methyl 4-(3-bromopropyl)benzoate

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

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

Procedure: A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4. the reaction mixture was heated under reflux for 20 h saturated aqueous NaHCO3was added The aqueous solution was washed with EtOAc (3×) dried (MgSO4) filtered concentrated Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided

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

Procedure: Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one (296 mg, 0.809 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (276 mg, 1.07 mmol) over 72 h. Purification by medium pressure chromatography (1:1 hexanes:EtOAc) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (250 mg). 1H NMR (CDCl3) (selected peaks) δ7.92 (d, 2H), 7.21 (d, 2H), 7.05 (m, 2H), 6.92 (m, 2H), 3.86 (s, 3H), 3.76 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 0.81 (s, 9 H). Purification by medium pressure chromatography (1:1 hexanes:EtOAc)

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

Procedure: Analogous to the procedure described for Example 1A, Step D, 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (5.116 g, 12.08 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (3.41 g, 13.3 mmol) over 20 h. Purification by medium pressure chromatography using a solvent gradient (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (5.38 g). 1H NMR (CDCl3) δ7.93 (d, 2H), 7.56 (d, 2H), 7.43 (m, 3H), 7.34 (m, 3H), 7.23 (m, 2H), 7.12 (m, 1H), 3.89 (m, 1H), 3.87 (s, 3H), 3.64 (m, 1H), 3.49 (m, 1H), 2.95-2.61 (m, 5H), 2.30 (m, 2H), 2.01 (m, 1H), 1.89-1.70 (m, 3H), 1.59-1.24 (m, 4H), 0.84 (s, 9H), −0.04 (d, 3H), −0.16 (d, 3H). Purification by medium pressure chromatography

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

Procedure: Analogous to the procedure described in Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (254.7 mg, 0.697 mmol) was alkylated with NaHMDS (1M in THF, 0.84 mL, 0.84 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (200 mg, 0.778 mmol). Purificaton by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (275.3 mg). 1H NMR (CDCl3) (selected peaks) δ7.94 (d, 2H), 7.23 (m, 3H), 6.87 (m, 3H), 3.88 (s, 3H), 3.86 (m, 1H), 3.63 (m, 1H), 3.50 (m, 1H), 2.94 (m, 1H), 0.84 (s, 9H).

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

Procedure: Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (250 mg, 0.602 mmol) was alkylated with NaHMDS (1M in THF, 0.72 mL, 0.72 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (170 mg, 0.663 mmol) to yield 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (300 mg). MS 592.1 (M+1).

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

Procedure: To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (3.20 g, 9.21 mmol) in DMF (30 mL) at 0° C. was added NaHMDS (1M in THF, 11.5 mL, 11.5 mmol). After 1 h, 4-(3-bromo-propyl)-benzoic acid methyl ester (2.84 g, 11.0 mmol) was added and the reaction mixture was stirred at 70° C. for 18 h. The DMF was removed in vacuo and the residue was dissolved in EtOAc. The organic solution was washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography (30% EtOAc in hexanes) to yield 3.39 g of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ7.92 (m, 2H), 7.25-7.09 (m, 7H), 3.86 (s, 3H), 3.80 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 2.90 (m, 1H), 2.78-2.57 (m, 4H), 2.38-2.18 (m, 2H), 0.83 (s, 9H); MS 524.1 (M+1). The DMF was removed in vacuo the residue was dissolved in EtOAc The organic solution was washed with water dried (MgSO4) filtered concentrated The residue was purified by medium pressure chromatography (30% EtOAc in hexanes)

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

Procedure: A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3 was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4. the reaction mixture was heated under reflux for 20 h The aqueous solution was washed with EtOAc (3×) dried (MgSO4) filtered concentrated Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided

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

Procedure: Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one (296 mg, 0.809 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (276 mg, 1.07 mmol) over 72 h. Purification by medium pressure chromatography (1:1 hexanes:EtOAc) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (250 mg). 1H NMR (CDCl3) (selected peaks) δ7.92 (d, 2H), 7.21 (d, 2H), 7.05 (m, 2H), 6.92 (m, 2H), 3.86 (s, 3H), 3.76 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 0.81 (s, 9H). Purification by medium pressure chromatography (1:1 hexanes:EtOAc)

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

Procedure: Analogous to the procedure described for Example 1A, Step D, 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (5.116 g, 12.08 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (3.41 g, 13.3 mmol) over 20 h. Purification by medium pressure chromatography using a solvent gradient (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (5.38 g). 1H NMR (CDCl3) δ7.93 (d, 2H), 7.56 (d, 2H), 7.43 (m, 3H), 7.34 (m, 3H), 7.23 (m, 2H), 7.12 (m, 1H), 3.89 (m, 1H), 3.87 (s, 3H), 3.64 (m, 1H), 3.49 (m, 1H), 2.95–2.61 (m, 5H), 2.30 (m, 2H), 2.01 (m, 1H), 1.89–1.70 (m, 3H), 1.59–1.24 (m, 4H), 0.84 (s, 9H), −0.04 (d, 3H), −0.16 (d, 3H). Purification by medium pressure chromatography

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

Procedure: Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (200 mg, 0.455 mmol) was alkylated with NaHMDS (1M in THF, 0.55 mL, 0.55 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (128 mg, 0.501 mmol) to yield 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (173.1 mg). 1H NMR (CDCl3) δ7.94 (d, 2H), 7.32 (m, 2H), 7.25–7.19 (m, 3H), 7.09 (m, 1H), 6.98 (d, 2H), 6.88–6.81 (m, 3H), 3.88 (s, 3H), 3.84 (m, 1H), 3.64 (m, 1H), 3.50 (m, 1H), 2.95 (m, 1H), 2.76–2.57 (m, 4H), 2.37 (m, 2H), 2.03 (m, 1H), 1.92–1.67 (m, 3H), 1.56 (m, 1H), 1.46–1.25 (m, 3H), 0.84 (s, 9H), −0.04 (d, 3H), −0.15 (d, 3H).

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

Procedure: Analogous to the procedure described in Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (254.7 mg, 0.697 mmol) was alkylated with NaHMDS (1M in THF, 0.84 mL, 0.84 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (200 mg, 0.778 mmol). Purificaton by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (275.3 mg). 1H NMR (CDCl3) (selected peaks) δ7.94 (d, 2H), 7.23 (m, 3H), 6.87 (m, 3H), 3.88 (s, 3H), 3.86 (m, 1H), 3.63 (m, 1H), 3.50 (m, 1H), 2.94 (m, 1H), 0.84 (s, 9H).