[1,1'-Biphenyl]-4-carboxylic acid, (3aR,4R,5R,6aS)-4-[(1E,3S)-3-[[(1,1-diMethylethyl)diMethylsilyl]oxy]-5- phenyl-1-pentenyl]hexahydro-2-oxo-2H-cyclopenta[b]furan-5-yl ester synthesis

Yield:865087-09-8 76%

Reaction Conditions:

with 1H-imidazole in dichloromethane; for 1 - 2 h;Product distribution / selectivity;Heating / reflux;

Steps:

3; 5 (3aR,4R,5R,6aS)-4-[3S-(t-Butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5

Example 3 (3aR,4R,5R,6aS)-4-[3S-(t-Butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5 A mixture of alcohols 6 and 6a with 6/6a ratio about 97:3 by HPLC (15.4 g, 32.0 mmol), CH₂Cl₂ (75 mL), t-BuMe₂SiCl (7.2 g, 48.0 mmol) and imidazole (6.5 g, 96.0 mmol) was refluxed for 1 h and mixed with 10% aq. citric acid (50 mL). The aqueous layer was separated and extracted with CH₂Cl₂ (50 mL). The combined organic layers were dried over Na₂SO₄, filtered through the column with silica gel (30 g) and concentrated in vacuo. The residue was crystallized from MTBE to give 16.2 g (76%) of (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one 5 as MTBE solvate with 99.8% purity by HPLC: mp 60-64° C.; [α]²⁰_D-84° (c 1, MeCN); ¹H NMR (CDCl₃) 8.04 (d, J=8 Hz, 2H), 7.60 (m, 4H), 7.42 (m, 3H), 7.15 (m, 5H), 5.58 (m, 2H), 5.22 (q, J=5.5 Hz, 1H), 5.01 (t, J=5.5 Hz, 1H), 4.12 (q, J=5.5 Hz, 1H), 3.18 (s, 3H), 2.69 (m, 7H), 2.20 (m, 1H), 1.79 (m, 2H), 1.17 (s, 9H), 0.85 (s, 9H), -0.02 (d, J=12 Hz, 6H). The x-ray powder diffraction pattern of crystalline MTBE solvate of compound 5 has characteristic peaks expressed in degrees 2θ at approximately 6.5, 7.1, 12.2, 12.5, 13.1, 13.6, 14.6, 15.0, 15.8, 16.2, 16.3, 17.0, 17.3, 18.0, 18.2, 18.8, 19.5, 19.7, 20.5, 20.8, 21.0, 21.8, 22.2, 23.0, 23.3, 24.2, 25.5, 26.5 and 26.7.IR DRIFTS (KBr): 2949, 2931, 2854, 1765,1715,1607,1361, 1266, 1203,1170, 1118, 1095, 1080, 972, 912, 852, 839, 775, 745, and 699 cm^-1.Compound 5 MTBE solvate was characterized by ¹H NMR (CDCl₃), powder x-ray diffractometry, IR DRIFTS (KBr) spectroscopy, DSC and TGA as set forth above and in FIGS. 6, 7, 8, 9 and 10; A solution of (-)-DIP-Chloride (282.3 g, 0.88 mol) in CH₂Cl₂ (500 mL) was added dropwise during 2 h to a stirred solution of ketone 7 (210.0 g, 0.44 mol) in CH₂Cl₂ (1.6 L) at -25 to -30° C. The mixture was stirred 12 h at the same temperature, heated to -3° C. and treated with 10% aq. NH₄Cl (400 mL). The obtained mixture was stirred for 1 h at rt. The aqueous layer was separated and extracted with CH₂Cl₂ (2×150 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to a half of volume. A mixture of the residue and imidazole (179.8 g, 2.64 mol) was treated with a solution of t-BuMe₂SiCl (265.3 g, 1.76 mol) in CH₂Cl₂ (500 mL). The resulted suspension was refluxed for 2 h, cooled to 10° C. and quenched by addition of 10% aq citric acid (1.5 L). The phases were separated, the organic one was washed with water (300 mL) and 10% NaHCO₃ (300 mL), dried over Na₂SO₄, filtered and passed through silica gel (250 g). The column was washed with CH₂Cl₂ (2 L) and the combined filtrates were evaporated under reduced pressure. The residue (350 g) was crystallized from MTBE (2.4 L) to give 232.0 g of crude lactone 5 MTBE solvate (0.6% of 5a) as white solid. The crude product was re-crystallized from MTBE (2 L) affording 217 g (72% from ketone 7) of lactone 5 MTBE solvate (0.02% of 5a) as white crystalline powder.

References:

US2009/163596,2009,A1 Location in patent:Page/Page column 11-13