piperidin-4-ol;hydrochloride

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

Procedure: To a solution of 4-hydroxypiperidine hydrochloride (3.0 g, 21.8 mmol) in a mixture of methylene chloride (90 ml) and pyridine (15 ml) were added chloroformic acid p-nitrobenzyl ester (15.4 g, 72.0 mmol) and triethylamine (13.1 ml, 93.8 mmol) in an ice bath. The mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, yield 48%) as pale yellow crystals. the completion of the reaction the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution The obtained organic layer was washed with saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on a silica gel column

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

Procedure: To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine (10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1 mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA (12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL). The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL), dried (MgSO4) and concentrated in vacuo. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid. m/z (ES+)=367 [M+H]+; RT=3.28 min. The solvent was removed in vacuo the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL) The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL) dried (MgSO4) concentrated in vacuo The product was chromatographed on silica gel eluting with ethyl acetate

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

Procedure: To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine (10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1 mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA (12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL). The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL), dried (MgSO4) and concentrated in vacuo. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid. m/z (ES+)=367 [M+H]+; RT=3.28 min. The solvent was removed in vacuo the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL) The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL) dried (MgSO4) concentrated in vacuo The product was chromatographed on silica gel eluting with ethyl acetate

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

Procedure: 561 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 688 mg of 4-hydroxypiperidine hydrochloride in methanol, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, the residue was mixed with tetrahydrofuran, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, to give a colorless oil, which was dissolved in 20 ml of tetrahydrofuran. 1.02 g of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 11(a)] were added to the resulting solution, and the mixture was stirred at 60° C. for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.26 g (yield 95%) of the title compound as a colorless oil. At the end of this time, the solvent was removed by distillation under reduced pressure the residue was mixed with tetrahydrofuran, and insoluble materials were filtered off The filtrate was concentrated by evaporation under reduced pressure to give a colorless oil, which the mixture was stirred at 60° C. for 5 hours At the end of this time, the solvent was removed by distillation under reduced pressure the residue was partitioned between ethyl acetate and water The organic layer was dried over anhydrous magnesium sulfate concentrated by evaporation under reduced pressure The resulting residue was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

Procedure: 561 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 688 mg of 4-hydroxypiperidine hydrochloride in methanol, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, the residue was mixed with tetrahydrofuran, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, to give a colorless oil, which was dissolved in 20 ml of tetrahydrofuran. 1.02 g of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 11(a)] were added to the resulting solution, and the mixture was stirred at 60° C. for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.26 g (yield 95%) of the title compound as a colorless oil. At the end of this time, the solvent was removed by distillation under reduced pressure the residue was mixed with tetrahydrofuran, and insoluble materials were filtered off The filtrate was concentrated by evaporation under reduced pressure to give a colorless oil, which the mixture was stirred at 60° C. for 5 hours At the end of this time, the solvent was removed by distillation under reduced pressure the residue was partitioned between ethyl acetate and water The organic layer was dried over anhydrous magnesium sulfate concentrated by evaporation under reduced pressure The resulting residue was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

Procedure: To a solution of (E)-ethyl 4-styrylbenzoic acid (300 mg, 1.3 mmol) and DIPEA (270 uL, 2.1 mmol) in DMF (5 mL) was added EDC (280 mg, 1.5 mmol), HOBt (270 mg, 2.0 mmol) and 4-hydroxypiperidine hydrochloride (258 mg, 1.8 mmol). The reaction was stirred at room temperature for 18 h. The reaction was diluted with water (10 mL) and (4-hydroxypiperidin-1-yl)(4-styrylphenyl)methanone was isolated (390 mg, 98%) as a white solid by vacuum filtration; 1H-nmr (400 MHz, CDCl3) δ 7.58 (d, J=8.0 Hz, 2H), 7.56-7.52 (m, 2H), 7.44-7.34 (m, 5H), 6.95 (d, 1H), 6.89 (d, 1H), 4.21-4.08 (m, 1H), 4.03-3.96 (m, 1H), 3.81-3.48 (m, 1H), 3.47-3.16 (m, 2H), 2.08-1.79 (m, 2H), 1.71-1.42 (m, 2H); LCMS (214 nM) 3.32 min (>98%); MS (ESI) m/z=308.1.

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

Procedure: 2-(n-Propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIV) (1.6 g, 7.1 mmol) was added to n-butanol (10 mL) followed by potassium carbonate (4.9 g, 35.5 mmol) and piperidin-4-ol hydrochloride (632 mg, 10.7 mmol). The mixture was stirred in an autoclave equipped with a stirrer at 130° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (pet ether/EtOAc=3/1) to yield 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolo[2,3-d]pyrimidine (1.2 g, 75%) as a yellow solid. LCMS (ESI) m/z=290 (M+H)+. equipped with a stirrer at 130° C. for 16 h the mixture was extracted with EtOAc (3×50 mL) The combined organic layers were washed with water with a brine solution, and dried over anhydrous Na2SO4 The solvents were removed in vacuo the residue was purified by flash column chromatography (pet ether/EtOAc=3/1)

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

Procedure: 2-(n-Propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIV) (1.6 g, 7.1 mmol) was added to n-butanol (10 mL) followed by potassium carbonate (4.9 g, 35.5 mmol) and piperidin-4-ol hydrochloride (632 mg, 10.7 mmol). The mixture was stirred in an autoclave equipped with a stirrer at 130° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (pet ether/EtOAc=3/1) to yield 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolo[2,3-d]pyrimidine (1.2 g, 75%) as a yellow solid. LCMS (ESI) m/z=290 (M+H)+. equipped with a stirrer at 130° C. for 16 h the mixture was extracted with EtOAc (3×50 mL) The combined organic layers were washed with water with a brine solution, and dried over anhydrous Na2SO4 The solvents were removed in vacuo the residue was purified by flash column chromatography (pet ether/EtOAc=3/1)

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

Procedure: The starting material is prepared as follows: The mixture 268 of diphenylmethanol, 200 g of 4-hydroxypiperidine hydrochloride and 28.8 g of p-toulenesulfonic acid monohydrate is stirred and heated to 160° while reducing the pressure to 0.2 mm Hg with a vacuum pump for 3 hours. It is cooled to 80°, dissolved in 500 ml of ethanol and the solution cooled to 10°. The resulting suspension is filtered, the residue washed with isopropanol and dried at 60°, to yield the 4-diphenylmethoxy-piperidine hydrochloride. It is suspended in 1,800 ml of water, converted into the free base with 125 ml of aqueous ammonia and extracted with diethyl ether and the extract evaporated. The starting material is prepared heated to 160° for 3 hours It is cooled to 80° the solution cooled to 10° The resulting suspension is filtered the residue washed with isopropanol dried at 60°

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

Procedure: The starting material is prepared as follows: The mixture 268 of diphenylmethanol, 200 g of 4-hydroxypiperidine hydrochloride and 28.8 g of p-toulenesulfonic acid monohydrate is stirred and heated to 160° while reducing the pressure to 0.2 mm Hg with a vacuum pump for 3 hours. It is cooled to 80°, dissolved in 500 ml of ethanol and the solution cooled to 10°. The resulting suspension is filtered, the residue washed with isopropanol and dried at 60°, to yield the 4-diphenylmethoxy-piperidine hydrochloride. It is suspended in 1,800 ml of water, converted into the free base with 125 ml of aqueous ammonia and extracted with diethyl ether and the extract evaporated. The starting material is prepared heated to 160° for 3 hours It is cooled to 80° the solution cooled to 10° The resulting suspension is filtered the residue washed with isopropanol dried at 60°

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

Procedure: 2-(n-Propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIV) (1.6 g, 7.1 mmol) was added to n-butanol (10 mL) followed by potassium carbonate (4.9 g, 35.5 mmol) and piperidin-4-ol hydrochloride (632 mg, 10.7 mmol). The mixture was stirred in an autoclave equipped with a stirrer at 130° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (pet ether/EtOAc=3/1) to yield 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolo[2,3-d]pyrimidine (1.2 g, 75%) as a yellow solid. LCMS (ESI) m/z=290 (M+H)+. equipped with a stirrer at 130° C. for 16 h the mixture was extracted with EtOAc (3×50 mL) The combined organic layers were washed with water with a brine solution, and dried over anhydrous Na2SO4 The solvents were removed in vacuo the residue was purified by flash column chromatography (pet ether/EtOAc=3/1)

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

Procedure: To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine (10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1 mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA (12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL). The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL), dried (MgSO4) and concentrated in vacuo. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid. m/z (ES+)=367 [M+H]+; RT=3.28 min. The solvent was removed in vacuo the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL) The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL) dried (MgSO4) concentrated in vacuo The product was chromatographed on silica gel eluting with ethyl acetate