492 was isolated in 88-91% yield for the two steps (eq 6).
Thus, the synthesis of ABT-492 was accomplished in 70%
overall yield over nine transformations from trifluorobenzoic
acid.
keeping the temperature <20 °C. After separating layers,
the organic layer is washed with water (83 kg).
After a second run, the organic layers are combined and
distilled under a vacuum, and ethanol is added twice as a
chase distillation. The slurry was heated to ∼45 °C until all
the solids dissolve. The solution is cooled to 0 °C, and water
(112 kg) is added to the resulting slurry. Following filtration,
the wetcake is washed with a cold 50% aqueous ethanol
solution and dried under a vacuum to give 85.6 kg of ethyl
(2,4,5-trifluorobenzoyl)acetate 5 as a white solid (94% yield
from 2,4,5-trifluorobenzoic acid).
1H NMR (CDCl3) (keto) δ 7.75 (ddd, J ) 10.8, 10.8, 6.0
Hz, 1H), 7.02 (ddd, 1H), 4.27 (q, J ) 7.2 Hz, 2H), 3.95 (d,
4.2 Hz, 2H), 1.35 (t, J ) 7.3 Hz, 3H); (enol) δ 12.72 (s,
1H), 7.85 (ddd, J ) 10.5, 9.6, 6.6 Hz, 1H), 6.96 (ddd, J )
10.5, 10.5, 6.6 Hz, 1H), 5.84 (s, 1H), 4.23 (q, J ) 7.2 Hz,
2H), 1.27 (t, J ) 7.4 Hz, 3H).
3-(2,4,5-Trifluorophenyl)-2-(N-[6′-amino-3′,5′-difluoro]-
aminopyridine)methylene-3-oxopropionic Acid, Ethyl Es-
ter (7). Ketoester 5 (83.2 kg, 338 mol) and triethylortho-
formate (80.1 kg, 540.7 mol) are heated to reflux (∼140 °C)
and stirred for 30 min. Acetic anhydride (103.5 kg, 1014
mol) is then added, and heating continued for about 12 h.
Then the mixture was cooled and diluted with NMP (210
kg) and acetonitrile (161 kg) and stirred. Water (3.0 kg, 169
mol) is added to the solution, which was then stirred for 10
min to decompose excess triethylorthoformate.
The resulting solution is added to a suspension of 2,6-
diamino-3,5-difluoropyridine, 6 (57.4 kg, 395 mol), NMP
(210 kg), and acetonitrile (161 kg). The reaction typically is
complete in <1 h, and the resulting homogeneous solution
is added to water (662 kg) over 2 h, precipitating the yellow
product. The product is filtered, and the wetcake was washed
with a solution of acetonitrile (161 kg) and water (102 kg).
The wetcake is then washed with water (600 kg) and dried
at 60 °C to provide 120 kg (93%) of the vinylagous amide
7, as a mixture of E and Z isomers
Mp 157-160 °C; 1H NMR (CDCl3, 300 MHz) (E-isomer)
δ 1.15 (t, 3H), 4.16 (q, 2H), 4.64 (br s, 2H), 6.90 (m, 1H),
7.22 (t, 1H), 7.32 (m, 1H), 9.03 (d, 1H), 12.44 (bd, 1H);
(Z-isomer) δ 1.03 (t, 3H), 4.11 (q, 2H), 4.60 (br s, 2H), 6.90
(m, 1H), 7.20 (t, 1H), 7.48 (m, 1H), 8.90 (d, 1H), 11.17 (bd,
1H). Anal. Calcd for C17H12F5N3O3: C, 50.88; H, 3.01; N,
10.47. Found: C, 50.83; H, 2.70; N, 10.32.
1-(6-Amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-isobu-
tyryloxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-car-
boxylic Acid, Ethyl Ester, 2c. To a solution of vinylagous
amide, 7 (115 kg, 286 mol), LiCl (24.3 kg, 573 mol, 1.99
equiv) in NMP (768.6 kg) is added DBU (46.1 kg, 303 mol,
1.06 equiv) over 1 h 40 min, maintaining the internal
temperature at 35 °C. The reaction temperature is then
adjusted to 23 ( 5 °C, and the reaction is stirred for 2 h.
When the cyclization is complete azetidine hydrochloride
(33.9 kg, 309 mol, 1.08 equiv) is added followed by DBU
(109.2 kg, 717 mol, 2.5 equiv) over 2 h. The reaction
temperature is then adjusted to 23 ( 5 °C. After the addition
is complete, isobutyric anhydride (99.7 kg, 630 mol, 2.2
equiv) is added and the reaction is stirred 1 h at 35 °C and
The mechanism of the acid-catalyzed NCS chlorination
reaction is unclear. It has been proposed that treatment of
NCS with HClO4 in hexanes, where the NCS is insoluble,
-
generates Cl+ ClO4 as the reactive chlorinating species.12
However, it also seems reasonable that, under the current
conditions, where NCS is soluble, the active oxidant could
be a protonated form of NCS.14
In conclusion, we have developed new chlorination
reaction conditions for the installation of chlorine at the
8-position of a quinolone substrate, which were employed
in the synthesis of the quinolone antibiotic ABT-492. These
conditions are notable for their mildness, which permitted
their use in the presence of an acid-sensitive azetidine moiety.
Experimental Section
Ethyl 2,4,5-trifluorobenzoyl acetate (5).1515 A reactor
is charged with 2,4,5-trifluorobenzoic acid (1a, 139.5 kg,
792 mol), toluene (613 kg), and DMF (8.4 kg, 14 mol %),
followed by thionyl chloride (139.4 kg, 1.58 equiv). The
contents are brought up to 60 ( 5 °C and mixed until the
starting acid is consumed (typically 3 h). (Caution: A large
amount of outgassing is observed in this process.) After
cooling the contents to 25 °C, the solution is distilled under
vacuum until approximately 750 L are left. Fresh toluene
(600 kg) is added, and a second distillation was brought down
to 750 L. The final acid chloride solution is then used without
further purification.
Potassium ethyl malonate (50.8 kg, 298 mol), magnesium
chloride (34.5 kg, 362 mol), and toluene (130 kg) are cooled
to ∼0 °C, and THF (265 kg) is added while keeping the
temperature <10 °C. The slurry is cooled again to 0 °C,
and triethylamine (75 kg, 742 mol) is charged. The suspen-
sion is warmed to 50 °C and held for 1 h at which point the
solution becomes visibly thinner. The free flowing suspension
is recooled to 0 °C and stirred for 1 h. The acid chloride
toluene solution (163 Kg) precooled to 0 °C is charged to
the enolate over 50 min while keeping it <10 °C (the reactor
jacket was set at -10 °C). Typically the reaction is complete
within 10 min.
The yellow suspension is slowly added to hydrochloric
acid (309 kg of water and 98 kg of concentrated HCl),
(14) A mechanism in which N-chlorination on the substrate is followed by
chlorine transfer to the 8-position is considered unlikely. During the
chlorination reactions, we have observed by HPLC compounds which are
consumed by the bisulfite quench. Though we have not unequivocally
assigned their structures, we believe that they are in fact N-chlorinated
byproducts.
(15) Hay, A. M.; Hobbs-Dewitt, S.; MacDonald, A. A.; Ramage, R. Synthesis
1999, 1979-1985.
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Vol. 10, No. 4, 2006 / Organic Process Research & Development