tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate

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:

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (905 mg, 3.7 mmol, commercially available from Alrich), sodium hydride, 95% (24 mg, 4.6 mmol) and THF (10 mL), and the mixture was stirred under N2 for 15 minutes, after which time a solution of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (700 mg, 3.7 mmol, commercially available from Aldrich) in THF (10 mL) was added to the sodium hydride mixture at 0° C. The reaction mixture was heated to 65° C. for 15 hours. Water was added to the cooled reaction mixture and the mixture was extracted with ethyl acetate. The organic solvent was concentrated under reduced pressure and the resulting solid was purified by silica column chromatography eluting with 5% methanol in dichloromethane, to give 1.2 g (78 5 yield) of tert-butyl 4-(3-(5-chloro-2-methyl-4-nitrophenoxy) propyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 6.92 (s, 1H), 3.92 (t, 2H), 3.06 (m, 4H), 2.62 (m, 4H), 2.36 (m, 2H), 2.34 (s, 3H), 1.84 (m, 2H), 1.42 (s, 9H). MS (EI): 414 (MH+). the mixture was extracted with ethyl acetate The organic solvent was concentrated under reduced pressure the resulting solid was purified by silica column chromatography eluting with 5% methanol in dichloromethane

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

Procedure: To 0.5 g (2.05 mmol) of tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate, 0.3 g (2.46 mmol) of 4-hydroxybenzaldehyde and 1 g (3.07 mmol) of resin-supported triphenyl-phosphine (3 mmol/g of resin) diluted in 14.5 ml of anhydrous tetrahydrofuran, is added dropwise at 0° C. under argon 0.614 ml (3.07 mmol) of diisopropyldiazene-1,2-dicarboxylate. The reaction mixture is stirred at room temperature for 20 h. The solid is filtered then rinsed in dichloromethane. The filtrate is concentrated and diluted in a sodium hydroxide solution (1M) and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 4:6 to 100% ethyl acetate) to yield 0.58 g of tert-butyl 4-(3-(4-formylphenoxy)propyl)piperazine-1-carboxylate in the form of a colourless oil. The solid is filtered then rinsed in dichloromethane The filtrate is concentrated diluted in a sodium hydroxide solution (1M) the product is extracted several times with ethyl acetate dried over magnesium sulfate concentrated The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 4:6 to 100% ethyl acetate)

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

Procedure: The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 2 h, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (48%). being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1)

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

Procedure: The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, and being stirred for 19 h to obtain the title compound (85%).

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

Procedure: The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 19 h, and being recrystallized with EtOAc to obtain the title compound (45%). being recrystallized with EtOAc

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl piperazine-1-carboxylate (2.75 g, 14.8 mmol), 1-bromo-3-propanol (1.43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 95° C. for 4 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (300 mL) and washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave a tan solid 2.88 g (80% yield). The solvent was removed under reduced pressure washed with water, brine dried over sodium sulfate concentrated under reduced pressure

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl piperazine-1-carboxylate (2.75 g, 14.8 mmol), 1-bromo-3-propanol (1.43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 95° C. for 4 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (300 mL) and washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave a tan solid 2.88 g (80% yield). The solvent was removed under reduced pressure washed with water, brine dried over sodium sulfate concentrated under reduced pressure