Morpholinyl)butylamine (306) (2.02 g, 12.8 mmol) was added to a stirred solution of chloride 21 (1.89 g, 8.5 mmol) and Et3N (1.8 mL, 12.8 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 62 (2.57 g, 88%) as pale yellow solid: mp (MeOH/EtOAc) 151-152° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.78 (br s, 1H, NH), 3.78 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.50 (br dd, J=6.6, 5.9 Hz, 2H, CH2N), 2.95-3.02 (m, 4H, H-6, H-8), 2.45 (br t, J=4.4 Hz, 4H, 2×CH2N), 2.40 (t, J=7.0 Hz, 2H, CH2N), 2.15 (p, J=7.5 Hz, 2H, H-7), 1.67-1.74 (m, 2H, CH2), 1.58-1.64 (m, 2H, CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 66.9 (2), 58.5, 53.7 (2), 41.3, 33.1, 32.3, 27.4, 25.7, 24.0. Anal. Calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.9; H, 7.2; N, 20.5%. at reflux temperature for 16 h The solvent was evaporated the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL) The organic fraction was dried the solvent evaporated The residue was purified by chromatography eluting with a gradient (0-10%) of MeOH/DCM