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1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinamine dihydrochloride[ No CAS ]
trans-N-(3-fluoro-5-methyl-2-nitrophenyl)-1-(4-propoxycyclohexyl)-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 18h;
Description 25. frans-lambda/-(3-Fluoro-5-methyl-2-nitrophenyl)-1 -(4-propoxycyclohexyl)- 4-piperidinamine (D25); A stirred solution of <strong>[932373-92-7]3,5-difluoro-4-nitrotoluene</strong> (D3, 0.17g) in dimethylformamide (5ml) at room temperature under argon was treated with diisopropylethylamine (0.7ml) and trans- 1-[4-(propoxy)cyclohexyl]-4-piperidinamine dihydrochloride (D22, 0.31 g) and heated at 8O0C for 18h. The cooled reaction was diluted with ethyl acetate and washed three times with water then dried, evaporated and chromatographed (Biotage KP-NH-silica column eluting with 0-15% ethyl acetate/hexane) to give the title compound (0.12g).
1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride[ No CAS ]
[ 932373-92-7 ]
[ 932373-93-8 ]
Yield
Reaction Conditions
Operation in experiment
With tetra-(n-butyl)ammonium iodide; sodium carbonate; In 1-methyl-pyrrolidin-2-one; at 50℃; for 3h;
A mixture of 1 ,3-difluoro-5-methyl-2-nitrobenzene (1g), 1-(tetrahydro-2H-pyran-4- yl)-4-piperidinamine, dihydrochloride (1.63g), sodium bicarbonate (1.94g) and tetrabutyl ammonium iodide (100mg) in NMP (15ml) was slowly heated at about 500C for 3 hours. After cooling to about 25C, the reaction mixture was added to ethyl acetate (15ml) and saturated brine (15ml). The layers were separated and the aqueous extracted with ethyl acetate (15ml). The combined ethyl acetate layers were then washed with saturated brine (4 x 4ml), dried with 2g anhydrous sodium sulphate then concentrated under vacuum. The residue was heated with acetonitrile (4ml) to about 600C to give a solution, then cooled to 0 to 5C and stirred for 1 hour. The solid was filtered, washed with chilled acetonitrile (2ml), then dried at 40-450C under high vacuum to give the title compound as an orange solid (0.83g).300MHz NMR in CDCI3. TMS as reference at 0.0 ppm. delta(ppm): 1.62(4H) m; 1.76 (2H) m; 2.05 (2H) m; 2.30 (3H) s; 2.42 (2H) m; 2.51 (1 H) m; 2.88 (2H) m; 3.390 (2H) m; 3.49 (1 H) m; 4.05 (2H) m; 6.23 (.1H) d; 6.36 (1H) s; 7.51 (1 H) m;
A mixture of (3,5-difluoro-4-nitrophenyl)acetic acid (41 g), potassium carbonate (24.6g) and DMF (205ml) was slowly heated to about 5O0C for 30 minutes. The reaction was then cooled to about 250C and quenched into 2M HCI (1025ml) and hexane (400ml) and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (400ml). The combined hexane layers were washed with saturated brine ( 2 x 200ml), then dried with anhydrous sodium EPO <DP n="63"/>sulphate and the solution was concentrated to give the title compound as a low melting solid (26g).300MHz NMR in CDCI3. TMS as reference at 0.0 ppm. delta(ppm): 2.44(3H) s; 6.91 (2H) d
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 0.5h;
A mixture of (3,5-difluoro-4-nitrophenyl)acetic acid (D36, 41 g), potassium carbonate(24.6g) and DMF (205ml) was slowly heated to about 500C for 30 minutes. The reaction was then cooled to about 25C and quenched into 2M HCI (1025ml) and hexane (400ml) and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (400ml). The combined hexane layers were washed with saturated brine (2 x 200ml), then dried with anhydrous sodium sulphate and the solution was concentrated to give the title compound as a low melting solid (26g).
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 0.5h;
Description 3. 3,5-Difluoro-4-nitrotoluene (D3); A mixture of S.delta-difluoro^-nitrophenylacetic acid (D2, 1.Og), potassium carbonate (0.6g), and dimethylformamide (5ml) was stirred at 500C for 30min then cooled and partitioned between 2M hydrochloric acid and hexane. Drying, evaporation and chromatography (2Og silica, 0-20% ethyl acetate in hexane) gave the title compound as a yellow oil, 0.65g.
1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinamine dihydrochloride[ No CAS ]
N-(3-fluoro-5-methyl-2-nitrophenyl)-1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation;
Description 62. lambda/-(3-Fluoro-5-methyl-2-nitrophenyl)-1 -[trans-lambda -methyl-4- (methyloxy)cyclohexyl]-4-piperidinamine (D62); <n="71"/>(D62)Diisopropylethylamine (0.55ml_, 3.23mmole) and 2, 6-difluoro-4-methyl-1 -nitrobenzene (206mg, 1.19mmole) were added to a solution of 1-[frans-4-(methyloxy)-1- methylcyclohexyl]-4-piperidinamine dihydrochloride (di HCI salt of D57, 306mg, 1.02mmole) in N,N-dimethylformamide (5ml) under argon. The reaction was heated at 100C in a microwave reactor for 30min and then for a further 30min. The mixture was poured on to sat. NaHCO3 solution (5OmL) and extracted with EtOAc (3x). The combined organics were washed sequentially with brine, H2O and brine, dried (Na2SO4) and concentrated via rotary evaporation. The crude residue was purified by SCX (5g) and then chromatographed (silica, CH2CI2-0.5% NH3 /9.5% MeOH /90% CH2CI2) to yield the title compound (157mg, 41 %) as an orange oil which solidified on standing to give an orange solid. MH+ 380.
cis-1-(4-methoxycyclohexyl)-4-piperidinamine dihydrochloride[ No CAS ]
trans-1-(4-methoxycyclohexyl)-4-piperidinamine dihydrochloride[ No CAS ]
cis-N-(3-fluoro-5-methyl-2-nitrophenyl)-1-(4-methoxycyclohexyl)-4-piperidinamine[ No CAS ]
trans-N-(3-fluoro-5-methyl-2-nitrophenyl)-1-(4-methoxycyclohexyl)-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 72h;
Description 9. cis and frans-lambda/-(3-Fluoro-5-methyl-2-nitrophenyl)-1-(4- methoxycyclohexyl)-4-piperidinamine (D9a, D9b)(D9a) (D9b); A stirred solution of <strong>[932373-92-7]3,5-difluoro-4-nitrotoluene</strong> (D3, 0.65g) in dimethylformamide (15ml) at room temperature under argon was treated with diisopropylethylamine (2.0ml) and 1-[4- (methoxy)cyclohexyl]-4-piperidinamine dihydrochloride (D8, cis:trans mixture, 0.8g) and heated at 5O0C for 72h. The cooled reaction was diluted with ethyl acetate and washed three times with water then dried, evaporated and chromatographed (Biotage KP-NH- silica column eluting with 0-25% ethyl acetate/hexane) to give the cis (D9a, 250mg) and trans (D9b, 140mg) isomers of the title compound.
trans-1-(4-ethoxycyclohexyl)-4-piperidinamine dihydrochloride[ No CAS ]
trans-N-(3-fluoro-5-methyl-2-nitrophenyl)-1-(4-ethoxycyclohexyl)-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 18h;
Description 23. frans-lambda/-(3-Fluoro-5-methyl-2-nitrophenyl)-1 -(4-ethoxycyclohexyl)-4- piperidinamine (D23) ; <n="54"/>A stirred solution of <strong>[932373-92-7]3,5-difluoro-4-nitrotoluene</strong> (D3, 0.17g) in dimethylformamide (5ml) at room temperature under argon was treated with diisopropylethylamine (0.7ml) and trans- 1-[4-(ethoxy)cyclohexyl]-4-piperidinamine dihydrochloride (D18, 0.3g) and heated at 8O0C for 18h. The cooled reaction was diluted with ethyl acetate and washed three times with water then dried, evaporated and chromatographed (Biotage KP-NH-silica column eluting with 0-15% ethyl acetate/hexane) to give the title compound (0.12g).
1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine[ No CAS ]
N-(3-fluoro-5-methyl-2-nitrophenyl)-1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃;
Description 36. lambda/-(3-Fluoro-5-methyl-2-nitrophenyl)-1 -[frans-1 -methyl-4- (propyloxy)cyclohexyl]-4-piperidinamine (D36); A stirred mixture of <strong>[932373-92-7]3,5-difluoro-4-nitrotoluene</strong> (D3, 170mg, 0.98mmole), 1-[frans-1- methyl-4-(propoxy)cyclohexyl]-4-piperidinamine (D35, 250mg, 0.98mmole) and diisopropylethylamine (0.2ml, 1.17mmole) in dimethylformamide (20ml) was heated at 5O0C overnight under an argon atmosphere. The mixture was washed with sat. NaHCC>3 solution then extracted with dichloromethane. The organic phase was eluted through an SCX cartridge, washed with methanol and the compound was collected by elution with 2M NH3 in MeOH. The solvent was removed under vacuum to leave a red solid, which was chromatographed on silica eluting with 20-60% EtOAc/DCM to afford the title compound (320mg, 79%). MH+ = 408.
1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinamine dihydrochloride[ No CAS ]
1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-N-(3-fluoro-5-methyl-2-nitrophenyl)-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 1h;Microwave irradiation;
Description 48. 1 -[frans-4-(Ethyloxy)-1 -methylcyclohexyl]-lambda/-(3-fluoro-5-methyl-2- nitrophenyl)-4-piperidinamine (D48); A solution of 1 ,3-difluoro-5-methyl-2-nitrobenzene (183mg, 1.06mmole) and 1-[frans-4- (ethyloxy)-1-methylcyclohexyl]-4-piperidinamine dihydrochloride (D47, 300mg, 0.962mmole) in N,N-dimethylformamide (5ml) under argon was treated with <n="65"/>diisopropylethylamine (0.49ml, 2.88 mmole) and the reaction mixture heated at 11 O0C for 60mins in a microwave reactor. The resulting mixture was then concentrated under vacuum, the residue treated using dil. NaHCOs solution (50ml) and then extracted using ethyl acetate (3x50ml). The combined extract was dried (MgSO4) and concentrated under vacuum to give crude material as an orange residue. The residue was then chromatographed on silica eluting 0-10% methanol/dichloromethane to yield the title compound (150mg, 40%) as an orange residue. MH+ = 394.
1-(cis-3-propoxycyclohexyl)-4-piperidinamine[ No CAS ]
N-(3-fluoro-5-methyl-2-nitrophenyl)-1-(cis-3-propoxycyclohexyl)-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;
A stirred solution of 1-(cis-3-propoxycyclohexyl)-4-piperidinamine (D9, 150mg, 0.63mmole) in N,N-dimethylformamide (4ml) under argon was treated with diisopropylethylamine (0.23ml, 1.3mmole) and <strong>[932373-92-7]3,5-difluoro-4-nitrotoluene</strong> (D34, 138mg, O.deltaOmmole) then stirred at room temperature for 20 hours. The solution was concentrated under vacuum and the residue treated with 10% Na2CC>3 solution and extracted with dichloromethane. The extract was dried (Na2SO4) and concentrated under vacuum. The residue was chromatographed on silica gel eluting with 0-10% methanol/dichloromethane to afford the title compound as a yellow oil (175mg, 71%). MH+ 394.
1-[3-(methoxymethyl)cyclobutyl]-4-piperidinamine dihydrochloride[ No CAS ]
cis-N-(5-methyl-3-fluoro-2-nitrophenyl)-1-[3-(methoxymethyl)cyclobutyl]-4-piperidinamine[ No CAS ]
trans-N-(5-methyl-3-fluoro-2-nitrophenyl)-1-[3-(methoxymethyl)cyclobutyl]-4-piperidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 18h;
A mixture of 1-[3-(methoxymethyl)cyclobutyl]-4-piperidinamine (D43, 180mg), N, N- dimethylformamide (5ml), diisopropylethylamine (0.5ml), and <strong>[932373-92-7]3,5-difluoro-4-nitrotoluene</strong> (D37, 120mg) was heated at 5O0C for 18h. The solution was then cooled, diluted with ethyl acetate and washed three times with water, then dried, and concentrated under vacuum and chromatographed (12+M Biotage NH column, 0-15% ethyl acetate in hexane) to afford the title compound as a mixture of isomers (100mg).
N,N′-((diazene-1,2-diylbis(3,5-difluoro-4,1-phenylene))bis-(methylene))bis(4-((4,5-dihydroisoxazol-3-yl)oxy)-N,N-dimethylbut-2-yn-1-aminium) bromide[ No CAS ]
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