A facile and scaleable synthesis of 3-O-decladinose-6-methyl-10,11- dehydrate-erythromycin-3-one-2′-acetate, an important intermediate for ketolide synthesis

Article abstract of DOI:10.1021/op060001x

A facile and scaleable synthetic process of compound 2, an important intermediate for synthesis of ketolide semisynthetic antibiotics, was developed starting from commercially available clathromycin with an overall yield of ～74%. This synthetic pathway wa

Full text of DOI:10.1021/op060001x

Organic Process Research & Development 2006, 10, 446−449
A Facile and Scaleable Synthesis of
3
-O-Decladinose-6-methyl-10,11-dehydrate-erythromycin-3-one-2′-acetate, an
Important Intermediate for Ketolide Synthesis
Xin Wei and Qidong You*
Department of Medicinal Chemistry, China Pharmaceutical UniVersity,Nanjing, Jiangsu 210009, PR, China
Abstract:
Scheme 1
A facile and scaleable synthetic process of compound 2, an
important intermediate for synthesis of ketolide semisynthetic
antibiotics, was developed starting from commercially available
clathromycin with an overall yield of ∼74%. This synthetic
pathway was composed of four steps from compound 3 which
could be prepared from clathromycin without using expensive
reagents such as EDC‚HCl (1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride) or more active reagents such as
methanesulfonic anhydride. This new process was efficient and
practical as demonstrated by scale-up to prepare more than 1
kg of pure compound 2.
Introduction
Ketolides, such as telithromycin (1), were called the third
generation of semisynthetic macrolide derivatives with
excellent activity against susceptible and resistant strains to
erythromycin in vitro and in vivo.
to the carbonyl group, and dehydration of the 11-hydroxy
group to produce a double bond at the 10,11-position
(Scheme 1).
In this strategy for synthesizing 2, the oxidation of the
3
-hydroxy group should be carried out with a selective
oxidizing agent since there are another two hydroxy groups
at the 11 and 12 positions at the same time. Another problem
in this strategy was the dehydration of the 11-hydroxy group
to form the 10,11-double bond. The hydroxy group on the
1
1-position was inactive for dehydration and should be
converted to ester (such as mesylate), an easily leaving group,
to increase its dehydration ability. In this paper, we describe
the successful development of a practical and scaleable
process for the synthesis of 2.
Results and Discussion
It was reported that compound 2 was usually synthesized3
from clathromycin as starting material through decladinose
on the 3-position to form the 3-hydroxy group, selective
oxidation of the 3-hydroxy group to the carbonyl group by
EDC‚HCl/DMSO, selective methanesulfonylation of the 11-
hydroxy group by the active reagent methanesulfonic anhy-
dride, and then formation of the double bond on the 10,11-
positions by removing the formed methanesulfonic acid ester
group in the presence of DBU (1,5-diazabicyclo[5,4,0]-
undecen-5-ene) (Scheme 2).
-6
These new compounds were generated from erythromycin,
in which the cladinosyl-sugar moiety at the 3-position was
changed to a carbonyl group. Telithromycin was approved
for marketing in Germany and the UK in 2001. In the
preparation of ketolides, compound 2, 10,11-didehydro-11-
deoxy-3-O-de-[(2,6-dideoxy-3-methyl-3-O-methyl-R-L-ribo-
hexopyranosyl)oxy]-6-O-methyl-3-oxoerythromycin-2′-ac-
etate, is an important intermediate.1
-2
The strategy of most synthetic pathways to 2 in the
literature was composed of decladinose on the 3-position to
form the 3-hydroxy group, oxidation of the 3-hydroxy group
(
3) Agouridas, C.; Denis, A.; Auger, J., et al. J. Med. Chem. 1998, 41, 4080-
100.
4) Jean-Francois, C. (FR); Alain, B. (FR). EP0596802, 1994-05-11.
4
(
*
To whom correspondence should be addressed. E-mail: youqd@cpu.edu.cn.
(5) Jean-Francois, C. (FR); Alain, B.; Alexis, D. (FR); Constantin, A. (FR);
Odile L M (FR). US5527780, 1996-06-18.
(6) Toshifumi, A. (JP); Katsuo, H. (JP); Shigeo, M. (JP); Masato, K. (JP).
WO9209614, 1992-06-11.
(
(
1) Jerome, L.; Klein, O. Pediatr Infect Dis. 2000, 20(4), 427-432.
2) Hartinez-Martinez, L,; Pascual, A.; Suarez, A. et al. Antimicrob Agents
Chemother. 1998, 42(12), 3290-3298.
4
46
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10.1021/op060001x CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/22/2006

Scheme 2
Figure 1. The crystal structure of 4′′.
UV absorption. The m/z 594 molecular ion was less 36 mass
units than the expected product 4.
The reason the byproduct 4′ was produced in this step
was that EDC‚HCl, a strong dehydration agent, removed a
2
mole of H O to form 10,11-olifen in the presence of
pyridinum trifluroacetate, and then the hydroxyl group on
the 12-position was activated to attack the carbonyl group
on the 9-position to afford 9,12-hemiacetal.The byproduct
Scheme 3
4
′ was treated by methanol to form 4′′ (Scheme 3). The
structure of 4′′ was determined by X-ray analysis in Figure
7
1
. The stereochemistry for double bond at C10 and C11
was determined as Z-configuration by X-ray crystallography.
In the oxidation step by EDC‚HCl and DMSO system,
the next problem was the purification of the products 4. The
byproduct 4′ could only be removed by silica column
chromatography, which increased the costs and limited the
output of the products. This uneconomic and inconvenient
handling process was less useful for pharmaceutical industry.
In the above procedure, the selection of EDC‚HCl and
DMSO as oxidation reagents and the generation of the
byproduct 4′ was contributed to by the presence of two
hydroxyl groups on the 11,12-positions in the structure of
3
. To avoid using the expensive selective oxidation reagent
EDC‚HCl and producing the byproduct 4′, we considered
protecting the two hydroxyl groups on the 11,12-positions
of 3. The protective groups should be special to the two
hydroxyl groups on the 11,12-positions and should be easily
removed after the oxidation of the hydroxyl group on the
3
-position. After trying more methods, we found that the
carbonate group was a suitable protecting group for the two
hydroxyl groups on 11,12-positions of 3. According to the
idea, we designed a novel synthetic process for preparation
of the important intermediate 2 for semisynthetic ketolide
antibiotics (Scheme 4).
In this process, the selective oxidation of the 3-hydroxy
group to the 3-ketone group was very important because there
are three hydroxyl groups in compound 3. This selective
oxidation was performed by the EDC‚HCl and DMSO
system. A large quantity of the expensive reagent EDC‚HCl
was used for this oxidation. This reagent was not only
expensive but also difficult to obtain on commercial scale.
However, during the oxidation of 3 to prepare 4 as described
In this process, the 3 was first treated by BTC (bis-
(
1
trichloromethanol)carbonate), “Triphosgene”, to produce
1,12-carbonate 6. Now 6 only had a free 3-hydroxyl group
8
which could be oxidized by common oxidation agents. In
practice, most of the oxidation reagents, such as the NCS,
3
-6
in the literature,
we found the yield of oxidation was
variable. In this procedure, we always got an unexpected
byproduct 4′ in addition to the desired product 4. This new
compound 4′ had a molecular ion at m/z 594 with strong
(
7) Zhao,Y.; You, Q.; Shen, W. Bioorganic & Medicinal Chemistry Lett.. 2003,
13, 10, 1805-1807.
(8) George, B. E.; Eric, H.; Keith, F. A. US 4921839, 1990-03-01.
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447

Scheme 4
performed on a JASCO PU-2080 plus system using a HiQsil
C18W column(4.6 mm × 150 mm, 5 µm) run at a flow rate
3 2
of 1.0 mL/min with CH OH and H O (80:20), and was
detected at UV 254 nm. All chemicals and reagents were
purchased and used without further purification unless
otherwise mentioned.
3
-O-De-[(2,6-dideoxy-3-methyl-3-O-methyl-r-L-ribo-
hexopyranosyl)oxy]-6-O-methyl-cyclic 11,12-carbonate-
erythromycin 2′-acetate (6). To a stirred solution of 3-O-
de-[(2,6-dideoxy-3-methyl-3-O-methyl-R-L-ribohexopyran-
3
osyl)oxy]-6-O-methylerythromycin 2′-acetate 3 (200 g, 317
mmol) and dry pyridine (140 mL) in dry methylene chloride
(1500 mL) at 0 °C was added dropwise a solution of bis-
(trichloromethanol)carbonate (BTC) (66.7 g, 224.7 mmol)
of dry methylene chloride (800 mL). The mixture was stirred
for about 23 h at room temperature and then cooled to 0 °C.
The mixture was poured into a saturated solution of sodium
chloride (2000 mL) and extracted with methylene chloride
PCC, and so on, used in organic synthesis, could be used
for oxidation of 6 to produce 7. The yield of the oxidation
step was very high without any byproducts. The experimental
handling for preparing 7 from 6 was more convenient by
simple treatment. After getting 7 with the 3-carbonyl group,
the next step was to introduce the C-C double bond at the
(
8
3 × 1000 mL); the extracts were washed with water (3 ×
00 mL) and dried over MgSO . Evaporation of the solution
4
afforded 198 g (95.1%) of crude 6 as a light-yellow foam,
its purity is enough for the next step synthesis.
Compound 6 was purified by column chromatography
eluting with 10:4:1 petroleum ether(60-90 °C)/acetone/
triethylamine as a white solid for structure analysis, mp 92-
10,11-positions. From the view of organic synthesis, it was
important to change the 11-hydroxyl group to an easily
leaving group which could be eliminated in the presence of
bases to form a C-C double bond. In the original literature,
the 11-hydroxyl group of 4 was converted to 11-methylsul-
fonate. The methylsulfonate, a more active group, could bring
more complex reaction results. In our procedure, the 11,12-
carbonate group of 7 was also a moderately active leaving
9
3 °C, purity: 98.885% (HPLC). IR (KBr) 3540, 1814, 1741,
-
1 1
1
715 cm . H NMR (300 MHz, CDCl3£): δ 0.91(t, J ) 7
CH ), 1.13 (s, 3H, 6-CH ), 1.24 (s, 3H, 12-
), 2.09 (s, 3H, 2′-OCOCH ), 2.26 (s, 6H, N(CH ), 2.47-
q, J ) 7 Hz, 1H,10-CH), 2.97 (s, 3H, 6-O-CH ), 3.49 (m,
H, 3-CH and 5′-CH), 3.87 (q, J ) 6.5 Hz, 1H, 2-CH), 4.20
Hz, 3H, CH
CH
3
2
3
3
3
3
3 2
)
group which was treated by DBU to form a C-C double
(
2
3
bond on the 10,11-positions to produce the desired product
2
without being further purified by column chromatography
(d, J ) 9 Hz, 1H, 5-CH), 4.42 (d, J ) 7 Hz, 1H, 11-CH),
(Scheme 4). This new procedure for the preparation of 2
4
.62 (dd, J ) 2 and 10 Hz, 1H, 13-CH). 4.88 (dd, J ) 8 and
from clathromycin was more efficient and economical since
it avoided the use of the expensive and uncommon oxidation
agent EDC‚HCl and the more active reagent methanesulfonic
anhydride.
1
0 Hz, 1H, 2′-CH), 5.12(d, J ) 7.5 Hz, 1H, 1′-CH). MS
+
(ESI) m/e: 658 (M + H)
3
-O-De-[(2,6-dideoxy-3-methyl-3-O-methyl-R-D-ribo-
hexopyranosyl)oxy]-6-O-methyl-3-oxo-cyclic 11,12-car-
bonate-erythromycin 2′-acetate (7). Method I. To a stirred
solution of N-chlorosuccinimide (60 g, 450 mmol) in dry
methylene chloride (1000 mL) at 0 °C, was added dropwise
methyl sulfide (44.8 mL, 746 mmol). A white precipitate
appeared immediately. The mixture was cooled to -5 °C,
and a solution of crude 6 (196 g, 298.4 mmol) in dry
methylene chloride (1000 mL) was added dropwise over 30
min. Stirring was continued for 3 h at -5 °C before a solution
of triethylamine(44.7 g, 440 mmol) was added dropwise over
In summary, we have developed a practical and scaleable
process for the synthesis of 2 from commercially available
materials. A simple isolation and purification procedure was
used in the large-scale preparation of the product without
column chromatography. The efficiency and practicality of
the process were demonstrated by the synthesis of more than
1
kg of pure 2 with an overall ∼74% yield.
Experimental Section
1
General Remarks. H NMR spectra were recorded on a
2
0 min. After warming to room temperature, the organic
ACF-300 Bruker instrument. The electrospray ionization
(
2
ESI) mass spectra were obtained using a Finnigan FTMS-
000 spectrometer. IR spectra were obtained using a Nicolet
layer was washed with 1% hydrochloric acid (700 mL), and
water (2 × 700 mL) and dried over anhydrous magnesium
sulfate. Evaporation of the solvent afforded 183.6 g (94%)
of the crude 7 as a yellow foam, its purity is enough for the
next step synthesis.
The compound 7 was purified by column chromatography
eluting with 10:4:1 petroleum ether (60-90 °C)/acetone/
triethylamine as a white solid for structure analysis, mp105-
106 °C, purity: 98.844% (HPLC).
Impact 410 (KBr) spectrometer. All melting points were
measured on a MEL-TEMP Π apparatus and are uncorrected.
HPLC analyses for 6 and 7 were performed on a Shimadzu
LC-10A system using a Shimadzu VP-ODS column(4.6 mm
×
150 mm, 5 µm) run at a flow rate of 1.0 mL/min with
CH CN and buffer A (0.008 mol/L CH COONH in H O)
40:60) with Evaporative Light Scattering Detector (Polymer
Laboratories PL-ELS2100, evaporator: 110 °C, nebuliser:
5 °C, gas flow: 2.1 L/min). Analytical HPLC for 2 was
3
3
4
2
(
Method II. To a stirred solution of crude 6 (196 g, 298.4
mmol) in dry methylene chloride (2000 mL), was added PCC
4
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(
396 g, 1835.4 mmol) at room temperature. The mixture was
J ) 6.5 Hz, 1H, 2-CH), 4.21 (d, J ) 9 Hz, 1H, 5-CH), 4.42
(d, J ) 7 Hz, 1H, 11-CH), 4.63 (dd, J ) 2 and 10 Hz, 1H,
13-CH). 4.89 (dd, J ) 8 and 10 Hz, 1H, 2′-CH), 5.13 (d, J
stirred for 24 h at 30 °C. The brown precipitate formed was
filtered off and washed with methylene chloride (3 × 400
mL). The organic layer was washed with a saturated solution
of sodium bicarbonate (4 × 800 mL) and water (600 mL)
+
) 7.5 Hz, 1H, 1′-CH). MS (ESI) m/e 656 (M + H) .
10,11-Didehydro-11-deoxy-3-O-de-[(2,6-dideoxy-3-meth-
yl-3-O-methyl-r-L-ribohexopyranosyl)oxy]-6-O-methyl-3-
oxo-erythromycin-2′-acetate (2). To a stirred solution of
crude 7 (180 g, 274.8 mmol) in acetone (2000 mL), was
added DBU (104 mL, 685.4 mmol). The mixture was
refluxed for 14 h and then cooled to room temperature. After
evaporation of the acetone, the residue was dissolved in
methylene chloride (1000 mL), washed with saturated
solution of sodium chloride (5 × 300 mL), and dried over
anhydrous magnesium sulfate. After evaporation of the
solution, a crude product was afforded as a light-yellow foam.
The crude product was added to ethyl acetate (300 mL) and
then stirred for 30 min. The white solid that formed was
separated by suction filtration, washed with cold ethyl acetate
(2 × 50 mL), and dried under vacuum to give 136 g (81%)
pure 2 as white solid, mp 218-219 °C, purity: 98.397%
4
and was dried over MgSO . After evaporation of the solvent
to afford 186.7 g (95.6%) of the crude 7 as a yellow foam,
its purity was enough for the next step synthesis.
Method III. To a stirred solution of crude 6 (98 g,149.2
mmol) in dry methylene chloride (2000 mL) was added PDC
(
345 g, 917.7 mmol) at room temperature, and the mixture
was stirred for 55 h. The brown precipitate that formed was
filtered off and washed with methylene chloride (2 × 200
mL). The organic layer was washed with a saturated solution
of sodium bicarbonate (4 × 500 mL) and water (400 mL)
4
and was dried over MgSO . Evaporation of the solvent
afforded 82.8 g (84.8%) of the crude 7 as a yellow foam, its
purity was enough for the next step synthesis.
Method IV. To a stirred solution of oxalyl chloride (22
g,173 mmol) in dry methylene chloride (400 mL) at -78
°
-
1 1
C was added dropwise the solution of DMSO (27 g, 345.7
(HPLC). IR (KBr) 1747, 1713, 1670 cm . H NMR (300
MHz, CDCl3£): δ 0.89 (t, J ) 7 Hz, 3H, CH CH ), 1.24 (s,
3H, 12-CH ), 1.45 (s, 3H, 6-CH ), 2.03 (s, 3H, 10-CH ), 2.10
(s, 3H, 2′-OCOCH ), 2.27 (s, 6H, N(CH ), 2.91 (s, 3H,
6-O-CH ), 3.49 (m, 2H, 3-CH and 5′-CH), 3.85 (q, J ) 6.5
mmol) in dry methylene chloride (100 mL) over 10 min.
Then a solution of 6 (75.6 g,115 mmol) in dry methylene
chloride (1000 mL) was added to this solution over 50 min.
The mixture was then stirred for 2 h at -60 °C before a
solution of triethylamine (67.8 g, 667 mmol) was added
dropwise over 20 min. After warming to room temperature,
the organic layer was washed with 1% hydrochloric acid (700
mL), a saturated solution of sodium bicarbonate (2 × 500
mL) and water ( 3× 700 mL) and was dried over anhydrous
magnesium sulfate. Evaporation of the solvent afforded 50.7
g (67.4%) of the crude 7 as a yellow foam, its purity was
enough for the next step synthesis.
3
2
3
3
3
3
3 2
)
3
Hz, 1H, 2-CH), 4.23 (d, J ) 9 Hz, 1H, 5-CH), 4.87 (dd, J
) 8 and 10 Hz, 1H, 2′-CH), 4.98 (dd, J ) 2 and 10 Hz, 1H,
13-CH), 5.04 (s, 1H, 12-OH), 5.13 (d, J ) 7.5 Hz, 1H, 1′-
CH), 6.68 (s, 1H, 11-CH).
+
MS (ESI) m/e 612 (M + H)
Acknowledgment
We thank Jiangsu Hengrui Pharmaceutical Company for
financial support.
-
1
1
IR (KBr) 1812,1748,1713 cm . H NMR (300 MHz,
CDCl3£): δ 0.92 (t, J ) 7 Hz, 3H, CH CH ), 1.15 (s, 3H,
), 2.11 (s, 3H, 2′-OCOCH ),
), 2.48 (q, J ) 7 Hz, 1H, 10-CH), 2.92
), 3.47 (m, 2H, 3-CH and 5′-CH), 3.85 (q,
3
2
6
2
-CH
3
), 1.27 (s, 3H, 12-CH
3
3
Received for review January 3, 2006.
OP060001X
.27(s, 6H, N(CH )
3 2
(s, 3H, 6-O-CH
3
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