http://www.google.com/patents/WO1996029325A1?cl=en
KETOCONAZOLE 2R 4S
Example 7: (2 R ,4S)-(+)-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine (22, 4 S)-(+)-ketoconazole.
To a suspension of NaH (dispersed in 60-65% paraffin, 19.2 mg, 0.48 mmol) in anhydrous DMSO (3 ml),
1-acetyl-4-(hydroxyphenyl)piperazine (102 mg, 0.46 mmol) is added and the mixture is stirred for 1 hour at room temperature. Then, a solution of (2R,4R) – (+)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH3) (160 mg, 0.39 mmol) in anhydrous DMSO (5 ml) is added, and the mixture is heated at 80ºC for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with water
(20 ml) and extracted with CH2Cl2 (3 × 25 ml). The combined organic phases are washed with water (3 × 25), dried with Na2SO4 and the solvent is evaporated off under vacuum. The oily residue thus obtained is crystallized from an acetone:ethyl acetate mixture to give (2R,4S)-(+)-ketoconazole ( (2R, 4 S) -V , Ar 2,4-dichlorophenyl, Y = CH , Z = COCH3 ) ( 110 mg , 5 3 % yie ld ) as a white solid, m.p. 155-156°C (lit. 154-156ºC), [α]D 20 = + 8.99 (c = 0.4, CHCl3) (lit. [α]D 25 = + 8.22, c = 0.4, CHCl3), with e.e. > 99% (determined by HPLC using the chirai stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1% of diethylamine, as the eluent; (+)-Ketoconazole retention time 73,28 min. (-)-Ketoconazole, retention time 79.06 min).
IR (KBr), ʋ : 2875, 1645, 1584, 1511, 1462, 1425, 1250, 103S, 313 cm-1.
1H NMR (500 MHz, CDCl3), δ : 2.12 (s, 3H, COCH3),
3.02 (m, 2H, 3-H2), 3.05 (m, 2H, 5-H2), 3.27 (dd, J= 9.5
Hz, J’=7.0 Hz, 1H) and 3.70 (dd, J=9.5 Hz, J’=5.0 Hz, 1 H) (4″-CH2), 3.60 (m, 2H, 6-H2), 3.76 (m, 2H, 2-H2), 3.73 (dd, J=8.0 Hz, J’=5.0 Hz, 1H) and 3.86 (dd, J=8.0 Hz, J’=6.5 Hz, 1H) (5″-H2), 4.34 (m, 1H, 4″-H), 4.40 (d, J=15.0 Hz, 1H) and 5.00 (d, J=15.0 Hz, 1H) (CH2-N), 4.34
(m, 1H, 4″-H), 6.76 [d, J = 9.0 Hz, 2H, 2'(C6' )-H], 6.88
[d, J=9.0 Hz, 2H, C3'(C5)-H], 6.96 (s, 1H, imidazole 5- H), 6.99 (s, 1H, imidazole 4-H), 7.25 (dd, J=8.5 Hz, J’=2.0 Hz, 1H, 5″‘-H), 7.46 (d, J=2.0 Hz, 1H, 3″‘-H),
7.53 (s, 1H, imidazole 2-H), 7.57 (d, J=8.5 Hz, 1H,
6″‘-H).
13C NMR (75.4 MHz, CDCI3), δ : 21.3 (CH3, COCH3), 41.4 (CH2, C2), 46.3 (CH2, C6), 50.6 (CH2, C3), 51.0 (CH2, C5), 51.2 (CH2, CH2-N), 67.6 [CH2, C5" and 4"-CH2), 74.7 (CH, C4"), 108.0 (C, C2"), 115.2 [CH, C2'(6')], 118.8 [CH, C3'(5')], 121.2 (CH, imidazole C5), 127.2 (CH, C5″‘), 128.5 (CH, imidazole C4), 129.5 (CH, C6′”), 131.3 (CH, C3″‘), 133.0 (C, C2″‘), 134.6 (C, C1′”), 135.8 (C, C4″‘), 138.8 (CH, imidazole C2), 145.6 (C, C1′), 152.8 (C, C4′), 168.9 (C, CO).
