2-oxaspiro[4.4]nonane-1,3-dione

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxaspiro[4.4]nonane-1,3-dione (522 mg, 3.39 mmol) in anhydrous EtOH (15 ml) was allowed to stir at 70° C. for 22 hours under nitrogen. The reaction mixture was concentrated to give a crude 1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxylic acid (compound A, 672 mg). The product (86% purity) was used for next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.57-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.69 (s, 2H) 4.12 (q, J=7.2 Hz, 3H) 11.65 (br s, 1H). The reaction mixture was concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-oxaspiro[4.4]nonane-1,3-dione (3 g, 19.46 mmol) in toluene (2 ml), BnOH (2.023 ml, 19.46 mmol) was added. The reaction mixture was allowed to stir at 100° C. for 19 hours, and the reaction mixture was concentrated under reduced pressure. The obtained residue was recrystallized in DCM (15 ml) and 2,2,4-trimethylpentane (100 ml). The obtained colorless crystal was washed with a 10% solution of DCM/heptane (20 ml). The obtained solid was dried under reduce pressure to give 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (3.09 g); Retention time=1.56 minutes (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.58-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.75 (s, 2H) 5.11 (s, 2H) 7.28-7.37 (m, 5H) 11.80 (br s, 1H). the reaction mixture was concentrated under reduced pressure The obtained residue was recrystallized in DCM (15 ml) The obtained colorless crystal was washed with a 10% solution of DCM/heptane (20 ml) The obtained solid was dried

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxaspiro[4.4]nonane-1,3-dione (522 mg, 3.39 mmol) in anhydrous EtOH (15 ml) was allowed to stir at 70° C. for 22 hours under nitrogen. The reaction mixture was concentrated to give a crude 1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxylic acid (compound A, 672 mg). The product (86% purity) was used for next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.57-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.69 (s, 2H) 4.12 (q, J=7.2 Hz, 3H) 11.65 (br s, 1H). The reaction mixture was concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-oxaspiro[4.4]nonane-1,3-dione (3 g, 19.46 mmol) in toluene (2 ml), BnOH (2.023 ml, 19.46 mmol) was added. The reaction mixture was allowed to stir at 100° C. for 19 hours, and the reaction mixture was concentrated under reduced pressure. The obtained residue was recrystallized in DCM (15 ml) and 2,2,4-trimethylpentane (100 ml). The obtained colorless crystal was washed with a 10% solution of DCM/heptane (20 ml). The obtained solid was dried under reduce pressure to give 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (3.09 g); Retention time=1.56 minutes (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.58-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.75 (s, 2H) 5.11 (s, 2H) 7.28-7.37 (m, 5H) 11.80 (br s, 1H). the reaction mixture was concentrated under reduced pressure The obtained residue was recrystallized in DCM (15 ml) The obtained colorless crystal was washed with a 10% solution of DCM/heptane (20 ml) The obtained solid was dried

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: N-benzothiazol-2-yl-4-piperazin-1-yl-benzamide trifluoroacetate (40 mg) was mixed with 2-oxa-spiro[4,4]nonane-1,3-dione (30 mg) in DMF (5 mL) containing triethylamine (0.1 mL) and the mixture was stirred foe 5 hrs. Solvents were evaporated and the residue was treated with ethyl acetate and hydrochloric acid solution (0.1N). The precipitate from the organic layer was filtered to give 1-(2-{4-[4-(benzothiazol-2-ylcarbamoyl)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-cyclopentanecarboxylic acid as a white solid (30 mg). LCMS calc for C26H28N4O4S (m/e) 492, obsd 493. Solvents were evaporated the residue was treated with ethyl acetate and hydrochloric acid solution (0.1N) The precipitate from the organic layer was filtered

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 10 mL round bottomed flask, equipped with a reflux condenser, were added 4-(quinolin-2-ylmethoxy)-N1-(4-(trifluoromethyl)benzyl)benzene-1,2-diamine (53 mg, 0.12 mmol), 2-oxaspiro[4.4]nonane-1,3-dione (19 mg, 0.12 mmol) and acetonitrile (1.3 mL). The flask was heated to 80° C. for 72 hours. The mixture was concentrated and the residue was dissolved in ethanol (2 mL) followed by the slow addition of HCl (0.6 mL, 12 N). The mixture was then heated to 80° C. until the starting material had been consumed. The reaction mixture was cooled to RT, concentrated to dryness and the resulting residue was dissolved in THF (3.4 mL) and methanol (3.4 mL). To this solution was added LiOH (3.6 mL, 1 M aq.) and the reaction was monitored by LCMS until the ester was consumed. The reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc. The aqueous layer was further extracted with EtOAc (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C32H28F3N3O3, 559.21; m/z found, 5602 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.58-7.44 (m, 3H), 7.35 (s, 1H), 7.14-6.85 (m, 4H), 5.32 (s, 4H), 3.04 (s, 2H), 2.43-2.14 (m, 2H), 1.75-1.31 (m, 7H). To a 10 mL round bottomed flask, equipped with a reflux condenser The mixture was concentrated the residue was dissolved in ethanol (2 mL) followed by the slow addition of HCl (0.6 mL, 12 N) The mixture was then heated to 80° C. until the starting material had been consumed The reaction mixture was cooled to RT concentrated to dryness the resulting residue was dissolved in THF (3.4 mL) To this solution was added LiOH (3.6 mL, 1 M aq.) was consumed The reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc The aqueous layer was further extracted with EtOAc (3×20 mL) The combined organics were dried over sodium sulfate filtered concentrated to dryness The crude residue was purified

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N1-(3-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (1.0 g, 2.4 mmol) in acetonitrile (20 mL) was added 2-oxaspiro[4.4]nonane-1,3-dione (420 mg, 2.7 mmol) and the solution heated to 80° C. for 8 h. The solution was cooled to RT and concentrated to dryness. To this residue was added acetic acid (15 mL) and the resulting solution was heated to 80° C. for 3 h. The solution was cooled, concentrated to dryness and the resulting residue was taken up in toluene/MeOH (15 mL; 3:1). The solution was treated with TMSCHN2 (1.5 mL, 3 mmol, 2 M in hexanes) dropwise (bubbling observed). The mixture was stirred at RT for 30 min and then concentrated to dryness. The residue was purified using FCC to provide 1.12 g of the title compound. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.5, 1H), 8.09 (d, J=8.7, 1H), 7.82 (d, J=8.2, 1H), 7.75-7.69 (m, 2H), 7.56-7.52 (m, 1H), 7.40 (d, J=7.9, 1H), 7.35 (d, J=2.2, 1H), 7.20 (s, 1H), 7.18-7.14 (m, 1H), 7.05-7.02 (m, 1H), 6.99-6.96 (m, 1H), 6.89-6.86 (m, 1H), 5.42 (s, 2H), 5.33 (s, 2H), 3.62 (s, 3H), 3.08 (s, 2H), 2.26-2.20 (m, 2H), 1.87-1.80 (m, 2H), 1.77-1.64 (m, 4H); 584.0 (M+H) m/z The solution was cooled to RT concentrated to dryness To this residue was added acetic acid (15 mL) the resulting solution was heated to 80° C. for 3 h The solution was cooled concentrated to dryness concentrated to dryness The residue was purified

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 10 mL round bottomed flask, equipped with a reflux condenser, were added 4-(quinolin-2-ylmethoxy)-N1-(4-(trifluoromethyl)benzyl)benzene-1,2-diamine (53 mg, 0.12 mmol), 2-oxaspiro[4.4]nonane-1,3-dione (19 mg, 0.12 mmol) and acetonitrile (1.3 mL). The flask was heated to 80° C. for 72 hours. The mixture was concentrated and the residue was dissolved in ethanol (2 mL) followed by the slow addition of HCl (0.6 mL, 12 N). The mixture was then heated to 80° C. until the starting material had been consumed. The reaction mixture was cooled to RT, concentrated to dryness and the resulting residue was dissolved in THF (3.4 mL) and methanol (3.4 mL). To this solution was added LiOH (3.6 mL, 1 M aq.) and the reaction was monitored by LCMS until the ester was consumed. The reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc. The aqueous layer was further extracted with EtOAc (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C32H28F3N3O3, 559.21; m/z found, 5602 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.58-7.44 (m, 3H), 7.35 (s, 1H), 7.14-6.85 (m, 4H), 5.32 (s, 4H), 3.04 (s, 2H), 2.43-2.14 (m, 2H), 1.75-1.31 (m, 7H). To a 10 mL round bottomed flask, equipped with a reflux condenser The mixture was concentrated the residue was dissolved in ethanol (2 mL) followed by the slow addition of HCl (0.6 mL, 12 N) The mixture was then heated to 80° C. until the starting material had been consumed The reaction mixture was cooled to RT concentrated to dryness the resulting residue was dissolved in THF (3.4 mL) To this solution was added LiOH (3.6 mL, 1 M aq.) was consumed The reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc The aqueous layer was further extracted with EtOAc (3×20 mL) The combined organics were dried over sodium sulfate filtered concentrated to dryness The crude residue was purified

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N1-(3-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (1.0 g, 2.4 mmol) in acetonitrile (20 mL) was added 2-oxaspiro[4.4]nonane-1,3-dione (420 mg, 2.7 mmol) and the solution heated to 80° C. for 8 h. The solution was cooled to RT and concentrated to dryness. To this residue was added acetic acid (15 mL) and the resulting solution was heated to 80° C. for 3 h. The solution was cooled, concentrated to dryness and the resulting residue was taken up in toluene/MeOH (15 mL; 3:1). The solution was treated with TMSCHN2 (1.5 mL, 3 mmol, 2 M in hexanes) dropwise (bubbling observed). The mixture was stirred at RT for 30 min and then concentrated to dryness. The residue was purified using FCC to provide 1.12 g of the title compound. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.5, 1H), 8.09 (d, J=8.7, 1H), 7.82 (d, J=8.2, 1H), 7.75-7.69 (m, 2H), 7.56-7.52 (m, 1H), 7.40 (d, J=7.9, 1H), 7.35 (d, J=2.2, 1H), 7.20 (s, 1H), 7.18-7.14 (m, 1H), 7.05-7.02 (m, 1H), 6.99-6.96 (m, 1H), 6.89-6.86 (m, 1H), 5.42 (s, 2H), 5.33 (s, 2H), 3.62 (s, 3H), 3.08 (s, 2H), 2.26-2.20 (m, 2H), 1.87-1.80 (m, 2H), 1.77-1.64 (m, 4H); 584.0 (M+H) m/z The solution was cooled to RT concentrated to dryness To this residue was added acetic acid (15 mL) the resulting solution was heated to 80° C. for 3 h The solution was cooled concentrated to dryness concentrated to dryness The residue was purified

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

Procedure: With a method similar to that used for the preparation of 4-(4-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidin-1-yl)-2,2-dimethyl-4-oxo-butyric acid, 1-[2-(4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}1-piperidin-1-yl)-2-oxo-ethyl]cyclopentanecarboxylic acid was prepared from 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and 2-oxa-spiro[4,4]nonane-1,3-dione. LCMS for C30H33Cl2N3O4 calcd. (m/e) 569, observed 570 (M+H).