An Efficient Semi-Synthetic Method to Construct Docetaxel
ture until starting material (11) disappeared on TLC.
Water was added and the mixture was stirred for 0.5 h.
The reaction mixture was then filtered, and the cake was
washed with toluene. The combined organic layer was
washed with water, brine, dried over anhydrous MgSO4.
Chromatography gave 12 (10.5 g, yield 72.1%) and 13
(2.62 g, yield 25.0%) as white solids. Data for com-
pound 12: m.p.: 152-154 ℃; [α]2D5 −38.8 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 8.08 (d, J=8.0
Hz, 2H), 7.68 (t, J=7.5 Hz, 1H), 7.56 (t, J=7.5 Hz,
2H), 7.51 (d, J=8.0 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H),
7.16 (t, J=7.5 Hz, 1H), 6.22-6.18 (m, 1H), 6.01 (d,
J=10.8 Hz, 1H), 5.88 (t, J=10.8 Hz, 1H), 5.62 (dd,
J=10.8, 15.0 Hz, 2H), 5.55 (dd, J=10.8, 11.8 Hz, 1H),
4.96 (d, J=10.8 Hz, 1H), 4.89 (d, J=15.0 Hz, 1H),
4.78-4.72 (m, 2H), 4.58 (d, J=11.8 Hz, 1H), 4.29 (d,
J=8.5 Hz, 1H), 4.13 (d, J=8.5 Hz, 1H), 3.84 (d, J=
7.1 Hz, 1H), 2.65-2.59 (m, 1H), 2.42 (s, 3H), 2.17 (s,
3H), 2.04-1.99 (m, 1H), 1.89 (s, 3H), 1.88-1.86 (m,
1H), 1.81 (s, 3H), 1.45 (s, 18H), 1.19 (s, 3H), 1.11 (s,
3H); 13C NMR (125 MHz, CDCl3) δ: 200.9, 170.2,
169.5, 169.3, 166.8, 153.1, 153.0, 152.9, 143.4, 135.6,
133.9, 131.4, 130.1, 129.2, 129.0, 128.8, 128.6, 128.5,
94.2, 83.8, 82.9, 80.3, 79.1, 78.7, 77.3, 76.3, 76.2, 74.4,
72.7, 71.1, 60.2, 56.1, 46.8, 42.9, 34.5, 33.2, 27.9, 26.2,
22.4, 21.0, 20.3, 14.6, 10.7; FT-IR (KBr) ν: 2910, 1775,
1750, 1735, 1710 cm−1; ESI: 1320.1; (M +Na + );
ESI-HRMS calcd for C56H65Cl6NNaO21 1320.2078,
found 1320.2067.
Data for compound 13: m.p.: 163 -164 ℃;
[α]2D5 −56.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 8.07 (dd, J=0.75, 8.0 Hz, 2H), 7.62 (t, J=7.5 Hz,
1H), 7.49 (t, J=7.5 Hz, 2H), 6.26 (s, 1H), 6.20 (t, J=
4.5 Hz, 1H), 5.68 (d, J=7.0 Hz, 1H), 5.57 (dd, J=7.0,
10.5 Hz, 1H), 4.98 (d, J=8.0 Hz, 1H), 4.90 (d, J=11.5
Hz, 1H), 4.80-4.75 (m, 2H), 4.60 (d, J=11.8 Hz, 1H),
4.33 (d, J=8.5 Hz, 1H), 4.17 (d, J=8.5 Hz, 1H), 3.93
(d, J=7.0 Hz, 1H), 2.66-2.60 (m, 1H), 2.35 (s, 3H),
2.26 (dd, J=3.5, 9.0 Hz, 2H), 2.21 (s, 3H), 2.06-2.02
(m, 1H), 2.02 (s, 3H), 1.85 (s, 3H), 1.73 (brs, 1H), 1.24
(s, 3H), 1.18 (s, 3H); 13C NMR (125 MHz, CDCl3) δ:
200.8, 170.1, 169.9, 166.8, 153.2, 153.1, 143.2, 133.8,
131.8, 130.0, 129.1, 128.7, 94.2, 83.7, 80.7, 79.2, 78.8,
77.4, 77.1, 76.5, 76.2, 74.2, 69.5, 56.2, 47.1, 43.0, 35.5,
33.2, 26.3, 22.4, 21.2, 20.6, 14.9, 10.7; FT-IR (KBr) ν:
2905, 1770, 1755, 1715 cm−1; ESI calcd for
C56H65Cl6NNaO21 1320.2, found 1320.4 (M+Na+).
N'-Boc-2'-acetyl-docetaxel (14): To a solution of 12
(1.00 g, 0.77 mmol) in acetic acid (5 mL) and methanol
(50 mL) was added zinc power (1.5 g, activated before
use). The mixture was refluxed for 0.5 h. After cooling
and filtration, the filtrate was concentrated under the
reduced pressure. The residue was dissolved in ethyl
acetate, washed with saturated aqueous sodium bicar-
bonate, water, brine and dried over anhydrous MgSO4.
Chromatography gave 14 (620 mg, yield 84.8%) as a
white solid. Data for compound 14: m.p.: 144-146 ℃;
[α]2D5 −45.6 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 8.07 (d, J=8.0 Hz, 2H), 7.67 (t, J=7.5 Hz,
1H), 7.56 (t, J=7.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H),
7.30 (t, J=7.5 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H), 5.99 (d,
J=10.8 Hz, 1H), 5.85 (t, J=8.5 Hz, 1H), 5.61 (d, J=
11.0 Hz, 1H), 5.57 (d, J=7.0 Hz, 1H), 5.14 (s, 1H),
4.93 (d, J=8.5 Hz, 1H), 4.27 (d, J=8.5 Hz, 1H), 4.25
-4.20 (m, 1H), 4.15-4.13 (m, 2H), 3.84 (d, J=7.0 Hz,
1H), 2.56-2.51 (m, 1H), 2.39 (s, 3H), 2.17 (s, 3H),
1.85 (dd, J=9.0, 15.0 Hz, 1H), 1.81-1.78 (m, 1H),
1.83 (s, 3H), 1.74 (s, 2H), 1.69 (s, 3H), 1.56 (s, 1H),
1.45 (s, 18H), 1.10 (s, 3H), 1.04 (s, 3H); 13C NMR (125
MHz, CDCl3) δ: 211.5, 170.1, 169.4, 166.9, 152.9,
139.2, 135.3, 133.8, 130.1, 129.4, 129.0, 128.8, 128.6,
128.4, 84.3, 82.9, 80.6, 78.8, 76.5, 75.0, 74.4, 72.7, 71.7,
71.4, 60.3, 57.5, 46.4, 42.8, 36.8, 34.9, 27.9, 26.3, 22.4,
20.6, 20.3, 14.2, 9.9; FT-IR (KBr) ν: 3420, 2900, 1770,
1755, 1730 cm−1; ESI: 973.0 (M+Na+); ESI-HRMS
calcd for C50H63NNaO17 972.3994, found 972.4014.
2'-Acetyl-docetaxel (15):[10] To a solution of 14 (500
mg, 0.53 mmol) in CH2Cl2 (20 mL) was added trifluoro-
acetic acid (72.5 mg, 0.64 mmol, 1.2 equiv.) at room
temperature. After the reaction finished, the mixture
was washed with saturated aq. NaHCO3 solution, water,
brine and dried over anhydrous MgSO4. Chromato-
graphy gave 15 (400 mg, yield 88.9%) as a white solid.
Data for compound 15: m.p.: 176-177 ℃; [α]2D5 −39.5
(c 1.0, MeOH); 1H NMR (500 MHz, CDCl3) δ: 8.11 (d,
J=7.5 Hz, 2H), 7.60 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.5
Hz, 2H), 7.41-7.38 (m, 2H), 7.32-7.27 (m, 3H), 6.24
(brs, 1H), 5.69 (d, J=3.0 Hz, 1H), 5.51 (d, J=10.0 Hz,
1H), 5.49-5.55 (m, 1H), 5.40 (brs, 1H), 5.22 (d, J=9.2
Hz, 1H), 5.22 (s, 1H), 4.96 (d, J=9.1 Hz, 1H), 4.31 (d,
J=9.0 Hz, 1H), 4.28-4.25 (m, 2H), 4.20 (d, J=9.0 Hz,
1H), 3.92 (d, J=7.1 Hz, 1H), 2.58-2.55 (m, 1H), 2.43
(s, 3H), 2.08 (s, 3H), 2.04 (s, 2H), 1.93 (s, 3H), 1.88-
1.83 (m, 2H), 1.74 (s, 3H), 1.33 (s, 9H), 1.20 (s, 3H),
1.17 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 211.4,
171.2, 170.1, 168.3, 167.0, 155.2, 139.0, 137.4, 135.6,
133.6, 130.1, 129.3, 128.8, 128.7, 128.1, 126.3, 84.2,
81.0, 80.4, 78.8, 76.5, 75.0, 74.4, 72.0, 71.7, 60.4, 57.6,
46.4, 43.1, 36.8, 35.6, 28.1, 26.3, 22.6, 21.0, 20.9, 20.3,
14.1, 9.9; FT-IR (KBr) ν: 3410, 2900, 1740, 1710 cm−1;
ESI: calcd for C45H55NNaO15 872.3, found 872.7 (M+
Na+).
Docetaxel (1): To a solution of 15 (340 mg, 0.40
mmol) in THF (5.0 mL) was added saturated aq. Na-
HCO3 solution (1.0 mL) and hydrogen peroxide (30%,
1.0 mL). The reaction mixture was stirred at room tem-
perature until starting material 15 disappeared on TLC.
The mixture was acidified to pH=6-7 by adding 1
mol/L aqueous citric acid solution and then introduced
into water (100 mL). The precipitation was filtered,
washed with cold water and dried to give the product-
Docetaxel 1 (300 mg, yield 92.8%). Data for compound
1
1: m.p.: 232-234 ℃; [α]2D5 −36.2 (c 1.0, EtOH); H
NMR (500 MHz, CDCl3) δ: 8.15-8.10 (m, 2H), 7.62-
7.58 (m, 1H), 7.53-7.49 (m, 2H), 7.40-7.37 (m, 5H),
6.22 (t, J=9.0 Hz, 1H), 5.68 (d, J=7.0 Hz, 1H), 5.46 (d,
Chin. J. Chem. 2013, 31, 31—36
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
33