Synthesis of carbon-14 labelled gemifloxacin

Article abstract of DOI:10.1002/jlcr.866

A new antibacterial agent gemifloxacin was labelled with carbon-14 for studies of pharmacokinetics and metabolism, the label was located in position 3 of the quinolone ring system. The overall radiochemical yield of the 14-step synthesis, starting from [2-¹⁴C]sodium acetate was 16.6%, and the radiochemical purity 97.5%.

Full text of DOI:10.1002/jlcr.866

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 779–786.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.866
Research Article
Synthesis of carbon-14 labelled gemifloxacin
Hyun Il Shin1,3,*, Jong Gill Rim1, Ki Seung Lee1, Young Seok Kim1, Do
Hyun Nam2, Hyun Ik Shin2, Jay Hyok Chang2, Chang Young Oh3 and Won
Hun Ham3
1 Korea RadioChemicals Center, Suwon 440-745, South Korea
2 LG Life Sciences Ltd, R&D Park, P.O. Box 61, Yu-Sung, Daejon 305-380, South
Korea
3 College of Pharmacy, SungKyunKwan University, Suwon 440-746, South Korea
Summary
A new antibacterial agent gemifloxacin was labelled with carbon-14 for studies of
pharmacokinetics and metabolism, the label was located in position 3 of the quino-
lone ring system. The overall radiochemical yield of the 14-step synthesis, starting
from [2-14C]sodium acetate was 16.6%, and the radiochemical purity 97.5%.
Copyright # 2004 John Wiley & Sons, Ltd.
Key Words: 14C-labelling; LB20304a; factive; Gemifloxacin
Introduction
Gemifloxacin1 (7-(3-aminomethyl-4-methyloxyiminopyrrolidin-1-yl)-1-cyclo-
propyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
methanesulfonate, or SB 265805, or LB20304a, or FactiveTM) is a
fluoroquinolone antibacterial agent which possesses an enhanced affinity for
topoisomerase IV. Compared to earlier quinolones, gemifloxacin has an
improved spectrum of antibacterial activity notably against Gram-positive
bacteria. It also displays superior activity against methicillin-resistant
Staphylococcus aureus (MRSA), key respiratory tract pathogens such as
Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and
has great potential to become a once-daily drug of choice for the treatment of
respiratory tract infection. Urinary tract pathogens including Escherichia coli
and Proteus mirabilis are also very susceptible towards Gemifloxacin. To
facilitate the pharmacokinetic and metabolic studies of gemifloxacin, we
*Correspondence to: Hyun Il Shin, Korea RadioChemicals Center, SK Chemicals R&D Center Building,
600 Jeongja 1-dong, Jangan-gu, Suwon-si, Gyeonggi-do, 440-745, South Korea. E-mail: hishin@krcc.co.kr
Copyright # 2004 John Wiley & Sons, Ltd.
Received 4 May 2004
Revised 24 June 2004
Accepted 30 June 2004

780
H. I. SHIN ET AL.
required the 14C-labelled compound. In order that the carbon-14 label be in a
metabolically stable position, a radiosynthesis was desired to insert the label in
position 3 of the heterocyclic quinolone ring system.
Results and discussion
Several routes for preparing carbon-14 labelled quinolone compounds in
different positions are known. [4-14C]quinolone carboxylic acids were obtained
from substituted [carbonyl-14C]benzoyl derivatives.2,3 Use of [2-14C]malonates
as the starting material, led to labelling of position 3 of quinolone
compounds.4–6 Labelled substituents were introduced at the nitrogen (the
position 1 or position 7) of the quinolone compounds by substitution
reactions.7,8 Gemifloxacin was labelled at position 3 of the quinolone system
starting from 2,6-chloro-5-fluoro-nicotinoyl chloride and [2-14C]diethyl
malonate as shown in Schemes 1 and 2. The starting material, [2-14C]diethyl
malonate, was prepared in six steps from [2-14C]sodium acetate in an overall
62.7% yield (Scheme 1). Enolization of [2-14C]diethyl malonate with
magnesium ethoxide in diethyl ether at room temperature and subsequent
reaction with nicotinoyl chloride 2 gave the acylated diethyl malonate 3 in
89% yield. Compound 3 was converted to the keto propionic acid ethyl ester 4
by hydrolysis and decarboxylation in the presence of a catalytic amount of
p-toluenesulfonic acid in a combined yield of 54% after chromatographic
purification. In this reaction, we found prolonged reaction time caused double
decarboxylation to result in the increase of acetophenone type by-product.
After the formation of the dimethylamino acrylic acid ethyl ester 5 from the
reaction of propionic acid ethyl ester 4 with N,N-dimethylformamide dimethyl
acetal and acetic anhydride at room temperature, treatment of cyclopropy-
lamine displaced the dimethylamine group to give the acrylic acid ethyl ester 6
in 94% yield. Two reaction conditions were employed for the synthesis of 5:
(1) use of triethyl orthoformate/acetic anhydride, and (2) use of N,N-
dimethylformamide dimethyl acetal/acetic anhydride. The latter reagent
O
OH
*
*
a
c
*
CNCH3COOH
d
*
b
CH3COONa
BrCH3COOH
CH3COOH
*
OH
O
O
O
OAg
OAg
OEt
OEt
f
e
* = 14C
*
*
O
O
Scheme 1. Synthesis of [2-14C]diethyl malonate: (a) HCl gas; (b) red P, AcCl,
Br2, 958C, 6 h; (c) 30% K2CO3, NaCN, H2O, 958C, 1 h; (d) 5 N NaOH, 958C,
2 h; (e) 2 N NaOH, AgNO3, H2O, rt, 1 h; (f) EtI, 958C, 3 h
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 779–786

SYNTHESIS OF CARBON-14 LABELLED GEMIFLOXACIN
781
O
O
O
O
O
O
OEt
OEt
F
F
F
F
OH
OEt
Cl
b
*
c
a
*
Cl
N
Cl
Cl
N
Cl
Cl
N
Cl
Cl
N
Cl
O
1
4
3
2
d
O
O
O
O
O
N
O
O
N
O
F
F
F
F
*
*
*
*
OEt
NH
OEt
OH
OEt
g
e
f
Cl
N
Cl
Cl
N
Cl
N(CH )
3 2
Cl
N
Cl
N
8
6
5
7
N
O
H N
h
NH.2HCl
2
9
O
N
O
O
N
O
F
F
*
*
OH
OH
i
14
N
N
N
N
* =
C
N
N
CH SO H
3
3
O
O
H N
10
H N
2
2
14
C-gemifloxacin
Scheme 2. Synthesis of 14C-gemifloxacin: (a) SOCl2, cat. DMF, benzene,
1108C, 3 h; (b) [2-14C]diethyl malonate, magnesium ethoxide, diethyl ether, rt,
2 h; (c) p-TsOH, H2O, 100–1208C, 3 h; (d) DMFDA, Ac2O, CH2Cl2, rt, 2 h; (e)
cyclopropyl amine, EtOH, rt, 1 h; (f) K2CO3, DMF, 908C, 2 h; (g) c-HCl,
AcOH, 1208C, 4 h; (h) DBU, CH3CN, rt, 22 h; (i) CH3SO3H, CH2Cl2/EtOH(7/
3), 08C, 1 h
afforded 6 in higher yield (68 vs 94%). Intramolecular ring closure reaction of
6 to the carboxylic acid ethyl ester 7 was carried out in anhydrous DMF at
908C in the presence of anhydrous K2CO3. 7 was obtained in 83% yield after
purification on silica gel. Hydrolysis of 7 was performed using hydrochloric
acid and acetic acid at 1208C to afford the carboxylic acid 8 in a quantitative
yield. Coupling of 8 with the pyrrolidine 9 was carried out in anhydrous
acetonitrile at room temperature using DBU to give the carboxylic acid 10 in
high yield (88%). Finally, 14C-gemifloxacin was obtained by salt formation of
10 with methanesulfonic acid in dichloromethane/ethanol at 08C in 81% yield.
The overall radiochemical yield of 14C-gemifloxacin from [2-14C]sodium
acetate in a 14-step sequence was 16.6%, and the radiochemical purity 97.5%.
Experimental
General
Reagents and solvents were purchased from Aldrich or Fluka and used
without further purification. [2-14C]Diethyl malonate was synthesized from
Copyright # 2004 John Wiley & Sons, Ltd.
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H. I. SHIN ET AL.
[2-14C]sodium acetate (Perkin Elmer Life Sciences). Radioactivity was
measured by a Tri-carb 2100TR liquid scintillation counter (Packard) using
ULTIMA FLO M (Packard) as a liquid scintillation cocktail. High
performance liquid chromatography (HPLC) was performed using a 1100
series (Agilent) instrument. Radiochemical purity (RCP) was determined
either by an automatic TLC-linear analyzer Tracemaster 20 (EG&G Berthold)
or by a HPLC radioactivity monitor LB506C-1 (EG&G Berthold) equipped
with a pump, LB 5035 (EG&G Berthold) and with Flo-scint II (Packard) as
the liquid scintillation cocktail. The HPLC was run on a C18 m-Bondapak
column (Millipore-Waters). All reactions were monitored by TLC (silica gel 60
F254 plate, Merck), ultraviolet light, automatic TLC-linear analyzer Trace-
master 20, X-ray film (Konica) were used in TLC visualization. For column
chromatography, we employed silica gel 60 (230–400 mesh; ASTM, Merck).
All labelled materials were identified by chromatographic comparison with the
1
corresponding authentic unlabelled samples. H NMR spectra were recorded
on a Varian Unity 300 spectrometer; the chemical shifts are reported in parts
per million (ppm) relative to TMS in CDCl3 or DMSO-d6. Electron impact
mass spectra (EI-MS) were obtained on a LCQ DECA XP Plus LC-Mass
spectrometer (Thermo Finnigan). Elemental analyses were performed on an
EA 1110 elemental analyzer (CE Instruments). Unlabelled samples, prepared
by the same synthetic procedure, were used for mass spectra and elemental
analyses.
2-(2,6-Dichloro-5-fluoro-pyridine-3-carbonyl)-[2-14C]malonic acid diethyl
ester (3)
To a stirred solution of 2,6-dichloro-5-fluoro nicotinic acid (529 mg,
2.52 mmol) in benzene (4 ml) were added thionyl chloride (0.276 ml,
3.78 mmol) and a catalytic amount of DMF. The mixture was refluxed
at 1108C for 3 h, concentrated, and azeotroped with benzene (5 ml ꢀ 3) to
give 2,6-dichloro-5-fluoro nicotinoyl chloride. To a stirred solution of
[2-14C]diethyl malonate (366 mg, 2.29 mmol, 4.96 GBq) in diethyl ether (6 ml)
at room temperature was added magnesium ethoxide (314 mg, 2.74 mmol) and
then the mixture was stirred at room temperature for 2 h and concentrated.
To the residue in diethyl ether (4 ml) was added 2,6-dichloro-5-fluoro
nicotinoyl chloride in diethyl ether (3 ml) at 08C and then the mixture was
stirred at room temperature for 1 h. After quenching by 10% aqueous citric
acid (5 ml) at 08C, the aqueous layer was extracted with benzene (5 ml ꢀ 3).
The combined organic layers were washed with brine (3 ml), dried (Na2SO4),
filtered, and concentrated to give the malonic acid diethyl ester 3 (976 mg,
2.77 mmol, 4.41 GBq, yield: 89%) as an oil, which had a specific activity of
1.59 GBq/mmol: TLC RCP >95%, Rf=0.39, silica gel, hexane/ethyl
acetate=4/1).
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 779–786

SYNTHESIS OF CARBON-14 LABELLED GEMIFLOXACIN
783
3-(2,6-Dichloro-5-fluoro-pyridine-3-yl)-3-oxo-[2-14C]propionic acid ethyl
ester (4)
A mixture of 3 (976 mg, 2.77 mmol, 4.41 GBq) and p-toluenesulfonic
acid (8 mg) in H2O (2.3 ml) was stirred at 100–1208C for 3 h. The reaction
mixture was extracted with ethyl acetate (6 ml ꢀ 2) and the combined
organic layer was dried (MgSO4), filtered, and concentrated. The residue in
ethanol (1 ml) was sonicated, left to stand in a refrigerator for 1 h, filtered,
washed with cold hexane (1 ml), and dried in vacuo for 15 h to give the
propionic acid ethyl ester 4 (364 mg, 1.30 mmol, 2.04 GBq, yield: 46%) as a
white solid. A filtrate was purified by chromatography (SiO2, hexane/ethyl
acetate=9/1) to give additional 4 (60 mg, 0.214 mmol, 336 MBq, yield: 8%)
as a white solid. The combined 4 had a specific activity of 1.57 GBq/mmol:
TLC RCP>95%, Rf=0.45, silica gel, hexane/ethyl acetate=4/1; 1H
NMR (CDCl3/TMS) d 12.57 (s, 0.6 H, OH), 7.85 (d, J=7.5 Hz, 1 H, pyridine
CH), 5.83 (s, 0.6 H, CH), 4.30 (q, J=7.2 Hz, 1.2 H, CH2), 4.20 (q, J=7.2 Hz,
0.8 H, CH2), 4.09 (s, 0.8 H, CH2) 1.35 (t, J=7.2 Hz, 1.8 H, CH3), 1.26
(t, J=7.2 Hz, 1.2 H, CH3). EI-MS m/z 583 [2 M+Na]+; 302 [M+Na]+. Anal.
Calcd for C10H8Cl2FNO3: C, 42.38; H, 2.86; N, 4.86. Found: C, 42.53;
H, 2.88; N, 4.91.
3-Cyclopropylamino-2-(2,6-dichloro-5-fluoro-pyridine-3-carbonyl)-[2-14C]
acrylic acid ethyl ester (6)
To a stirred solution of 4 (424 mg, 1.51 mmol, 2.37 GBq) in dichloromethane
(4 ml) at 08C were added N,N-dimethylformamide dimethyl acetal
(360 mg, 3.02 mmol) and acetic anhydride (308 mg, 3.02 mmol) and
then the mixture was stirred at room temperature for 2 h. The reaction
mixture was concentrated and azeotroped with toluene (4 ml) to give 5.
To a solution of 5 in ethanol (4 ml) at 08C was added cyclopropyl
amine (104 mg, 1.82 mmol) and then the mixture was stirred at room
temperature for 1 h and concentrated. The residue was purified (SiO2,
hexane/ethyl acetate=10/1) to give 6 (495 mg, 1.43 mmol, 2.23 GBq, yield:
94%) as a white solid, which had a specific activity of 1.56 GBq/mmol: TLC
RCP >95%, Rf=0.13, silica gel, hexane/ethyl acetate=4/1; 1H NMR
(CDCl3/TMS) d 8.36 (d, J=14.4 Hz, 0.2 H, pyridine CH), 8.28 (d,
J=14.4 Hz, 0.8 H, pyridine CH), 7.39 (d, J=7.2 Hz, 0.2 H, CH), 7.32 (d,
J=7.2 Hz, 0.8 H, CH), 4.03 (q, J=7.2 Hz, 1.6 H, CH2), 3.96 (q, J=7.2 Hz,
0.4 H, CH2), 3.02 (m, 1 H, CH2CHCH2), 1.04 (t, J=7.2 Hz, 2.4 H, CH3), 0.98–
0.84 (m, 4.6 H, CH3+CH2CHCH2). EI-MS m/z 347 [M+H]+. Anal. Calcd
for C14H13Cl2FN2O3: C, 48.13; H, 3.75; N, 7.93. Found: C, 48.18; H, 3.78;
N, 7.91.
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7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-
[14C]carboxylic acid ethyl ester (7)
A stirred supension of 6 (495 mg, 1.43 mmol, 2.23 GBq) and potassium
carbonate (216 mg, 1.56 mmol) in DMF (7 ml) was stirred at 908C for 2 h and
then the reaction mixture was diluted with H2O (10 ml) and extracted with
ethyl acetate (10 ml ꢀ 3). The combined organic layer was washed with brine
(10 ml), dried (MgSO4), concentrated, and purified (SiO2, hexane/ethyl
acetate=10:1 ! neat ethyl acetate) to give 7 (272 mg, 0.875 mmol, 1.86 GBq,
yield: 83%) as a white solid, which had a specific activity of 2.11 GBq/mmol:
1
TLC RCP >95%, Rf=0.50, silica gel, hexane/ethyl acetate=1/1; H NMR
(CDCl3/TMS) d 8.65 (s, 1 H, CH), 8.43 (d, J=7.8 Hz, 1 H, pyridine CH), 4.40
(q, J=7.2 Hz, 2 H, CH2), 3.65 (m, 1 H, CH2CHCH2), 1.41 (t, J=7.2 Hz, 3 H,
CH3), 1.35–1.02 (m, 4 H, CH2CHCH2). EI-MS m/z 311 [M+H]+. Anal. Calcd
for C14H12ClFN2O3: C, 53.37; H, 3.82; N, 8.79. Found: C, 53.40; H, 3.81; N,
8.79.
7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-
[14C]carboxylic acid (8)
A mixture of 7 (272 mg, 0.875 mmol, 1.86 GBq) and concentrated HCl (3.0 ml)
in acetic acid (3.0 ml) was stirred at 1208C for 4 h. The reaction mixture was
diluted with water (7 ml) and stirred at 08C for 2 h. The resulting solid was
filtered, washed with water (5 ml) and hexane (5 ml), and dried (P2O5) in vacuo
for 15 h to give 8 (251 mg, 0.888 mmol, yield: quantitative) as a white solid.
1
TLC RCP >95%, Rf=0.1–0.35, silica gel, chloroform/methanol=10/1; H
NMR (CDCl3/TMS) d 8.93 (s, 1 H, CH), 8.48 (d, J=6.9 Hz, 1 H, pyridine
CH), 3.81 (m, 1 H, CH2CHCH2), 1.43–1.10 (m, 4 H, CH2CHCH2). EI-MS m/z
283 [M+H]+. Anal. Calcd for C12H8ClFN2O3: C, 49.45; H, 2.97; N, 9.07.
Found: C, 49.46; H, 2.93; N, 9.09.
7-(3-Aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-
oxo-1,4-dihydro-[1,8]naphthyridine-3-[14C]carboxylic acid (10)
To a stirred suspension of 8 (251 mg, 0.888 mmol), unlabelled compound 8
(420 mg, 1.49 mmol), and pyrrolidine 9 (646 mg, 2.99 mmol) in acetonitrile
(14 ml) was added DBU (1.23 g, 8.08 mmol) at room temperature and then the
reaction mixture was stirred at room temperature for 22 h and diluted with
water (10 ml). After stirring for 20 min, the resulting slurry was filtered,
washed with ethanol/water (4/1, 10 ml) and ethanol (15 ml), and dried (P2O5)
in vacuo for 15 h to give 10 (810 mg, 2.08 mmol, yield: 87%) as a pale brown
solid. TLC RCP >97%, Rf=0.34, silica gel, CH2Cl2/EtOH/NH4OH/
1
CH3CN=4/4/2/1; H NMR (DMSO-d6/TMS) d 8.56 (s, 1 H, CH), d 7.99
(d, J=12.6 Hz, 1 H, pyridine CH), 4.55 (s, 2 H, pyrrolidine CH2), 4.17 (m, 1 H,
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 779–786

SYNTHESIS OF CARBON-14 LABELLED GEMIFLOXACIN
785
pyrrolidine CH2), 3.93 (m, 1 H, pyrrolidine CH2), 3.85 (s, 3 H, OCH3), 3.72 (m,
1 H, CH2CHCH2), 3.04 (m, 1 H, pyrrolidine CH), 2.86 (m, 1 H, pyrrolidine
CH2), 2.74 (m, 1 H, pyrrolidine CH2), 1.03–1.21 (m, 4 H, CH2CHCH2). EI-MS
m/z 390 [M+H]+. Anal. Calcd for C18H22FN5O4: C, 48.98; H, 5.20; N, 15.68.
Found: C, 48.95; H, 5.22; N, 15.70.
7-(3-Aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-
oxo-1,4-dihydro-[1,8]naphthyridine-3-[14C]carboxylic acid methanesulfonate
(14C-gemifloxacin)
To a stirred solution of 10 (810 mg, 2.08 mmol) in dichloromethane/ethanol
(7/3, 33 ml) was added methanesulfonic acid (190 mg, 1.98 mmol) at 08C and
then the mixture was stirred at 08C for 1 h. The resulting solid was filtered,
washed with cold dichloromethane (3 ml), and dried (P2O5) in vacuo for 15 h to
give 14C-gemifloxacin (704 mg, 1.45 mmol, yield: 70%). A filtrate was
concentrated up to 9 ml and the resulting solid was filtered, washed with cold
dichloromethane (3 ml), and dried (P2O5) in vacuo for 15 h to give 14C-
gemifloxacin (114 mg, 0.235 mmol, yield: 11%). The specific activity of the
combined 14C-gemifloxacin (818 mg, 1.68 mmol) was measured as 784 MBq/
mmol: radio-HPLC RCP 97.5%, column m-Bondapak C18 (3.9 ꢀ 150 mm),
Eluant A=0.1% CF3COOH in H2O and B=0.1% CF3COOH in CH3CN,
Gradient: 0 ! 5 min; A/B=80/20, 5 ! 18 min; A/B=80/20 ! 5/95, 18 !
20 min; A/B=5/95, 20 ! 25 min; A/B=5/95 ! 80/20, Flow rate 1 ml/min,
Detector UV 272 nm, Temperature 308C, Retention time=15.1 min, TLC
RCP >97.9%, Rf= 0.32, silica gel, CH2Cl2/EtOH/NH4OH/CH3CN= 4/4/2/
1
1; H NMR (DMSO-d6/TMS) d 8.59 (s, 1 H, CH), 8.05 (d, J=12.9 Hz, 1 H,
pyridine CH), 4.57 (s, 2 H, pyrrolidine CH2), 4.37 (m, 1 H, pyrrolidine CH2),
3.90 (s, 3 H, OCH3), 3.84 (m, 1 H, pyrrolidine CH2), 3.71 (m, 1 H,
CH2CHCH2), 3.41 (m, 1 H, pyrrolidine CH), 3.31 (s, 3 H, NH+3 ), 3.23–3.10
(m, 2 H, pyrrolidine CH2), 2.33 (s, 3 H, SO3CH3), 1.24–1.04 (m, 4 H,
CH2CHCH2). EI-MS m/z 390 [M+H]+. Anal. Calcd for C19H24FN5O7S: C,
42.53; H, 5.39; N, 13.05; S, 5.73. Found: C, 42.47; H, 5.38; N, 13.01; S, 5.74.
Acknowledgements
We wish to thank members of the Analysis Group of SK Chemicals Co. Ltd,
R&D Center for the NMR, mass, and elemental analysis.
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