methyl (2S)-2-hydroxy-3-phenylpropanoate

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

Procedure: To methyl 2(S)-hydroxy-3-phenylpropionate (5.0 g) and pyridine (8.78 g) in methylene chloride (50 ml) was dropwise added phenyl chlorocarbonate (4.78 g) under cooling at 0°-10° C. over 30 minutes. After the dropwise addition, the mixture was stirred at said temperature for 60 minutes, washed with 10% hydrochloric acid and water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. As a result, 9.51 g of methyl 2(S)-phenoxycarbonyloxy-3-phenylpropionate was obtained as a pale yellow, oily substance. under cooling at 0°-10° C. over 30 minutes After the dropwise addition for 60 minutes washed with 10% hydrochloric acid and water dried over magnesium sulfate concentrated to dryness under reduced pressure

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

Procedure: To methyl 2(S)-hydroxy-3-phenylpropionate (5.0 g) and pyridine (8.78 g) in methylene chloride (50 ml) was dropwise added phenyl chlorocarbonate (4.78 g) under cooling at 0°-10° C. over 30 minutes. After the dropwise addition, the mixture was stirred at said temperature for 60 minutes, washed with 10% hydrochloric acid and water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. As a result, 9.51 g of methyl 2(S)-phenoxycarbonyloxy-3-phenylpropionate was obtained as a pale yellow, oily substance. under cooling at 0°-10° C. over 30 minutes After the dropwise addition for 60 minutes washed with 10% hydrochloric acid and water dried over magnesium sulfate concentrated to dryness under reduced pressure

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

Procedure: Prepared from 4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenol and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester according to the procedure in Example 8 to provide the title compound as a white solid: mp 215-217: NMR (DMSO-d6): δ8.17 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.85 (d, J=4 Hz, 2H), 7.39-7.30 (m, 5H), 7.22 (dd, J=7 Hz, 1H), 7.16 (dd, J=7, 1 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 5.41 (s, 1H), 3.43 (dd, J=6, 1 Hz, 2H), 2.36 (s, 3H), 1.56 (s, 3H); MS (+FAB): [M+H]+, 745; Anal. Calc. for C31H22I2O4S: C, 50.02, H, 2.98, N, 0.00. Found: C,47.59, H, 2.98, N, 0.13.

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

Procedure: A solution of commercially available (S)-2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1 g) in methanol (125 mL) was refluxed with removal of water using 3A molecular sieves for 17 h. The solution was concentrated and dissolved in ether. The ether solution was washed with saturated sodium bicarbonate, brine and concentrated to provide the title compound as a white solid (5.32 g, 98%): NMR (CDCl3); δ7.36-7.20 (m, 5H), 4.47 (ddd, J=5, 6, 7 Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5, 14 Hz, 1H), 2.97 (dd, J=7, 14 Hz), 2.69 (d, J=6 Hz, 1H). The solution was concentrated dissolved in ether The ether solution was washed with saturated sodium bicarbonate, brine concentrated

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

Procedure: A solution of commercially available (S)-2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1 g) in methanol (125 mL) was refluxed with removal of water using 3A molecular sieves for 17 h. The solution was concentrated and dissolved in ether. The ether solution was washed with saturated sodium bicarbonate, brine and concentrated to provide the title compound as a white solid (5.32 g, 98%): NMR (CDCl3); δ7.36-7.20 (m, 5H), 4.47 (ddd, J=5, 6, 7 Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5, 14 Hz, 1H), 2.97 (dd, J=7, 14 Hz), 2.69 (d, J=6 Hz, 1H). The solution was concentrated dissolved in ether The ether solution was washed with saturated sodium bicarbonate, brine concentrated

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

Procedure: To a solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (5.0 g, 12.1 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (3.3 g, 18.3 mmol), and triphenylphosphine (4.8 g, 18.3 mmol) in anhydrous benzene (50 mL) at room temperature under nitrogen was added dropwise diethyl azodicarboxylate (2.6 mL, 18.3 mmol) over a period of 25 min. The reaction mixture was heated for 2 h, then stirred at room temperature for 3 days. The crude reaction mixture was adsorbed onto silica gel and chromatographed twice with petroleum ether:ethyl acetate (95:5) to yield the title compound as a white foamy solid (4.5 g, 65%): NMR (DMSO-d6): δ8.18 (d, 1H), 7.64 (ddd, 1H), 7.53-7.43 (m, 2H), 7.38-7.24 (m, 5H), 7.00 (s, 2H), 4.80 (t, 1H), 3.58 (s, 3H), 3.31 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.55 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 572/574; Anal. Calc. for C32H29BrO3S: C, 67.01; H, 5.10; N, 0.00. Found: C, 66.33; H, 5.09; N, 0.09; Analytical HPLC indicates a major component (94.39%). The reaction mixture was heated for 2 h The crude reaction mixture chromatographed twice with petroleum ether:ethyl acetate (95:5)

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

Procedure: To a solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (5.0 g, 12.1 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (3.3 g, 18.3 mmol), and triphenylphosphine (4.8 g, 18.3 mmol) in anhydrous benzene (50 mL) at room temperature under nitrogen was added dropwise diethyl azodicarboxylate (2.6 mL, 18.3 mmol) over a period of 25 min. The reaction mixture was heated for 2 h, then stirred at room temperature for 3 days. The crude reaction mixture was adsorbed onto silica gel and chromatographed twice with petroleum ether:ethyl acetate (95:5) to yield the title compound as a white foamy solid (4.5 g, 65%): NMR (DMSO-d6): δ8.18 (d, 1H), 7.64 (ddd, 1H), 7.53-7.43 (m, 2H), 7.38-7.24 (m, 5H), 7.00 (s, 2H), 4.80 (t, 1H), 3.58 (s, 3H), 3.31 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.55 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 572/574; Anal. Calc. for C32H29BrO3S: C, 67.01; H, 5.10; N, 0.00. Found: C, 66.33; H, 5.09; N, 0.09; Analytical HPLC indicates a major component (94.39%). The reaction mixture was heated for 2 h The crude reaction mixture chromatographed twice with petroleum ether:ethyl acetate (95:5)

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

Procedure: Prepared from of 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (Example 21) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: mp 243-245° C.: NMR (DMSO-d6); δ11.30 (broad s, 1H), 8.23, 8.22 (2d, J=3 Hz, 1H), 8.06, 8.04 (2d, J=3 Hz, 1H), 7.95 (t, J=2, 1H), 7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.45 (d, J=8 Hz, 1H),7.34-7.24 (m, 6H), 5.28 5.22 (2t, J=6 Hz, 1H), 3.40-3.23 (m, 2H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H), 1.59 1.57 (2s, 3H); MS (+FAB): 2 bromine isotope pattern 653, 655 , 657; Anal. Calc. for C29H21Br2NO5S: C, 53.15; H, 3.23; N, 2.14. Found: C, 53.77; H, 3.73; N, 2.04.

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

Procedure: Prepared from of 2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (Example 21) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: mp 243-245° C.: NMR (DMSO-d6); δ11.30 (broad s, 1H), 8.23, 8.22 (2d, J=3 Hz, 1H), 8.06, 8.04 (2d, J=3 Hz, 1H), 7.95 (t, J=2, 1H), 7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.45 (d, J=8 Hz, 1H),7.34-7.24 (m, 6H), 5.28 5.22 (2t, J=6 Hz, 1H), 3.40-3.23 (m, 2H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H), 1.59 1.57 (2s, 3H); MS (+FAB): 2 bromine isotope pattern 653, 655 , 657; Anal. Calc. for C29H21Br2NO5S: C, 53.15; H, 3.23; N, 2.14. Found: C, 53.77; H, 3.73; N, 2.04.

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

Procedure: Prepared from 2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 18) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: NMR (DMSO-d6); δ13.3 (broad band, 1H), 8.20 (d, J=8 Hz, 1H), 7.70(s, 2H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.51(ddd, J=8, 7, 1 Hz, 1H), 7.40-7.25(m, 6H), 5.21(t, J=7 Hz, 1H), 3.75(s, 2H), 3.32(dd, J=4, 3 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 1.63(s, 3H), 1.02 (t, J=7 Hz, 6H) MS [(+)FAB]: [M+H]+@ 758, 3 bromine isotope pattern, 758(25%), 760(80%), 762(75%), 764(35%), 689(100%); Anal HPLC, Primesphere 5C-18 column, eluent 62% acetonitrile for 15 minutes indicated 97.8%purity; High Resolution MS (FAB)+ve: Calculated Sample Mass: 759.95556 for formula C33H31NO3Br3 as [M+H], Measured Mass 759.97370 mass deviation: 18.14 mmu.

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

Procedure: Diethylazodicarboxylate (0.262 mL, 1.67 mmol) was added dropwise to a stirred, room temperature solution of 2,6dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.60 g, 1.11 mmol), and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) and benzene (5 mL) and the solution was heated in an 80° C. oil bath for 6 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.76 g, 97%): mp 174-175° C.: NMR (DMSO-d6); δ8.21 (ddd, J=8,1,1 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.73 (d, J=2 Hz, 1H),7.67 (ddd, J=8, 6, 1 Hz, 1H), 7.53 (ddd, J=8, 7, 1 Hz, 1H), 7,43 (d, J=8 Hz, 1H), 7.35-7.24 (m, 5H), 5.11 (dd, J=7, 6 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, 13, 6 Hz, 1H), 3.40 (dd, 13, 7 Hz, 1H), 2.44 (d, J=1 Hz, 3H), 1.60 (d, J=1 Hz, 3H); MS (+FAB): 3 bromine isotope pattern 700(20%), 702 (70%), 704 (75%), 706 (25%); Anal. Calc. for C30H23Br3O3S: C, 51.23; H, 3.30; N, 0.00. Found: C, 51.52; H, 3.36; N, 0.12. Upon cooling to room temperature was added The reaction mixture was concentrated chromatographed (95:5 petroleum ether:ethyl acetate)

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

Procedure: Diethylazodicarboxylate (0.262 mL, 1.67 mmol) was added dropwise to a stirred, room temperature solution of 2,6dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.60 g, 1.11 mmol), and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) and benzene (5 mL) and the solution was heated in an 80° C. oil bath for 6 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.76 g, 97%): mp 174-175° C.: NMR (DMSO-d6); δ8.21 (ddd, J=8,1,1 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.73 (d, J=2 Hz, 1H),7.67 (ddd, J=8, 6, 1 Hz, 1H), 7.53 (ddd, J=8, 7, 1 Hz, 1H), 7,43 (d, J=8 Hz, 1H), 7.35-7.24 (m, 5H), 5.11 (dd, J=7, 6 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, 13, 6 Hz, 1H), 3.40 (dd, 13, 7 Hz, 1H), 2.44 (d, J=1 Hz, 3H), 1.60 (d, J=1 Hz, 3H); MS (+FAB): 3 bromine isotope pattern 700(20%), 702 (70%), 704 (75%), 706 (25%); Anal. Calc. for C30H23Br3O3S: C, 51.23; H, 3.30; N, 0.00. Found: C, 51.52; H, 3.36; N, 0.12. Upon cooling to room temperature was added The reaction mixture was concentrated chromatographed (95:5 petroleum ether:ethyl acetate)