Practical synthesis and molecular structure of a potent broad-spectrum antibacterial isothiazoloquinolone

Article abstract of DOI:10.1021/op700014t

We report the synthesis of the new 2-sulfonylquinolone ethyl 1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylate (5). Sulfone 5 is a key intermediate used in the optimized synthesis of the isothiazoloquinolone 9-cyclopropyl-6-fluoro-8- methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (1), a potent broad-spectrum antibacterial agent that is effective against clinically important resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA). Our synthetic method is free of chromatographic purification and amenable to large-scale synthesis. The molecular structures of 1, 9-cyclopropyl-6,7-difluoro-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione (4), 5, and ethyl 2-cyclopropylamino-6,7-difluoro-8-methoxy-4-oxo-4H- thiochromene-3-carboxylate (10) were established unambiguously using multinuclear NMR spectroscopy and X-ray crystallography.

Full text of DOI:10.1021/op700014t

Organic Process Research & Development 2007, 11, 389−398
Practical Synthesis and Molecular Structure of a Potent Broad-Spectrum
Antibacterial Isothiazoloquinolone
Akihiro Hashimoto,† Godwin C. G. Pais,† Qiuping Wang,† Edlaine Lucien,† Christopher D. Incarvito,‡ Milind Deshpande,†
Barton J. Bradbury,† and Jason A. Wiles*,†
Achillion Pharmaceuticals, Inc., 300 George Street, New HaVen, Connecticut 06511, U.S.A., and X-ray Crystallographic
Facility, Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520, U.S.A.
Abstract:
We report the synthesis of the new 2-sulfonylquinolone ethyl
1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-
1,4-dihydroquinoline-3-carboxylate (5). Sulfone 5 is a key
intermediate used in the optimized synthesis of the isothiaz-
oloquinolone 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpy-
ridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (1), a potent
broad-spectrum antibacterial agent that is effective against
clinically important resistant organisms such as methicillin-
resistant Staphylococcus aureus (MRSA). Our synthetic method
is free of chromatographic purification and amenable to large-
scale synthesis. The molecular structures of 1, 9-cyclopropyl-
6,7-difluoro-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-di-
one (4), 5, and ethyl 2-cyclopropylamino-6,7-difluoro-8-methoxy-
4-oxo-4H-thiochromene-3-carboxylate (10) were established
unambiguously using multinuclear NMR spectroscopy and
X-ray crystallography.
Figure 1. Structures and numbering scheme of isothiazolo-
quinolones.
resistant Staphylococcus aureus (MRSA), (ii) good selectivity
for bacterial enzymes over human topoisomerase II, and (iii)
desirable in vitro toxicity profiles. Compound 16,7 (Figure
1) exhibited the most desirable balance of antibacterial
activity (e.g, MRSA MIC90 ) 0.5 µg/mL), enzyme selectivity
(e.g., S. aureus topoisomerase IV IC50 ) 0.7 µM vs human
topoisomerase II EC2 ) 100 µM), and cytotoxicity (e.g., rat
hepatocyte CC50 >100 µM). ITQ 1 also demonstrated good
efficacy in an in vivo murine thigh model of infection
employing MRSA. Our original synthesis6 of 1, however,
was impractical for the preparation of large quantities of
material necessary for preclinical development because it
required multiple chromatographic purifications and unsuit-
able reaction conditions (e.g., the use of potentially dangerous
reagents). Here, we describe a practical synthesis of 1 that
takes advantage of a new 2-sulfonylquinolone intermediate.
The synthesis is improved using this intermediate because
(i) a potentially dangerous oxidant (m-chloroperbenzoic
acid8) is no longer required, (ii) the new oxidant (Oxone,
potassium peroxymonosulfate) does not require stoichiomet-
ric control, and (iii) chromatographic purification is not
required.
Introduction
Isothiazoloquinolones (ITQs) are a class of potent anti-
bacterial agents that, like the related fluoroquinolones, act
by inhibiting type II bacterial topoisomerases.1-3 Recently,
we reported ITQs containing functionalized aryls and het-
eroaryls at the 7-position of various 6- and 8-substituted cores
(Figure 1).4-7 Several of these compounds demonstrated (i)
excellent in vitro antibacterial activities against methicillin-
* To whom correspondence should be addressed. Telephone: +1-203-624-
7000. Fax: +1-203-752-5454. E-mail: jwiles@achillion.com.
† Achillion Pharmaceuticals, Inc.
‡ Yale University.
(1) Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.; Shen, L.; Pernet, A. G.
Drugs Exp. Clin. Res. 1988, 14, 379-383.
(2) Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.; Shen, L.; Pernet, A. G.
In Quinolones, Proceedings of an International Telesymposium; Fernandes,
P. B., Ed.; Prous Science Publishers: Barcelona, Spain, 1989; pp 37-45.
(3) Chu, D. T. W.; Fernandes, P. B. Antimicrob. Agents Chemother. 1989, 33,
131-135.
(4) Wiles, J. A.; Wang, Q.; Lucien, E.; Hashimoto, A.; Song, Y.; Cheng, J.;
Marlor, C. W.; Ou, Y.; Podos, S. D.; Thanassi, J. A.; Thoma, C. L.;
Deshpande, M.; Pucci, M. J.; Bradbury, B. J. Bioorg. Med. Chem. Lett.
2006, 16, 1272-1276.
(5) Wiles, J. A.; Song, Y.; Wang, Q.; Lucien, E.; Hashimoto, A.; Cheng, J.;
Marlor, C. W.; Ou, Y.; Podos, S. D.; Thanassi, J. A.; Thoma, C. L.;
Deshpande, M.; Pucci, M. J.; Bradbury, B. J. Bioorg. Med. Chem. Lett.
2006, 16, 1277-1281.
Results and Discussion
We devised a strategy for the synthesis of 1 (Scheme 1)
that relied on Suzuki-Miyaura cross coupling of boronic
acid 2 with 7-bromo ITQ 3 to form the necessary biphenyl
linkage.6 We elected to prepare the requisite 7-bromo ITQ
3 from the corresponding 7-fluoro analogue 4, using a
Sandmeyer-type transformation, rather than directly from 2,5-
difluoro-4-bromo-3-methoxybenzoic acid because the starting
acid for 4, 2,4,5-trifluoro-3-methoxybenzoic acid, is readily
available from several commercial suppliers. ITQ 4 was
(6) Wang, Q.; Lucien, E.; Hashimoto, A.; Pais, G. C. G.; Nelson, D. M.; Song,
Y.; Thanassi, J. A.; Marlor, C. W.; Thoma, C. L.; Cheng, J.; Podos, S. D.;
Ou, Y.; Deshpande, M.; Pucci, M. J.; Buechter, D. D.; Bradbury, B. J.;
Wiles, J. A. J. Med. Chem. 2007, 50, 199-210.
(7) Pucci, M. J.; Cheng, J.; Podos, S. D.; Thoma, C. L.; Thanassi, J. A.;
Buechter, D. D.; Mushtaq, G.; Vigliotti, G. A., Jr.; Bradbury, B. J.;
Deshpande, M. Antimicrob. Agents Chemother., in press.
(8) Rao, A. S.; Mohan, H. R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley & Sons: Chichester, U.K., 1995; pp 1192-
1198.
10.1021/op700014t CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/16/2007
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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389

Scheme 1
Scheme 2
prepared as outlined in Scheme 2. This optimized sequence
of transformations overcomes the limitations of previous
syntheses of 16 and related ITQs9,10 that require several
chromatographic purifications and reagents (e.g., m-chlo-
roperbenzoic acid) not amenable to large-scale synthesis.
Most importantly, the improved synthesis described in this
report deviates from previous methods that do not exploit
the benefits of the novel sulfone 5 (vide infra).
The synthesis of 4 began with conversion of commercially
available 2,4,5-trifluoro-3-methoxybenzoic acid to the cor-
responding acid chloride 6 using thionyl chloride (Scheme
2). Conversion of an acid chloride to a â-keto ester is
accomplished typically via treatment with monoethyl mal-
onate in the presence of >2 equiv of n-butyllithium.11 Unlike
our previous synthesis,6 we opted for a more process-friendly
method that eliminated the use of n-butyllithium, the
formation of butane gas, and the need for low-temperature
conditions: compound 6 was treated with ethyl potassium
malonate in the presence of magnesium chloride and tri-
ethylamine to generate â-keto ester 7 after acidic workup.
Compound 7 was purified readily by recrystallization,
avoiding column chromatography, to give the desired product
in high yield (77% yield from the starting acid). â-Keto ester
7 was then reacted with potassium hydroxide and cyclopropyl
isothiocyanate in dimethylformamide under phase-transfer
conditions (using tetrabutylammonium bromide as catalyst)
to afford thiolate 8, rather than under the anhydrous
conditions used in our original synthesis6 that employed
sodium hydride and generated hydrogen gas. Thiolate 8 was
not isolated but methylated in situ to give 9 and byproduct
10, the latter of which formed via intramolecular displace-
ment of the C-2 fluoride of 8 by its thiolate anion.10 Using
g1.5 equiv of cyclopropyl isothiocyanate in this two-step
transformation suppressed the formation of byproduct 10 to
∼10%. The molecular structure of 10 was determined via
X-ray crystallography (Figure 2).
After aqueous workup, product 9 (containing ∼10% 10)
was refluxed in toluene with potassium tert-butoxide, avoid-
ing the use of hydrogen-forming sodium hydride used in our
original synthesis,6 to furnish quinolone intermediate 11.
Sulfide 11 was next oxidized using Oxone in a methanol-
(9) Chu, D. T. W. J. Heterocycl. Chem. 1990, 27, 839-843.
(10) Chu, D. T. W.; Claiborne, A. K. J. Heterocycl. Chem. 1990, 27, 1191-
1195.
(11) Wierenga, W.; Skulnick, H. I. J. Org. Chem. 1979, 44, 310-311.
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Figure 2. Structure of thiochromone 10 as determined by
X-ray diffraction. ORTEP view showing the atom-labeling
scheme with thermal ellipsoids drawn at 30% probability.
Intramolecular bonding exists between O(2) and amino proton
H(1) forming a six-membered ring that possesses a mean planar
deviation of 0.047 Å. The interatomic distances are 1.93 and
2.61 Å for H(1)‚‚‚O(2) and N(1)‚‚‚O(2), respectively, and the
N(1)-H(1)‚‚‚O(2) angle is 139.0°. The molecular rings are
coplanar with a total mean deviation of 0.06 Å for S(1)-C(1-
9). Selected bond lengths (Å) and angles (deg) with estimated
standard deviations for 10: N(1)-H(1), 0.82(2); S(1)-C(8),
1.7413(19); S(1)-C(9), 1.7458(17); N(1)-C(9), 1.334(2); N(1)-
C(14), 1.433(2); C(1)-C(9), 1.401(2); C(1)-C(10), 1.480(2);
O(2)-C(10), 1.2233(19); O(3)-C(10), 1.335(2); C(1)-C(2),
1.449(2); O(1)-C(2), 1.228(2); C(2)-C(3), 1.495(2); C(3)-C(8),
1.386(3); C(8)-S(1)-C(9), 102.68(9); C(1)-C(9)-S(1), 125.05(12);
C(9)-C(1)-C(2), 123.26(15); C(1)-C(2)-C(3), 119.37(15); C(8)-
C(3)-C(2), 123.76(15); C(3)-C(8)-S(1), 124.45(13).
water solvent system to generate sulfone 5, which crystallized
directly from the reaction mixture. We also found that urea
hydrogen peroxide in formic acid effected the oxidation of
11 to generate 5. CAUTION: The latter reaction, howeVer,
was difficult to control (highly exothermic) and, therefore,
was not suitable for large-scale synthesis. The molecular
structure of sulfone 5 was determined via X-ray diffraction
(Figure 3A). Sulfone 5 crystallizes in the monoclinic space
group P21/c with two crystallographically independent, but
chemically equivalent, molecules in the asymmetric unit and
four molecules in the unit cell. As shown in Figure 3B, the
two independent molecules possess different orientations of
the peripheral sulfone, ester, methoxy, and cyclopropyl
groups relative to the core (quinolone) two-ring system.
Development of the above process for the synthesis of
sulfone 5 enabled the subsequent preparation of ITQ 4 in
kilogram quantities. Sulfone 5 was next converted (Scheme
2) to the mildly air-sensitive thiol 12 upon treatment with
excess sodium hydrosulfide hydrate. To prevent oxidative
degradation, isolated 12 (unpurified) was reacted immediately
with hydroxylamine-O-sulfonic acid under basic conditions
(using potassium phosphate, avoiding the use of carbon
dioxide forming sodium bicarbonate used in our original
synthesis6) to afford 4 in high yield (51% overall from 7
Figure 3. Structure of sulfone 5 as determined by X-ray
diffraction. ORTEP view of one of the two crystallographically
independent molecules of 5 (molecule 1) showing the atom-
labeling scheme with thermal ellipsoids drawn at 30% prob-
ability (A) and view of the two independent molecules (B). The
molecular rings are coplanar with a total mean deviation of
0.08 Å for both N(1)-C(1-9) and N(1′)-C(1′-9′). There are
no significant intermolecular contacts. Selected bond lengths
(Å) and angles (deg) with estimated standard deviations for 5:
C(1)-C(2), 1.351(5); C(1′)-C(2′), 1.365(5); S(1)-C(1), 1.822(4);
S(1′)-C(1′), 1.818(4); O(3)-C(11), 1.193(4); O(3′)-C(11′),
1.203(4); O(4)-C(11), 1.348(4); O(4′)-C(11′), 1.338(4); C(2)-
C(11), 1.520(5); C(2′)-C(11′), 1.510(5); C(2)-C(3), 1.451(5);
C(2′)-C(3′), 1.453(5); O(5)-C(3), 1.233(4); O(5′)-C(3′), 1.225-
(4); C(3)-C(4), 1.476(5); C(3′)-C(4′), 1.468(5); C(4)-C(9),
1.396(5); C(4′)-C(9′), 1.391(5); N(1)-C(9), 1.407(4); N(1′)-
C(9′), 1.396(4); N(1)-C(1), 1.378(4); N(1′)-C(1′), 1.375(4);
C(1)-N(1)-C(9), 117.2(3); C(1′)-N(1′)-C(9′), 118.2(3); C(2)-
C(1)-N(1), 124.0(3); C(2′)-C(1′)-N(1′), 123.2(3); C(1)-C(2)-
C(3), 120.8(3); C(1′)-C(2′)-C(3′), 120.2(3); C(2)-C(3)-C(4),
114.0(3); C(2′)-C(3′)-C(4′), 114.6(3).
without any special handling or purification during the five-
step transformation).
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391

diffraction (Figure 5). Slow evaporation of a solution of 4
in trifluoroacetic acid yielded crystals suitable for X-ray
structural determination. ITQ 4 cocrystallizes with trifluo-
roacetic acid in a ratio of 1:2. The crystal lattice possesses
an intricate hydrogen-bonding network as illustrated in Figure
5. Two adjacent ITQ molecules interact via N(1)-H(1)‚‚‚
O(1) hydrogen bonds with H(1)‚‚‚O(1) distances of 1.89 Å.
This interaction is reciprocated, and an eight-membered ring
is formed. The cocrystallized solvent molecules are hydrogen
bound to the two carbonyl groups via O(5)-H(5)‚‚‚O(1) and
O(7)-H(7)‚‚‚O(2) interactions. H‚‚‚O distances are 1.89 and
1.75 Å for H(5) and H(7), respectively.
We next converted fluoride 4 to bromide 3 (Scheme 3),
which was necessary for the subsequent installation of the
7-pyridinyl group via Suzuki-Miyaura cross coupling. We
performed a three-step conversion that followed our earlier
method.6 Unlike our previous method, however, we used
4-methoxybenzylamine rather than the cost-prohibitive 2,4-
dimethoxybenzylamine to generate 15 via selective displace-
ment of the C-7 fluoride. Compound 15 was then debenzyl-
ated with trifluoroacetic acid to give 16, which was treated
with tert-butyl nitrite in the presence of cupric bromide14,15
to give 3 (45% yield based on 4).
Finally, bromide 3 was reacted with commercially avail-
able boronic acid 2 under Suzuki-Miyaura cross-coupling
conditions to generate 1 (Scheme 4). Using g2 equiv of 2
in the Suzuki-Miyaura reaction eliminates the competing
debromination reaction of 3. We found that tetrakis(triph-
enylphosphine)palladium(0) was a highly effective catalyst
for cross coupling, whereas several commercially available
polymer-supported palladium catalysts caused substantial
debromination of 3 (40-80%). Initially, we relied on
purification of 1 using preparative HPLC.6 This method of
purification, however, is not suitable for large-scale synthesis,
and the palladium contamination of the purified material
(∼450 ppm) is unacceptable for a potential active pharma-
ceutical ingredient.16 Instead, ITQ 1 was isolated by iso-
electric precipitation at pH ∼7, acidified, triturated, stirred
in solution over activated charcoal and MP-TMT17 (pal-
ladium-scavenging resin), and neutralized to afford analyti-
cally pure material (99% purity by HPLC with <40 ppm
palladium detected by ICP-MS) in 49% yield. Overall, ITQ
1 was synthesized in 9% yield over 11 steps starting from
2,4,5-trifluoro-3-methoxybenzoic acid.
Figure 4. Selected 13C and 15N NMR data of ITQ 4 and related
compounds.
For our initial synthesis of ITQ 4,6 we oxidized methyl
sulfide 11 to the corresponding sulfoxide (not shown) using
m-chloroperbenzoic acid following standard protocol.9,10 This
sulfoxide was then converted to 4 via treatment with
anhydrous sodium hydrosulfide, followed by hydroxylamine-
O-sulfonic acid. Our new methodology, using sulfone 5, is
critical for the practical synthesis of intermediate 4, offering
advantages over the previous sulfoxide method that precluded
large-scale synthesis when considering the following. (i)
Preparation of sulfone intermediate 5 avoids the use of
m-chloroperbenzoic acid, which is potentially explosive and
requires purification before use.8 (ii) The process illustrated
in Scheme 2 also eliminates the need for stoichiometric
control of the oxidant. Oxone, the oxidant used to prepare
5, may simply be used in excess. (iii) The need for
chromatographic purification of the sulfoxide is eliminated
as sulfone 5 crystallizes easily from the reaction mixture.
(iv) The rate of reaction of the sulfone with sodium
hydrosulfide (generating 12 en route to ITQ 4) is greater
(∼3-fold) than that of the corresponding sulfoxide.
The HRMS and multinuclear NMR (1H, 13C, 15N, and 19F)
spectroscopic data of ITQ 4 are fully consistent with its
assigned structure. Specifically, the proton-carbon and
carbon-carbon connectivities of 4, based on COSY, HMQC,
and HMBC experiments, are similar to those (unpublished)
of the known ITQ 139 (Figure 4). In addition, we labeled 4
with 15N via reaction of 12 with [15N]hydroxylamine-O-
sulfonic acid.12 The 13C NMR spectrum of [2-15N]-4 is
identical to that of 4 except the resonance of C-3 appears as
a doublet (J ) 3.5 Hz) rather than a singlet, indicating the
15N-2-N/13C-3-C coupling of the annelated isothiazolo ring.
The 15N NMR spectrum of [2-15N]-4 shows one resonance
in the amido region at 105.4 ppm, consistent with the
presence of the isothiazolo moiety. Both the 13C and 15N
NMR spectroscopic data of 4 are also in excellent agreement
with those of the structurally related isothiazolopyridone 14
(Figure 4) for which the solid-state structure was reported.13
Furthermore, we confirmed the structure of 4 by X-ray
The assigned structure of ITQ 1 is consistent with
multinuclear NMR (1H, 13C, and 19F) spectroscopic data.
Crystals of 1 suitable for X-ray crystallographic analysis
(TFA salt) were obtained via recrystallization from aqueous
ethanol. In contrast to ITQ 4 (Figure 5) and the related
(14) Doyle, M. P.; Siegfried, B.; Dellaria, J. F., Jr. J. Org. Chem. 1977, 42,
2426-2431.
(15) Haight, A. R.; Bailey, A. E.; Baker, W. S.; Cain, M. H.; Copp, R. R.;
DeMattei, J. A.; Ford, K. L.; Henry, R. F.; Hsu, M. C.; Keyes, R. F.; King,
S. A.; McLaughlin, M. A.; Melcher, L. M.; Nadler, W. R.; Oliver, P. A.;
Parekh, S. I.; Patel, H. H.; Seif, L. S.; Staeger, M. A.; Wayne, G. S.;
Wittenberger, S. J.; Zhang, W. Org. Process Res. DeV. 2004, 8, 897-902.
(16) Bien, J. T.; Lane, G. C.; Oberholzer, M. R. Top. Organomet. Chem. 2004,
6, 263-283.
(12) Jime´nez, J. A.; Claramunt, R. M.; Mo´, O.; Ya´n˜ez, M.; Wehrmann, F.;
Buntkowsky, G.; Limbach, H.-H.; Goddard, R.; Elguero, J. Phys. Chem.
Chem. Phys. 1999, 1, 5113-5120.
(13) Wiles, J. A.; Hashimoto, A.; Thanassi, J. A.; Cheng, J.; Incarvito, C. D.;
Deshpande, M.; Pucci, M. J.; Bradbury, B. J. J. Med. Chem. 2006, 49, 39-
42.
(17) Welch, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; DaSilva, J.;
Henderson, D.; Laing, B.; Mathre, D. J.; Spencer, S.; Bu, X.; Wang, T.
Org. Process Res. DeV. 2005, 9, 198-205.
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Figure 5. Structure of ITQ 4 as determined by X-ray diffraction. ORTEP view showing the atom-labeling scheme with thermal
ellipsoids drawn at 30% probability (top) and view of the hydrogen-bonding network in the crystal lattice (bottom). ITQ 4 cocrystallizes
with TFA (solvent) in a ratio of 1:2. The molecular rings of 4 are coplanar with a total mean deviation of 0.07 Å for S(1)-N(1,2)-
C(1-10). Selected bond lengths (Å) and angles (deg) with estimated standard deviations for 4‚2TFA: O(5)-H(5), 0.78(2); O(7)-
H(7), 0.86(2); N(1)-H(1), 1.05(2); C(2)-C(10), 1.3817(19); S(1)-C(10), 1.7245(16); S(1)-N(1), 1.6986(13); N(1)-C(1), 1.3521(19);
O(1)-C(1), 1.2496(16); C(1)-C(2), 1.4508(19); C(2)-C(3), 1.429(2); O(2)-C(3), 1.2322(17); C(3)-C(4), 1.4715(19); C(4)-C(9),
1.4063(19); N(2)-C(9), 1.4115(19); N(2)-C(10), 1.3601(17); C(2)-C(10)-S(1), 112.94(11); N(1)-S(1)-C(10), 89.42(7); C(1)-N(1)-
S(1), 116.65(10); N(1)-C(1)-C(2), 109.23(11); C(10)-C(2)-C(1), 111.74(13); C(10)-N(2)-C(9), 117.39(11); N(2)-C(10)-C(2),
125.30(14); C(10)-C(2)-C(3), 120.39(13); C(2)-C(3)-C(4), 114.34(12).
Scheme 3
Scheme 4
0.08 Å for S(1)-N(1,2)-C(1-10). The torsion angle C(6)-
C(7)-C(11)-C(15) is 48.0°. Hydrogen-bonding exists be-
tween the ion pair of salt 1 as illustrated in Figure 6. The
interatomic distances for the hydroxyl hydrogen bond are
isothiazolopyridone 14,13 salt 1 crystallizes as the enol rather
than as the keto tautomer18 (Figure 6). The central tricyclic
ring system of 1 is planar with a total mean deviation of
(18) For an overview of isothiazolones and their tautomers, see: (a) Taubert,
K.; Kraus, S.; Schulze, B. Sulfur Reports 2002, 23, 79-121. (b) Siegemund,
A.; Taubert, K.; Schulze, B. Sulfur Reports 2002, 23, 279-319.
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393

Figure 6. Structure of ITQ 1 (TFA salt) as determined by X-ray diffraction. ORTEP view showing the atom-labeling scheme with
thermal ellipsoids drawn at 30% probability (top), view of the hydrogen-bonding that exists between the ion pair (middle), and
view of the hydrogen-bonded chains that propagate in the crystal lattice along the crystallographic bc-diagonal axis (bottom). Selected
bond lengths (Å) and angles (deg) with estimated standard deviations for 1‚TFA: N(3)-H(3), 0.97(3); O(1)-H(1), 0.89(3); C(2)-
C(10), 1.388(3); S(1)-C(10), 1.717(2); S(1)-N(1), 1.6717(19); N(1)-C(1), 1.311(3); O(1)-C(1), 1.333(3); C(1)-C(2), 1.436(3); C(2)-
C(3), 1.439(3); O(2)-C(3), 1.239(2); C(3)-C(4), 1.487(3); C(2)-C(10)-S(1), 110.19(15); N(1)-S(1)-C(10), 94.21(10); C(1)-N(1)-
S(1), 109.78(15); N(1)-C(1)-C(2), 117.32(18); C(10)-C(2)-C(1), 108.49(18).
1.76 and 2.62 Å for H(1)‚‚‚O(5) and O(1)‚‚‚O(5), respec-
tively, and the O(1)-H(1)‚‚‚O(5) angle is 163.3°. The
interatomic distances for the amino hydrogen bond are 1.70
and 2.64 Å for H(3)‚‚‚O(4) and N(3)‚‚‚O(4), respectively,
and the N(3)-H(3)‚‚‚O(4) angle is 161.4°. These interactions
form infinitely extending chains that propagate along the
crystallographic bc-diagonal axis as illustrated in Figure 6
(bottom).
Conclusion
We described the synthesis and molecular structure of the
new 2-sulfonylquinolone ethyl 1-cyclopropyl-6,7-difluoro-
2-methanesulfonyl-8-methoxy-4-oxo-1,4-dihydroquinoline-
3-carboxylate (5). Sulfone 5 is a key intermediate used in
the practical synthesis of the potent antibacterial ITQ 1.
Compound 1 was prepared in 9% yield over 11 steps. We
characterized ITQs 1 and 4 thoroughly using several
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techniques, which included the first 15N NMR spectroscopic
and X-ray crystallographic investigations. The synthesis of
ITQ 1 via sulfone 5 is convenient, scaleable, and does not
require chromatographic purification. The validity of the
latter has been demonstrated especially in the final palladium-
catalyzed cross-coupling step that produced high-purity 1
(99%) that contained <40 ppm of residual palladium.
for 2 h and then cooled to rt. To the reaction mixture was
then added water (100 mL), and it was then acidified (pH
∼1-2) with 6 N HCl and mixed vigorously. The organic
layer was separated, and the aqueous layer was extracted
with EtOAc (∼20 mL), and then the organic layers were
combined and evaporated. To the crude material was added
EtOH (200 mL) and water (80 mL), and the mixture was
heated (∼50 °C) and then cooled. At 25-30 °C, a few seed
crystals were added and stirred. The mixture was stirred at
20 °C for 30 min and then cooled to 10 °C and stirred for
30 min. The crystals that formed were collected and washed
with 70% v/v aq EtOH (∼100 mL) and dried to afford 7
(21.3 g, 77%, 2 steps). Mp 59-60 °C. Compound 7 existed
as a ∼10:1 keto/enol mixture of tautomers at room temper-
Experimental Section
General Methods. All nonaqueous reactions were per-
formed under an atmosphere of dry Ar (99.99%) using oven-
dried glassware. Melting points were recorded on an
Electrothermal Model IA9100 digital melting point apparatus;
the reported values are the average of three measurements.
NMR spectra were recorded at ambient temperature, unless
noted otherwise, using either a Bruker Avance 300 spec-
trometer (1H at 300.1 MHz, 13C at 75.5 MHz, and 19F at
282.4 MHz) or a Bruker Avance 500 spectrometer (15N at
50.7 MHz). All 13C, 15N, and 19F NMR spectra were
ature in DMSO-d6. 1H NMR (DMSO-d6): δ 1.18 (t, JH-H
)
7.0 Hz, keto CO2CH2CH3), 4.02 (t, JH-F ) 1.0 Hz, keto
OCH3), 4.09 (d, JH-F ) 3.0 Hz, keto CH2CO2Et), 4.12 (q,
JH-H ) 7.0 Hz, keto CO2CH2CH3), 7.65 (ddd, JH-F ) 11.0
Hz, 8.5 Hz, 6.5 Hz, keto aromatic H-6). 19F NMR (DMSO-
d6): δ -143.2 (dd, JF-F ) 22.0 Hz, 12.5 Hz, keto), -139.7
(dd, JF-F ) 22.0 Hz, 12.5 Hz, keto), -129.8 (apparent t,
JF-F ) 12.5 Hz, keto). HRMS m/z calcd for C12H11F3NaO4
([M + Na]+), 299.0507; found, 299.0498. Anal. Calcd for
C12H11F3O4: C, 52.18; H, 4.01; O, 23.17. Found: C, 52.44;
H, 4.00; O, 23.27.
broadband 1H decoupled. The chemical shifts for 1H and 13
C
are reported in parts per million (δ) relative to external TMS
and were referenced to signals of residual protons in the
deuterated solvent. The chemical shifts for 15N and 19F are
reported in parts per million (δ) relative to external liquid
1
NH3 and CFCl3, respectively. H and 13C NMR data were
assigned via two-dimensional correlation experiments (1H-
Ethyl 3-Cyclopropylamino-3-methylsulfanyl-2-(2,4,5-
trifluoro-3-methoxybenzoyl)acrylate (9). A mixture of 7
(30.0 g, 109 mmol), KOH (7.5 g, 85%), and n-Bu4NBr (0.35
g, 1.09 mmol) in DMF (300 mL) was stirred for 30 min at
rt. The mixture was then cooled to 0 °C, and to it was added
c-PrNCS dropwise (15.2 mL, 164 mmol). After the mixture
stirred for 16 h at rt, MeI (7.5 mL, 121 mmol) was then
added to the reaction mixture, which continued to stir for 3
h. The reaction mixture was quenched with water (800 mL)
and saturated aq NH4Cl (270 mL) and extracted with EtOAc
(2 × 400 mL). The combined organic layers were washed
with water (60 mL) and brine (60 mL) and evaporated to
dryness under reduced pressure. The residue was dissolved
in toluene (50 mL) and evaporated; this process was repeated
twice. The final residue was used in the next reaction without
purification. An analytical sample (light yellow solid) was
obtained via flash column chromatographic purification on
silica gel (eluent: 0-20% v/v EtOAc in hexanes). Mp 46-
1
1
1H COSY, H-13C HMQC, and H-13C HMBC) and the
usual principles of NMR spectroscopy (the magnitudes of
coupling constants and chemical shifts). The purity of
compounds was determined via HPLC-MS on a Waters
X-bridge C18 150 mm × 4.6 mm 3.5 µm column using a
20-min gradient elution of increasing concentrations of CH3-
CN in water (5-95%) containing 0.1% TFA with a flow
rate of 1.0 mL/min and UV detection at 254 nm. Low-
resolution mass spectra were recorded on a Thermo Finnigan
Surveyor MSQ instrument (operating in APCI mode) equipped
with a Gilson liquid chromatograph. High-resolution mass
spectrometric analyses (ESI using NaI as internal standard)
were performed at the W. M. Keck Foundation Biotechnol-
ogy Resource Laboratory (Yale University, New Haven, CT);
the reported exact masses are the average of five measure-
ments. Elemental analyses were performed at Atlantic
Microlab, Inc. (Norcross, GA). Determinations of trace
quantities of residual Pd (ICP-MS) were performed at West
Coast Analytical Service (Santa Fe Springs, CA).
1
47 °C. H NMR (DMSO-d6): δ 0.75 (m, 2H, c-Pr-CH2),
0.90 (m, 5H, overlapping CO2CH2CH3 and c-Pr-CH2), 2.46
(s, 3H, SCH3), 2.93 (br, 1H, c-Pr-CH), 3.83 (q, JH-H ) 7.0
Hz, 2H, CO2CH2CH3), 3.95 (s, 3H, OCH3), 7.10 (ddd, JH-F
) 10.5 Hz, 8.5 Hz, 6.0 Hz, 1H, aromatic H-6), 10.87 (br,
1H). 19F NMR (DMSO-d6): δ -151.7 (br d, JF-F ) 22.0
Hz, 1F), -141.8 (dd, JF-F ) 22.0 Hz, 13.5 Hz, 1F), -135.9
(br, 1F). LRMS (C17H18F3NO4S) m/z (%) 390 ([M + H]+,
96), 344 (100), 296 (42). Anal. Calcd for C17H18F3NO4S:
C, 52.44; H, 4.66; N, 3.60. Found: C, 52.39; H, 4.62; N,
3.55.
Ethyl 2-Cyclopropylamino-6,7-difluoro-8-methoxy-4-
oxo-4H-thiochromene-3-carboxylate (10). Byproduct 10
was obtained via flash column chromatographic separation
from 9 (vide supra). 1H NMR (CDCl3): δ 0.84 (m, 2H, c-Pr-
Ethyl 3-Oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)pro-
pionate (7). A mixture of 2,4,5-trifluoro-3-methoxybenzoic
acid (20.7 g, 100 mmol), SOCl2 (42.8 g, 360 mmol), and
NaCl (∼100 mg) in EtOAc (200 mL) was refluxed for 4 h,
cooled to rt, and concentrated under reduced pressure.
Toluene (50 mL) was added, and evaporated under reduced
pressure; this procedure was repeated twice. The resulting
residue was dried in vacuo for 18 h to give 6. A mixture of
potassium ethylmalonate (23.7 g, 139 mmol) and MgCl2
(29.6 g, 312 mmol) in EtOAc (260 mL) was stirred for 30
min at rt. Et3N (41.8 mL, 300 mmol) was then added, and
the mixture continued to stir for 30 min. To this mixture, a
solution of EtOAc (40 mL) containing acid chloride 6 (from
above) was added slowly. The reaction mixture was refluxed
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
395

CH2), 1.05 (m, 2H, c-Pr-CH2), 1.40 (t, JH-H ) 7.0 Hz, 3H,
CO2CH2CH3), 2.72 (m, 1H, c-Pr-CH), 4.15 (d, JH-F ) 2.5
Hz, 3H, OCH3), 4.37 (q, JH-H ) 7.0 Hz, 2H, CO2CH2CH3),
8.04 (dd, JH-F ) 11.0 Hz, 7.5 Hz, 1H, aromatic H-5), 10.33
(br, 1H). 19F NMR (CDCl3): δ -150.2 (d, JF-F ) 20.5 Hz,
1F), -135.8 (d, JF-F ) 20.5 Hz, 1F). LRMS (C16H15F2NO4S)
m/z (%) 356 ([M + H]+, 100), 310 (36).
136.1 (dd, JC-F ) 4.5 Hz, 1.5 Hz), 141.4 (dd, JC-F ) 10.0
Hz, 1.5 Hz), 148.3 (dd, JC-F ) 253.0 Hz, 16.0 Hz), 149.4
(dd, JC-F ) 249.0 Hz, 12.5 Hz), 153.6, 163.9, 175.0 (d, JC-F
) 2.0 Hz). 19F NMR (DMF-d7): δ -146.5 (d, JF-F ) 21.0
Hz, 1F), -138.3 (d, JF-F ) 21.0 Hz, 1F). LRMS (C17H17F2-
NO6S) m/z (%) 402 ([M + H]+, 20), 356 (100). Anal. Calcd
for C17H17F2NO6S: C, 50.87; H, 4.27; N, 3.49. Found: C,
50.73; H, 4.21; N, 3.43.
Ethyl 1-Cyclopropyl-6,7-difluoro-8-methoxy-2-meth-
ylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (11).
t-BuOK (11.0 g, 98 mmol) was added to a solution of 9
(from above) in toluene (300 mL) at rt. The resulting reaction
mixture was refluxed for 16 h, cooled to rt, and diluted with
water (270 mL). The aqueous layer was separated and
extracted with EtOAc (130 mL). The combined organic
layers were washed with water (60 mL) and brine (60 mL)
and evaporated to dryness. The remaining residue was used
in the next step without further purification. An analytical
sample (colorless solid) was obtained via flash column
chromatographic purification on silica gel (eluent: 0-50%
v/v EtOAc in hexanes). Mp 125 °C. 1H NMR (DMF-d7): δ
0.79 (m, 2H, c-Pr-CH2), 1.20 (m, 2H, c-Pr-CH2), 1.30 (t,
JH-H ) 7.0 Hz, 3H, CO2CH2CH3), 2.75 (s, 3H, SCH3), 3.97
(m, 1H, c-Pr-CH), 4.14 (d, JH-F ) 2.0 Hz, 3H, OCH3), 4.29
(q, JH-H ) 7.0 Hz, 2H, CO2CH2CH3), 7.64 (dd, JH-F ) 10.0
Hz, 8.5 Hz, 1H, aromatic H-5). 13C NMR (DMF-d7): δ 11.7
(br, c-Pr-CH2), 13.7 (CO2CH2CH3), 17.7 (SCH3), 37.2 (c-
Pr-CH), 61.1 (CO2CH2CH3), 62.3 (d, JC-F ) 6.0 Hz, OCH3),
105.7 (d, JC-F ) 19.0 Hz, CH, C-5), 122.4, 124.3 (dd, JC-F
) 6.0 Hz, 2.0 Hz), 137.0 (dd, JC-F ) 4.0 Hz, 1.5 Hz), 140.8
(dd, JC-F ) 11.5 Hz, 1.5 Hz), 147.6 (dd, JC-F ) 251.0 Hz,
15.5 Hz), 148.7 (dd, JC-F ) 248.0 Hz, 12.5 Hz), 156.6, 165.2,
171.6 (d, JC-F ) 1.5 Hz). 19F NMR (DMF-d7): δ -148.7
(d, JF-F ) 21.5 Hz, 1F), -139.9 (d, JF-F ) 21.5 Hz, 1F).
LRMS (C17H17F2NO4S) m/z (%) 370 ([M + H]+, 100), 324
(20). Anal. Calcd for C17H17F2NO4S: C, 55.28; H, 4.64; N,
3.79. Found: C, 55.23; H, 4.60; N, 3.72.
Ethyl 1-Cyclopropyl-6,7-difluoro-2-methanesulfonyl-
8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5).
Water (240 mL), followed by Oxone (229 g, 373 mmol),
was added to a suspension of 11 (from above) in MeOH
(690 mL). The reaction mixture was heated with stirring at
55-60 °C for 3 h. The reaction mixture was cooled to rt,
diluted with water (450 mL), and stirred at ∼5 °C (ice bath)
for 30 min. The resulting crystals were collected by filtration,
washed with water (2 × 150 mL), and dried in vacuo to
afford 5 (24.0 g). This material was used in the next step
without further purification. An analytical sample (colorless
solid) was obtained via recrystallization from EtOAc/
hexanes. Mp 177-178 °C. 1H NMR (DMF-d7): δ 0.62 (m,
1H, c-Pr-CH2), 1.11 (m, 2H, c-Pr-CH2), 1.29 (m, 1H, c-Pr-
CH2), 1.32 (t, JH-H ) 7.0 Hz, 3H, CO2CH2CH3), 3.76 (s,
3H, SO2CH3), 4.18 (m, 1H, c-Pr-CH), 4.21 (d, JH-F ) 2.0
Hz, 3H, OCH3), 4.33 (q, JH-H ) 7.0 Hz, 2H, CO2CH2CH3),
7.64 (dd, JH-F ) 10.0 Hz, 8.5 Hz, 1H, aromatic H-5). 13C
NMR (DMF-d7): δ 8.9 (c-Pr-CH2), 12.5 (c-Pr-CH2), 13.5
(CO2CH2CH3), 37.3 (c-Pr-CH), 44.5 (SO2CH3), 61.9 (CO2CH2-
CH3), 62.2 (d, JC-F ) 6.5 Hz, OCH3), 105.4 (d, JC-F ) 19.5
Hz, CH, C-5), 123.0, 124.4 (dd, JC-F ) 6.5 Hz, 1.5 Hz),
9-Cyclopropyl-6,7-difluoro-8-methoxy-9H-isothiazolo-
[5,4-b]quinoline-3,4-dione (4). NaSH‚xH2O (5.8 g, x ≈ 1.2,
Aldrich) was added to solution of 5 (24.0 g, 60 mmol) in
DMF (240 mL). The resulting mixture was stirred at rt for
5 h, diluted with water (620 mL), acidified with 6 N HCl
(to pH ∼1-2), and extracted with EtOAc (2 × 150 mL).
CAUTION: Toxic hydrogen sulfide gas is eVolVed. This
procedure must be carried out in a well-Ventilated hood with
proVisions for preVenting loss of H2S to the atmosphere (e.g.,
a trap containing 20% aq NaOH). The combined organic
layers were washed with water (60 mL) and brine (60 mL),
dried over Na2SO4, and evaporated under reduced pressure.
To prevent oxidative degradation, isolated thiol 12 was used
directly without further purification. The residue containing
12 was dissolved in a mixture of THF (240 mL), water (240
mL), and K3PO4 (69.0 g, 300 mmol) at 0 °C. H2NOSO3H
(28.0 g, 248 mmol) was then added portionwise, and the
resulting mixture was stirred at rt overnight. THF was
removed under reduced pressure, and the mixture was
acidified with 6 N HCl to pH 2. The resulting precipitate
was collected, washed with water (3 × 50 mL), washed
(while stirring ∼10 min) with TBME (3 × 50 mL), and dried
in vacuo to afford 4 (17.8 g, 51% yield from 7) as a cream-
colored solid. An analytical sample was obtained via
1
recrystallization from DMF. Mp 250 °C (dec). H NMR
(DMF-d7): δ 1.23 (m, 2H, c-Pr-CH2), 1.31 (m, 2H, c-Pr-
CH2), 3.98 (m, 1H, c-Pr-CH), 4.16 (d, JH-F ) 1.5 Hz, 3H,
OCH3), 7.92 (dd, JH-F ) 10.5 Hz, 9.0 Hz, 1H, aromatic H-5).
13C NMR (DMF-d7): δ 11.1 (c-Pr-CH2), 35.9 (c-Pr-CH),
63.0 (d, JC-F ) 6.0 Hz, OCH3), 107.1 (d, JC-F ) 18.0 Hz,
CH, C-5), 107.3 (C-3a), 123.1 (dd, JC-F ) 7.5 Hz, 5.5 Hz,
C-4a), 133.9 (dd, JC-F ) 5.5 Hz, 4.0 Hz, C-8a), 140.0 (dd,
JC-F ) 12.0 Hz, 1.0 Hz, C-OCH3, C-8), 147.7 (dd, JC-F
)
247.0 Hz, 12.5 Hz, C-6 or C-7), 148.3 (dd, JC-F ) 251.0
Hz, 15.5 Hz, C-6 or C-7), 164.6 (C-3), 171.0 (d, JC-F ) 2.0
Hz, C-4), 171.6 (C-9a). 15N NMR (DMF-d7, -50 °C): δ
-105.4 (s, N-2). 19F NMR (DMF-d7): δ -146.9 (d, JF-F
)
21.5 Hz, 1F), -141.2 (d, JF-F ) 21.5 Hz, 1F). LRMS
(C14H10F2N2O3S) m/z (%) 325 ([M + H]+, 100). HRMS m/z
calcd for C14H10F2N2NaO3S ([M + Na]+), 347.0278; found,
347.0269. Anal. Calcd for C14H10F2N2O3S: C, 51.85; H,
3.11; N, 8.64. Found: C, 51.83; H, 3.15; N, 8.65.
9-Cyclopropyl-7-(4-methoxybenzylamino)-6-fluoro-8-
methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione (15). To
a stirred solution of 4 (11.1 g, 34.3 mmol) in dimethylac-
etamide (200 mL) was added 4-methoxybenzylamine (18
mL, 137 mmol). The reaction mixture was stirred at 90 °C
for 18 h, cooled to rt, and diluted with EtOAc (460 mL).
The organic layer was washed with 2 N HCl (4 × 200 mL)
to remove excess 4-methoxybenzyl amine, washed with brine
396
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

Table 1. Crystallographic data for compounds 1, 4, 5, and 10
1‚CF3CO2H
4‚2CF3CO2H
5
10
empirical formula
C22H17F4N3O5S
511.45
C18H12F8N2O7S
552.36
C17H17F2NO6S
401.38
C16H15F2NO4S
355.35
fw (g mol-1
)
crystal dimenions (mm3)
0.20 × 0.20 × 0.10
0.35 × 0.20 × 0.20
0.10 × 0.10 × 0.05
monoclinic
P21/c (#14)
24.528(5)
7.1340(14)
21.125(4)
90
114.89(3)
90
3353.0(12)
8
0.20 × 0.20 × 0.20
crystal system
space group
a (Å)
b (Å)
c (Å)
R (deg)
â (deg)
γ (deg)
V (Å3)
triclinic
triclinic
triclinic
P1h (#2)
P1h (#2)
P1h (#2)
8.2971(17)
9.7116(19)
14.452(3)
81.00(3)
8.6649(17)
9.1625(18)
14.151(3)
79.77(3)
8.8361(18)
9.6639(19)
10.439(2)
101.76(3)
99.69(3)
81.81(3)
66.27(3)
1048.9(4)
2
1.619
2.33
123(2)
74.02(3)
74.16(3)
1032.6(4)
2
1.776
2.76
173(2)
113.51(3)
768.7(3)
2
1.535
2.54
Z
F
calcd (g cm-3
)
1.590
2.52
123(2)
µ (Mo KR) (cm-1
)
temp (K)
173(2)
total data collected
no. of indep reflns
9166
8913
14 391
6440
5529 (Rint ) 0.0393)
5529/0/324
0.524 and -0.510
0.0533, 0.1499
1.067
5385 (Rint ) 0.0368)
5385/0/365
0.566 and -0.435
0.0598, 0.1858
1.262
8698 (Rint ) 0.0681)
8698/0/487
1.860 and -0.606
0.0778, 0.2018
1.042
3972 (Rint ) 0.0317)
3972/0/221
0.636 and -0.549
0.0507, 0.1581
1.089
no. of data/restraints/parms
largest diff peak and hole (e Å-3
)
b
Ra, Rw
GOF
a R ) Σ||Fo| - |Fc||/Σ|Fo| for all I > 2σ(I). b Rw ) {Σ[w(Fo - Fc2)2]/Σ[w(Fo2)2]}1/2
.
2
(2 × 200 mL), dried over Na2SO4, and concentrated under
reduced pressure to afford 15 as a dark brown oil. This
material was used in the next step without further purifica-
(C-OCH3, C-8), 156.0 (d, JC-F ) 245.0 Hz, C-F, C-6),
165.2 (C-3), 171.6 (C-4), 172.3 (C-9a). 19F NMR (DMF-
d7): δ -111.2 (s). LRMS (C14H10BrFN2O3S) m/z (%) 385
([M + H]+, 100). HRMS m/z calcd for C14H10BrFN2NaO3S
([M + Na]+), 406.9477; found, 406.9473. Anal. Calcd for
C14H10BrFN2O3S‚0.15TFA: C, 42.69; H, 2.54; N, 6.96.
Found: C, 42.49; H, 2.68; N, 7.22. The stoichiometry of
the TFA was confirmed by 19F NMR spectroscopy.
1
tion. H NMR (DMSO-d6): δ 0.84 (m, 2H), 1.11 (m, 2H),
3.61 (s, 3H), 3.67 (s, 3H), 3.76 (m, 1H), 4.48 (s, 2H), 6.83
(d, JH-H ) 8.5 Hz, 2H), 7.26 (d, JH-H ) 8.5 Hz, 2H), 7.51
(d, JH-F ) 13.0 Hz, 1H). LRMS (C22H20FN3O4S) m/z (%)
442 ([M + H]+, 100).
7-Bromo-9-cyclopropyl-6-fluoro-8-methoxy-9H-isothi-
azolo[5,4-b]quinoline-3,4-dione (3). To a stirred solution
of 15 (crude from above, 12.3 g, 28 mmol) in CH2Cl2 (100
mL) was added TFA (6 mL). The reaction mixture was
stirred at rt for 4 h and concentrated under reduced pressure
to give 16 (TFA salt) as a red oil. To a stirred solution of
t-BuONO (12 mL, 100 mmol) and CuBr2 (28 g, 123 mmol)
in CH3CN (170 mL) was added dropwise a mixture of the
crude TFA salt of 16 (from above) in CH3CN (50 mL) at 67
°C. After the addition was complete (∼10 min), the reaction
mixture was cooled to rt, and saturated aq NH4Cl was added.
The product was extracted with CHCl3 (2 × 400 mL). This
organic layer was washed with brine (2 × 250 mL), dried
over Na2SO4, and evaporated under reduced pressure. A
mixture of the remaining oil in 10% v/v MeOH in EtOAc
(300 mL) was refluxed for 20 min with stirring. The
remaining solid was removed at rt by filtration and washed
with 50% v/v EtOAc in hexanes (2 × 100 mL). The filtrate
was evaporated under reduced pressure to give 3 as a red
solid (5.9 g, 45% yield from 4). An analytical sample was
obtained via preparative HPLC purification.4 1H NMR
(DMF-d7): δ 1.16 (m, 2H, c-Pr-CH2), 1.27 (m, 2H, c-Pr-
CH2), 3.94 (m, 1H, c-Pr-CH), 3.97 (s, 3H, OCH3), 7.89 (d,
JH-F ) 8.5 Hz, 1H, H-5). 13C NMR (DMF-d7): δ 12.0 (c-
Pr-CH2), 36.0 (c-Pr-CH), 62.8 (OCH3), 107.6 (d, JC-F ) 24.0
Hz, CH, C-5), 108.0 (C-3a), 112.9 (d, JC-F ) 22.0 Hz, C-Br,
C-7), 132.6 (C-4a), 134.6 (d, JC-F ) 2.0 Hz, C-8a), 149.8
9-Cyclopropyl-7-(2-methylpyridin-4-yl)-6-fluoro-8-meth-
oxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione (1). Under an
atmosphere of Ar, Pd(PPh3)4 (1.81 g, 1.6 mmol), 2-methyl-
4-pyridinylboronic acid (2, 12.8 g, 93 mmol), and 1 M aq
NaHCO3 (400 mL) were added to a solution containing 3
(12.0 g, 32 mmol) and DMF (800 mL). The resulting mixture
was heated at 110 °C for 18 h and evaporated to dryness
under reduced pressure. The isolated dark brown solid was
partially dissolved in water (120 mL) and neutralized with
concd HCl. The remaining solid was collected by filtration
and washed with water (240 mL). The solid was dissolved
in TFA (24 mL) and concentrated under reduced pressure
to give a brown residue. This residue was triturated with
water (240 mL). The solid that formed was collected by
filtration, washed with water (120 mL), and washed with
EtOAc (2 × 120 mL). The collected solid was dissolved in
a mixture of MeOH (240 mL) and concd HCl (12 mL) and
stirred over activated charcoal (1.2 g) at rt for 1 h. The
charcoal was removed by filtration, and a small aliquot was
removed and concentrated under reduced pressure. The
remaining residue contained 191 ppm (ICP-MS) of residual
palladium. The filtrate from above was stirred consequently
over MP-TMT resin (3.2 g, 0.96 mmol/g, Argonaut Tech-
nologies) at rt for 24 h. The resin was removed by filtration,
and the filtrate was concentrated under reduced pressure. The
remaining residue was partially dissolved in water (120 mL)
and neutralized with 40% aq NaOH. The solid was collected
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
397

by filtration, washed with water (2 × 36 mL), and dried in
vacuo to give 1 (6.1 g, 49%) as a tan solid. Mp 248-249
°C (dec). 1H NMR (DMSO-d6): δ 1.01 (m, 2H, c-Pr-CH2),
1.10 (m, 2H, c-Pr-CH2), 2.50 (s, 3H, pyridinyl CH3), 3.37
(s, 3H, OCH3), 3.76 (m, 1H, c-Pr-CH), 7.28 (d, JH-H ) 5.0
Hz, 1H, pyridinyl H-5), 7.35 (s, 1H, pyridinyl H-3), 7.75
(d, JH-F ) 9.5 Hz, 1H, ITQ H-5), 8.55 (d, JH-H ) 5.0 Hz,
1H, pyridinyl H-6). 13C (DMSO-d6, 70 °C): δ 10.8 (c-Pr-
CH2), 23.6 (pyridinyl CH3), 35.0 (c-Pr-CH), 62.1 (OCH3),
106.1 (d, JC-F ) 24.0 Hz, C-5), 106.8 (C-3a), 121.6 (d, JC-F
) 1.0 Hz, pyridinyl C-5), 123.5 (d, JC-F ) 1.0 Hz, pyridinyl
C-3), 126.5 (d, JC-F ) 18.0 Hz, C-7), 128.0 (d, JC-F ) 8.0
Hz, C-4a), 132.7 (d, JC-F ) 2.0 Hz, C-8a), 138.5 (pyridinyl
C-4), 148.5 (d, JC-F ) 4.5 Hz, C-8), 148.6 (pyridinyl C-6),
154.8 (d, JC-F ) 246.5 Hz, C-6), 157.7 (pyridinyl C-2), 163.8
(C-3), 170.3 (d, JC-F ) 2.5 Hz, C-4), 170.8 (C-9a). 19F NMR
(DMSO-d6): δ -119.0 (s). LRMS (C20H16FN3O3S) m/z (%)
398 ([M + H]+, 100). HRMS m/z calcd for C20H17FN3O3S
([M + H]+), 398.0975; found, 398.0964. Analytical HPLC:
tR 8.95 min (98.9% purity). Residual Pd (ICP-MS): 39.0
ppm. Anal. Calcd for C20H16FN3O3S‚0.5H2O: C, 59.10; H,
4.22; N, 10.34. Found: C, 59.21; H, 3.93; N, 10.30.
solved by direct methods and expanded using Fourier
techniques (SHELXTL v.6.12 software package). Non-
hydrogen atoms were refined anisotropically, and hydrogen
atoms, with exceptions noted below, were treated as idealized
contributions. For ITQ 1, protons H(1) and H(3) were located
from the residual electron difference map and refined with
isotropic displacement parameters. For ITQ 4 and thio-
chromone 10, amino proton H(1) was located from the
residual electron difference map and refined with isotropic
displacement parameters. ITQ 4 cocrystallized with solvent
(trifluoroacetic acid) in a ratio of 1:2. The hydroxyl protons
H(5) and H(7) of the solvent molecules were located from
the residual electron difference map and refined with
isotropic displacement parameters. One of the solvent
molecules possessed positional disorder of the CF3 group.
The disorder was effectively modeled using alternative sites
for F(6-8) with an occupancy factor ratio of 65:35. All
components of disorder were refined using anisotropic
displacement parameters. Crystal data and structure refine-
ment details for 1, 4, 5, and 10 are given in Table 1.
Acknowledgment
X-ray Crystallography. Crystals of 1 were obtained as
follows. ITQ 1 was dissolved in TFA and concentrated under
reduced pressure; the remaining solid was recrystallized from
aq EtOH to give crystals of 1‚TFA. Crystals of 4, 5, and 10
were obtained by slow evaporation of solutions of TFA,
formic acid, and EtOAc/hexanes, respectively. All measure-
ments were made on a Nonius KappaCCD diffractometer
with graphite-monochromated Mo KR radiation (λ ) 0.710 73
Å), and intensity data were collected using the ω-scan mode.
The data were corrected for Lorentz and polarization effects,
and no absorption correction was applied. The structures were
We thank Xiaoling Wu (Yale University) for collecting
15N NMR spectroscopic data.
Supporting Information Available
X-ray crystallographic data for compounds 1, 4, 5, and
10 in CIF format. This information is available free of charge
via the Internet at http://pubs.acs.org.
Received for review January 21, 2007.
OP700014T
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Vol. 11, No. 3, 2007 / Organic Process Research & Development