Novel synthesis of telithromycin

Article abstract of DOI:10.3184/174751913X13574995608294

A novel synthesis route for telithromycin was developed based on a 11,12-cylic carbonate protection strategy to prevent formation of 9,12-hemiacetal by-product. Through a 11,12-carbonate-6-O-methylerythromycin intermediate, telithromycin was synthesised from 6-O-methylerythromycin in five steps with 33% overall yield.

Full text of DOI:10.3184/174751913X13574995608294

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 107
FEBRUARY, 107–109
Novel synthesis of telithromycin
Zhiling Caoa*, Bing Liua, Weiwei Liua, Guowei Yaob, Wenjie Liua and Qianqian Wanga
aSchool of Chemical Engineering, Jiangsu Key Laboratory of Marine Biotechnology, Huaihai Institute ofTechnology, Lianyungang 222005,
P. R. China
bSchool of Life Science, Beijing Institute ofTechnology, Beijing 100081, P. R. China
A novel synthesis route for telithromycin was developed based on a 11,12-cylic carbonate protection strategy to
prevent formation of 9,12-hemiacetal by-product. Through a 11,12-carbonate-6-O-methylerythromycin intermediate,
telithromycin was synthesised from 6-O-methylerythromycin in five steps with 33% overall yield.
Keywords: telithromycin, ketolide, 11,12-carbonate-6-O-methylerythromycin, synthesis
Erythromycin, the typical macrolide, was discovered in early
1952. Since then, macrolide antibiotics demonstrated broad
spectrum antimicrobial activity and were used primarily for
the treatment of penicillin-resistant sreptococcus pneumoniae
infections.1 However, resistance to macrolides such as erythro-
mycin, azithromycin and clathromycin has been frequently
observed in the past 20 year.2 In the progress of searching
for new antimicrobial agents, ketolides were developed as a
new major class of semisynthetic erythromycin derivatives.
Ketolides are characterised by the displacement of cladinose
attached to the macrolide ring of 6-O-methylerythromycin ring
at C-3 position with a ketone moiety.3 Telithromycin (1) is the
first ketolide introduced into clinical practice in later 2001 and
has shown good activity against macrolide-resistant bacteria.4
Telithromycin has a C-11, C-12 carbamate group on which
a pyridinyl imidazole moiety is attached through a propyl
chain.
cyclic carbonate. We also report the mild and efficient oxida-
tion of the C-3 hydroxyl group to a ketone with DMSO–P2O5
system.
Results and discussion
6-O-Methylerythromycin has four free hydroxyl groups. The
C-2′ and C-4″ hydroxyl group are more reactive and could be
selectively acetylated with 4-(N,N-dimethylamino)pyridine
(DMAP) catalysis. As shown in Scheme 2, treatment of 3 with
triphosgene (BTC) at 0 °C afforded the cyclic carbonate 4 in
high yield and purity. Then selective hydrolysis of cladinose
sugar with a mixture of 1.0 M HCl/EtOH gave des-cladinose
compound 5. The C-3 hydroxyl was subsequently oxidised
with DMSO activated by P2O5 (according to Taber)12 to ketone.
The ketolide intermediate 6 was obtained in 75% yield from
carbonate 4. No hemiacetal by-products were observed in
above hydrolysis and oxidation steps.
In the previous synthesis of telithromycin, ketone moiety
was introduced at C-3 position of 6-O-methylerythromycin (2,
clarythromycin) via acid hydrolysis of the cladinose sugar and
oxidation of the C-3 hydroxyl group under Pfizner–Moffat
conditions.5–7 This procedure was problematic and resulted in
low yields mainly because of the hemiacetalisation side reac-
tion between the C-12 hydroxyl group and the C-9 ketone
group. The acidic environment easily induced the intramolecu-
lar hemiacetalisation to form stable 9,12-hemiacetal by-
products (Scheme 1).8–9 An alternative method for synthesis
of telithromycin was achieved by introduction of a cyclic
carbamate at C-11, C-12 before hydrolysis of cladinose sugar
and oxidation of the C-3 hydroxyl group.10 However, this
carbamate ring which carries side chain is not stable to acid
treatment and the synthetic route is not convergent. Velvadapu
et al. recently reported the total synthesis of (−)-4,8,10-trides-
methyl telithromycin in 42 steps.11
Synthesis of the 10,11-anhydro-12-O-imidazolyl carbonyl
derivative 7 was a two-step, one-pot sequence proceeding in
75% yield. The carbonate 6 was firstly decomposed to a enone
intermediate through β-elimination in the presence of sodium
bis(trimethylsilyl)amide (NaHDMS). Subsequent treatment of
the γ-hydroxy enone with excess carbonyl diimidazole (CDI)
and NaHDMS in THF afforded the 12-O-acyl imidazolide 7.
Finally, reaction of compound 7 with the pyridinyl imidazole
side chain in 95% aq. CH3CN gave telithromycin, and this
method was similar to the procedure of Baker and co-workers
which involved an intramolecular aza-Michael addition.13
In summary, we have developed a new procedure for the
efficient synthesis of telithromycin (1) from 6-O-methyleryth-
romycin in 33% yield over five steps. The present method
could efficiently prevent the formation of the 9,12-hemiacetal
by-product by using a cyclic carbonate as a protecting group
for the C-11, 12-diol moiety. DMSO activated with P2O5
was found to be a mild and convenient reagent for efficiently
oxidation of the C-3 hydroxy of 6-O-methylerythromycin.
Reaction of the C-9 ketone group with the C-12 hydroxyl
was critical for the formation of 9,12-hemiacetal derivates of
6-O-methylerythromycin. We now describe the strategy devel-
oped for the synthesis of telithromycin involving protection
of the C-11,12-diol moiety of 6-O-methylerythromycin as a
Experimental
All melting points were taken in open capillary tubes and are uncor-
rected. IR spectra were recorded with a Bruker TENSOR 27 FT-IR
spectrometer. NMR spectra were obtained on a Bruker Avance
300 MHz spectrometer in CDCl3, and tetramethylsilane (TMS) was
used as the internal standard. Electrospray ionisation mass (ESI-MS)
spectra were performed on an Agilent 1100 series mass spectrometer.
Elemental microanalysis was performed using a Perkin Elmer 2400
analyser. Column chromatography was carried out using silica gel
(200–300 mesh). 4-[4-(3-Pyridinyl)imidazol-1-yl]-1-butylamine was
prepared following the procedure previously described.14
2′,4″-Di-O-acetyl-6-O-methylerythromycin (3): To a solution of 2
(12.0 g, 16 mmol) in CH2Cl2 (60 mL) was added acetic anhydride
(3.7 g, 36 mmol). The mixture was stirred for 6 h at room temperature.
The result solution was washed with saturated NaHCO3 solution,
water and brine, dried, and evaporated to gave 4 (12.2 g, 91%), white
solid, m.p. 239–241 °C. IR (KBr)(vmax, cm−1): 3386, 2974, 1748, 1578,
1425, 1166, 991; 1H NMR δ: 5.08 (dd, J = 10.9, 2.0 Hz, 1H), 5.00 (d,
Scheme 1
* Correspondent. E-mail: zhilingcao@yahoo.com.cn

108 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 2
J = 4.9 Hz, 1H), 4.82–4.64 (m, 3H), 4.32 (dq, J = 12.1, 6.0 Hz, 1H),
3.99 (s, 1H), 3.82–3.67 (m, 3H), 3.62 (d, J = 6.4 Hz, 1H), 3.36 (s, 3H),
3.21 (s, 1H), 3.03 (s, 3H), 2.88 (dd, J = 16.4, 7.2 Hz, 1H), 2.81–2.65
(m, 1H), 2.57 (dt, J = 17.2, 8.8 Hz, 1H), 2.42 (d, J = 15.1 Hz, 1H), 2.29
(s, 6H), 2.11 (s, 3H), 2.06 (s, 3H), 2.00–1.82 (m, 2H), 1.68 (s, 3H),
1.76–1.40 (m, 3H), 1.37 (s, 3H), 1.32–1.04 (m, 22H), 0.96 (d, J =
7.6 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR δ: 220.7, 175.1, 170.0,
169.6, 99.6, 95.4, 79.8, 78.2, 77.9, 77.3, 73.8, 72.3, 71.6, 68.8, 66.9,
62.8, 62.7, 50.1, 48.9, 44.8, 44.5, 40.3, 38.3, 38.2, 36.8, 34.8, 30.8,
21.2, 20.7, 20.7, 20.5, 19.3, 17.9, 17.5, 15.7, 15.5, 11.9, 10.1, 8.6; MS
(ESI) m/z, (%): 832 (M+ + H, 100); Anal. Calcd for C42H73NO15: C,
60.63; H, 8.84; N, 1.68. Found: C, 60.51; H, 8.63; N, 1.73%.
2′,4″-Di-O-acetyl-11,12-carbonate-6-O-methylerythromycin (4): A
stirred solution of 3 (10 g, 12 mmol) in CH2Cl2 (40 mL) containing
anhydrous pyridine (5.7 g, 72 mmol) was cooled to –5 °C, and a solu-
tion of triphosgene (3.6 g, 12 mmol) in CH2Cl2 (30 mL) was added
dropwise during 30 min. The mixture was stirred at 0 °C for 8 h or
until complete consumption of starting material was observed, then
excess of triphosgene was destroyed by the slow addition of ice water
(20 mL). The water layer of the reaction mixture was separated, and
the organic layer was washed with brine, dried, and evaporated. The
residue was purified by column chromatography on silica gel using
(ethyl acetate–hexane 1:2) to give 3 (9.2 g, 89%), m.p. 240–242 °C. IR
(KBr)(vmax, cm−1): 3476, 2977, 2836, 1746, 1734, 1578, 1445, 1169,

JOURNAL OF CHEMICAL RESEARCH 2013 109
1056; 1H NMR δ: 5.01 (dd, J = 10.4, 2.4 Hz, 1H), 4.94 (d, J = 4.8 Hz,
1H), 4.77–4.61 (m, 3H), 4.58 (s, 1H), 4.28 (dq, J = 12.3, 6.1 Hz, 1H),
3.76 (d, J = 8.5 Hz, 1H), 3.68 (dd, J = 9.4, 5.9 Hz, 1H), 3.54 (d, J =
6.8 Hz, 1H), 3.33 (s, 3H), 2.96 (s, 3H), 2.94–2.54 (m, 5H), 2.39 (d,
J = 15.2 Hz, 1H), 2.26 (s, 5H), 2.09 (s, 3H), 2.03 (s, 3H), 1.93–1.50
(m, 7H), 1.47 (s, 2H), 1.34 (s, 3H), 1.28–1.03 (m, 19H), 0.92 (d,
J = 7.5 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR δ: 212.5, 175.9,
170.0, 169.5, 153.6, 99.7, 95.2, 84.5, 80.3, 79.2, 78.2, 78.1, 76.7, 76.7,
76.2, 75., 72.3, 71.5, 67.1, 62.7, 49.8, 49.0., 44.8, 44.0, 40.3, 39.1,
38.3, 37.4, 34.7, 30.8, 21.6, 21.2, 21.1, 20.7, 20.5, 19.6, 17.8, 17.7,
15.2, 12.8, 12.3, 9.8, 8.5; MS (ESI) m/z, (%): 858 (M+ + H, 100);Anal.
Calcd for C43H71NO16: C, 60.19; H, 8.34; N, 1.63. Found: C, 60.07; H,
8.47; N, 1.60%.
2′-O-Acetate-3-O-descladinosyl-3-hydroxy-11,12-carbonate-6-O-
methylerythromycin (5): To a suspension of 4 (9.5 g, 11.1 mmol) in
ethanol (50 mL) was added aqueous 1 M HCl (100 mL). The mixture
was stirred at room temperature for 6 h and neutralised with concen-
trated ammonium hydroxide. The precipitate was collected, washed
with ice-cold water, and dried to obtain 5 (7.3 g, 90%), m.p. 77–80 °C.
IR (KBr)(vmax, cm−1): 3396, 2977, 1815, 1740, 1670, 1145, 1166, 995;
1H NMR δ: 5.11 (dd, J = 10.8, 2.2 Hz 1H), 4.77–4.73 (m, 1H), 4.75 (s,
1H), 4.63 (d, J = 7.6 Hz, 1H), 3.73 (d, J = 2.3 Hz, 1H), 3.50–3.47 (m,
2H), 2.98–2.95 (m, 1H), 2.92 (s, 3H), 2.77–2.70 (m, 2H), 2.60–2.55
(m, 1H), 2.26 (s, 6H), 2.07 (s, 3H), 1.95–1.80 (m, 2H), 1.90–1.70 (m,
2H), 1.69–1.56 (m, 3H), 1.54 (s, 3H), 1.40–1.25 (m, 7H), 1.23 (d,
J = 6.0 Hz, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.11 (d, J = 7.1 Hz, 3H), 0.95
(d, J = 7.4 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR δ: 212.4, 175.1,
169.9, 154.1, 99.7, 84.9, 81.0, 80.8, 78.0, 74.9, 71.4, 68.7, 63.0, 49.4,
45.2, 44.1, 40.6, 38.4, 37.3, 35.9, 30.9, 22.0, 21.4, 21.0, 19.2, 18.3,
15.3, 12.88, 12.76, 10.00, 7.75; MS (ESI) m/z, (%): 658 (M+ + H,
100); Anal. Calcd for C33H55NO12: C, 60.26; H, 8.43; N, 2.13. Found:
60.09; H, 8.58; 2.14%.
2′-O-Acetate-3-O-descladinosyl-3-keto-11,12-carbonate-6-O-
methylerythromycin (6): A stirred solution of 5 (12.3 g, 18.7 mmol) in
CH2Cl2 (50 mL) containing DMSO (10 mL) was cooled to 0~5 °C and
P2O5 (5.3 g, 37.4 mmol) was added. The reaction mixture was stirred
at room temperature for 4 h, triethylamine (6.6 g, 65.4 mmol) was
added and the reaction mixture was stirred for another 1 h. Water
(30 mL) was carefully added to quench the reaction, and the mixture
was extracted with CH2Cl2 (30 mL×2). The combined CH2Cl2 extract
was washed with water and brine, dried and concentrated in vacuo.
Crystallisation of the residue from acetone/water gave 6 (10.2 g,
83%), m.p. 105–107 °C. IR (KBr)(vmax, cm−1): 3395, 2976, 1815,
1810, 1731, 1664, 1458, 1167, 1081; 1H NMR δ: 4.99 (dd, J = 10.2,
2.6 Hz, 1H), 4.72 (dd, J = 10.5, 7.6 Hz, 1H), 4.61 (s, 1H), 4.37 (d,
J = 7.6 Hz, 1H), 4.15 (d, J = 7.9 Hz, 1H), 3.78 (q, J = 6.8 Hz, 1H), 3.52
(dt, J = 15.5, 6.0 Hz, 1H), 3.02–2.92 (m, 2H), 2.68–2.60 (m, 2H), 2.63
(s, 3H), 2.24 (s, 6H), 2.04 (s, 3H), 1.95–1.80 (m, 1H), 1.75–1.70 (m,
1H), 1.68–1.60 (m, 1H), 1.55–1.60 (m, 1H), 1.53 (s, 3H), 1.38 (d,
J = 6.8 Hz, 3H), 1.30 (s, 6H), 1.23 (d, J = 6.1 Hz, 3H), 1.18 (d, J =
6.8 Hz, 3H), 1.14 (d, J = 1.3 Hz, 3H), 1.12 (s, 3H), 0.88 (t, J = 7.4 Hz,
3H); 13C NMR δ: 212.8, 203.9, 170.0, 169.0, 153.7, 101.4, 84.4, 80.8,
78.2, 78.1, 71.5, 69.1, 63.3, 51.0, 49.5, 47.4, 43.7, 40.6, 39.2, 38.0,
22.3, 30.4, 21.3, 20.9, 19.6, 17.8, 16.0, 14.0, 13.5, 12.4, 10.2; MS
(ESI) m/z, (%): 656 (M+ + H, 100), 614 (10); Anal. Calcd for
C33H53NO12: C, 60.44; H, 8.15; N, 2.14. Found: C, 60.22; H, 8.02;
2.20%.
2′-O-Acetate-3-O-descladinosyl-3-keto-10,11-anhydro-12-O-imid-
azolylcarbonyl-6-O-methylerythromycin (7): A solution of NaHDMS
(1.0 M in THF, 20.0 mL) was added to a 0 °C solution of the 6 (4.5 g,
7.7 mmol) and CDI (4.97 g, 30.7 mmol) in THF (50 mL). The mixture
was stirred at 0 °C for 2 h and then at room temperature for another
2 h. The reaction solution was adjusted to pH 8.0 with saturated aq.
KH2PO4 and extracted with ethyl acetate (30 mL×2). The combined
organic layers were washed with brine before being dried and evapo-
rated. Crystallisation of the residue from acetone/hexanes gave 7 as a
white foam (4.0 g, 75%). IR (KBr)(vmax, cm−1): 3393, 2975, 2879,
1735, 1578, 1449, 1077; 1H NMR δ: 8.09 (s, 1H), 7.37 (s, 1H), 7.07
(s, 1H), 6.79 (s, 1H), 5.69 (dd, J = 9.8, 3.2 Hz, 1H), 4.74 (dd, J = 10.1,
7.8 Hz, 1H), 4.35 (d, J = 7.5 Hz, 1H), 4.12 (d, J = 8.6 Hz, 1H), 3.74
(q, J = 6.8 Hz, 1H), 3.54–3.46 (m, 1H), 3.20–3.10 (m, 1H), 3.08–2.88
(m, 1H), 2.77 (s, 3H), 2.72–2.60 (m, 1H), 2.26 (s, 6H), 2.06 (s, 3H),
2.00–1.52 (m, 6H), 1.86 (s, 3H), 1.83 (d, J = 1.2 Hz, 3H), 1.37 (d,
J = 6.9 Hz, 3H), 1.29 (s, 3H), 1.24–1.22 (m, 6H), 1.13 (d, J = 7.4 Hz,
3H), 0.95 (t, J = 7.6 Hz, 3H); 13C NMR δ: 205.2, 170.0, 169.1, 146.2,
138.7, 138.4, 137.3, 131.1, 117.3, 102.1, 84.8, 81.1, 78.8, 77.4, 71.6,
69.3, 63.8, 51.3, 50.5, 47.6, 40.8, 40.5, 39.1, 30.6, 22.9, 21.6, 21.1,
20.9, 20.4, 19.1, 15.2, 14.2, 13.5, 10.6; MS (ESI) m/z, (%): 706 (M+ +
H, 63), 594 (100). The data agree with the literature.5
Telithromycin (1): 4-[4-(3-Pyridinyl)imidazol-1-yl]-1-butylamine
(1.84 g, 8.5 mmol) was added to a solution of 7 (2.0 g, 2.84 mmol)
in CH3CN/H2O (95:5, 40 mL), and the reaction mixture was stirred at
50 °C for 24 h. The mixture was added 0.5 M NaH2PO4 (30 mL) and
extracted with ethyl acetate (3×20 mL). The combined organic layers
were washed with water, dried, filtered, and concentrated in vacuo.
The residue was dissolved in 25 ml of methanol and stirred for 10 h.
Evaporation of methanol yielded a crude product that was crystallised
from CH2Cl2/hexanes to give 1 (1.66 g, 72%); white solid, m.p. 187–
189 °C (lit.6 186–188 °C). IR (KBr)(vmax, cm−1): 3433, 2974, 1748,
1711, 1578, 1446, 1166, 991; 1H NMR δ: 8.95 (s, 1H), 8.44 (d, J = 3.6,
1H), 8.08 (dt, J = 8.5, 1.5 Hz, 1H), 7.54 (s, 1H), 7.34 (s, 1H), 7.28 (dd,
J = 9.0, 5.0 Hz, 1H), 4.91 (dd, J = 11.0, 2.2 Hz, 1H), 4.28 (d, J = 7.2,
1H), 4.22 (d, J = 8.8, 1H), 4.02–3.98 (m, 2H), 3.85 (q, J = 6.8 Hz, 1H),
3.78–3.62 (m, 2H), 3.55 (s, 1H), 3.59–3.50 (m, 1H), 3.22 (dd,
J = 10.0, 7.2 Hz, lH), 3.12 (q, J = 7.0 Hz, 1H), 3.08–3.04 (m, 1H), 2.60
(s, 3H), 2.56–2.50 (m, 1H), 2.44–2.41 (m, 1H), 2.34 (s, 6H), 1.95–
1.54 (m, 10H), 1.46 (s, 3H), 1.36 (d, J = 7.2 Hz, 3H), 1.32–1.21
(m, 9H), 1.16 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.82 (t,
J = 7.2 Hz, 3H); 13C NMR δ: 216.4, 203.8, 170.1, 157.5, 147.8, 146.7,
139.4, 138.0, 132.2, 130.5, 123.7, 115.7, 104.0, 82.4, 79.9, 78.4, 77.7,
70.5, 69.6, 66.4, 60.5, 51.5, 50.0, 47.7, 47.1, 45.1, 42.8, 40.5, 39.8,
39.2, 28.8, 24.5, 22.5, 21.3, 19.9, 18.6, 15.9, 14.9, 14.6, 14.1, 10.7;
MS (ESI) m/z, (%): 812 (M+ + H, 64), 655 (26), 406 (100).
We thank the Open-ended Funds of Jiangsu Key Laboratory
of Marine Biotechnology, Huaihai Institute of Technology
(No. 2011HS001) and the Major Program of the Natural
Science Research Foundation of the Jiangsu Higher Education
Institutions (No. 10KJA170003)
Received 1 October 2012; accepted 30 December 2012
Paper 1201548 doi: 10.3184/174751913X13574995608294
Published online: 13 February 2013
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