ethyl piperidine-1-carboxylate

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

Procedure: To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 446-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1). The crude reaction mixture is purified by mass-trigger preparative RP LC-MS

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

Procedure: Polymer-bound piperidinecarboxylic acid, ethyl ester resin (0.25 g, 0.283 mmol) was swollen with a solution of MeOH (1 ml) in THF (4 ml) in a QUICKFIT test-tube. After addition of sodium methoxide (0.28 ml, 0.028 mmol, 1M solution in MeOH) the resulting suspension was stirred overnight at reflux. The reaction suspension was cooled down to room temperature and the resin was washed using VACMASTER station with DCM (4×3 ml), MeOH (2×3 ml) and then dried under vacuum. FT-IR (2% w/w KBr disk): C=0 1736 cm−1 (ester); 163 cm−1 (amide). at reflux the resin was washed dried under vacuum

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

Procedure: Polymer-bound piperidinecarboxylic acid, ethyl ester resin (0.25 g, 0.283 mmol) was swollen with a solution of MeOH (1 ml) in THF (4 ml) in a QUICKFIT test-tube. After addition of sodium methoxide (0.28 ml, 0.028 mmol, 1M solution in MeOH) the resulting suspension was stirred overnight at reflux. The reaction suspension was cooled down to room temperature and the resin was washed using VACMASTER station with DCM (4×3 ml), MeOH (2×3 ml) and then dried under vacuum. FT-IR (2% w/w KBr disk): C=0 1736 cm−1 (ester); 163 cm−1 (amide). at reflux the resin was washed dried under vacuum

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

Procedure: 12.1 ml. of ethylchloroformate are added to a solution of 19.4 g of 1-benzyl-4-(p-chlorophenoxy)piperidine in 220 ml. of benzene and the solution is refluxed for 18 hours. The benzene and benzylchloride is removed under reduced pressure to give the N-ethoxycarbonylpiperidine as an uncrystallizable yellow oil. The N-ethoxycarbonylpiperidine is dissolved in 210 ml. of ethanol and 130 ml. of 45% aqueous potassium hydroxide are added. The solution is refluxed for 12 hours under nitrogen, cooled, most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether phase is extracted with 3 N hydrochloric acid, the acid extract is basified with 6N sodium hydroxide, and the basic solution is extracted with benzene. The benzene is dried and removed under reduced pressure to give a colorless oil. The oil is dissolved in 200 ml. of ether, the solution is cooled and stirred and 200 ml. of a saturated ethereal-HCl solution is slowly added. The salt forms and is collected. The salt is recrystallized from absolute ethanol to give 4-(p-chlorophenoxy)piperidine hydrochloride. The solution is refluxed for 12 hours under nitrogen is removed under reduced pressure the resultant oily dispersion is extracted with ether The ether phase is extracted with 3 N hydrochloric acid the acid extract the basic solution is extracted with benzene The benzene is dried removed under reduced pressure to give a colorless oil The oil is dissolved in 200 ml The salt forms and is collected The salt is recrystallized from absolute ethanol

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

Procedure: 12.1 ml. of ethylchloroformate are added to a solution of 19.4 g of 1-benzyl-4-(p-chlorophenoxy)piperidine in 220 ml. of benzene and the solution is refluxed for 18 hours. The benzene and benzylchloride is removed under reduced pressure to give the N-ethoxycarbonylpiperidine as an uncrystallizable yellow oil. The N-ethoxycarbonylpiperidine is dissolved in 210 ml. of ethanol and 130 ml. of 45% aqueous potassium hydroxide are added. The solution is refluxed for 12 hours under nitrogen, cooled, most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether phase is extracted with 3 N hydrochloric acid, the acid extract is basified with 6N sodium hydroxide, and the basic solution is extracted with benzene. The benzene is dried and removed under reduced pressure to give a colorless oil. The oil is dissolved in 200 ml. of ether, the solution is cooled and stirred and 200 ml. of a saturated ethereal-HCl solution is slowly added. The salt forms and is collected. The salt is recrystallized from absolute ethanol to give 4-(p-chlorophenoxy)piperidine hydrochloride. The solution is refluxed for 12 hours under nitrogen is removed under reduced pressure the resultant oily dispersion is extracted with ether The ether phase is extracted with 3 N hydrochloric acid the acid extract the basic solution is extracted with benzene The benzene is dried removed under reduced pressure to give a colorless oil The oil is dissolved in 200 ml The salt forms and is collected The salt is recrystallized from absolute ethanol

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

Procedure: 12.1 ml. of ethylchloroformate are added to a solution of 19.4 g of 1-benzyl-4-(p-chlorophenoxy)piperidine in 220 ml. of benzene and the solution is refluxed for 18 hours. The benzene and benzylchloride is removed under reduced pressure to give the N-ethoxycarbonylpiperidine as an uncrystallizable yellow oil. The N-ethoxycarbonylpiperidine is dissolved in 210 ml. of ethanol and 130 ml. of 45% aqueous potassium hydroxide are added. The solution is refluxed for 12 hours under nitrogen, cooled, most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether phase is extracted with 3 N hydrochloric acid, the acid extract is basified with 6N sodium hydroxide, and the basic solution is extracted with benzene. The benzene is dried and removed under reduced pressure to give a colorless oil. The oil is dissolved in 200 ml. of ether, the solution is cooled and stirred and 200 ml. of a saturated ethereal-HCl solution is slowly added. The salt forms and is collected. The salt is recrystallized from absolute ethanol to give 4-(p-chlorophenoxy)piperidine hydrochloride. The benzene and benzylchloride is removed under reduced pressure

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

Procedure: To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 446-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1). The crude reaction mixture is purified by mass-trigger preparative RP LC-MS

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

Procedure: In a similar manner to the previous Example, 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (0.4 g from 1.0 g of 40% pure material) and 1-ethoxycarbonyl-piperidine (158 mg) were reacted together in the presence of sodium triacetoxyborohydride (296 mg) in dichloromethane (15 ml) containing glacial acetic acid (60 mg) to give after workup and chromatography cis-7-(4-N-ethoxycarbonyl)piperazin-1-ylcyclohexyl)-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and trans-7-(4-N-ethoxycarbonyl)-piperazin-1-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.

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

Procedure: In a similar manner to the previous Example, 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (0.4 g from 1.0 g of 40% pure material) and 1-ethoxycarbonyl-piperidine (158 mg) were reacted together in the presence of sodium triacetoxyborohydride (296 mg) in dichloromethane (15 ml) containing glacial acetic acid (60 mg) to give after workup and chromatography cis-7-(4-N-ethoxycarbonyl)piperazin-1-ylcyclohexyl)-5-(4-phenoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and trans-7-(4-N-ethoxycarbonyl)-piperazin-1-ylcyclohexyl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium acetate (0.04 mmol, 10 mg) was stirred with 1,3-bis(diphenylphosphino)propane (18 mg, 0.04 mmol) in DMF (0.5 mL) for 10 minutes. A mixture of 2-fluoro-4-iodo-5-methyl pyridine (0.42 mmol, 100 mg), ethyl-1-piperidinecarboxylate (0.5 mmol, 0.08 mL) and cesium carbonate (275 mg, 2 equiv) in DMF (1.5 mL) was then added, stirred vigorously, and heated in the microwave to 160° C. for 10 minutes. The resulting black mixture was poured onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes gradient) to afford 61 mg of the title compound as a yellow oil (54%). Rt=6.70 minutes; MS FIA 267.1 (M+1). was then added The resulting black mixture was poured onto a silica gel column purified by flash chromatography (ethyl acetate/hexanes gradient)

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

Procedure: Polymer-bound piperidinecarboxylic acid, ethyl ester resin (0.25 g, 0.283 mmol) was swollen with a solution of MeOH (1 ml) in THF (4 ml) in a QUICKFIT test-tube. After addition of sodium methoxide (0.28 ml, 0.028 mmol, 1M solution in MeOH) the resulting suspension was stirred overnight at reflux. The reaction suspension was cooled down to room temperature and the resin was washed using VACMASTER station with DCM (4×3 ml), MeOH (2×3 ml) and then dried under vacuum. FT-IR (2% w/w KBr disk): C=0 1736 cm−1 (ester); 163 cm−1 (amide). at reflux the resin was washed dried under vacuum

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

Procedure: 12.1 ml. of ethylchloroformate are added to a solution of 19.4 g of 1-benzyl-4-(p-chlorophenoxy)piperidine in 220 ml. of benzene and the solution is refluxed for 18 hours. The benzene and benzylchloride is removed under reduced pressure to give the N-ethoxycarbonylpiperidine as an uncrystallizable yellow oil. The N-ethoxycarbonylpiperidine is dissolved in 210 ml. of ethanol and 130 ml. of 45% aqueous potassium hydroxide are added. The solution is refluxed for 12 hours under nitrogen, cooled, most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether phase is extracted with 3 N hydrochloric acid, the acid extract is basified with 6N sodium hydroxide, and the basic solution is extracted with benzene. The benzene is dried and removed under reduced pressure to give a colorless oil. The oil is dissolved in 200 ml. of ether, the solution is cooled and stirred and 200 ml. of a saturated ethereal-HCl solution is slowly added. The salt forms and is collected. The salt is recrystallized from absolute ethanol to give 4-(p-chlorophenoxy)piperidine hydrochloride. The solution is refluxed for 12 hours under nitrogen is removed under reduced pressure the resultant oily dispersion is extracted with ether The ether phase is extracted with 3 N hydrochloric acid the acid extract the basic solution is extracted with benzene The benzene is dried removed under reduced pressure to give a colorless oil The oil is dissolved in 200 ml The salt forms and is collected The salt is recrystallized from absolute ethanol