1-propan-2-ylpiperidin-4-one

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: To a stirred and refluxing mixture of 48 parts of 1-(1-methylethyl)-4-piperidinone, 1 part of 4-methylbenzene-sulfonic acid and 540 parts of methylbenzene is added dropwise a solution of 30 parts of benzenamine in 90 parts of methylbenzene. Upon completion, the whole is stirred and refluxed for 3 hours with water-separator. The reaction mixture is evaporated, yielding 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzenamine as a residue. refluxing Upon completion, the whole is stirred The reaction mixture is evaporated

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

Procedure: A 200-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a heating mantle, a standard condenser with a N2 inlet, a 50-mL addition funnel, and a glass stopper. A mixture containing 3,4-dimethoxybenzylamine (8.36 g, 50 mmol), paraformaldehyde (3.15 g, 105 mmol) and CH3OH (35 mL) was made acidic with the addition of glacial acetic acid (3.0 g, 50 mmol). Stirring the mixture under N2 for 20 min was followed by the dropwise addition of 1-isopropyl-4-piperidinone (42, 7.06 g, 50 mmol) and glacial acetic acid (3.0 g, 50 mmol) in CH3OH (25 mL) over 1.25 h. Boiling of the mixture was continuous for an additional 23 h. This new mixture was evaporated to give a red viscous oil. After dissolving the oil in H2O (100 mL), the solution was extracted (ether, 2×100 mL), the latter being discarded. Chilling (ice water bath) of the water layer below 10° C., followed by basification (pH~12) with KOH pellets (6.6 g, 100 mmol), produced an orange suspension which was extracted (CH2Cl2, 4×80 mL). Combined extracts were dried (Na2SO4, overnight), filtered, and concentrated to give a crude oil. This oil was digested in 250 mL of Skelly B (bp 60°-68° C.) for 0.5 h and the supernatant was decanted. Evap-oration of the solvent gave an oil which, when distilled (175°-205° C./10-4 mm Hg), afforded a yellow oil. Adding Skelly B induced crystallization to give 4.32 g (26%) of off white ketone (23); mp 79.5°-80.5° C. IR (KBr) cm-1 3095, 3015 (Ar--H), 2980, 2955, 2920, 2855, 2810 (C--H), 1745 (C=O), 1620, 1605 (C=C); 1H NMR (DCCl3) δ1.03 (d, 6 H, CH3, J=6.6 Hz), 2.59 [bs, 2 H, H(1,5)], 2.81-2.90 [m, 5 H, ring protons and CH(CH3)2 ], 2.98 (dd, 2 H, ring protons, J=10.7 Hz, J'=3.2 Hz), 3.08 (dd, 2 H, ring protons, J=10.7 Hz, J'=2.99 Hz), 3.47 (s, 2 H, ArCH2), 3.87 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.80-6.92 (m, 3 H, Ar--H); 13C NMR (DCCl3) ppm 18.17 (CH3), 46.85 [C(1,5)], 53.40 [CH(CH3)2 ], 53.86 [C(2,4)], 55.76, 55.86 (OCH3), 58.01 [C(6,8)], 60.93 (ArCH2), 110.60, 111.46, 120.68 131.30, 148.04, 148.90 (Ar--C), 215.27 (C=O); 15N NMR (DCCl3) ppm 39.66 [N(7)], 40.93 [N(3)]. Anal. Calcd. for C19H28N2O3 : C, 68.65; H, 8.49. Found: C, 68.70; H, 8.53. A 200-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer a heating mantle, a standard condenser with a N2 inlet, a 50-mL addition funnel Boiling of the mixture was continuous for an additional 23 h This new mixture was evaporated to give a red viscous oil the solution was extracted (ether, 2×100 mL) Chilling (ice water bath) of the water layer below 10° C. produced an orange suspension which was extracted (CH2Cl2, 4×80 mL) Combined extracts were dried (Na2SO4, overnight) filtered concentrated to give a crude oil This oil was digested in 250 mL of Skelly B (bp 60°-68° C.) for 0.5 h the supernatant was decanted Evap-oration of the solvent gave an oil which, when distilled (175°-205° C./10-4 mm Hg) afforded a yellow oil Adding Skelly B crystallization

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

Procedure: 3-(4-phenoxyphenyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 2) (221 mg, 0.572 mmol), 1-isopropyl-4-piperidone(89 mg, 0.63 mmol), sodium triacetoxyborohydride (182 mg, 0.86 mmol) and glacial acetic acid(40 ul, 0.63 mmol) were mixed with 3 ml of 1,2-dichloroethane. After stirring at room temperature overnight, 2 ml of water was added followed by solid sodium bicarbonate until PH reached about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed, dried and evaporated. The residue was purified by flash column chromatography to give 132 mg of 1-[1-(1-isopropyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO) 0.99(d, J=6.54 Hz, 6H), 1.42(m, 2H), 1.72(d, J=11.41 Hz, 2H), 1.88(d, J=9.61 Hz, 2H), 2.14(s, 3H), 2.16(m, 6H), 2.66(m, 2H), 2.83(d,J=10.98 Hz, 2H), 2.98(d,J=8.25 Hz, 2H), 4.62(m, 1H), 7.16(m, 5H), 7.44(m, 2H), 7.67(d, J=8.69 Hz, 2H), 8.23(s, 1H); LC/MS (MH+=512) The layers were separated the aqueous layer was extracted with dichloromethane The combined organic layer was washed dried evaporated The residue was purified by flash column chromatography

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

Procedure: 3-(4-phenoxyphenyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 2) (221 mg, 0.572 mmol), 1-isopropyl-4-piperidone(89 mg, 0.63 mmol), sodium triacetoxyborohydride (182 mg, 0.86 mmol) and glacial acetic acid(40 ul, 0.63 mmol) were mixed with 3 ml of 1,2-dichloroethane. After stirring at room temperature overnight, 2 ml of water was added followed by solid sodium bicarbonate until PH reached about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed, dried and evaporated. The residue was purified by flash column chromatography to give 132 mg of 1-[1-(1-isopropyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO) 0.99(d, J=6.54 Hz, 6H), 1.42(m, 2H), 1.72(d, J=11.41 Hz, 2H), 1.88(d, J=9.61 Hz, 2H), 2.14(s, 3H), 2.16(m, 6H), 2.66(m, 2H), 2.83(d,J=10.98 Hz, 2H), 2.98(d,J=8.25 Hz, 2H), 4.62(m, 1H), 7.16(m, 5H), 7.44(m, 2H), 7.67(d, J=8.69 Hz, 2H), 8.23(s, 1H); LC/MS (MH+=512) The layers were separated the aqueous layer was extracted with dichloromethane The combined organic layer was washed dried evaporated The residue was purified by flash column chromatography

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

Procedure: Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and 0.873 gm (6.2 mMol) 1-isopropyl-4-piperidone, 1.02 gm (64.2%) of the title compound were recovered as a tan powder.

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

Procedure: Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and 0.873 gm (6.2 mMol) 1-isopropyl-4-piperidone, 1.02 gm (64.2%) of the title compound were recovered as a tan powder.

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

Procedure: The title compound (111.0 mg) was prepared from 372 μL of 1-isopropyl-piperidin-4-one, 270 μL of benzylamine, and 0.38 g of (2-nitro-vinyl)-benzene as in Example 41. The product was diluted with EtOAc and malic acid (39.0 mg) was added. The solids that formed were collected by filtration to give the title compound as a maleate salt. MS (ESI): exact mass calculated for C23H26N2, 330.21; found, m/z 331.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.33 (m, 6H), 7.30-7.27 (m, 1H), 7.23-7.19 (m, 3H), 7.14 (s, 1H), 6.25 (s, 2H), 5.15 (s, 2H), 3.74-3.66 (m, 1H), 2.96-2.91 (br m, 2H), 1.41 (d, J=6.6 Hz, 6H). was added The solids that formed were collected by filtration

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

Procedure: The title compound (111.0 mg) was prepared from 372 μL of 1-isopropyl-piperidin-4-one, 270 μL of benzylamine, and 0.38 g of (2-nitro-vinyl)-benzene as in Example 41. The product was diluted with EtOAc and malic acid (39.0 mg) was added. The solids that formed were collected by filtration to give the title compound as a maleate salt. MS (ESI): exact mass calculated for C23H26N2, 330.21; found, m/z 331.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.33 (m, 6H), 7.30-7.27 (m, 1H), 7.23-7.19 (m, 3H), 7.14 (s, 1H), 6.25 (s, 2H), 5.15 (s, 2H), 3.74-3.66 (m, 1H), 2.96-2.91 (br m, 2H), 1.41 (d, J=6.6 Hz, 6H). was added The solids that formed were collected by filtration

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

Procedure: Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and 0.873 gm (6.2 mMol) 1-isopropyl-4-piperidone, 1.02 gm (64.2%) of the title compound were recovered as a tan powder.