Alternative synthesis and the determination of absolute configuration of docetaxel, an anticancer drug

Article abstract of DOI:10.1080/00397911.2011.584649

A simple, efficient, and alternative synthetic route for docetaxel with better control on the protection-deprotection sequence has been developed. The process is easily scalable and commercially viable, and critical impurities can be controlled efficiently. For the first time, absolute configuration of docetaxel was determined unambiguously by single-crystal X-ray diffraction.

Full text of DOI:10.1080/00397911.2011.584649

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Alternative Synthesis and the
Determination of Absolute Configuration
of Docetaxel, an Anticancer Drug
N. M. Sekhar a , Peddy Vishweshwar b , Palle V. R. Acharyulu c &
Yerramilli Anjaneyulu d
a Research and Development, Integrated Product Development,
Dr. Reddy's Laboratories Ltd. , Bachupally, Qutubullapur , Andhra
Pradesh , India
b Department of Analytical Research , Discovery Research, Dr.
Reddy's Laboratories Ltd. , Hyderabad , Andhra Pradesh , India
c Ecologic Technologies Pvt. Ltd. , Hyderabad , Andhra Pradesh ,
India
d Institute of Science and Technology, Center for Environmental
Science, J. N. T. University , Hyderabad , Andhra Pradesh , India
Accepted author version posted online: 12 Jan 2012.Published
online: 02 Aug 2012.
To cite this article: N. M. Sekhar , Peddy Vishweshwar , Palle V. R. Acharyulu & Yerramilli Anjaneyulu
(2012) Alternative Synthesis and the Determination of Absolute Configuration of Docetaxel, an
Anticancer Drug, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:23, 3482-3492, DOI: 10.1080/00397911.2011.584649
To link to this article: http://dx.doi.org/10.1080/00397911.2011.584649
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Synthetic Communications1, 42: 3482–3492, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.584649
ALTERNATIVE SYNTHESIS AND THE DETERMINATION
OF ABSOLUTE CONFIGURATION OF DOCETAXEL, AN
ANTICANCER DRUG
N. M. Sekhar,1 Peddy Vishweshwar,2 Palle V. R. Acharyulu,3
and Yerramilli Anjaneyulu4
1Research and Development, Integrated Product Development, Dr. Reddy’s
Laboratories Ltd., Bachupally, Qutubullapur, Andhra Pradesh, India
2Department of Analytical Research, Discovery Research, Dr. Reddy’s
Laboratories Ltd., Hyderabad, Andhra Pradesh, India
3Ecologic Technologies Pvt. Ltd., Hyderabad, Andhra Pradesh, India
4Institute of Science and Technology, Center for Environmental Science, J. N.
T. University, Hyderabad, Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract A simple, efficient, and alternative synthetic route for docetaxel with better control
on the protection–deprotection sequence has been developed. The process is easily scalable
and commercially viable, and critical impurities can be controlled efficiently. For the first
time, absolute configuration of docetaxel was determined unambiguously by single-crystal
x-ray diffraction.
Keywords Absolute configuration; anticancer; 10-deacetyl baccatin III; docetaxel and
non-small cell lung cancer (NSCLC)
Received February 18, 2011.
DRL Communication No. IPDO IPM-0021.
Address correspondence to Palle V. R. Acharyulu, Ecologic Technologies Pvt. Ltd., Plot No. 56,
Road No. 5, ALEAP Industrial area, Pragathinagar Kukatpally, Hyderabad 500 072, Andhra Pradesh,
India. E-mail: pallevr@gmail.com
3482

ALTERNATIVE SYNTHESIS OF DOCETAXEL
3483
INTRODUCTION
Docetaxel (1), an analog of paclitaxel (2), was obtained by semisynthesis from
10-deacetyl baccatin III (3), which was extracted from the needles of the European
yew tree Taxus baccata L.[1,2] Docetaxel (1) is an antineoplastic agent that acts by
promoting the assembly of tubulin into stable microtubules and inhibits their
disassembly, which leads to a marked decrease of free tubulin and eventually to
cancer cell death. The binding of docetaxel (1) to microtubules does not alter the
number of protofilaments.[3,4] Docetaxel (1) has better bioavailability[3] than
paclitaxel (2) and hence is extensively used in the treatment of cancer, specifically
breast cancer and non-small-cell lung cancer (NSCLC). See Fig. 1.
There are several synthetic routes reported in the literature for the synthesis of
paclitaxel analog, docetaxel (1).[5–15] These synthetic routes involve mostly semisyn-
thetic procedures starting from 10-deacetyl baccatin III (10-DAB III) (3) The most
practical synthesis[14,15] of the paclitaxel analog docetaxel (1) involves introduction
of a side chain through selective protection and deprotection methodology.
Selective protection of 7,10-hydroxy groups of 10-DAB III (3) by 2,2,2-trichlor-
oethyl chloroformate (Troc-Cl) as per reported procedure generates several side
products [viz., 7-(2,2,2-trichloroethoxycarbonyl)-10-deacetyl baccatin III (7-troc
10-DAB III) (5), 10-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin III (10-troc
10-DAB III) (6), 7,10,13-(2,2,2-trichloroethoxycarbonyl)-10-deacetyl baccatin III
(7,10,13-troc 10-DAB III) (7), and 7,10-di-(2,2,2-trichloroethoxycarbonyl)-10-deacetyl
baccatin III (7,10-ditroc 10-DAB III) (4)] as shown in Scheme 1. These side products
should be controlled in the initial stages of the synthesis to avoid competitive reactions
in further sequence of reactions.
A tedious downstream process was involved during deprotection at the advanced
stage of the synthesis of docetaxel (1). The deprotection of the acetonide group in
coupled product (9), followed by protection of amino group using di-tert-butyldicar-
bonate [(BOC)2O] as reported in literature, generates several impurities, specifically
epimers of docetaxel.
Docetaxel (1) is a complex molecule that is sensitive to acid, base and
heat.[2,16,17] It is therefore important to reduce the cycle time during downstream
Scheme 1. Synthesis of 7,10-ditroc 10-DAB-III (4).

3484
N. M. SEKHAR ET AL.
process and also to avoid formation of side products that otherwise may carry
forward to the final product. Thus, the major disadvantage in the previously reported
synthetic schemes is extensive purification of the final product by column chromato-
graphy to control the impurities. The present synthetic scheme controls the formation
of critical impurities in addition to simplifying purification methods.
Herein, we report an alternative synthetic route for the synthesis of docetaxel
(1) using a modified protection–deprotection sequence. Further, we have determined
the absolute configuration of docetaxel (1) by single-crystal x-ray diffraction.
RESULTS AND DISCUSSION
The selective protection of 7,10-hydroxy groups of 10-deacetyl baccatin III (3)
by 2,2,2-trichloroethyl chloroformate (Troc-Cl) is challenging because of the presence
of other hydroxyl groups. There is a reactivity difference among the hydroxyl groups
present at different centers (7 > 10>13 > 1)[18,19] but the generation of impurities out
of unselective protection cannot be ruled out. Thus, there is a possibility of formation
of side products (5–7) along with 7,10-ditroc 10-deacetyl baccatin III (4). Hence, there
is an unmet need to design a process that can lead to the product in a better yield by
avoiding the formation of impurities. Strategically, we were able to control the unde-
sired compounds by limiting the molar equivalents of Troc-Cl to 3.5. Temperature
and rate of addition of reagent (1.5–2 ml=min) were also critical factors to obtain
good results as shown, in Table 1.
The synthesis of 7,10,13-protected 10-DAB III (9) from protected 10-DAB III
(4) has been reported in the literature.[14,15] Esterification of the side chain (8) with
protected 10-DAB III (4) has been well optimized to afford the desired purity and
good yield.[20] In contrast to the literature procedures, the Troc protecting groups
in compound 9 were first deprotected using zinc–acetic acid (AcOH) in methanol
(MeOH) to afford 13-protected 10-DAB III (10) in significantly good yields.
Treatment of 10 with formic acid (HCOOH) gave the corresponding amino
alcohol derivative of docetaxel (11), which was then taken up directly for the
subsequent protection with ditert butyldicarbonate [(BOC)2O] to afford docetaxel
(1)[20] as shown in Scheme 2. The product thus obtained was subjected to purification
Table 1. Effect of 2,2,2-trichloroethyl chloroformate (Troc-Cl) and temperature
HPLC (%)
Troc-Cl
(Eq.)
Temperature
(ꢀC)
Entry
4
5
6
7
3
1
2
3
4
5
6
7
8
2.0
3.0
3.5
3.5
3.5
3.5
4.0
4.5
25–30
25–30
20–25
25–30
30–35
35–40
25–30
25–30
17.7
24.4
94.5
96.2
90.2
87.4
86.5
33.3
24.6
30.2
0.5
33.6
34.6
0.8
NDa
0.2
21.8
8.6
0.9
1.3
0.5
0.2
0.1
0.05
0.2
0.1
7.7
9.9
ND
ND
0.1
ND
ND
ND
ND
ND
ND
11.4
64.2
ND
aND, not detected.

ALTERNATIVE SYNTHESIS OF DOCETAXEL
3485
Scheme 2. Alternative synthesis of docetaxel.
to afford the product 1 in good yield and quality, far superior compared to the
previous method reported and practiced. In addition, the reduced downstream
process could also reduce significantly the formation of critical impurities. This alter-
native process has also helped in reducing the epimers of docetaxel as the acetonide
deprotcetion was carried out in the last stage of the synthesis. The docetaxel (1), thus
obtained has excellent purity and is suitable for the preparation of dosage forms as
per regulatory agencies.[21]
Several attempts have been made to generate single crystals of docetaxel (1)
using different single and binary solvents by the slow evaporation method. Few crys-
tals of compound 1 were obtained by slow evaporation crystallization from dimethyl
sulfoxide (DMSO). The crystal structure reveals that the asymmetric unit consists of
one molecule of docetaxel (1) and one dmethylsulfoxide (DMSO) molecule. Hence the
crystal is DMSO solvate of docetaxel (1) with 1:1 stoichiometry; ORTEP is shown
in Fig. 2. Because the crystal consists of one heavy atom (sulfur), the absolute
Figure 1. Structures of 10-deacetyl baccatin III (10-DAB III) derivatives.

3486
N. M. SEKHAR ET AL.
Figure 2. ORTEP of docetaxel (1).DMSO with displacement ellipsoids drawn at the 50% probability level
for nonhydrogen atoms. H atoms are represented by circles of arbitrary size. Atoms are not labeled
for clarity. Ellipsoids with black color are carbons, red are oxygens, blue is nitrogen, and yellow is sulfur.
(Figure is provided in color online.)
configurations of 11 chiral centers in docetaxel (1) were determined. The configura-
tions are the same as those reported for docetaxel (1). The absolute configuration of
the chiral centers in docetaxel has not been reported in the literature.[22–25] To the
best of our knowledge, we report the determination of the absolute configuration
of docetaxel (1) by the single-crystal x-ray diffraction for the first time. The crystal
Figure 3. Crystal packing of docetaxel (1).DMSO inclusion complex, view down [010]. Notice that
docetaxel molecules form the host framework and DMSO molecules (shown with ball and stick model)
occupy the channels. Note: Carbons are in grey, oxygens in red, nitrogens in blue hydrogens in white,
and Sulfurs in yellow. (Figure is provided in color online.)

ALTERNATIVE SYNTHESIS OF DOCETAXEL
3487
structure shows that docetaxel (1) molecules are forming the host framework through
˚
hydrogen bonds with channels (approximate size 8.7 ꢁ 7.5 A) along [010], similar to
our previously reported inclusion complexes.[22] The DMSO guest solvent molecules
reside in the channels and hydrogen is bonded to the docetaxel (1) host framework
. . .
=
through strong OꢂH O S hydrogen bonds as shown in Fig. 3.
CONCLUSION
In conclusion, an alternative synthetic route for the preparation of docetaxel
has been reported. The new process is simple and scalable and involves a modified
protection–deprotection strategy to control the critical process-related substances.
The product could also be obtained in good yield with excellent purity and is suitable
for the preparation of dosage forms as required by regulatory agencies. For the first
time, absolute configuration of docetaxel has been determined unambiguously by
single-crystal x-ray diffraction.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Varian Mercury Plus and
Unity Inova at 400 and 500 MHz. High-resolution mass spectrographic (HRMS)
studies were performed on a Waters LCT Premier XE. The Fourier transform–
(FT-IR) infrared spectrum was recorded in the solid state KBR medium using a
Shimzdzu IR Prestige 21 FT-IR spectrophotometer. The optical rotation was carried
out on a Jasco DIP-370 polarimeter. Single-crystal x-ray data was collected on a
Rigaku AFC-7S diffractometer equipped with a Mercury CCD detector using Mo-Ka
radiation. The solvents and reagents were used without further purification.
7,10-Di(2,2,2-trichloroethoxycarbonyl)-10-deacetyl baccatin III (4)
10-Deacetyl baccatin III (100.0 g, 0.183 mol) was dissolved in pyridine (0.5 L). A
solution of 2,2,2-trichloroethyl chloroformate (87.4 mL, 0.635 mol) in dichloro-
methane (2.0 L) was added at 25–28 ꢀC for 45–60 min under a nitrogen atmosphere
and stirred at 25–30 ꢀC for 5–10 min at moderate speed. After checking the com-
pletion of reaction by thin-layer chromatography (TLC), the reaction mixture was
quenched with water (1.0 L). The organic layer was separated and washed with
10% hydrochloric acid (2.0 L ꢁ 3), saturated sodium bicarbonate solution (2.0 L),
and water (1.0 L). The organic layer was evaporated to less than three volumes, pre-
cipitated with 4.5 L of n-heptane, and stirred for 1 h at 25–30 ꢀC. The crude material
was filtered and crystallized with ethyl acetate = n-heptane (0.5 L=1.65 L). The crystal-
lized material was filtered and dried under vacuum at 45–50 ꢀC to obtain pure
7,10-ditroc 10-deactyl baccatin III (4) (148 g, yield: 90%, purity: 99% by HPLC).
Spectral data of the obtained compound are well in agreement with the reported
spectral data.[15]
1H NMR (400 MHz, DMSO-d6): d 0.97 (s, 3H, C-17H3), 1.0 (s, 3H, C-16H3),
1.7 (s, 3H, C-19H3), 1.84 (m, 1H, C-6Ha), 2.0 (s, 3H, C-18H3), 2.24 (s, 3H, Ac), 2.2
(m, 1H, C-14Ha), 2.3 (m, 1H, C-14Hb), 2.54 (m, 1H, C-6Hb), 3.83 (d, 1H, J ¼ 7.0 Hz,
Hz, C-3H), 4.04 (d, 1H, J ¼ 8.5 Hz, C-20Ha), 4.11 (d, 1H, J ¼ 8.5 Hz, C-20Hb), 4.68

3488
N. M. SEKHAR ET AL.
(m, 1H, C-13H), 4.68 (s, 1H, C-1 OH, D2O exchangeable), 4.77 (d, 1H, J ¼ 12.5, C-10
–OCOOCHaCCl3), 4.94 (d, 1H, J ¼ 12.5, C-10 –OCOOCHbCCl3), 4.97 (d, 1H,
J ¼ 12.5, C-7 –OCOOCHaCCl3), 5.0 (d, 1H, J ¼ 12.5, C-7–OCOOCHbCCl3), 5.02
(d, 1H, J ¼ 5.0 Hz, C-5H), 5.1 (br, 1H, C-13 OH, D2O exchangeable), 5.46 (d, 1H,
J ¼ 7.0 Hz, C-7H), 5.48 (d, 1H, J ¼ 5.0 Hz, C-2H), 6.17 (s, 1H, C-10 H), 7.58 (t, 2H,
J ¼ 7.5 Hz, m-Bz-H), 7.68 (t, 1H, J ¼ 7.5 Hz, p-Bz-H), 8.03 (d, 2H, J ¼ 7.5 Hz, o-Bz-
H). 13C NMR (400 MHz, DMSO-d6): d 10.34 (C-19), 15.05 (C-18), 20.57 (C-17),
22.17 (CH3 of Ac), 26.55 (C-16), 32.76 (C-6), 38.55 (C-14), 42.54 (C-15), 46.60
(C-3), 55.47 (C-8), 66.0 (C-13), 73.89 (C-7), 75.18 (C-20), 76.24 (C-10
–OCOOCH2CCl3), 76.48 (C-2), 76.57 (C-7 –OCOOCH2CCl3), 76.69 (C-1), 79.35
(C-4) 79.56 (C-10), 82.62 (C-5), 94.36 (C-7 –OCOOCH2CCl3), 94.61 (C-10
–OCOOCH2CCl3), 128.66 (C-m-Bz), 129.52 (C-o-Bz), 129.91 (C1-Bz), 133.31 (C-p-
Bz), 129.25 (C-11), 148.27 (C-12), 152.27 (C-7 –OCOOCH2CCl3), 152.61 (C-10
=
=
-OCOOCH2CCl3) 165.15 (C O of Bz), 170.05 (C O of Ac), 201.63 (C-9). HRMS
(EI) m=z calcd. for C35H38O14NaCl6 (M þ Na)þ: 915.0290; found: 915.0285. IR
(KBr) cmꢂ1: 3532, 3487, 2957, 2905, 1765, 1730, 1717, 1379, 1288, 1250, 1179,
25
1111, 1067, 721, 706. SOR: ½aꢃD ꢂ12.20o (c ¼ 1.0, DMSO).
10-Deacetylbaccatin III-13-O-[(4S,5R)-4-Phenyl-3-(tert-
butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidine-5-carboxylate] (10)
To the acetic acid (1.25 L, 10 vol) taken in a round-bottom flask, compound 9
(125 g, 0.104 mol) was added and stirred for 5–10 min, and subsequently methanol
(1.25 L, 10 vol) was added to the solution. Zinc dust (54.3 g, 0.83 mol) was charged
to the solution, heated to 55–60 ꢀC, and stirred for 30 min. After completion of the
reaction, it was filtered and washed with methanol (125 mL). The filtrate was slowly
added to 8.75 L of water over a period of 5–10 min, and then the suspension was
stirred for 1 h at 25–30 ꢀC. The white solid precipitate was filtered and washed with
water (250 mL). The solid was dissolved in ethyl acetate (1.25 L) and washed with
water (250 mL) and saturated sodium bicarbonate solution (250 mL). The organic
layer was concentrated under vacuum at 45–50 ꢀC to a minimum volume (500 mL)
and crystallized with n-heptane (2.5 L) to afford title compound 10 (76.6 g, yield:
86.7%, purity: 94% by HPLC).
1H NMR (400 MHz, DMSO-d6): d 1.02 [s, 3H, C-17H3), 1.08 (s, 3H, C-16H3),
1.08 (s, 9H, -C(CH3)3 of Boc], 1.52 (s, 3H, C-19H3), 1.63 [m, 1H, C-6Ha], 1.65 [s, 3H,
C(CH3)2), 1.74 (s, 3H, C(CH3)2], 1.77 (s, 3H, Ac), 1.82 (s, 3H, C-18H3), 2.07 (m, 1H,
C-14Ha), 2.25 (m, 1H, C-6Hb), 2.26 (m, 1H, C-14Hb), 3.71 (d, 1H, J ¼ 6.6 Hz, C-3H),
3.97 (d, 1H, J ¼ 8.1 Hz, C-20Ha), 4.02 (d, 1H, J ¼ 8.1 Hz, C-20Hb), 4.06 (m, 1H,
C-7H), 4.59 (d, 1H, J ¼ 6.5 Hz, C-20H), 4.69 (s, 1H, C-1 OH, D2O exchangeable),
4.86 (dd, 1H, J ¼ 9.2, 2.0 Hz, C-5H), 4.96 (br, 1H, C-10 OH, D2O exchangeable),
5.0 (br, 1H, C-7 OH, D2O exchangeable), 5.05 (br, 1H, C-30H), 5.13 (br, 1H,
C-10H), 5.45 (d, 1H, J ¼ 7.1 Hz, C-2), 6.08 (t, 1H, J ¼ 9.2 Hz, C-13H), 7.36 (m, 2H,
m-Ph-H), 7.41 (m, 2H, o-Ph-H), 7.43 (m, 1H, p-Ph-H), 7.60 (t, 2H, J ¼ 7.8 Hz,
m-Bz-H), 7.70 (t, 1H, J ¼ 7.2 Hz, p-Bz-H), 7.98 (d, 2H, J ¼ 6.94 Hz, o-Bz-H). 13C
NMR (400 MHz, DMSO-d6): d 9.72 (C-19), 13.80 (C-18), 20.74 (C-17), 21.16 (CH3
of Ac), 25.80 [CH3 of C(CH3)2], 26.51 [CH3 of C(CH3)2[, 26.51 [C-16), 27.58
(-C(CH3)3 of Boc], 35.44 (C-14), 36.46 (C-6), 42.95 (C-15), 45.99 (C-3), 57.05 (C-8),

ALTERNATIVE SYNTHESIS OF DOCETAXEL
3489
63.57 (C-30), 70.74 (C-7), 71.78 (C-13), 73.74 (C-10), 74.74 (C-2), 75.39 (C-20), 76.85
(C-1), 79.46 (C-t-Bu), 80.24 (C-4), 80.24 (C-20), 83.75 (C-5), 95.82 [C-C(CH3)2],
126.60 (C-m-Ph), 127.49 (C-p-Ph), 128.58 (C-o-Ph), 128.58 (C-m-Bz), 129.55 (C-o-
Bz), 130.06 (C1-Bz), 133.33 (C-p-Bz), 135.69 (C-11), 136.93 (C-12), 140.49
0
=
=
=
(C-1-Ph), 150.82 (C O of carbamate), 165.16 (C O of Bz), 169.74 (C O of C-1 ),
=
169.74 (C O of Ac), 209.42 (C-9). HRMS (EI) m=z calcd. for C46H58NO14 (M þ H)þ:
: 848.3857; found: 848.3846. IR (KBr) cmꢂ1: 3499, 2983, 1706, 1369, 1246, 1138, 1071,
25
773, 709. SOR: ½aꢃD ꢂ50.2o (c ¼ 1.0, MeOH).
Docetaxel (1)
Compound 10 (50 g, 0.0589 mol) was added to the formic acid (500 mL) taken in
a round-bottom flask at 15–20 ꢀC and stirred for 1–1.5 h. After completion of the reac-
tion, the formic acid was distilled under high vacuum below 20 ꢀC to obtain a syrupy
mass of compound 11. Water (0.5 L) was added to the mass and washed with ethyl
acetate (0.5 L ꢁ 2) and separated. To the aq. layer, ethyl acetate (0.5 L) was added
and stirred for 5 min. The pH of the reaction mixture was adjusted to 7.5–8.5 using
solid sodium bicarbonate (ꢄ54 g, 0.64 mol), and di-tert-butyldicarbonate (19.3 g,
0.091 mol) was added immediately in a single lot at 25–30 ꢀC and stirred for
1–1.5 h. After completion of the reaction, the organic layer was separated, washed
with water (0.5 L), and distilled to minimum volume. Acetonitrile (100 mL) was added
to the mass, followed by diisopropyl ether (0.75 L), and stirred for 1 h. The obtained
solid was filtered and dried for 2 h to afford the crude title compound 1 (30 g, yield:
63%, purity: > 96% by HPLC). Thus obtained, crude compound 1 was purified by
column chromatography using 230 to 400-mesh silica gel and 40–50% ethyl acetate =
petroleum ether as eluent. The fractions were distilled to minimum and precipitated
with petroleum ether to obtain 22 g of docetaxel (1) with purity > 99% by HPLC.
The column of purified docetaxel was optionally crystallized in acetone = disioproyl
ether to afford anhydrous crystalline docetaxel (1) with purity > 99.8% by HPLC.
Spectral Data of N-De-tert-butoxycarbonyl Docetaxel (11)
1H NMR (400 MHz, DMSO-d6): d 0.97 (s, 3H, C-17H3), 1.02 (s, 3H, C-16H3),
1.51 (s, 3H, C-19H3), 1.64 (m, 1H, C-6Ha), 1.68 (m, 1H, C-14Ha), 1.74 (s, 3H,
C-18H3), 1.82 (m, 1H, C-14Hb), 1.85 (br, 1H, C-1 OH, D2O exchangeable), 2.11
(s, 3H, Ac), 2.26 (m, 1H, C-6Hb), 3.3 (br, 1H, C-20 OH, D2O exchangeable), 3.4
(br, 1H, C-7 OH, D2O exchangeable), 3.64 (d, 1H, J ¼ 6.5 Hz, C-3H), 3.99 (m, 1H,
C-20Ha), 4.02 (m, 1H, C-30H), 4.04 (m, 1H, C-20Hb), 4.05 (m, 1H, C-7H), 4.08 (m,
1H, C-20H), 4.53 (br, 1H, C-10 OH, D2O exchangeable), 4.89 (d, 1H, J ¼ 10 Hz,
C-5H), 4.95 (br, 2H, NH2, D2O exchangeable), 5.08 (s, 1H, C-10H), 5.40 (d, 1H,
J ¼ 7.5 Hz, C-2), 5.87 (t, 1H, J ¼ 8.5 Hz, C-13H), 7.20 (m, 1H, p-Ph-H), 7.36 (m,
2H, m- Ph-H), 7.39 (m, 2H, o-Ph-H), 7.63 (t, 2H, J ¼ 7.5 Hz, m-Bz-H), 7.72 (t, 1H,
J ¼ 7.5 Hz, p-Bz-H), 7.95 (d, 2H, J ¼ 6.5 Hz, o-Bz-H). 13C NMR (400 MHz,
DMSO-d6): d 9.81 (C-19), 13.71 (C-18), 20.81 (C-17), 22.34 (CH3 of Ac), 26.54
(C-16), 35.04 (C-14), 36.47 (C-6), 42.91 (C-15), 45.97 (C-3), 57.00 (C-8), 58.08
(C-30), 69.75 (C-13), 70.80 (C-7), 73.79 (C-10), 74.77 (C-2), 75.43 (C-20), 76.87
(C-1), 76.87 (C-20), 80.29 (C-4), 83.73 (C-5), 127.47 (C-p-Ph), 128.04 (C-m-Ph),

3490
N. M. SEKHAR ET AL.
128.32 (C-o-Ph), 128.69 (C-m-Bz), 129.53 (C-o-Bz), 130.06 (C-1 Bz), 133.44 (C-p-Bz),
=
=
135.91 (C-12), 136.81 (C-11), 139.41 (C-1 Ph), 165.22 (C O of Bz), 169.67 (C O of
=
Ac), 172.62 (C O of C1 ), 209.38 (C-9). IR (KBr) cmꢂ1: 3422, 2984, 2955, 1722, 1583,
0
1452, 1371, 1271, 1244, 1177, 1107, 1070, 985, 773, 708. HRMS (EI) m=z calcd. for
25
C38H46NO12 (M þ H)þ: 708.3555; found: 708.3018. SOR: ½aꢃD ꢂ50.1o(c ¼ 1.0, MeOH).
Spectral Data of Docetaxel (1)
1H NMR (500 MHz, CDCl3): d 1.13 (s, 3H, C-17H3), 1.24 (s, 3H, C-16H3), 1.34
[s, 9H, -C(CH3)3 of Boc], 1.52 (br, 1H, C-7 OH, D2O exchangeable), 1.65 (br, 1H, C-1
OH, D2O exchangeable), 1.76 (s, 3H, C-19H3), 1.81 (m, 1H, C-6Ha), 1.86 (s, 3H,
C-18H3), 2.27 (m, 2H, C-14H2), 2.37 (s, 3H, Ac), 2.58 (m, 1H, C-6Hb), 3.37 (br
s, 1H, C-20 OH, D2O exchangeable), 3.91 (d, 1H, J ¼ 7.5 Hz, C-3H), 4.19 (d, 1H,
J ¼ 8.5 Hz, C-20Ha), 4.21 (br, 1H, C-10 OH, D2O exchangeable), 4.23 (dd, 1H,
J ¼ 11.0, 6.5 Hz, C-7H), 4.31 (d, 1H, J ¼ 8.5 Hz, C-20Hb), 4.62 (br s, 1H, C-20H),
4.94 (dd, 1H, J ¼ 11.5, 2.0 Hz, C-5H), 5.20 (s, 1H, C-10H), 5.26 (br d, 1H, J ¼ 6.0 Hz,
Hz, C-30H), 5.43 (d, 1H, J ¼ 9.0 Hz, NH, D2O exchangeable), 5.68 (d, 1H, J ¼ 8.5 Hz,
C-2H), 6.21 (t, 1H, J ¼ 8.5 Hz, C-13H), 7.32 (m, 1H, p-Ph-H), 7.38 (m, 2H, m-Ph-H),
7.39 (m, 2H, o-Ph-H), 7.50 (t, 2H, J ¼ 8.0 Hz, m-Bz-H), 7.61 (t, 1H, J ¼ 8.0 Hz, p-Bz-
H), 8.10 (d, 2H, J ¼ 8.0 Hz, o-Bz-H). 13C NMR (400 MHz, DMSO-d6): d 9.84 (C-19),
14.32 (C-18), 20.64 (C-17), 22.53 (CH3 of Ac), 26.44 (C-16), 28.18 [-C(CH3)3 of Boc],
35.71 (C-14), 36.88 (C-6), 43.06 (C-15), 46.47 (C-3), 56.22 (C-30), 57.67 (C-8), 71.92
(C-7), 72.37 (C-13), 73.69 (C-20), 74.53 (C-10), 74.87 (C-2), 76.61 (C-20), 78.78
(C-1), 80.19 [-C(CH3)3 of Boc)], 81.10 (C-4), 84.21 (C-5), 126.75 (C-m-Ph), 128.0
(C-p-Ph), 128.67 (C-m-Bz), 128.78 (C-o-Ph), 129.19 (C1-Bz), 130.14 (C-o-Bz),
=
133.66 (C-p-Bz), 135.95 (C-11), 138.43 (C-12), 138.43 (C-1Ph), 155.39 0(C O of carba-
=
=
=
mate), 166.99 (C O of Bz), 170.31 (C O of Ac), 172.70 (C O of C-1 ), 211.27 (C-9).
IR (KBr) cmꢂ1: 3536, 3459, 3432, 2979, 2904, 1723, 1706, 1492, 1369, 1264, 1249,
1167, 1098, 1072, 710. HRMS (EI) m=z calcd. for C43H53NO14Na (M þ Na)þ:
25
25
830.3364; found: 830.3383. SOR: ½aꢃD ꢂ40o(c ¼ 1.0, MeOH); lit.]26] ½aꢃD ꢂ38.5 to
ꢂ41.5o(c ¼ 1.0, MeOH)
Preparation of Docetaxel Dimethylsulfoxide (DMSO) Single Crystal
About 1.0 g of docetaxel (1) was dissolved in 5 mL of dimethylsulfoxide
(DMSO) and stirred for about 10 min. The solution was allowed to stand without
disturbance at ambient conditions for slow evaporation. A few crystals were observed
after 15 days, which were filtered carefully, collected and used for single-crystal x-ray
diffraction.
Crystal Data of 1
(C43H53NO14) . (C2H6SO), M ¼ 886.02, monoclinic, spaꢀce group P21,
˚
˚
˚
a ¼ 12.763(5) A, b ¼ 8.830(3) A, c ¼ 20.503(8) A, b ¼ 101.378(4) , V ¼ 2265.3(15)
A , T ¼ 298 K, Z ¼ 2, Dc ¼ 1.299 g cmꢂ3, m(Mo-Ka) ¼ 0.14 mmꢂ1, 25105 reflections
3
˚
measured, 9322 unique reflections, 7561 observed reflections [I > 2.0r(I)], R1_obs ¼
0.064, wR2_all ¼ 0.101. CCDC 769072 contains the supplementary crystallographic

ALTERNATIVE SYNTHESIS OF DOCETAXEL
3491
data for this article. These data can be obtained free of charge via http:\\www.
ccdc.cam.ac.uk\conts\retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033).
ACKNOWLEDGMENTS
The authors thank the management of Dr. Reddy’s Laboratories Ltd. for sup-
porting this work, and support from HPAI R&D and Discovery Research colleagues
is highly appreciated.
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