4-OXO-2-SPIRO(PIPERIDINE-4-YL)-BENZOPYRAN HYDROCHLORIDE

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

Procedure: To a stirred solution of the spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (53 mg, 0.21 mmol) in methanol (5 mL) at 0° C., was added sodium borohydride (38 mg, 1 mmol) in several portions. After 30 minutes the mixture was evaporated and then treated with concentrated hydrochloric acid (2 mL) for 30 min. Evaporation gave a residue which was hydrogenated with palladium on carbon (10%, 10 mg), H2 (1 atm) in ethanol for two hours. Filtration to remove the catalyst gave the crude intermediate (89 mg) which was used without further purification. After 30 minutes the mixture was evaporated treated with concentrated hydrochloric acid (2 mL) for 30 min Evaporation gave a residue which Filtration to remove the catalyst

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

Procedure: To a stirred solution of the spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (53 mg, 0.21 mmol) in methanol (5 mL) at 0° C., was added sodium borohydride (38 mg, 1 mmol) in several portions. After 30 minutes the mixture was evaporated and then treated with concentrated hydrochloric acid (2 mL) for 30 min. Evaporation gave a residue which was hydrogenated with palladium on carbon (10%, 10 mg), H2 (1 atm) in ethanol for two hours. Filtration to remove the catalyst gave the crude intermediate (89 mg) which was used without further purification. After 30 minutes the mixture was evaporated treated with concentrated hydrochloric acid (2 mL) for 30 min Evaporation gave a residue which Filtration to remove the catalyst

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

Procedure: This intermediate was prepared from α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid (903 mg, 2.3 mmol) and spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (535 mg, 2.11 mmol) (Elliott, J., et al, J. Med. Chem. 1992, 35, 3973-3976) by the procedure described in Example 25, Step A (1.25 g, 100%).

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

Procedure: This intermediate was prepared from α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid (903 mg, 2.3 mmol) and spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (535 mg, 2.11 mmol) (Elliott, J., et al, J. Med. Chem. 1992, 35, 3973-3976) by the procedure described in Example 25, Step A (1.25 g, 100%).

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMF (10 mL) and Et3N (1 mL) were added to 3-phenyl-1-pyridin-2-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (160 mg), 6-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (190 mg), EDCI (120 mg) and HOBT (90 mg), heated at 50° C. and stirred overnight. This was further stirred at 110° C. for 1 hour, then restored to room temperature, diluted with water, and its pH was adjusted at 1.5 with 1 N HCl added thereto. The formed crystal was taken out through filtration, washed with water, n-hexane and water, and dried in vacuum at 60° C. to obtain the title compound as a pale brown power. 1H-NMR (400 MHz, DMSO-d6) δ: 8.62-8.57 (1H, m), 8.44 (1H, d, J=2.2 Hz), 8.26 (1H, dd, J=8.0, 2.2 Hz), 8.16-8.06 (4H, m), 7.92 (1H, s), 7.55 (2H, t, J=8.0 Hz), 7.50-7.45 (1H, m), 7.41-7.34 (2H, m), 4.30-4.20 (2H, br m), 3.53 (2H, s), 3.01 (2H, s), 2.12-2.04 (2H, br m), 1.95-1.84 (2H, br m). MS [M+H]+=589. This was further stirred at 110° C. for 1 hour restored to room temperature added The formed crystal was taken out through filtration washed with water, n-hexane and water dried in vacuum at 60° C.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMF (10 mL) and Et3N (1 mL) were added to 3-phenyl-1-pyridin-2-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (160 mg), 6-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (190 mg), EDCI (120 mg) and HOBT (90 mg), heated at 50° C. and stirred overnight. This was further stirred at 110° C. for 1 hour, then restored to room temperature, diluted with water, and its pH was adjusted at 1.5 with 1 N HCl added thereto. The formed crystal was taken out through filtration, washed with water, n-hexane and water, and dried in vacuum at 60° C. to obtain the title compound as a pale brown power. 1H-NMR (400 MHz, DMSO-d6) δ: 8.62-8.57 (1H, m), 8.44 (1H, d, J=2.2 Hz), 8.26 (1H, dd, J=8.0, 2.2 Hz), 8.16-8.06 (4H, m), 7.92 (1H, s), 7.55 (2H, t, J=8.0 Hz), 7.50-7.45 (1H, m), 7.41-7.34 (2H, m), 4.30-4.20 (2H, br m), 3.53 (2H, s), 3.01 (2H, s), 2.12-2.04 (2H, br m), 1.95-1.84 (2H, br m). MS [M+H]+=589. This was further stirred at 110° C. for 1 hour restored to room temperature added The formed crystal was taken out through filtration washed with water, n-hexane and water dried in vacuum at 60° C.

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

Procedure: To a stirred solution of the spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (53 mg, 0.21 mmol) in methanol (5 mL) at 0° C., was added sodium borohydride (38 mg, 1 mmol) in several portions. After 30 minutes the mixture was evaporated and then treated with concentrated hydrochloric acid (2 mL) for 30 min. Evaporation gave a residue which was hydrogenated with palladium on carbon (10%, 10 mg), H2 (1 atm) in ethanol for two hours. Filtration to remove the catalyst gave the crude intermediate (89 mg) which was used without further purification. After 30 minutes the mixture was evaporated treated with concentrated hydrochloric acid (2 mL) for 30 min Evaporation gave a residue which Filtration to remove the catalyst

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

Procedure: This intermediate was prepared from α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid (903 mg, 2.3 mmol) and spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (535 mg, 2.11 mmol) (Elliott, J., et al, J. Med. Chem. 1992, 35, 3973-3976) by the procedure described in Example 25, Step A (1.25 g, 100%).

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

Procedure: The object product (29 mg, 31%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (50 mg), spiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride (60 mg) and potassium carbonate (50 mg).

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

Procedure: Triethylamine (0.50 mL, 0.36 g, 3.6 mmol) was added to a stirred, cooled (0° C.) mixture of (S)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionic acid (364 mg, 1 mmol), spiro[2H-1-benzopyran-2,4'-piperidin]-4-(3H)-one hydrochloride (U.S. Pat. No. 5,206,240, Example 67A) (254 mg, 1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) in dimethylformamide (5 mL) and the mixture was stirred at room temperature for 2 h. Aqueous sodium hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×20 mL), aqueous sodium hydrogen carbonate (saturated, 2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99.5:0.5 increasing to 98:2) to give the title compound as a colorless foam (248 mg, 44%). m/e (ES+) 563 (MH+). cooled the mixture was extracted with ethyl acetate (3×20 mL) The combined organic fractions were washed with aqueous citric acid (10%, 2×20 mL), aqueous sodium hydrogen carbonate (saturated, 2×20 mL) and brine (20 mL) dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with CH2Cl2 /MeOH (99.5:0.5 increasing to 98:2)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMF (10 mL) and Et3N (1 mL) were added to 3-phenyl-1-pyridin-2-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (160 mg), 6-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (190 mg), EDCI (120 mg) and HOBT (90 mg), heated at 50° C. and stirred overnight. This was further stirred at 110° C. for 1 hour, then restored to room temperature, diluted with water, and its pH was adjusted at 1.5 with 1 N HCl added thereto. The formed crystal was taken out through filtration, washed with water, n-hexane and water, and dried in vacuum at 60° C. to obtain the title compound as a pale brown power. 1H-NMR (400 MHz, DMSO-d6) δ: 8.62-8.57 (1H, m), 8.44 (1H, d, J=2.2 Hz), 8.26 (1H, dd, J=8.0, 2.2 Hz), 8.16-8.06 (4H, m), 7.92 (1H, s), 7.55 (2H, t, J=8.0 Hz), 7.50-7.45 (1H, m), 7.41-7.34 (2H, m), 4.30-4.20 (2H, br m), 3.53 (2H, s), 3.01 (2H, s), 2.12-2.04 (2H, br m), 1.95-1.84 (2H, br m). MS [M+H]+=589. This was further stirred at 110° C. for 1 hour restored to room temperature added The formed crystal was taken out through filtration washed with water, n-hexane and water dried in vacuum at 60° C.

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

Procedure: To a stirred solution of the spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (53 mg, 0.21 mmol) in methanol (5 mL) at 0° C., was added sodium borohydride (38 mg, 1 mmol) in several portions. After 30 minutes the mixture was evaporated and then treated with concentrated hydrochloric acid (2 mL) for 30 min. Evaporation gave a residue which was hydrogenated with palladium on carbon (10%, 10 mg), H2 (1 atm) in ethanol for two hours. Filtration to remove the catalyst gave the crude intermediate (89 mg) which was used without further purification. After 30 minutes the mixture was evaporated treated with concentrated hydrochloric acid (2 mL) for 30 min Evaporation gave a residue which Filtration to remove the catalyst