4-(2-CHLOROPHENOXY)PIPERIDINE HYDROCHLORIDE

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

Procedure: 4-(2-Chloro-phenoxy)-piperidine hydrochloride (0.067 g, 0.268 mmol) was dissolved in a mixture of acetonitrile (1.32 mL) and water (0.17 mL). To this mixture was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.134 mmol) and potassium carbonate (0.074 g, 0.536 mmol). The mixture was stirred at room temperature for 24 hrs and then concentrated in vacuo. The resulting white solid was suspended in ethyl acetate (5 mL) and an equal volume of water was added. The product was extracted into ethyl acetate (2×5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (46 mg, 68%). concentrated in vacuo an equal volume of water was added The product was extracted into ethyl acetate (2×5 mL) The pooled organic layers were dried over magnesium sulfate filtered concentrated in vacuo to afford an oil The residue was purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient)

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

Procedure: 4-(2-Chloro-phenoxy)-piperidine hydrochloride (0.067 g, 0.268 mmol) was dissolved in a mixture of acetonitrile (1.32 mL) and water (0.17 mL). To this mixture was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.134 mmol) and potassium carbonate (0.074 g, 0.536 mmol). The mixture was stirred at room temperature for 24 hrs and then concentrated in vacuo. The resulting white solid was suspended in ethyl acetate (5 mL) and an equal volume of water was added. The product was extracted into ethyl acetate (2×5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (46 mg, 68%). concentrated in vacuo an equal volume of water was added The product was extracted into ethyl acetate (2×5 mL) The pooled organic layers were dried over magnesium sulfate filtered concentrated in vacuo to afford an oil The residue was purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient)

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

Procedure: DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (55 mg, 0.29 mmol) in DMF (5 mL) followed by HOBt (43 mg, 0.32 mmol) and EDCI (140 mg, 0.7 mmol). After 2 minutes of stirring, 4-(2-chloro-phenoxy)-piperidine hydrochloride (98 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and the precipitate was collected. The precipitate was purified by recrystallisation from a mixture of 20% EtOAc in hexane (15 mL) and MeOH (0.1 mL) to afford the 80 mg (62.5% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 439.15, 98.75%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 2H), 7.48 (m, 2H), 7.34 (m, 2H), 7.1 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 2.0 (d, 2H), 1.8 (d, 2H). the resulting mixture was stirred at ambient temperature overnight the precipitate was collected The precipitate was purified by recrystallisation from a mixture of 20% EtOAc in hexane (15 mL) and MeOH (0.1 mL)

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

Procedure: DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (55 mg, 0.29 mmol) in DMF (5 mL) followed by HOBt (43 mg, 0.32 mmol) and EDCI (140 mg, 0.7 mmol). After 2 minutes of stirring, 4-(2-chloro-phenoxy)-piperidine hydrochloride (98 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and the precipitate was collected. The precipitate was purified by recrystallisation from a mixture of 20% EtOAc in hexane (15 mL) and MeOH (0.1 mL) to afford the 80 mg (62.5% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 439.15, 98.75%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 2H), 7.48 (m, 2H), 7.34 (m, 2H), 7.1 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 2.0 (d, 2H), 1.8 (d, 2H). the resulting mixture was stirred at ambient temperature overnight the precipitate was collected The precipitate was purified by recrystallisation from a mixture of 20% EtOAc in hexane (15 mL) and MeOH (0.1 mL)

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

Procedure: HOBt (57 mg, 0.42 mol) and DIPEA (137 mg, 1.06 mmole), EDCI.HCl (82 mg, 0.42 mol) followed by 4-(2-chloro-phenoxy)-piperidine hydrochloride (105 mg, 0.42 mol) were added to a stirred solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid (100 mg, 0.35 mmol) in DMF (2.0 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water. The product was extracted with ethylacetate and the organic layers were washed with brine and concentrated to afford 78 mg (46%) of 1-[4-(2-chloro-phenoxy)-piperidine-1-carbonyl]-cyclopropanecarboxylic acid biphenyl-4-ylamide. LCMS: 475.17 (M+1)+, 92.81%, 1H NMR (DMSO-d6): δ 9.8 (s, 1H), 7.8-7.5 (d, 2H), 7.7-7.6 (t, 4H), 7.5-7.4 (m, 3H), 7.4-7.2 (m, 3H), 7.0-6.9 (m, 1H), 4.7 (m, 1H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.0-1.8 (m, 2H), 1.7-1.6 (m, 2H), 1.4 (m, 2H), 1.3-1.2 (m, 2H). The product was extracted with ethylacetate the organic layers were washed with brine concentrated

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

Procedure: HOBt (57 mg, 0.42 mol) and DIPEA (137 mg, 1.06 mmole), EDCI.HCl (82 mg, 0.42 mol) followed by 4-(2-chloro-phenoxy)-piperidine hydrochloride (105 mg, 0.42 mol) were added to a stirred solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid (100 mg, 0.35 mmol) in DMF (2.0 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water. The product was extracted with ethylacetate and the organic layers were washed with brine and concentrated to afford 78 mg (46%) of 1-[4-(2-chloro-phenoxy)-piperidine-1-carbonyl]-cyclopropanecarboxylic acid biphenyl-4-ylamide. LCMS: 475.17 (M+1)+, 92.81%, 1H NMR (DMSO-d6): δ 9.8 (s, 1H), 7.8-7.5 (d, 2H), 7.7-7.6 (t, 4H), 7.5-7.4 (m, 3H), 7.4-7.2 (m, 3H), 7.0-6.9 (m, 1H), 4.7 (m, 1H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.0-1.8 (m, 2H), 1.7-1.6 (m, 2H), 1.4 (m, 2H), 1.3-1.2 (m, 2H). The product was extracted with ethylacetate the organic layers were washed with brine concentrated

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

Procedure: To a stirred solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid (0.075 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.11 g, 0.00085 mole), HOBt (0.038 g, 0.00028 mole) and EDCI.HCl (0.065 g, 0.00034 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.078 g, 0.00031 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.031 g (24%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-N-(5-phenyl-thiazol-2-yl)-propionamide. LC-MS purity: 456.11 (M+1)+, 93.27%, 1H NMR (CDCl3): δ 11.6 (s, 1H), 7.9 (d, 2H), 7.44 (t, 3H), 7.3 (d, 1H), 7.22 (d, 1H), 7.14 (s, 1H), 6.92 (d, 2H), 4.7 (s, 1H), 4.1 (m, 1H), 3.8 (m, 1H), 3.7-3.5 (m, 4H), 2.0 (d, 4H). the product was extracted with ethyl acetate The ethyl acetate layer was dried over sodium sulfate concentrated under reduced pressure

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

Procedure: To a stirred solution of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid (0.07 g, 0.00027 mole) in THF (3 mL) was added, 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.072 g, 0.00029 mol) followed by DIC (0.04 g, 0.00031 mole). The resulting mixture was heated to reflux for 4 hours then concentrated. The resulting residue was purified by column chromatography using neutral aluminium oxide (0.5% methanol in dichloromethane) to afford 0.045 g (37%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-propionamide. LC-MS purity: 457.1 (M+1)+, 84.85% 1H NMR (CDCl3): δ 8.2 (s, 2H), 7.5 (m, 4H), 7.2 (m, 1H), 7.0 (d, 2H), 4.7 (s, 1H), 4.2 (d, 1H), 3.8 (m, 1H), 3.6 (m, 5H), 2.0 (dd, 4H), 2.6 (bs, 3H). The resulting mixture was heated to reflux for 4 hours then concentrated The resulting residue was purified by column chromatography

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

Procedure: To a stirred solution of malonic acid monoethyl ester (1.2 g, 0.0089 mole) in DMF (10 mL) was added DIPEA (2.5 g, 0.02 mole), HOBt (1.3 g, 0.0097 mole) and EDCI.HCl (1.9 g, 0.0097 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (2 g, 0.0081 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 1.1 g (42%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 326.11 (M+1)+, 90.2%. To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (1.1 g, 0.0034 mole) in a mixture of THF (20 mL), methanol (4 mL) and H2O (4 mL) was added LiOH.H2O (0.286 g, 0.0068 mole) at ambient temperature. The resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.75 g (75%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid. the product was extracted with ethyl acetate The organic layers were dried over sodium sulfate concentrated under reduced pressure The resulting residue was purified by column chromatography

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

Procedure: To a stirred solution of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.0296 g, 0.00015 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.0382 g, 0.00015 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 0.032 g (53%) of 5-phenylamino-pyridine-2-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 465.16 (M+1)+, 98.06%, 1H NMR (DMSO-d6): δ 8.85 (s, 1H), 8.5 (t, 1H), 8.35 (d, 1H), 7.85 (d, 1H), 7.55 (dd, 1H), 7.4 (d, 1H), 7.3 (m, 4H), 7.2 (d, 2H), 7.0 (m, 2H), 4.75 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 1.95 (m, 3H), 1.7 (m, 2H). the resulting precipitate was isolated by filtration dried

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

Procedure: To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.029 g, 0.0001549 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.0382 g, 0.00015 mol) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to afford 0.037 g (62%) of N-{2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-6-phenylamino-nicotinamide. LCMS: 465.16 (M+1)+, 96.6%, 1H NMR (DMSO-d6): δ 9.4 (s, 1H), 8.8 (s, 1H), 8.4 (t, 1H), 8.0 (dd, 1H), 7.7 (d, 2H), 7.45 (d, 1H), 7.4 (m, 4H), 7.0 (d, 2H), 6.8 (d, 1H), 4.7 (m, 1H), 4.25 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.7 (q, 2H). the product was extracted with ethyl acetate The ethyl acetate was washed with brine solution dried over sodium sulfate concentrated under reduced pressure The resulting residue was purified by column chromatography

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

Procedure: To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol), HOBt (0.065 g, 0.000482 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 230-400 mesh (70% ethyl acetate in hexane) afforded 0.153 g (73%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 546.17 (M+1)+, 97.6%. the resulting precipitate was isolated by filtration Purification by column chromatography