Synthesis of trovafloxacin using various (1α,5α,6α)-3-azabicyclo[3.1.0]hexane derivatives

Article abstract of DOI:10.1039/a910340f

Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual (1α,5α,6α)-3-azabicyclo[3.1.0]hexane ring system. The prototype of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive formation of the exo or 6α-nitro derivative 4 are described, which leads to the key 6a-nitro-3-azabicyclo[3.1.0]hexane intermediate 10. The synthesis of 6a-amino-3-azabicyclo[3.1.0]hexane 16 and useful protected cxo 6-amino derivatives 15 and 17 follows from 10. These can be coupled with the 7-chloronaphthyridone 18 to yield protected trovafloxacin compounds 20-22 in good yield. The ethyl ester of trovafloxacin 21 can also be accessed from the product of coupling 19, derived from 18 and the exo 6-nitro-3-azabicyclo[3.1.0]hexane compound 12. Removal of protecting groups from 20-22 with methanesulfonic acid yields trovafloxacin mesylate from which trovafloxacin zwitterion 1 can be liberated with base treatment. Zwitterion l can also be prepared directly from 16 tosylate salt and naphthyridone-2-carboxylic acid 26. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a910340f

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Synthesis of trovafloxacin using various (1ꢀ,5ꢀ,6ꢀ)-3-
azabicyclo[3.1.0]hexane derivatives
Timothy Norris,* Tamim F. Braish, Michael Butters, Keith M. DeVries, Joel M. Hawkins,
Stephen S. Massett, Peter R. Rose, Dinos Santafianos and Constantine Sklavounos
1
Pfizer Central Research Laboratories, Groton, Connecticut 06340, USA
Received (in Cambridge, UK) 23rd December 1999, Accepted 20th March 2000
Published on the Web 28th April 2000
Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual (1α,5α,6α)-3-azabicyclo[3.1.0]hexane ring
system. The prototype of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive
formation of the exo or 6α-nitro derivative 4 are described, which leads to the key 6α-nitro-3-azabicyclo[3.1.0]hexane
intermediate 10. The synthesis of 6α-amino-3-azabicyclo[3.1.0]hexane 16 and useful protected exo 6-amino
derivatives 15 and 17 follows from 10. These can be coupled with the 7-chloronaphthyridone 18 to yield protected
trovafloxacin compounds 20–22 in good yield. The ethyl ester of trovafloxacin 21 can also be accessed from the
product of coupling 19, derived from 18 and the exo 6-nitro-3-azabicyclo[3.1.0]hexane compound 12. Removal of
protecting groups from 20–22 with methanesulfonic acid yields trovafloxacin mesylate from which trovafloxacin
zwitterion 1 can be liberated with base treatment. Zwitterion 1 can also be prepared directly from 16 tosylate salt
and naphthyridone-2-carboxylic acid 26.
Trovafloxacin 1 is a new and powerful antibiotic that is active
carried out at about Ϫ10 ЊC. The reaction can be carried out in
many solvents but toluene is preferred because removal of the
many tar like side products formed during the reaction is
somewhat easier. It appears that the reaction produces almost
exclusively the exo or 6α-nitro product 4. The endo or 6β-nitro
product 5 is detected at very low level, in the range 0.5–1.5%
relative to exo 4, in the presence of a base. The endo compound
5 can be formed by epimerization of 4 in the presence of potas-
sium carbonate in acetonitrile. The equilibrium favours the exo
form to a very significant extent and the endo–exo equilibrium
is approximately 2:98 when measured by HPLC. The endo
compound 5 has been isolated from the mother liquors of an
equilibrium mixture by fractional crystallization and fully
characterized by X-ray crystallography (see Fig. 1b).
against a wide variety of microorganisms.1 It contains the inter-
esting 3-azabicyclo[3.1.0]hexane ring system.2 This paper
describes the synthesis and chemistry of a number of new
(1α,5α,6α)-3-azabicyclo[3.1.0]hexanes and new naphthyridone
coupled intermediates that can be used to make trovafloxacin.
Possible mechanisms to interesting intermediates and the
formation of some side products are also discussed.
Steric hindrance is not a complete barrier to the synthesis
of 6-substituted endo 3-azabicyclo[3.1.0]hexane products. For
example, ethyl diazoacetate reacts with 1-benzyloxycarbonyl-
2,5-dihydropyrrole in the presence of rhodium acetate to form
both the 6α-ethoxycarbonyl and 6β-ethoxycarbonyl substituted
3-azabicyclo[3.1.0]hexane derivatives.5 In this case the 6β- or
endo isomer is a significant minor product, and the observed
endo:exo ratio is 1:2. Recently, other workers have described a
synthesis of 6β-isomers of the 3-azabicyclo[3.1.0]hexanes start-
ing from amino-chloroenamines, such as 1-benzyl-3-chloro-4-
(dibenzylamino)-1,2,3,6-tetrahydropyridine.6
The reaction of N-benzylmaleimide 2 and bromonitro-
We cannot definitively account for the selectivity of the reac-
tion between 2 and 3 in the presence of DMTHP to form 4 in
terms of a mechanistic pathway, but some pertinent comments
may be noted. The stereoselectivity in favour of the exo isomer
4 exceeds the thermodynamic ratio of 98:2 observed when
equilibrating 4 with potassium carbonate in acetonitrile. It is
possible that the cyclopropane ring forming reaction proceeds
mainly by an insertion process in which both bonds of the
cyclopropane ring are formed concomitantly. In this case, it
might be anticipated that at least some endo product 5 should
be formed as a measurable minor isomer in excess of 2% rela-
tive to exo product 4, since there is no great steric inhibition to
its formation. Similarly, if the cyclopropane bond forming pro-
cesses occurs consecutively, a diastereomeric pair of carbanions
6a and 6b, would be expected to form, which will give rise to exo
methane 3 in the presence of base3 is used to assemble the
bicyclic ring system of 4. Many bases can be used, but yields are
often below 15%. Amidine bases are useful, particularly 1,2-
dimethyl-1,4,5,6-tetrahydropyrimidine4 (DMTHP). This base
improves the yield to the 30–35% range when the reaction is
DOI: 10.1039/a910340f
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and endo products 4 and 5, respectively (see Scheme 1). For
similar steric reasons that would also be true of the concomi-
tant bond forming process, it seems improbable that kinetic
stereoselectivity could arise from face selectivity in the initial
Michael additon. In order to account for the observed selectiv-
ity† it may be that a more favoured reaction fate for carbanion
6b or its resultant endo product 5 (formed by either concomi-
tant or consecutive bond forming pathway) is the formation of
polymeric reaction tars. Certainly, in examples where reactions
are stressed, especially using reduced amounts of 3 and by leav-
ing the reaction mixture to stir for >12 hours at room temper-
ature prior to work up, even the exo product 4 decomposes.
The major monomeric product observed from this decompo-
sition process is the unexpected pyrrolo[3,4-e]isoindole-1,3,6,8-
(2H,7H)-tetrone derivative 7, isolated in 12% yield. Scheme 2
shows a possible pathway for its formation. In contrast, a more
expected hydrolysis of the imide group resulting from the
strained bicyclic ring system of 4 is not observed in the presence
of DMTHP under the reaction conditions described. This reac-
tion can be observed with excess bases and water, for example 4
gives rise to the cyclopropane hydrolysis product 8 in the pres-
ence of 1,1,3,3-tetramethylguanidine (Scheme 3). The struc-
tures of 7 and 8 have been confirmed by X-ray crystallography.
† It is possible that if the kinetics of equilibrium between the exo and
endo products, 4 and 5, are extremely rapid, under the conditions of
experimentation described, any endo 5 initially formed will be trans-
formed predominantly to exo 4.
Scheme 3
Among anionic bases for the reaction of 2 with 3, alkali
metal phenoxides, alkoxides, and bis(trimethylsilyl)amides give
lower yields of 4 than DMTHP. Considering that a non-
associating cation might be beneficial, novel tetraalkyl-
ammonium 2,6-di-tert-butylphenoxide bases 9 were tested.
These were prepared by combining the corresponding phenol
and tetraalkylammonium hydroxide in methanol–toluene with
azeotropic removal of water (Scheme 4). Tetrabutylammonium
Scheme 4
2,6-di-tert-butylphenoxide 9 (R1 = Bu, R2 = H) gave 42–49%
yields of 4 when used as base. Similar results have been
obtained using quaternary ammonium fluoride salts.7
Scheme 1
Scheme 2
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Reduction of 4 with diborane8 generated from sodium boro-
hydride and boron trifluoride–diethyl ether in THF yields 10,
the key intermediate9 in nearly quantitative yield (Scheme 5).
Fig. 1 (a) X-Ray derived molecular structure of 12 showing orien-
tation of exo nitro group (atoms N7,O8,O9) and conformation of 3-
azabicyclo[3.1.0]hexane ring system in its crystalline lattice. (b) X-Ray
derived molecular structure of 5 showing orientation of endo nitro
group in 2,4-dioxo-3-azabicyclo[3.1.0]hexane ring system in its crystal-
line lattice.
Scheme 5
the compound. Interestingly, the plane of the nitro group atoms
is nearly orthogonal to the plane of the cyclopropane ring. This
is in contrast to 5 in which the endo nitro group is rotated 90Њ
relative to the exo nitro group in 12 and is periplanar to the
pyrrolidine ring.
This intermediate can be used to synthesize a number of deriv-
atives (12, 15, 16 and 17) by four synthetic pathways that can be
used to access trovafloxacin. The nitro compound 10 can be
selectively reduced to the amine 13 using hydrogen at about
3–4 atm pressure, 50 ЊC in the presence of platinum on carbon
catalyst. The reduction can also be carried out with zinc–
hydrochloric acid or Raney nickel–hydrazine,3 but the catalytic
platinum reduction is most convenient. Products of cyclo-
propane ring opening are found in the reaction mixture using
these reagents. When 13 is produced by the Pt catalyst method
it can be used in synthesis without purification. Pure 13 can be
induced to crystallize, but not readily and often remains as an
oil. It is most readily purified and isolated in a crystalline form
as the mono-mesylate salt from propan-2-ol, by treatment with
an equivalent of methanesulfonic acid. Primary amine 13 is
protected with a tert-butyloxycarbonyl (t-Boc) group intro-
duced using di-tert-butyl dicarbonate (t-Boc anhydride) under
Schotten–Baumann conditions to yield 14. Compound 14 is
readily converted to the corresponding secondary amine 15 by
reductive removal of the N-benzyl function with hydrogen in
the presence of palladium on carbon catalyst.
Reduction of 10 with hydrogen in the presence of palladium
on carbon catalyst leads to the formation of the diamine 16,
which can be selectively protected on the primary amine by
forming the imine 17 as a syn and anti mixture. The benzylidene
functionality is introduced by refluxing 16 with benzaldehyde
and triethylamine (TEA) in propan-2-ol. Both 16 and 17 are
useful in further synthesis.
The N-benzyl group attached to 10 can be removed using
α-chloroethyl chloroformate10 (ACE-Cl) to form the intermedi-
ate 11; refluxing in methanol yields the hydrochloride salt 12.
Single crystal X-ray data have been obtained on the hydro-
chloride salt of 12, Fig. 1a, illustrating the stereochemistry of
Naphthyridone11 18 contains a reactive chlorine substituent
at the C-7 position which is easily displaced by nucleophiles
such as secondary amines. The 3-azabicyclo[3.1.0]hexane
intermediates 12, 15, 16 and 17 can be coupled with 18 in the
presence of TEA to yield a series of intermediates 19–22
(Scheme 6) in high yield which can be readily converted into
trovafloxacin also in high yield.
The nitro compound 19 is reduced to amine 21 using Raney
nickel–hydrazine, in 87% yield.12 Raney nickel–hydrogen or
zinc–methanesulfonic acid can be used also, but the yields are
lower. The Boc and ethyl ester protecting groups from 20 are
removed with methanesulfonic acid to yield trovafloxacin as its
mesylate salt, directly. Interestingly, the conditions of the reac-
tion can reverse the rate at which the two protecting groups are
removed. Typically if methanesulfonic acid is in a modest
excess with respect to 20 (mole ratio 3:1) and the reaction is
carried out at reflux in THF–water 1:1 reaction monitoring by
HPLC shows that the Boc group is lost first forming ethyl ester
21 as an intermediate. In contrast when the reaction is carried
out under similar conditions, except that the THF:water ratio
is adjusted to 9:1, then the rate of loss of the ethyl ester protect-
ing group is significantly accelerated and the Boc-acid 25 is the
predominant intermediate observed during reaction monitor-
ing by HPLC.‡
‡ Compound 25 was independently synthesized by treating trova-
floxacin mesylate salt with di-tert-butyl dicarbonate in the presence of
triethylamine, for the HPLC study.
J. Chem. Soc., Perkin Trans. 1, 2000, 1615–1622
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Scheme 7
Scheme 6
Imines derived from (1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]-
hexane such as 17, mentioned earlier, can be coupled with the
7-chloronaphthyridone 18 to yield the imine 22 which is very
labile and and when treated with THF–water 1:1 at reflux
produces trovafloxacin mesylate directly in 70% yield (Scheme
6). Trovafloxacin ethyl ester, 21, is observed as an intermediate
by HPLC, and forms readily during the initial stages of
reaction.
Perhaps most surprising is the coupling reaction of the
potentially bidentate intermediate 16 with 18, to yield mainly
trovafloxacin ethyl ester 21. Intermediate 16 contains a second-
ary and primary amine, both of which could potentially under-
go nucleophilic substitution reactions with the active chlorine
atom on the naphthyridone 18. It is believed that the primary
amine functionality is significantly less nucleophilic than would
be the case normally, due to the presence of the adjacent
banana bonds of the cyclopropyl moiety. A side product, 23,
derived from the coupling of 21 with another molecule of naph-
thyridone 18, is formed in the reaction mixture to the extent
of 5–10%, but no significant quantities of 24 derived from
coupling through the primary amine have been measured.
Trovafloxacin ethyl ester, 21 produced from the coupling of
16 and 18 is converted to trovafloxacin mesylate salt by treat-
ment with aqueous methanesulfonic acid. Various ratios of
THF–water at reflux can also be used as the reaction solvent
system. This mesylate salt readily yields trovafloxacin zwitter-
ion 1 on treatment with sodium bicarbonate and water of
hydration can be removed as an azeotrope with a suitable water
imiscible solvent, such as hexane or ethyl acetate. The conver-
sion of coupled intermediates 19–22 into 1 is noted in Scheme
7. The use of protecting groups on the side chain and the naph-
thyridone is not absolutely essential. Zwitterion 1 can also be
prepared directly in 75% yield by refluxing the di-tosylate salt
of diamine 16 with carboxylic acid 26 in methanol in the pres-
ence of TEA. Compound 27, the carboxylic acid analogue of
23, is similarly formed as a side product, but most of it remains
in the mother liquor and trovafloxacin zwitterion 1 containing
only traces of 27 is precipitated from the reaction liquor as it is
formed. Carboxylic acid 26 was easily prepared from the ester
18 by refluxing it in THF–water 9:1 in the presence of excess
methanesulfonic acid (Scheme 8).
Scheme 8
Experimental
Melting points were determined with an Electrothermal 9100
capillary melting point apparatus and are uncorrected. 1H
NMR (300 MHz) and 13C NMR (75.5 MHz) were obtained
with a Bruker 360 instrument. Diffuse Reflectance Infrared
Fourier Transform spectra (DRIFTS) were recorded on a
Nicolet Magna IR Spectrometer 550. GC/MS were completed
on a Hewlett Packard 5890 Series II Gas Chromatograph with a
Hewlett Packard 5971 Series Mass Selective Detector. Column
chromatography was performed on Scientific Adsorbents Inc.
silica gel (63–200 mesh). Thin-layer chromatography (TLC) was
run on E. Merck glass plates silica gel 60 F254, 250 µm layer
thickness with detection by 254 nm UV light. Microanalysis
was performed by Schwarzkopf Microanalytical Laboratory,
Woodside, NY. Solvents were used as supplied without further
purification or drying, except where noted. Hydrogenations
were carried out in a standard Parr shaker apparatus. Platinum
and nickel catalysts were purchased from Precious Metal Corp.,
Serverville, TN, USA and palladium catalysts from Engelhard,
Senaca, SC, USA.
These studies are illustrative of the many approaches that can
be used to synthesize this broad spectrum antibacterial agent
trovafloxacin, and collectively, help to establish its chemistry
and process impurity profile for routine manufacturing.
Bromonitromethane was purchased from Great Lakes
Chemical Co., West Lafayette, IN, USA. N-Benzylmaleimide
was made using the method of Arnold et al.13 Ethyl 7-chloro-1-
(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyr-
1618
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idine-3-carboxylate, 18, was purchased from Abbot Laborator-
ies, Chicago, IL. 1,2-Dimethyl-1,4,5,6-tetrahydropyrimidine was
obtained from Pfizer Ltd., Sandwich, England. Trovafloxacin
is the WHO approved name for (1α,5α,6α)-7-(6-amino-3-aza-
bicyclo[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid zwitterion.
from ethyl acetate–hexane gave crystals of endo isomer 5 (288
mg), mp 111–112 ЊC (Found: C, 58.5; H, 4.1; N, 11.4. C12H10-
N2O4 requires C, 58.5; H, 4.1; N, 11.4%); m/z 246 (Mϩ), 200
(Mϩ Ϫ NO2, 100%); δH(300 MHz; CDCl3) 7.3 (m, 5H, Ph), 4.82
(t, 1H, 6α), 4.54 (s, 2H, benzylic), 3.08 (d, 2H, 3-ring). The endo
structure was confirmed by single crystal X-ray analysis.
2,7-Dibenzylpyrrolo[3,4-e]isoindole-1,3,6,8(2H,7H)-tetrone, 7
(1ꢀ,5ꢀ,6ꢀ)-3-Benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]-
hexane, 4
DMTHP (2.28 cm3, 20.0 mmol) and toluene (10 cm3) were
added to a stirred mixture of N-benzylmaleimide (1.87 g, 10.0
mmol), bromonitromethane (0.56 cm3, 8.0 mmol), powdered
4 Å molecular sieves (6.74 g) and toluene (50 cm3) on an ice
bath over 7 minutes. The reaction mixture was allowed to slowly
warm to room temperature with stirring overnight, filtered
through filter aid, washed with 2 M dilute hydrochloric acid,
water, and brine, and concentrated to a foam. Flash chromato-
graphy on silica (25–40% ethyl acetate–hexane) yielded a yellow
solid 7 (0.19 g, 12%), mp 204–206 ЊC. Recrystallization from
dichloromethane–ether yielded yellow needles for X-ray crystal-
lography. δH(300 MHz; d6-DMSO) 8.25 (s, 2H), 7.3 (m, 10H),
4.8 (s, 4H).
(a) Using DMTHP. N-Benzylmaleimide (500 g, 2.67 mol),
90% bromonitromethane (831 g, 5.34 mol), powdered molecu-
lar sieves, 200 mesh (2020 g) and toluene (12 dm3) were stirred
under nitrogen at Ϫ10 ЊC. 1,2-Dimethyl-1,4,5,6-tetrahydro-
pyrimidine (616 g, 5.49 mol) was added slowly over about
3 hours maintaining the reaction temperature at <Ϫ8 ЊC
throughout the addition. After completion of the addition the
reaction mixture was stirred for 1.5 h at 25 ЊC, filtered under a
nitrogen atmosphere in a sealed pressure filter to remove sieves
and tar, and the sieves washed with toluene (2 dm3). The com-
bined filtrates were washed with 2 M dilute hydrochloric acid
(3 × 750 cm3), carbon treated (50 g) at 70 ЊC, 1 h, filtered, con-
centrated, and triturated with propan-2-ol (~4 dm3) to obtain
crystals of 4 (223 g, 34%), mp 116–118 ЊC (Found: C, 58.2; H,
4.1; N, 11.3. C12H10N2O4 requires C, 58.5; H, 4.1; N, 11.4%);
m/z 246 (Mϩ), 200 (Mϩ Ϫ NO2, 100%); δH(300 MHz; CDCl3)
7.3 (m, 5H, Ph), 4.54 (s, 2H, benzylic), 4.45 (s, 1H, 6β), 3.35
(s, 2H, 3-ring). This process has been carried out at industrial
scale.
Tetramethylguanidinium (1ꢀ,2ꢀ,3ꢁ)-2-(N-benzylcarbamoyl)-3-
nitrocyclopropanecarboxylate, 8
Tetramethylguanidine (2.6 cm3, 21 mmol) was added to a slurry
of 4 (0.5 g, 2.1 mmol) in toluene (5 cm3). After stirring for
2 days at room temperature a solid was isolated by filtration
to yield 8 (0.665 g, 83%). A portion was recrystallized from
ethanol–ethyl acetate yielding fine white needles for X-ray crys-
tallography. δH(300 MHz; d6-DMSO) 9.95 (t, 1H), 8.05 (s, 2H),
7.28 (m, 5H), 4.90 (t, 1H), 4.25 (d, 2H), 2.90 (s, 12H), 2.75 (dd,
1H), 2.60 (dd, 1H).
(b) Using 9 (where R1 ؍ H, R2 ؍ Bu). A slurry of tetrabutyl-
ammonium 2,6-di-tert-butylphenoxide, 9 (33.58 g, 75 mmol)
in dry toluene (450 cm3) was added to a stirred mixture of
N-benzylmaleimide (8.77 g, 47 mmol), bromonitromethane
(4.25 cm3, 61 mmol) and powdered 4 Å molecular sieves (30 g) in
dry toluene (30 cm3) under nitrogen at Ϫ19 ЊC over 1.5 h. After
stirring for 1 h at Ϫ19 ЊC, the reaction mixture was warmed to
0 ЊC, filtered using filter aid, stirred with cold 2 M dilute hydro-
chloric acid (250 cm3), and filtered again using filter aid. The
organic layer was washed with water and brine, treated with
activated charcoal, and concentrated to a semisolid (~23 g)
which was recrystallized from toluene–propan-2-ol yielding
4 (4.93 g, 43%), mp 116.5–117 ЊC. Analytical data as noted
above.
(1ꢀ,5ꢀ,6ꢀ)-3-Benzyl-6-nitro-3-azabicyclo[3.1.0]hexane, 10
Tetrahydrofuran (350 cm3), sodium borohydride (14.1 g, mmol)
and 4 (35.0 g, mmol) were stirred under nitrogen for 0.25 h and
then treated dropwise with boron trifluoride–THF complex
containing 21.5% BF3 (44.9 cm3) so that the exotherm was con-
trolled to <40 ЊC. After addition was completed the reaction
mixture was stirred for 3 h at 40 ЊC, quenched slowly with
water–THF 1:1 (70 cm3) to avoid excessive foaming and stirred
for 0.5 h at 50 ЊC to ensure the quench of unreacted diborane
generated in situ was completed. The quench formed a salt
slurry which was filtered and washed with THF (140 cm3), the
combined filtrate was partially concentrated, diluted with water
(350 cm3) and further concentrated to remove most of the THF
and extracted with ethyl acetate (140 cm3). The ethyl acetate
was concentrated to a clear product oil 10 (30.6 g, 97%). Elem-
ental analysis obtained from mesylate salt (Found: C, 49.8; H,
6.0; N, 9.1; S, 10.2. C12H14N2O2ؒCH4O3S requires C, 49.7; H,
5.8; N, 8.9; S, 10.2%); m/z 218 (Mϩ); δH(300 MHz; CDCl3) 7.3
(m, 5H, Ph), 4.63 (s, 1H, 6β), 3.6 (s, 2H, benzylic), 3.14 (d, 2H,
5-ring), 2.51 (m, 2H, 3-ring).
Tetra-n-butylammonium 2,6-di-tert-butylphenoxide, 9
(where R1 ؍ H, R2 ؍ Bu)
A solution of 2,6-di-tert-butylphenol (22.69 g, 110 mmol) in
toluene (10 cm3) was treated with a 1 M solution of tetrabutyl-
ammonium hydroxide in methanol (100 cm3, 100 mmol) under
nitrogen at ambient temperature. The resultant dark green solu-
tion was stirred for 1 h, concentrated under vacuum to a thick
residue, treated with toluene (2 × 100 cm3) and each aliquot
concentrated under vacuum to yield a green solid 9 (52.08 g,
116% weight recovery) which was used in the next step without
further purification. δH (300 MHz; CDCl3) 7.13 (d, J 9 Hz, 2H),
6.77 (t, J 9 Hz, 1H), 3.30 (m, 8H), 1.61 (m, 8H), 1.41 (s, 18H),
1.40 (m, 8H), 0.96 (t, J 7 Hz, 12H).
3-Azabicyclo[3.1.0]hexane derivatives derived from 10
(1ꢀ,5ꢀ,6ꢀ)-6-Nitro-3-azabicyclo[3.1.0]hexane hydrochloride,
12. Compound 10 (25.1 g, 115 mmol) and 1,2-dichloroethane
(115 cm3) were cooled to 0–5 ЊC and treated dropwise with 1-
chloroethyl chloroformate (25.3 g, 177 mmol) over 20 minutes.
The reaction mixture was warmed to 50–55 ЊC for 2–3 h, and
concentrated under vacuum to give a black residue. The residue
was dissolved in methanol (100 cm3) and heated to 55–60 ЊC for
3 h to yield a slurry, which was cooled to room temperature,
stirred for 18 h, treated with concentrated hydrochloric acid (10
cm3, 115 mmol) and stirred for 1.5 h. The product was isolated
by filtration, washed with chloroform (25 cm3) and dried under
vacuum to yield 12 (9.99 g, 53%). White crystals from water, mp
215–216 ЊC (decomp.) (Found: C, 36.4; H, 5.35; Cl, 21.9; N,
(1ꢀ,5ꢀ,6ꢁ)-3-Benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]-
hexane, 5
Isolation from equilibrium mixture. Compound 4, (60 g),
acetonitrile (400 cm3) and potassium carbonate were stirred at
room temperature for 1 h, the mixture was filtered and glacial
acetic acid (1 cm3) and water (1.6 dm3) were added to the filtrate
to crystallize out 4 which was removed by filtration. The filtrate
was extracted with toluene (1.2 dm3). The organic layer was
concentrated to yield a white solid (2.66 g) shown to contain
approximately 1:1 ratio of 4 and 5. Fractional crystallization
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16.8. C5H8N2O2ؒHCl requires C, 36.5; H, 5.5; Cl, 21.5; N,
17.0%); m/z 128 (Mϩ ϩ 1); δH(300 MHz; CDCl3) 9.78 (br s, 2H),
4.95 (t, J 2.0 Hz, 1H), 3.51 (d, J 12.1 Hz, 2H), 3.41 (dt, J 1.8 and
12.8 Hz, 2H), 2.87 (s, 2H). Structure confirmed by single crystal
X-ray analysis.
on carbon catalyst, water content 55% (10.0 g), water (125 cm3)
and propan-2-ol (250 cm3) were hydrogenated in a Parr appar-
atus at 50 ЊC, 3.5 atm, 24 h. The catalyst was filtered off and the
filtrate concentrated under vacuum to obtain a product oil, 16
(10.4 g, 91.7%), purity GC 83%. Material produced in this way
is convenient and satisfactory for direct use in synthesis. Purifi-
cation by column chromatography on silica gel using CHCl3–
CH3OH–concentrated NH4OH (55:35:10) yielded a clear
oil; m/z 96 (Mϩ Ϫ 2); δH(300 MHz; d4-CH3OH) 4.86 (s, NHs
and MeOH), 2.97 (2H, d, J 11.4 Hz), 2.77 (2H, dt, J 1.4 and
11.4 Hz), 2.06 (1H, t, J 2.2 Hz), 1.42 (2H, td, J 1.4 and 2.2 Hz);
δC(75.5 MHz; d4-CH3OH) 48.9, 32.5, 27.5.
(1ꢀ,5ꢀ,6ꢀ)-3-Benzyl-6-amino-3-azabicyclo[3.1.0]hexane, 13.
(1α,5α,6α)-3-Benzyl-6-nitro-3-azabicyclo[3.1.0]hexane,
10
(25.05 g, 114.8 mmol), 5% platinum on carbon catalyst, water
content 66% (10.02 g), and methanol (250 cm3) were hydrogen-
ated in a Parr apparatus at 50 ЊC, 3.5 atm, 24 h. The catalyst
was filtered off and the filtrate concentrated under vacuum to
obtain a product oil, 13 (20.24 g, 93.6%), purity GC 81.5%.
White crystals can be obtained from hexane, mp 99–102 ЊC
(hexanes). δH(300 MHz; CDCl3) 7.31–7.18 (m, 5H), 3.53 (s,
2H), 2.94 (d, J 8.8 Hz, 2H), 2.64 (s, 1H), 2.36 (dm, J 8.6 Hz,
2H), 1.53 (s, 2H), 1.32 (dd, J 1.9 and 3.3 Hz); δC (75.5 MHz;
CDCl3) 139.5, 128.5, 128.1, 126.7, 59.2, 54.5, 32.5, 25.8; m/z
189 (M ϩ H)ϩ. Elemental analysis obtained on mesylate salt
(Found: C, 54.7; H, 7.1; N, 9.75; S, 11.5. C12H16N2ؒCH4O3S
requires C, 54.9; H, 7.1; N, 9.85; S, 11.3%).
(1ꢀ,5ꢀ,6ꢀ)-6-Benzylideneamino-3-azabicyclo[3.1.0]hexane,
17. Compound 17 is formed in situ as an oil that readily under-
goes hydrolysis and is a mixture of syn and anti isomers. See
preparation of 22. It can be crystallized from propan-2-ol. Its
1H and 13C NMR were obtained. δH(300 MHz; CDCl3) 8.42 (s,
0.8H), 8.33 (s, 0.2H), 7.68–7.64 (m, 1.8H), 7.53 (t, J 7.4 Hz,
0.2H), 7.38–7.30 (m, 3H), 3.90 (s, 0.4H), 3.32 (s, 0.8H), 3.20 (d,
J 9.0 Hz, 0.8H), 3.15 (s, 0.2H), 3.07 (d, J 11.2 Hz, 0.2H), 2.94
(d, J 9.0 Hz, 0.8H), 2.86 (s, 0.2H), 2.58 (dd, J 9.0 and 3.0 Hz,
0.8H), 2.26 (dd, J 9.0 and 3.0 Hz, 0.8H), 2.02 (s, 0.4H), 1.90–
1.86 (m, 1.8H); δC(75.5 MHz; CDCl3) major isomer 157.6,
136.0, 130.0, 128.5, 127.6, 83.1, 51.8, 51.0, 26.6, 26.0.
(1ꢀ,5ꢀ,6ꢀ)-3-Benzyl-6-tert-butyloxycarbonylamino-3-aza-
bicyclo[3.1.0]hexane, 14. Ethyl acetate (225 cm3), di-tert-butyl
dicarbonate (30.8 g, 141 mmol) and 13 (21.6 g, 115 mmol) were
stirred at room temperature and a solution of sodium carbon-
ate (24.7 g, 233 mmol) and sodium hydroxide (9.35 g, 234
mmol) in water (200 cm3) was added at <30 ЊC. The two phase
reaction mixture was stirred for 3 h at 30 ЊC then separated and
the organic phase concentrated to 25% of its original volume
and treated with hexane (150 cm3). The resultant crystals were
isolated by filtration, washed with hexane (50 cm3) to obtain 14
as white needles (18.4 g, 56%), mp 132–133 ЊC (EtOAc–hexane)
(Found: C, 71.0; H, 8.45; N, 9.8. C17H24N2O2 requires C, 70.8;
H, 8.4; N, 9.7%); m/z 289 (Mϩ ϩ 1); δH(300 MHz; CDCl3) 7.29
(m, 5H, Ph), 4.62 (br s, NH), 3.61 (s, 2H benzylic) 3.1 (d,
2H, 5-ring), 2.92 (s, 1H, 6β), 2.50 (d, 2H, 5-ring), 1.56 (s, 2H,
3-ring), 1.4 (s, 9H); νmax(DRIFTS)/cmϪ1 3370 (NH), 1687
(urethane carbonyl).
Coupling reactions
Ethyl (1ꢀ,5ꢀ,6ꢀ)-7-(6-nitro-3-azabicyclo[3.1.0]hexan-3-yl)-1-
(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyr-
idine-3-carboxylate, 19. Acetonitrile (190 cm3), 18 (19.07 g,
50 mmol), 12 (9.88 g, 60 mmol), and triethylamine (15.3 g, 151
mmol) were heated to reflux (82 ЊC) for 6.5 h. The reaction
slurry was cooled to room temperature and treated with water
(115 cm3). The resulting product slurry was granulated at 0–
5 ЊC for 1 h. The product was collected by filtration as a white
solid, washed with 1:1 MeCN–water (50 cm3) and dried under
vacuum at 40 ЊC, to yield 19 (21.17 g, 89%), mp 248–249 ЊC
(Found: C, 55.5; H, 3.48; F, 12.0; N, 11.7. C22H17F3N4O5
requires C, 55.7; H, 3.6; F, 12.0; N, 11.8%); m/z 475 (Mϩ ϩ 1);
δH(300 MHz; CDCl3) 8.4 (s, 1H), 8.1 (d, 1H), 7.4 (m, 1H), 7.05
(m, 1H), 4.35 (q, 2H), 4.1 (s, 1H), 3.95 (m, 2H), 3.65 (m, 2H),
2.75 (s, 3H), 1.35 (t, 3H).
(1ꢀ,5ꢀ,6ꢀ)-6-tert-Butyloxycarbonylamino-3-azabicyclo[3.1.0]-
hexane, 15. Methanol (200 cm3), catalyst 10% palladium on
charcoal containing 55% water (10 g) and 14 (20 g, 101 mmol)
were hydrogenated on a Parr apparatus at room temperature
overnight, catalyst was filtered off, washed with methanol (20
cm3) and the combined filtrate concentrated and displaced with
cyclohexane (300 cm3). The resultant crystal slurry was further
concentrated to about 100 cm3 and the product isolated as
white crystals of 15 (12.2 g, 89%), mp 119–125 ЊC (cyclohexane)
(Found: C, 60.35; H, 9.3; N, 14.1. C10H18N2O2 requires C, 60.6;
H, 9.15; N, 14.1%); m/z 199 (Mϩ ϩ 1); δH(300 MHz; CDCl3) 4.8
(br s, NH), 3.13 (d, 2H, 5-ring), 3.0 (s, NH), 2.9 (d, 2H, 5-ring),
2.29 (s, 1H, 6β), 1.57 (s, 2H, 3-ring), 1.39 (s, 9H); νmax(DRIFTS)
cmϪ1 3321 (NH), 3174 (NH).
Ethyl
(1ꢀ,5ꢀ,6ꢀ)-7-(6-tert-butyloxycarbonylamino-3-aza-
bicyclo[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 20. Methanol
(75 cm3), 15 (5.5 g, 27.7 mmol), 18 (10.0 g, 26.1 mmol) and
triethylamine (4.7 cm3, 33.7 mmol) were heated to reflux for 1 h.
The reaction mixture was cooled to room temperature and
white product crystals isolated by filtration, washed with
methanol and dried under vacuum to yield 20 (14.2 g, 99%), mp
218–219.5 ЊC (Found: C, 58.65; H, 5.3; F, 9.6; N, 10.2. C27H27-
F3N4O5ؒCH4O requires C, 58.3; H, 5.4; F, 9.9; N, 9.7%); m/z 545
(Mϩ ϩ 1); δH(300 MHz; CDCl3) 8.49 (s, 1H), 8.0 (d, 1H), 7.43
(m, 1H), 7.02 (m, 2H), 4.33 (q, 2H), 3.79 (br s, 2H), 3.51 (br s,
2H), 2.56 (br s, 1H), 2.22 (s, 1H, 6β-H), 1.78 (br s, 2H), 1.40 (s,
9H), 1.33 (t, 3H).
(1ꢀ,5ꢀ,6ꢀ)-6-Amino-3-azabicyclo[3.1.0]hexane, 16. From
compound 15. (1α,5α,6α)-6-tert-Butyloxycarbonylamino-3-
azabicyclo[3.1.0]hexane, 15 (15.0 g, 75.8 mmol), methanol (300
cm3) and toluene-4-sulfonic acid (28.8 g, 151.6 mmol) were
heated to reflux for 2 h. The reaction solution was concentrated
to a crystal slurry, and the crystals isolated by filtration, washed
with methanol and dried under vacuum to yield the di-tosylate
salt of 16 (25.6 g, 76%), mp 247–248 ЊC (methanol) (Found: C,
51.5; H, 6.0; N, 6.3; S, 14.55. C5H10N2ؒC14H16O6S2 requires C,
51.8; H, 5.9; N, 6.3; S, 14.5%); m/z 96 (Mϩ Ϫ 2); δH(400 MHz;
d6-DMSO) 8.49 (br s, 5H, NH and SO3H), 7.51 (d, 2H, ABq),
7.12 (d, 2H, ABq), 3.3 (m, 4H 5-ring), 2.6 (s, 1H, 6β), 2.27 (s,
6H, ArMe), 2.11 (s. 2H, 3-ring).
Ethyl (1ꢀ,5ꢀ,6ꢀ)-7-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-
1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyr-
idine-3-carboxylate, Trovafloxacin ethyl ester, 21. From 16 and
18. Methanol (75 cm3), triethylamine (10 cm3, 71.7 mmol) and
16 (5.0 g, 51 mmol) were stirred at 50 ЊC and treated with a
slurry of 18 (15.0 g, 39.3 mmol) in methanol (150 cm3) over 3 h.
The reaction mixture was held at 50 ЊC for 3 h, concentrated,
treated with water (150 cm3), extracted with ethyl acetate (200
cm3) and washed with 0.1 M dilute hydrochloric acid and water.
The organic layer was concentrated to dryness to yield crude
trovafloxacin ethyl ester 21 (16.35 g, 93.6%). Crude product
From compound 10. (1α,5α,6α)-3-Benzyl-6-nitro-3-aza-
bicyclo[3.1.0]hexane, 10 (25.2 g, 115.5 mmol), 10% palladium
1620
J. Chem. Soc., Perkin Trans. 1, 2000, 1615–1622

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(HPLC 74%) was purified by chromatography using a silica gel
column eluted with ethyl acetate and then methanol to yield
pure trovafloxacin ethyl ester 21, m/z 445 (Mϩ ϩ 1) (Found: C,
59.4; H, 4.3; N, 12.7; F, 12.5. C22H18F3N4O3 requires C, 59.5; H,
4.3; F, 12.8; N, 12.6%); δH(300 MHz; CDCl3) 8.35 (s, 1H), 7.8
(d, 1H), 7. 35 (m, 1H), 7.05 (m, 2H), 4.35 (q, 2H), 3.6 (br s, 2H),
3.5 (br s, 2H), 2.05 (s, 1H), 1.57 (m, 2H), 1.51 (s, 2H), 1.39 (t,
3H).
to reflux. Benzaldehyde (15.0 g, 141 mmol) was added dropwise
over 15 minutes. The reaction was held at reflux for 4 h to form
imine 17 in situ. The orange solution was cooled to 40–50 ЊC,
naphthyridine derivative 18 (42.45 g, 111 mmol) and triethyl-
amine (13.1 g, 130 mmol) were added. The reaction slurry was
held at reflux for 16–18 h, cooled to 20 ЊC and stirred for 5 h.
The slurry was filtered and product isolated as a white solid to
yield 22, 57.12 g, 75.5% based on 5, 96.6% based on 18. White
solid recrystallized from acetonitrile, mp 148–155 ЊC (decomp.)
(Found: C, 63.5 ; H, 4.4; F, 10.35; N, 10.7. C29H23 F3N4O3ؒH2O
requires C, 63.3; H, 4.6; F, 10.35; N, 10.2%); m/z 533 (Mϩ ϩ 1);
δH(300 MHz; CDCl3) 8.33 (s, 1H), 8.29 (s, 1H), 7.97 (d, J 7.1
Hz, 1H), 7.58–7.61 (m, 2H), 7.46 (td, J 5.7 and 8.6 Hz, 1H),
7.31–7.35 (m, 3H), 6.97–7.08 (m, 2H), 4.31 (q, J 7.1 Hz, 2H),
3.80 (br s, 2H), 3.64 (br s, 2H), 2.75 (t, J 1.8 Hz, 1H), 2.13 (s,
2H), 1.32 (t, J 7.1 Hz, 3H); νmax(KBr)/cmϪ1 1730, 1697, 1632.
This reaction also forms 23. This can be formed as a signifi-
cant product by adjusting the mole ratio of 16:18 to 1:2 in the
above procedure.
Ethyl
(1ꢀ,5ꢀ,6ꢀ)-7-(6-{[6-ethoxycarbonyl-8-(2,4-difluoro-
phenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-
amino}-3-azabicyclo[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-
fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 23.
(Found: C, 58.0; H, 3.6; F, 13.8; N, 10.7. C39H28F6N6O6ؒH2O
requires C, 57.9; H, 3.7; F, 14.1; N, 10.4%); δH(300 MHz; d6-
DMSO) 8.53 (s, 1H), 8.47 (s, 1H), 8.16 (br s, 1H), 7.91 (d, J 9.0
Hz, 1H), 7.87 (d, J 6.9 Hz, 1H), 7.84–7.76 (m, 2H), 7.61 (td,
J 9.7 and 2.7 Hz, 1H), 7.37–7.32 (m, 1H), 7.22 (br t, J 8.6 Hz,
1H), 4.16–4.25 (m, 4H), 3.45 (m, 4H), 2.07 (s, 1H), 1.79 (br s,
2H), 1.23–1.29 (m, 6H); m/z 791 (M ϩ H)ϩ; νmax(DRIFTS)/
cmϪ1 3325, 3116, 3075, 3060, 2983, 2936, 2919, 2871, 1723,
1694, 1633, 1571, 1550, 1511.
Trovafloxacin mesylate salt
From 20. Tetrahydrofuran (125 cm3), 20 (12.5 g, 23 mmol),
and water (125 cm3) were treated with 97% methanesulfonic
acid (5.5 g, 55.5 mmol) and heated to reflux for 17–24 h. The
reaction solution was cooled to 45 ЊC, treated with activated
carbon (0.3 g) for 1 h and filtered. The filtrate was concentrated
under vacuum to approximately 50% of its original volume to
give a white crystal slurry, cooled to 5–10 ЊC, granulated for 4 h,
washed with cold THF, filtered and dried to yield trovafloxacin
mesylate (11.8 g, 90%), mp 253–256 ЊC (decomp.) (Found: C,
49.3; H, 3.75; F, 11.2; N, 11.0; S, 6.3. C20H15F3N4O3ؒCH4O3S
requires C, 49.2; H, 3.7; F, 11.1; N, 10.9; S, 6.3%); δH(300 MHz;
d6-DMSO) 8.85 (s, 1H), 8.17 (br m, 2H), 8.11 (d, 1H), 7.83 (m,
2H), 7.62 (m, 2H), 7.37 (m, 2H), 3.67 (br s, 3H), 2.45 (s, 1H),
2.37 (s, 3H), 2.08 (s, 2H). Trovafloxacin mesylate salt can also
be isolated as a monohydrate.
21 From nitro compound, 19. (a) Zinc–methanesulfonic acid
reduction. Acetonitrile (50 cm3), water (50 cm3), 19 (10.0 g, 21.1
mmol) and zinc dust (6.9 g, 105.5 mmol) were treated with
methanesulfonic acid (70%, 25.5 cm3, 241 mmol) resulting in
an exotherm to 40 ЊC. The orange-yellow reaction mixture
was warmed to 50–55 ЊC for 3 h, cooled to room temperature,
treated with water (100 cm3) and filter aid (1 g), and stirred for
0.25 h. The resultant slurry was filtered to give a deep amber
solution, basified to pH 10.1 using 50% NaOH, extracted with
dichloromethane (250 cm3) and filtered to remove insolubles.
Dichloromethane was removed by evaporation to yield crude
trovafloxacin ethyl ester 21 (2.57 g, 27.4%). Crude product was
purified by chromatography and analytical data as reported
above.
(b) Raney nickel–hydrazine reduction. Tetrahydrofuran (100
cm3), Raney nickel A-5000 (0.87 g), 19 (2.0 g, 4.22 mmol) and
water (100 cm3) were stirred at 20 ЊC, a solution of 98% hydra-
zine (1 ml, ~31.2 mmol) in THF (5 cm3) and water (5 cm3) was
added slowly at 20–30 ЊC. The reaction mixture was stirred at
25 ЊC for 1.5 h, catalyst was removed by filtration and the fil-
trate concentrated under vacuum to obtain a pale yellow solid,
which was treated with ethyl acetate (100 cm3) and further con-
centrated to give a slurry. Product was isolated by filtration,
washed with water and dried under vacuum to yield 21 (1.64 g,
87%). Analytical data as reported above.
From trovafloxacin ethyl ester, 21. Trovafloxacin ethyl ester
21 (1.54 g, 3.46 mmol) and water (25 cm3) were treated with
methanesulfonic acid (38.4 mmol) for 18 h at 45–50 ЊC. The
reaction mixture was cooled to room temperature and the
product was isolated by suction filtration and dried under
vacuum to yield trovafloxacin mesylate salt (1.48 g, 83%).
Analytical data as reported above.
From imine 22. Tetrahydrofuran (250 cm3), 22 (25.05 g, 47
mmol), and water (250 cm3) were treated with 97% methane-
sulfonic acid (13.3 g, 138 mmol) and heated to reflux for 24 h.
The reaction solution was cooled to 45 ЊC, treated with acti-
vated carbon (2.5 g) for 1 h and filtered. The filtrate was con-
centrated under vacuum to approximately 25% of its original
volume to give a white crystal slurry, cooled to 15–25 ЊC,
granulated for 4 h and filtered to yield trovafloxacin mesylate
(16.86 g, 70.0%). Analytical data as noted above.
(c) Raney nickel–hydrogen reduction. Tetrahydrofuran (36
cm3), Raney nickel A-5000 (0.86 g), 19 (2.0g) and water (8 cm3)
were hydrogenated in a Parr apparatus at 3.3 atm, 25 ЊC for 3 h,
catalyst was removed by filtration and the filtrate concentrated
under vacuum to dryness to obtain a pale yellow solid. This was
treated with ethanol (30 cm3) at reflux to give a clear solution,
on cooling a slurry was obtained. White product was isolated
by filtration, washed with water and dried under vacuum to
yield 21 (863 mg, 46%). Analytical data as reported above.
Trovafloxacin zwitterion, 1
From mesylate salt of 1. Trovafloxacin mesylate salt (15.0 g,
29.3 mmol), and water (75 cm3) were stirred at 50 ЊC and the
pH adjusted to 8.5 by addition of saturated sodium hydrogen
carbonate solution (~ 50 cm3). The resultant slurry was cooled
to 25 ЊC, filtered and the product residue, washed with water
(120 cm3), and the wet cake dried by refluxing in ethyl acetate to
remove water azeotropically. It was then dried under vacuum to
yield trovafloxacin zwitterion, 1 (11.5 g, 94%), mp 225–228 ЊC
(decomp.) (Found: C, 57.4; H, 3.6; F, 13.9; N, 13.4. C20H15-
F3N4O3 requires C, 57.7; H, 3.6; F, 13.7; N, 13.5%); δH(300
MHz; d6-DMSO) 8.81 (s, 1H), 8.03 (d, J 12.7 Hz, 1H), 7.80 (td,
J 6.0 and 8.7 Hz), 7.63 (m, 1H), 7.35 (tm, J 8.6 Hz, 1H), 3.2–3.8
(br m, 4H), 1.92 (s, 1H), 1.53 (s, 2H).
Ethyl (1ꢀ,5ꢀ,6ꢀ)-7-(6-benzylideneamino-3-azabicyclo[3.1.0]-
hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylate, 22. Nitro compound, 10 (30.9
g, 142 mmol), propan-2-ol (310 cm3), water (30 cm3), and 10%
Pd on carbon, 50% water content (12.3 g) were hydrogenated at
50 psi and 50 ЊC for 18–24 h in a Parr shaker. The catalyst was
filtered off and the pale yellow filtrate was azeotropically dis-
tilled at constant volume to remove water. The resulting solu-
tion was treated with triethylamine (46 g, 456 mmol) and heated
From 16 di-tosylate salt and 26. Carboxylic acid 26 (500 mg,
1.41 mmol), di-tosylate salt of 16 (624 mg, 1.41 mmol), triethyl-
J. Chem. Soc., Perkin Trans. 1, 2000, 1615–1622
1621

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amine (0.6 cm3, 4.23 mmol) and methanol (5 cm3) were refluxed
for 16 h. White solid was collected by filtration, refluxed in THF
and re-isolated to give 1 (450 mg, 75%). Analytical data as
reported above. Compound 27 was isolated from the mother
liquor by chromatography. Analytical data for side product 27
reported below.
γ = 90.0Њ, V = 3970.8(9) Å3, space group Pbca, Z = 8, Dx = 1.273
g cmϪ3, colorless prisms, crystal dimensions 0.10 × 0.11 × 0.22
mm, µ(Cu-Kα) = 0.792 mmϪ1
.
C5H9N2O2ϩClϪ, 12, M = 164.6, monoclinic, a = 8.035(2) Å,
b = 7.702(2) Å, c = 12.185(2) Å, α = 90.0Њ, β = 95.25 (3)Њ, γ =
90.0Њ, V = 750.9(3) Å3, space group P21/c, Z = 4, Dx = 1.456 g
cmϪ3, colorless needles, crystal dimensions 0.17 × 0.22 × 0.36
(1ꢀ,5ꢀ,6ꢀ)-7-(6-tert-Butyloxycarbonylamino-3-azabicyclo-
[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-
oxo-1,8-naphthyridine-3-carboxylic acid, 25
mm, µ(Cu-Kα) = 4.075 mmϪ1
.
Data collection and processing
Trovafloxacin mesylate salt (15.6 g), triethylamine (5.6 g), tetra-
hydrofuran (135 cm3), and water (15 cm3) were treated with di-
tert-butyl dicarbonate (7.6 cm3) over 0.5 h at 25 ЊC and held for
4 h at 25 ЊC to obtain a white slurry. The slurry was filtered, the
white residue was stirred with water (100 cm3) for 16 h at 25 ЊC,
re-isolated and re-treated. The white solid was dried under
vacuum to remove water to yield 25, mp 234–236 ЊC (Found: C,
58.0; H, 4.4; N, 10.9; F, 11.35. C25H23F3N4O5 requires C, 58.1;
H, 4.5; F, 11.0; N, 10.85%); m/z 517 (Mϩ ϩ 1); δH(300 MHz;
CDCl3) 8.55 (s, 1H), 7.92 (d, 2H), 7.35 (m, 1H), 7.04 (m, 2H),
4.1–3.1 (v br s, 2H exchange D2O), 3.68 (t, 1H, 6β), 3.21 (br s,
2H, 5-ring), 2.13 (br s, 2H, 5-ring), 1.73 (m, 2H, 3-ring), 1.36 (s,
9H).
Siemens R3m/v diffractometer, ω/2θ mode with ω scan
width = 1.2Њ plus Kα-separation, ω-scan speed 4 deg minϪ1
,
graphite monochromated Cu-Kα (λ = 1.54178 Å) radiation; for
C12H10N2O4, (5), 1175 reflections measured with 892 (I > 3.0σ),
for C24H16N2O4, (7), 1027 reflections measured with 808
ϩ
(I > 3.0σ), C5H14N3 C12H11N2O5Ϫ, (8), 2035 reflections meas-
ured with 1147 (I > 3.0σ), for C5H9N2O2ϩClϪ, (12), 764 reflec-
tions measured with 521 (I > 3.0σ).
Structure analysis and refinement
Trial structures were obtained using direct methods. These trial
structures were refined in a full matrix least-squares fashion
ultimately using anisotropic temperature factors for the non-
hydrogen atoms. All crystallographic calculations were facili-
tated by the Siemens SHELXTL PLUS computer programs.
The hydrogen positions were calculated wherever possible.
Methyl hydrogens and hydrogen on nitrogen were located by
difference Fourier techniques and then idealized by calculation.
The hydrogen atoms were added to the structure factor calcu-
lations but were not refined. The final data fit criteria were as
follows: for C12H10N2O4, (5), final difference map, ϩ0.25 to
Ϫ0.23 e ÅϪ3, R = 5.26%, GOF = 1.40; for C31H36N2O3, (7), final
difference map, ϩ0.27 to Ϫ0.25 e ÅϪ3, R = 7.29%, GOF = 1.03;
7-Chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid, 26
Tetrahydrofuran (450 cm3), water (50 cm3), methanesulfonic
acid (127 cm3) and 18 (50 g) were refluxed for 1 h, cooled to
25 ЊC, isolated product crystals, washed with tetrahydrofuran,
and dried under vacuum at 100 ЊC to obtain 26 (41.3 g, 89%),
mp 250 ЊC (Found: C, 50.4; H, 1.7; Cl, 9.9; F, 16.0; N, 8.0.
C15H6ClF3N2O3 requires C, 50.8; H, 1.7; Cl, 10.0; F, 16.1; N,
7.9%); δH(300 MHz; d6-DMSO) 13.9 (s, 1H), 9.09 (s, 1H), 8.77
(d, J 7.5 Hz, 1H), 7.86 (td, J 5.9 and 8.8 Hz, 1H), 7.66 (ddd,
ϩ
for C5H14N3 C12H11N2O5Ϫ, (8), final difference map, ϩ0.31
to Ϫ0.29 e ÅϪ3, R = 7.86%, GOF = 1.06; for C5H9N2O2ϩClϪ,
(12), final difference map, ϩ0.49 to Ϫ0.36 e ÅϪ3, R = 9.57%,
GOF = 1.92.
J 2.7, 9.0 and 11.8 Hz, 1H), 7.39 (tm, J 8.6 Hz, 1H); νmax
-
(DRIFTS)/cmϪ1 3130, 3060, 2947, 2885, 2821, 2723, 2637,
2594, 1734, 1641, 1623, 1579, 1544, 1516.
Full details of the crystallographic results have been
deposited with the Cambridge Crystallographic Data Centre.
CCDC reference number 207/416.
(1ꢀ,5ꢀ,6ꢀ)-7-(6-{[6-Carboxy-8-(2,4-difluorophenyl)-3-fluoro-5,8-
dihydro-5-oxo-1,8-naphthyridin-2-yl]amino}-3-azabicyclo-
[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-
oxo-1,8-naphthyridine-3-carboxylic acid, 27
Acknowledgements
Side product 27 was obtained from the mother liquor after
chromatography as a sesquihydrate (Found: C, 55.2; H, 2.9; F,
15.3; N, 11.0. C35H20F6N6O6ؒ1¹ H2O requires C, 55.2; H, 3.0; F,
15.0; N, 11.0%); δH(300 MHz; d6-DMSO) 14.85 (br s, 2H) 2.85
(s, 1H), 8.80 (s, 1H), 8.56 (br s, 1H), 8.07 (d, J 5.7 Hz, 1H), 8.04
(d, J 3.6 Hz, 1H), 7.84–7.82 (m, 2H), 7.64 (td, J 9.7 and 2.5 Hz,
1H), 7.40–7.36 (m, 2H), 7.25 (br s, 1H), 3.50 (br s, 4H), 2.14
(s, 1H), 1.87 (br s, 2H); m/z 735 (M ϩ H)ϩ; νmax(DRIFTS)/cmϪ1
3304, 3064, 2882, 1726, 1631, 1546, 1505.
Single crystal X-ray structural data for 5, 7, 8 and 12 were
generated by Dr Jon Bordner and Ms Debra DeCosta in Pfizer
Central Research X-Ray Crystallography Laboratory. We thank
Mr R. Friedmann for providing an independent synthesis of 25.
¯
²
References
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H. Watson, Synlett, 1996, 1100.
Crystal data collected for compounds 5, 7, 8 and 12
C12H10N2O4, 5, M = 246.2, monoclinic, a = 6.267(1) Å, b =
19.626(3) Å, c = 9.565(1) Å, α = 90.0Њ, β = 104.94(1)Њ, γ = 90.0Њ,
4 H. Baganz and L. Domaschke, Chem. Ber., 1962, 95, 1840.
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A. G. Pernet, J. Med. Chem., 1986, 29, 2364.
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1999.
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Chem., 1991, 44, 323.
V = 1142.1(3) Å3, space group P21/n, Z = 4, Dx = 1.432 g cmϪ3
,
colorless needles, crystal dimensions 0.06 × 0.08 × 0.30 mm,
µ(Cu-Kα) = 0.927 mmϪ1
.
C24H16N2O4, 7, M = 396.4, monoclinic, a = 4.718(1) Å, b =
31.996(5) Å, c = 6.432(1) Å, α = 90.0Њ, β = 92.15(3)Њ, γ = 90.0Њ,
V = 970.3(3) Å3, space group P21, Z = 2, Dx = 1.357 g cmϪ3
,
yellow needles, crystal dimensions 0.04 × 0.11 × 0.28 mm,
µ(Cu-Kα) = 0.769 mmϪ1
.
ϩ
C5H14N3 C12H11N2O5Ϫ, 8, M = 380.4, orthorhombic, a =
20.135(1) Å, b = 9.706(1) Å, c = 20.318(4) Å, α = 90.0Њ, β = 90.0Њ,
1622
J. Chem. Soc., Perkin Trans. 1, 2000, 1615–1622