A novel method to synthesize docetaxel and its isomer with high yields

Article abstract of DOI:10.1002/jhet.5570420430

Side chains of docetaxel and its isomer were obtained through Staudinger cycloaddition and catalytic hydrogenation of chlorophenyl intermediates, using chlorobenzaldehyde as starting material. Syntheses of three novel chiral azetidinone derivatives through the Staudinger cycloaddition reaction of chlorophenyl chiral amine Schiff base with different substituted positions were described and their ring-opening reaction under the catalysis of Pd/MgCO ₃ or Pd/C to afford side chains of docetaxel and its isomer in high yields was investigated. Finally, docetaxel and its isomer were obtained. Single crystal of (3S,4R)-3-hydroxy-N-[(S)(1-phenyl)ethyl]-4 -(2′-chlorophenyl) -2-azetidinone (4c) was obtained, the configuration of which was determined by X-ray diffraction. Because of the mild cyclization reaction condition and convenient asymmetric resolution operation when p-chlorobenzaldehyde was employed instead of benzaldehyde, the yield of cyclization and hydrogenation increased dramatically and the total yield of docetaxel was higher than the result in literature. When o-chlorobenzaldehyde was employed instead of benzaldehyde an isomer of docetaxel was obtained by the same way.

Full text of DOI:10.1002/jhet.5570420430

May-Jun 2005
679
A Novel Method to Synthesize Docetaxel and its Isomer
With High Yields
Chuan-Min Qi,* Yun-Feng Wang, Ling-Chun Yang
*Department of Chemistry, Beijing Normal University, Beijing 100875, China
Received March 6, 2004
Side chains of docetaxel and its isomer were obtained through Staudinger cycloaddition and catalytic
hydrogenation of chlorophenyl intermediates, using chlorobenzaldehyde as starting material. Syntheses of
three novel chiral azetidinone derivatives through the Staudinger cycloaddition reaction of chlorophenyl chi-
ral amine Schiff base with different substituted positions were described and their ring-opening reaction
under the catalysis of Pd/MgCO or Pd/C to afford side chains of docetaxel and its isomer in high yields was
3
investigated. Finally, docetaxel and its isomer were obtained. Single crystal of (3S,4R)-3-hydroxy-N-[(S)-
(1-phenyl)ethyl]-4 -(2'-chlorophenyl) -2-azetidinone (4c) was obtained, the configuration of which was
determined by X-ray diffraction. Because of the mild cyclization reaction condition and convenient asym-
metric resolution operation when p-chlorobenzaldehyde was employed instead of benzaldehyde, the yield of
cyclization and hydrogenation increased dramatically and the total yield of docetaxel was higher than the
result in literature. When o-chlorobenzaldehyde was employed instead of benzaldehyde an isomer of doc-
etaxel was obtained by the same way.
J. Heterocyclic Chem., 42, 679 (2005).
Docetaxel has been thought as one of as an anticancer
Results and Discussion.
pharmaceutical with the most remarkable curative effects,
and passed clinical trials of mammary gland cancer, lung
cancer, stomach cancer and crown cancer at the end of
1990's. In 1996, it was authorized by Food and Drug
Administration (FDA) and applied in clinic [1,2]. Due to
its complex structure, great difficulty exists in the total
synthesis of docetaxel. Since 10-deacetylbaccatin £ (10-
DAB£), with a ring structure similar to docetaxel, was
extracted in large scale from European Taxus baccata,
effective semisynthesis were started to reduce synthetic
difficulty and cost of docetaxel dramatically [3-5].
Considering that the key procedure, synthesis of the side
chain that joined with 10-DAB£ and (3R,4S)-3-hydroxy-
4-(p-chlorophenyl)-2-(α-phenylethyl)azetidinone can pro-
ceed in high yield, it would become an effective and cheap
way to synthesize docetaxel if the chlorine atom can be
reduced to a hydrogen atom. Hence, the following reaction
route was designed for the synthesis of docetaxel and its
isomer (Scheme).
Configurations of β-Lactams and Side Chain Compounds.
Chiral Schiff bases were employed to afford two
diastereoisomers containing the β-amide ring via the
Staudinger cycloaddition reaction. The structure of 4c
has been proven by X-ray diffraction (Figure), and the
configuration found to be 3S,4R. The (3S,4R)-β-propio-
lactam (4c), which was obtained via the Staudinger
cycloaddition reaction using the Schiff base of the chiral
amine and aromatic aldehyde was deposited in the
Cambridge date base (CCDC 252696). Compounds 4a and
4b were determined to be 3R,4S configuration on the
1
basis of H-NMR, H-HCOSY, optical activity and com-
parison with the structure of 4c. In the ring-opening and
hydrogenation reactions, the products retain their origi-
nal configuration hence the side chain compounds have
the same configurations as that of the corresponding
β-lactams.

680
C.-M. Qi, Y.-F. Wang, L.-C. Yang
Vol. 42

May-Jun 2005
A Novel Method to Synthesize Docetaxel and its Isomer With High Yields
681
Figure. X-ray crystal structure of (3S,4R)-3-hydroxy-4-(2'-chlorophenyl)-2-(α-phenylethyl)azetidinone.
Hydrogenation.
a cyclization temperature of -5-10 °C was appropriate and
the reaction time was shortened, evidently to simplify the
operation.
The Pd content in the catalyst plays a key role in the
reduction of the chlorine atom. When Pd/MgCO or Pd/C
3
Due to the viscosity of the intermediate propiolactam 3a,
its isomers cannot be resolved by recrystallization. We
used the way that the hydroxy group is released through
hydrolysis to resolve the propiolactam, then recrystallized
in mixture of ethyl acetate and n-hexane (7:1) to afford 4a
(3R,4S)-3-hydroxy-4-(p-chlorophenyl)-2-(α-phenylethyl)-
azetidinone in high yield (the total yield of the preceding
three steps was about 76%). Compared with the corre-
sponding product using benzaldehyde as starting material,
this method not only gave higher yields than the literature
method [4], but also with a convenient and quick recrystal-
lization operation. The total yield of 4c (3S,4R)-3-
hydroxy-4-(2'-chlorophenyl)-2-(α-phenylethyl)azetidi-
none was about 22%.
containing 3% Pd was employed, only N-phenylethyl was
reduced to ethylbenzene after reacting for 8 h at 50 °C. As
the reaction time is increased, the formation of by-products
also greatly increased with only partial reduction of chlo-
rine atoms. Both phenylethyl groups and chlorine atoms
can be reduced if the content of Pd increased to 10% under
the same reaction conditions. The reaction is complete in 3
h and Pd/MgCO or Pd/C containing 8-20% Pd was
3
employed for catalytic hydrogenation. The optimum tem-
perature of catalytic hydrogenation is 35-45 °C with alco-
hol as solvent. When methanol and ethanol are used, good
catalytic effects are observed.
Synthesis.
After the treatment of 4a, 4b and 4c with HCl, the ring-
opening products underwent catalytic hydrogenation directly
The acetoxyacetyl chloride, used in the preparation of β-
lactams adopting benzaldehyde as starting materials, is
very sensitive to water. Considering that dropwise addition
of the acyl chloride/chloroform solution is a long proce-
dure, trace amounts of water in chloroform can react with
the acyl chloride to afford the corresponding carboxylic
acid, which was precipitates out and does not react further.
This results in dramatically lower yields therefore the chlo-
by Pd/MgCO or Pd/C with nearly 100% yields. The yields
3
of 5a and 5c were 69.8% and 66.5% respectively.
Both of the side chain of docetaxel (8a) and its isomer
(8c), obtained through hydrolysis of the ester directly,
reacted with the parent ring without purification. Side
chain 8a and the parent ring reacted according to the litera-
ture [7] to give the docetaxel. Similarly, side chain (8c) of
the isomer reacted with the parent ring to afford docetaxel
isomer.
Because of the mild cyclization reaction conditions and
the convenient asymmetric resolution operation when
employing p-chlorobenzaldehyde instead of benzaldehyde,
the yields of cyclization and hydrogenation increased dra-
matically. The total yield of docetaxel was higher than that
reported in the literature [7]. Considering the high yields
and convenient operation, the cost of docetaxel synthesis
decreased greatly by this method and will be suitable for
roform must be adequately dried with anhydrous CaCl
before use.
2
In this reaction, as far as the mechanism was concerned,
the acyl chloride reacts first with triethylamine to form the
ketene like intermediate via loss of HCl followed by
Stautinger cycloaddition with the Schiff base to form the β-
lactam. According to the literature method [7], we found
that the optimum temperature for dropwise addition of the
acyl chloride is -20 °C followed by raising the temperature
above 0 °C, for a reaction time of 4-6 hours. However,
when p-chlorobenzaldehyde is used instead benzaldehyde

682
C.-M. Qi, Y.-F. Wang, L.-C. Yang
Vol. 42
White crystal (2.29 g) was obtained in 68.1% total yield by recrys-
substantive commercial production and provides the foun-
dation for further efforts to increase access to it.
20
tallization a mixture of ethyl acetate and n-hexane (8:1). [α]
+212
D
(c1.0, MeOH); mp 154-157 °C; IR (KBr) 3259, 2991, 2900, 1719
-1 1
cm ; H NMR (CDCl 500MHz): δ 7.26-7.42 (m, 9H, Ar), 5.10 (d,
3,
EXPERIMENTAL
1H, J=4.7Hz, CHOH), 5.03 (d, 1H, J=4.7Hz, CHN), 4.94 (q, 1H,
13
J=7.17Hz, CHCH ), 1.50 (d, 3H, J=7.17Hz, CHCH ); C NMR
3
3
Melting points were determined on RY-1 melting point appara-
tus and uncorrected. Infrared spectra were recorded on a Hitachi
260-50 spectrophotometer. H-NMR spectra were measured with
(CDCl 500MHz): δ 169.9, 140.9, 134.3, 132.4, 130.2,129.7, 129.2,
129.2, 128.4, 127.3, 127.1, 77.7, 77.5, 59.5, 55.0.
3,
1
Anal. Calcd for C
H NO Cl: C, 67.66; H, 5.34; N, 4.64.
17 16 2
a Brucker-500 MHz spectrometer using TMS as an internal stan-
dard. Optical activity was performed using a Perkin-Elmer 241
MC polarimeter. Schiff base of the substituted benzaldehyde was
synthesized according to the literature method [6].
Found C, 67.51; H, 5.30; N, 4.57.
(3S,4R)-3-Hydroxy-4-(2'-chlorophenyl)-2-(α-phenylethyl)aze-
tidinone (4c).
White crystal (0.71 g) was obtained in 21.9% total yield by
Preparation of Pd/MgCO or Pd/C Catalyst.
3
recrystallization a mixture of ethyl acetate and n-hexane (4:1).
20
[α]
–153 (c1.0, MeOH); mp 157-158 °C; IR (KBr) 3322,
To a 50 mL flask was added active carbon or MgCO and 0.1%
D
3
-1 1
2992, 2987, 1732 cm , H NMR (CDCl 500MHz): δ 7.26-7.39
PdCl and stirred for 2 h at room temperature until the solution
3,
2
(m, 9H, Ar), 5.09 (s, 2H, CHOH and CHN), 4.54 (dd, 1H,
became clear and the color of MgCO turned from white to red.
3
J=7.17Hz, CHCH ), 3.48 (bs, 1H, OH), 1.90 (d, 3H, J=7.17Hz,
After the resulting mixture was filtered, the solid obtained was
washed with water and dried to afford fresh Pd catalyst loaded
3
13
2+
CHCH ); C NMR (CDCl 500MHz): δ 169.9, 140.9, 134.3,
3
3,
132.4, 130.2,129.7, 129.2, 129.2, 128.4, 127.3, 127.1 77.7, 77.5,
59.5, 55.0.
with MgCO or carbon black. Then the catalyst was added in 30
mL methanol and pre-activated in the hydrogen atmosphere. The
3
Anal. Calcd for C
H NO Cl: C, 67.66; H, 5.34; N, 4.64.
target Pd/MgCO or Pd/C catalyst obtained after filtration and
17 16 2
3
Found C, 67.51; H, 5.30; N, 4.57.
drying is red before pre-activation black after pre-activation.
Synthesis of new azetidinone derivatives 4a, 4b and 4c.
The Catalytic Ring-opening Reaction and Hydrogenation of β-
Lactams to Obtain Compounds 5a and 5c.
To a 100 mL three-necked flask were added Schiff base 2 dis-
solved in 20 mL trichloromethane and triethylamine (0.021 mol, 2.9
mL). The mixture was stirred and cooled to -5-0 °C, followed by
dropwise addition of acetoxyacetyl chloride (0.012 mol, 1.6 mL) in
15 mL of trichloromethane. Then the reaction continued for 2-4 h at
room temperature and acidified with 20 mL 2.7 M HCl. The result-
ing solution was washed twice with water (20 mL) and the organic
To a 100 mL flask were added 4 (12 mmol) and 45 mL of a sat-
urated solution of HCl in methanol. After the mixture was stirred
for 3-8 h and the solvent was removed, the resulting solid was
dissolved in water and neutralized by 7.5 M NaOH in an ice-
water bath. The organic layer obtained by extracting with CH Cl
2
2
(35 mL x 3). After removal of solvent, (2*,3*)-2-hydroxy-3-[(S)-
(1'-phenyl)]amino-3- substituted phenyl-methyl propionate was
obtained in 85-95% yield as yellow liquid.
layer was separated and dried with MgSO . After removal of sol-
vent, 3-ester-4-(substitutedphenyl)-2-(α-phenylethyl) azetidinone
was obtained as a brown viscous solution.
4
The catalyst was swollen in 20 mL methanol and 8 mL glacial
acetic acid and pre-activated in a hydrogen atmosphere, followed
by addition of the ring-opened products 5a or 5c (6 mL). After
stirring for 8-12 h at room temperature and in hydrogen atmos-
phere, the catalyst and solvent were removed, then water and
CH Cl were added. The resulting mixture was neutralized with
To a 100 mL three-necked flask were added 3 M KOH (13 mL)
and THF (15 mL), then a mixture of 3-ester-4-(substituted-
phenyl)-2-(α-phenylethyl) azetidinone and THF (9 mL) was
added dropwise at -1-3 °C. After stirring for 2.5 h, the pH of the
resulting solution was adjusted to 9 by addition of 30 mL satu-
rated NaHCO , and the organic layer was extracted with ethyl
2
2
3
3 N NaOH under stirring in the ice-water bath. Removal of the
solvent, from the organic layer, affords a light yellow solid.
Recrystallizion with ethyl acetate/isopropyl ether (2/1) gave
white lamellar crystal.
acetate (20 mL x 3) and dried using MgSO . After removal of
solvent, a yellow solid was obtained. The target product and its
isomer were resolved by recrystallization.
4
(3R,4S)-3-Hydroxy-4-(p-chlorophenyl)-2-(α-phenylethyl) aze-
tidinone (4a).
(2R,3S)-Methyl 2-Hydroxy-3-amino-3-phenylpropionate (5a).
20
This compound was obtained in 51.3% yield; [α] = -22
White crystal (1.63 g) was obtained in 50.3% total yield by
D
(C=1.0, MeOH); mp 103-106 °C (lit. [8] mp:106-108 °C);
[α] = -22 (C=1.0, MeOH)]; IR (KBr) 3345, 3293 (N-H), 3065
(O-H), 2912 (C-H), 1742 (C=O), 1604 (C=C), 1214, 1171, 1089
(C-O); H NMR (CDCl , 500MHz): δ 7.20-7.42 ( m, 5H, Ar),
4.35 (d, 1H, CHN/CHOH), 4.33 (d, 1H, CHN/CHOH), 3.80 (s,
3H, OCH ); C NMR (CDCl 125MHz): δ 174.17 (C=O),
142.22, 128.98, 128.13, 127.12 (6C, Ar), 75.28, 58.23, 53.07.
recrystallization in a mixture of ethyl acetate and n-hexane (5:1).
20
20
[α]
+158 (c1.0, MeOH); mp 141-142.5 °C; IR (KBr) 3260,
D
D
-1
1
2991, 2989, 1723 cm ; H NMR (CDCl 500MHz): δ 7.16-7.58
3,
1
(m, 9H, Ar), 5.06 (d, 1H, J=4.3Hz, CHOH), 4.95 (d, 1H,
3
J=4.3Hz, CHN), 4.55 (q, 1H, J=7.17Hz, NCHCH ), 3.51 (bs, 1H,
3
13
13
OH), 1.45 (d, 3H, J=7.17Hz, CHCH ); C NMR (CDCl
3
3,
3
3,
500MHz): β 169.7, 139.7, 134.9, 134.1, 130.4, 129.2, 129.0,
128.5, 127.6, 77.7, 77.5, 62.0, 52.7.
(2S,3R)-Methyl 2-Hydroxy-3-amino-3-phenylpropionate (5c).
Anal. Calcd for C
H NO Cl: C, 67.66; H, 5.34; N, 4.64.
17 16 2
20
This compound was obtained in 46.5% yield; [δ] = +30
Found C, 67.39; H, 5.22; N 4.71.
D
(C=1.0, MeOH); mp 112-114 °C; IR (KBr) 3345, 3293 (N-H),
(3R,4S)-3-Hydroxy-4-(2', 4'-dichlorophenyl)-2-(α-phenylethyl)
azetidinone (4b).
3039 (O-H), 2912 (C-H), 1742 (C=O), 1605 (C=C), 1215, 1171,
1
1089 (C-O); H NMR (CDCl 500MHz): δ 7.28-7.43 (m, 5H,
3,

May-Jun 2005
A Novel Method to Synthesize Docetaxel and its Isomer With High Yields
683
Ar), 4.36 (d, 1H, CHN/CHOH), 4.35 (d, 1H, CHN/CHOH), 3.81
the hydrolysis of the ester group according to literature method [7]
The authors need to put in a detailed procedure for the preparation
here. The reference is not enough. Two crude products, (2*,4S,5R)
N-tert-butoxycarbonyl-2-(4'-methoxy)phenyl-4-phenyl-1,3-oxa-
zolidine-5-formic acid (8a) and (2*,4R,5S) N-tert-butoxycar-
bonyl-2-(4'-methoxy)phenyl-4-phenyl-1,3-oxazolidine-5-formic
acid (8c), were obtained. These crude products can be directly
reacted in the following steps without purification.
13
(s, 3H, OCH ), C NMR (125MHz, CDCl ): δ 174.17 (C=O),
3
3
142.23, 128.99, 128.14, 127.12 (6C, Ar), 75.27, 58.23, 53.08.
Anal. Calcd. for C NO : C, 61.54; H, 6.67; N, 7.18.
H
10 13
3
Found C, 61.83; H, 6.79; N 7.20.
Protection of Amino Group to Synthesis of Compounds 6a and
6c [7,9].
The reaction of the side chain 8a with the parent ring was car-
ried out according to literature procedure [7]. The docetaxel was
obtained and the result was consistent with that in the corre-
sponding reference. The side chain (8c) of the isomer was reacted
with the parent ring in a similar manner to afford the docetaxel
isomer in higher yield.
(2R,3S)-Methyl 2-Hydroxy-3-(N-tert-butoxycarbonyl)amino-3-
phenylpropionate (6a).
20
This compound was obtained in 93% yield; [α] = -7.5
D
20
(C=1.0, CHCl ); mp: 132-133 °C (lit. [7,9] mp: 135 °C); [α]
=
3
D
-7 (C=1.0, CHCl )]; IR (KBr) 3508 (N-H), 3381 (O-H), 2973 (C-
3
H), 1733 (O=COCH ), 1688 (O=CNH), 1518 (N-C), 1249,
3
1
1099.93 (C-O); H NMR (CDCl 500MHz): δ (s, 1H, NH), 3.87
(s, 3H, OCH ), 3.15 (bs, 1H, OH), 1.44 (s, 9H, (CH ) C);
(2*,4S,5R) N-tert-Butoxycarbonyl-2-(4'-methoxy)phenyl-4-
phenyl-1,3-oxazolidine-5-formic Acid (8a).
3,
13
C
3
3 3
NMR (CDCl 125MHz): δ 173.83, 155.21, 139.49, 129.04,
128.16, 127.12, 81.15, 73.92, 56.45, 53.52, 28.66.
3,
This compound has mp 134~138 °C; IR (KBr): 3135 (COO-
H), 2977 (C-H), 1754 (O=COH), 1679 (O=CN); H NMR
1
(DMSO, 500 MHz): δ 11.46 (br, 1H, COOH), 7.38- 6.83 (m, 9H,
Ar), 6.32 (bs, 1H, PhCH/O=CCH), 5.14 (bs, 1H, PhCH/
(2S,3R)-Methyl 2-Hydroxy-3-(N-tert-butoxycarbonyl)amino-3-
phenylpropionate (6c).
O=CCH), 4.69 (bs, 1H, NCHO), 3.75 (bs, 3H, PhOCH ), 0.96 (s,
3
20
This compound was obtained in 91% yield; [α]
= 21
D
13
9H, (CH ) C); C NMR (125 MHz, CDCl ): δ 172.2 (HOC=O),
3 3
3
(C=1.0, CHCl ); mp: 119-121 °C; IR (KBr) 3509 (N-H), 3381
(O-H), 2972 (C-H), 1733 (O=COCH ), 1689 (O=CNH), 1517
(N-C), 1249, 1099 (C-O); H NMR (CDCl 500MHz): δ 7.29-
7.39 (m, 5H, Ar), 5.41(d, 1H, J=9Hz, CHN/CHOH), 5.24 (d, 1H,
3
160.2 (t-BuOC=O), 154.6 (=CHOCH ), 139.2, 132.0, 129.3,
3
3
128.3, 127.6, 121.8, 114.9, (6C, Ar), 91.4, 82.3, 81.2, 63.2, 56.5
1
3,
(ArOCH ), 38.6((CH ) C).
3
3 3
J=9Hz, CHN/CHOH), 4.50 (s, 1H, NH), 3.87 (s, 3H, OCH ),
(2*,4R,5S) N-tert-Butoxycarbonyl-2-(4'-methoxy)phenyl-4-
phenyl-1,3-oxazolidine-5-formic Acid (8c).
3
13
1.44 (s, 9H, (CH ) C); C NMR (CDCl , 125MHz): δ 173.8,
3 3
3
155.5, 139.5, 129.0, 128.2, 127.1, 80.7, 73.9, 56.5, 53.5, 28.7.
Anal. Calcd for C NO : C, 61.02; H, 7.12; N, 4.75. Found
C, 61.27; H, 7.31; N 4.93.
This compound has mp 129~132 °C; IR (KBr): 3134
(COOH), 2977 (C-H), 1753 (O=COH), 1679 (O=CN); H NMR
(DMSO, 500 MHz): δ 11.48 (br, 1H, COOH), 7.37- 6.80 (m, 9H,
Ar), 6.29 (bs, 1H, PhCH/O=CCH), 5.11 (bs, 1H, PhCH/O=CCH),
H
15 21
5
1
Cyclization Protection of Amino and Hydroxy Group [7].
4.70 (bs, 1H,NCHO), 3.73 (bs, 3H, PhOCH ), 0.95 (s, 9H,
3
(2*,4S,5R)-Methyl N-tert-Butoxycarbonyl-2-(4'-methoxy)-
phenyl-4-phenyl-1,3-oxazolidine-5- methionate (7a).
13
(CH ) C); C NMR (CDCl , 125 MHz): δ 172.2 (HOC=O),
3 3
3
160.2 (t-BuOC=O), 154.6 (=CHOCH ), 139.2, 132.0, 129.3,
3
For recrystallization a mixture of ethyl acetate and n-hexane
128.3, 127.6, 121.8, 114.9, (6C, Ar), 91.4, 82.3, 81.2, 63.2, 56.5
20
was used to go give 7a in 94% yield; [α] = -59 (C=1.0,
(ArOCH ), 38.6((CH ) C).
D
3
3 3
CHCl ); mp:100-102 °C (lit. [7] No data); IR (KBr) 2977 (C-H),
3
Protection of 10-DAB 9 (Preparation of 10).
1743 (O=COCH ), 1699 (O=CN), 1613 (C=C), 1245, 1132 (C-
3
1
O); H NMR (DMSO, 500MHz): δ 7.41, 7.32, 6.97 (m, 9H, Ar),
10-DAB (2 mmol, 1.09 g) was dissolved in pyridine (16 ml)
6.34 (bs, 1H, PhCH/O=CCH), 5.22 (bs, 1H, PhCH/O=CCH),
under an N atmosphere, 2,2,2-trichloroethyl chloroformate (6.7
2
4.67 (bs, 1H,NCHO), 3.78 (s, 3H, O=COCH ), 3.55 (bs, 3H,
mmol, 0.85 ml) was added dropwise at temperature of 0 to -3 °C
then place the flask was placed in a water bath at 20 to 30 °C, the
reaction ended with stirring at 25 °C for one hour. The reaction
mixture was then poured into ice (33 g) after cooling by ice-salt
bath, an appropriate quantity of acid was added to neutralize the
pyridine, then the mixture was extracted with dichloromethane (3
x 30 ml), the organic phase was dried with magnesium sulfate
and recrystallized in ethyl acetate to afford pure protected 10-
3
PhOCH ), 0.97 (s, 9H, (CH ) C).
3
3 3
Anal. Calcd for C
H
NO : C, 66.81; H, 6.58; N, 3.39. Found
23 27
6
C, 66.96; H, 6.59; N 3.26.
(2*,4R,5S)-Methyl N-tert-Butoxycarbonyl-2-(4'-methoxy)-
phenyl-4-phenyl-1,3-oxazolidine-5-methionate (7c).
For recrystallization a mixture of toluene and isopropyl ether
20
1
was used to give 7c; mp: 96-98 °C; [α] = 61 (C=1.0, CHCl );
DAB; H NMR (CDCl , 500 MHz): δ 8.13 (d, 2H, J=7.5Hz),
D
3
3
yield: 91%; IR (KBr) 2977 (C-H), 1742 (O=CO), 1699 ( O=CN ),
1613 (C=C), 1245, 1132 (C-O); H NMR (DMSO, 500MHz): δ
7.64 (t, 1H, J=7.5Hz), 7.52 (t, 2H, J=7.5Hz), 6.31 (s, 1H), 5.66 (d,
1H, J=7.5Hz), 5.61 (m, 1H), 5.00 (d, 1H), 4.93 (m, 1H), 4.82 and
4.78 (2d, 2H, J=12Hz), 4.92 and 4.63 (2d, 2H, J=12Hz), 4.35 and
4.18 (2d, 2H, J=9Hz), 4.00 (d, 1H, J=7Hz), 2.65 (m, 1H), 2.33
(m, 2H), 2.33 (s, 3H), 2.19 (s, 3H), 2.10 (m, 1H), 2.05 (m, 1H),
1.87 (s, 3H), 1.18 (s, 3H), 1.15 (s, 3H).
1
7.41, 7.32, 6.97(m, 9H, Ar), 6.34 (bs, 1H, PhCH/O=CCH), 5.22
(bs, 1H, PhCH/O=CCH), 4.67 (bs, 1H, NCHO), 3.78 (s, 3H,
O=COCH ), 3.55 (bs, 3H, PhOCH ), 0.97 (s, 9H, (CH ) C).
3
3
3 3
Anal. Calcd for C
H NO : C, 66.81; H, 6.58; N, 3.39. Found
23 27 6
C, 69.02; H, 6.61; N 3.18.
Connection of Side Chain and Master Ring (Preparation of 11).
Preparation of Docetaxel and its Isomer.
To a 25 ml flask, 10 (0.3 mmol, 0.265 g), 8a or 8c (0.32 mmol,
0.132 g), DCC (0.9 mmol) and DMAP (0.06 mmol) were added
The side chains of docetaxel and its isomer were synthesized by

684
C.-M. Qi, Y.-F. Wang, L.-C. Yang
Vol. 42
consecutively, followed by 3 ml toluene to dissolve the solid , the
reaction was complete after 2 h stirring at room temperature.
The mixture then was washed with water (2 x 2 ml) and dried
with anhydrous magnesium sulfate. The solvent was removed by
distillation under reduced pressure to afford a pale yellow oil that
can be used in the next reaction.
74.8,74.5,73.7,72.4,72.0,57.7, 56.2, 46.5, 43.1, 37.0,35.7,28.2
(3C, t-Bu), 26.5, 22.6, 20.7, 14.4, 9.9.
Isomer of Docetaxel.
(2S,3R)-N-Carboxy-3-phenylisoserine, N-tert-butyl ester, 13-
ester with 5β-20-epoxy-12α,4,7β,10β,13α-hexahydroxytax-11-
en-9-one 4-acetate 2-benzoate was obtained as an eluant from
Deprotection of Acetal (Preparation of 12).
ethyl acetate/petroleum ether (7:10) in 43% yield, mp 169~171
1
Compound 11 (0.3 mmol) PTSA (0.33 mmol) and 15 ml
methanol were added to a 25 ml flask and stirred at 25 °C for 2 h
at which time the reaction is complete. Removal of the solvent by
distillation gave a white solid, which was then dissolved in 10 ml
ethyl acetate, washed with both water and saturated sodium car-
bonate and dried with anhydrous magnesium sulfate. Crude prod-
uct 12 was obtained as yellow oil after distillation of solvent. The
oil was purified by flash chromatography (acetate:petrol ether =
1:3) to give 12 as a white solid.
°C; H NMR (CDCl , 500 MHz): δ 8.08 (d, 2H, J=7.5Hz, Ar),
3
7.64 (t, 1H, J=7.5Hz, Ar), 7.50 (t, 2H, J=7.5Hz, Ar), 7.28-7.44
(m, 5H, Ar), 6.24 (m, 1H), 5.70 (d, 1H, J=7Hz), 5.40 (d, 1H,
J=9Hz), 5.28 (s, 1H), 5.27 (br d, 1H), 5.00 (d, 1H, J=9Hz), 4.51
(bs, 1H), 4.33 and 4.20 (2d, 2H, J=8.5Hz), 4.30 (dd, 1H), 3.99 (d,
1H, J=7Hz), 3.40 (bs, 1H), 2.65 (m, 1H), 2.29 (s, 3H), 2.07 (s,
3H), 1.88 (m, 1H), 1.79 (s, 3H), 1.42 (s, 9H, C(CH ) ), 1.27 (s,
3 3
13
3H), 1.16 (s, 3H); C NMR (125NHz, DMSO): δ 211.5 (C=O),
173.0, 170.2 (C=O), 166.5, 155.6 (C=O), 141.1, 138.0, 137.3,
134.1, 130.5, 130.1, 129.2, 129.1, 128.4 (13C of Cl-Ph, Bz and
C=C), 84.8, 81.6, 79.1, 77.0, 76.5, 75.2, 71.9, 58.0, 57.2, 47.8,
47.1, 43.5, 34.5, 28.9 (3C, t-Bu), 27.4, 25.2, 21.5, 14.8, 10.2;
Deprotection of Hydroxyl (Preparation of Docetaxel and Isomer
of Docetaxel).
+
First, the zinc granules were treated with dilute hydrochloric
acid, washed with methanol and dried for further use. Then, com-
pound 17 (0.3 mmol) was dissolved in 2 ml methanol followed
by addition of 0.5 ml acetic acid and three grains of the granu-
lated zinc. The reaction was allowed to proceed at 65 °C for
about 1.5 h. The reaction mixture was filtered to remove the zinc
and solid that had formed and the crude product, which was
obtained after removal of solvent by distillation, was purified by
flash chromatography (elute: acetate:petrol ether = 1:1) to afford
a white solid in 59% overall yield.
MS(m/z,%): 807(M , 37).
Acknowledgments.
We thank the National Natural Science Foundation of China
(Project 20171008 and 20371009) for the financial support.
REFERENCES AND NOTES
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[5] I. Ojima, S. Lin and S. Chakravarty, J. Org. Chem., 63, 1637
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1957 (1990).
Docetaxel.
This compound has mp 174~177 °C; IR (KBr): 3434.8 (OH-
1
and NH ), 2978.2 and 2933.5 (C-H), 1713.3 (O=C), 1245.6; H
2
NMR (CDCl , 500 MHz): δ 8.12 (d, 2H, J=7.5Hz, Ar), 7.64 (t,
3
1H, J=7.5Hz, Ar), 7.52 (t, 2H, J=7.5Hz, Ar), 7.43-7.39 (m, 4H,
Ar), 7.35-7.34 (m, 1H, Ar), 6.23 (m, 1H), 5.69 (d, 1H, J=7Hz),
5.49 (br d, 1H), 5.29 (br d, 1H), 5.24 (s, 1H), 4.96 (d, 1H
J=9.3Hz), 4.64 (br, 1H), 4.33 and 4.20 (dd, 2H, J=8.5Hz), 4.25
(dd, 1H), 3.93 (d, 1H, J=7Hz), 3.45 (bs, 1H), 2.63-2.56 (m, 1H),
2.40 (s, 3H), 1.89 (s, 3H), 1.86 (m, 1H), 1.77 (s, 3H), 1.36 (s, 9H,
13
C(CH ) ), 1.30 (s, 3H),1.15(s, 3H); C NMR (125 MHz,
3 3
DMSO): δ 211.4 (C=O), 172.8,170.3 (C=O), 167.1, 155.4
(C=O), 138.5, 135.9, 133.7, 130.2, 129.2, 128.8, 128.7, 128.1,
126.8 (13C of Cl-Ph, Bz and C=C), 84.2, 81.1, 78.8,