An improved non-chromatographic scale-up synthesis of a new 1,6,7,8-substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a potent bacterial topoisomerase inhibitor

Full text of DOI:10.1080/00304941003680731

Organic Preparations and Procedures International, 42:151–160, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304941003680731
An Improved Non-chromatographic Scale-up
Synthesis of a New 1,6,7,8-Substituted-4-oxo-1,4-
dihydroquinoline-3-carboxylic Acid as a Potent
Bacterial Topoisomerase Inhibitor
Xun Li,1 Scott Youells,1 Ronald K. Russell,1 Armin Roessler,2
Tobias Schmid,2 Roger Faessler,2 Michele A. Weidner-Wells,1
Eugene B. Grant,1 and Mark J. Macielag1
1Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh &
McKean Roads, P. O. Box 776, Spring House, PA, USA
2Cilag AG, Cilag CH-Schaff Oper, Hochstrasse 201, CH-8205 Schaffhausen,
Switzerland
7-[4-(2-Amino-1-chloroethylidene)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (10) is a potent bacterial topoisomerase
inhibitor. In vitro, compound 10 is two-fold more potent than gemifloxacin when tested
against ciprofloxacin-resistant Streptococcus pneumoniae clinical isolates (MIC90
=
1 µg/mL); it is also more potent than ciprofloxacin and gemifloxacin when tested against
a collection of methicillin-resistant Staphylococcus aureus (MIC90 = 2 µg/mL) and
coagulase-negative staphylococci isolates (MIC90 = 1 µg/mL).1,2 In order to prepare
100 g of compound 10 to facilitate in vivo investigation, it was decided to attempt to
improve some of the steps of the original discovery medicinal chemistry (Discovery)
route, an eight-step convergent synthesis with merely 6% overall yield of 10,1,2 and
address the scale up issues that were identified in the following steps: first, the high
exothermicity of the use of sodium hydride (NaH) to generate triethyl 2-chloro-2-
phosphonoacetate anion in the Horner-Wadsworth-Emmons reaction and its quenching
(Step 1, Schemes 1), second, the reduction of ester 2 using DIBALH resulted in a 44%
yield of alcohol 3 after chromatography (Step 2, Schemes 1), third, the product 4 of
Mitsunobu reaction also required chromatographic purification (Step 3, Schemes 1),
fourth the preparation of difluoroborate ester 7 required a large excess (11.9 equiv) of
borontrifluoride etherate and extended reaction times (48–72 h), but gave only moderate
to fair yields (50–78%) of 7 by precipitation of the crude product with diethyl ether
Received September 25, 2009; in final form February 3, 2010.
Address correspondence to Xun Li, Johnson & Johnson Pharmaceutical Research & Develop-
ment, L.L.C., Welsh & McKean Roads, P. O. Box 776, Spring House, PA 19477, USA. E-mail:
xli6@its.jnj.com
151

152
Li et al.
X
(EtO)2OP
CO2Et
X
CO2Et
X
O
2a
, DIBALH, THF
OH
K2CO3, EtOH
20 °C, 4 h
-78 °C, 20 h;
10 °C, 2 h
step 1
step 2
N
N
N
Boc
Boc
Boc
1
2a, X = Cl
2b, X = F
(99%)
3a, X = Cl
3b, X = F
(68%)
O
O
N
Cl
Cl
3a
1). TFA (6.0 eq),
, phthalimide
N
CH2Cl2, 20 °C, 2 h
2). NaHCO3
DIAD, PPh3, 2-MeTHF
- 10 to 20 °C, 18 h
O
O
step 3
step 4
N
N
H
Boc
4
(70%)
5 (99%)
Scheme 1
(Step 1, Scheme 2), and fifth, a long reaction time (total 72 h) for Steps 2 and 3 (of
Scheme 2) that gave only low to moderate yield of product 9.1,2 Herein, we report an
improved non-chromatographic scale up process for acid 10 and its hydrochloride salt 11
in 22% and 19% overall yields, respectively.
O
5, TEA,
O
N
7
BF3-Et2O, K2CO3
THF, 60 °C, 6 h
F
F
CO2H
MeCN
F
F
CO2BF2
80 °C, 24 h
N
step 1
step 2
O
O
Me
Me
6
(99%)
O
O
CO2H
F
TEA, EtOH
72 °C, 2 h;
20 °C, 18 h
O
F
CO2BF2
O
N
O
N
O
N
N
N
N
O
step 3
O
Me
Me
Cl
Cl
9 (47%)
8
O
N
O
F
CO2H
F
CO2H HCl, EtOH
0 °C, 5 min;
NH2NH2, EtOH
65 °C, 2 h
HCl
NH2
20 °C, 20 min
NH2
Cl
N
N
N
O
O
step 5
step 4
Me
Me
Cl
11 (90%)
10
(99%)
Scheme 2

1,6,7,8-Substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid
153
The two key building blocks, 2-[2-chloro-2-(piperidin-4-ylidene)ethyl]isoindoline-
1,3-dione (5) and [1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-
quinolinecarboxylato-κO3]-difluoroboron (7), were coupled in Step 6 to afford 8 via
the displacement of the 7-fluoro group of compound 7 by the cyclic secondary amine
of compound 5. Compound 5 was prepared from commercially available tert-butyl 4-
oxopiperidine-1-carboxylate (1) by a four-step synthetic sequence (Scheme 1). Although
the Discovery procedure produced a high yield (95%) of chloroalkylidene ester 2a by the
Horner-Wadsworth-Emmons reaction of compound 1 (Step 1),3–5 both the deprotonation of
triethyl 2-chloro-2-phosphonoacetate using NaH in THF and the quench of the completed
reaction were highly exothermic. The non-exothermic one-pot reaction process, originally
developed for the synthesis of fluoroalkylidene carboxylate ester 2b (the precursor of 3b),6
was also found useful for the preparation of 3a. In practice, the treatment of triethyl 2-
chloro-2-phosphonoacetate with K2CO3 in absolute EtOH and follow by addition of 1 at
ambient temperature for 4 h afforded 2a in quantitative yield via a non-exothermic reaction
and without the need for chromatographic purification. Reduction of 2a to the correspond-
ing allylic alcohol 3a using DIBALH in toluene led to a 44% yield of 3a and required
chromatographic purification (Step 2, Scheme 1). When toluene was replaced by THF as
the solvent and the reaction was quenched with 40% Rochelle’s solution,7 3a was obtained
in 62% yield without chromatography. The hydroxy group of 3a was converted to the pro-
tected amine 4 using phthalimide under Mitsunobu reaction conditions,8–10 and a 73% yield
of pure 4 was obtained after recrystallization of the crude product from EtOAc/toluene (1/9).
At this point, the Boc-protecting group of compound 4 was cleaved with trifluoroacetic
acid (TFA) to afford the cyclic secondary amine 5 as a free base after aqueous alkaline
workup.
Difluoroborate ester 7 was readily prepared form commercially available 1-
cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6) in
quantitative yield, after the treatment of 6 with a slight excess of BF3·Et2O (1.35 equiv)
and using K2CO3 (1.15 equiv) as an acid scavenger in refluxing THF for 6 h (Step 1,
Scheme 2). The addition of an inorganic base (K2CO3) to this reaction was a key improve-
ment to the Discovery route, since K2CO3 reacted efficiently with the by-product HF and
formed insoluble KF salt, which precipitated out of the system, and drove the reaction to the
completion.11 The displacement of the 7-fluoro group of difluoroborate ester 7 with cyclic
amine 5 led the borate ester intermediate 8, which was not isolated and underwent alcohol-
ysis in situ to the penultimate acid intermediate 9 in 47% yield (Steps 2 and 3, Scheme 2).12
Attempts to improve the yield of 8 by replacement of Et3N with N-methylpyrrolidine or by
changing the solvent from MeCN to DMF were not fruitful and resulted in only a 35–48%
yield of 8. The moderate yields of steps 2 and 3 could be attributed to the simultaneous
occurrence of two competitive processes: the desired coupling of 5 and 7 to intermediate
8 and the cleavage of difluoroborate ester 7 (by HF generated in Step 2) back to starting
acid 6 (∼26%, MH+ = 296), which in turn, formed an insoluble salt pair with amine 5 in
MeCN.
The phthalimide protecting group of 9 was cleaved by treatment with eight equiv of
hydrazine in refluxing methanol for 1 h to afford a mixture of the desired amine product 10
and the by-product, phthalhydrazide (Step 4, Scheme 2).13,14 Use of 4.0 equiv of hydrazine
resulted in incomplete conversion (< 60% of 10) after refluxing for 3 h while 6.0 equiv

154
Li et al.
of hydrazine gave 90% of 10 over the same time frame. When MeCN was added to
the warm alcoholic mixture of 10 and phthalhydrazide, the by-product precipitated in
nearly quantitative yield as a crystalline white solid that was easily removed by filtration.
Concentration of the filtrate resulted in crude 10, which was recrystallized from a mixture
of MeOH and MeCN to provide pure crystalline free base 10 in a good yield (80%). Finally,
compound 10 was converted to its hydrochloride salt, which was recrystallized from EtOH
to afford pure crystalline HCl salt of 11 (99.9 HPLC area%) in excellent yield (90%) as a
crystalline solid.
The use of inorganic base/acid as an alternative to hydrazine for cleavage of phthalimide
8 was also investigated.15,16 The reaction of difluoroborate ester 7 with 5 hydrochloride
salt17 under modified reaction and work-up conditions resulted in quantitative yield of 8
as a solid of 77% chemical purity (HPLC area%) (Step 1, Scheme 3). After treatment with
30% aqueous NaOH, compound 8 was completely hydrolyzed to dicarboxylate sodium
salt 12 in situ, which upon subsequent treatment with conc. H2SO4 resulting in 64%
yield of 10 in fair chemical purity (93%, HPLC area%) along with demethylated 13 (6%)
as a major by-product. As in the hydrazine cleavage conditions, this alternative route
successfully afforded the desired final product 10 without chromatographic purification. In
spite of the reasonable yield and purity of 10 obtained from these alternative conditions,
the method would need to be further improved to meet the requirements of scale up
production.
O
-
F
CO2 Na+
1. Et3N, DMF
40 °C, 5 h
30% NaOH
MeCN/H2O
O
O
7
5
HCl salt
+
HN
8
+Na-O
N
N
2. EtOAc,
TBME
step 1
(77%)
78 °C, 3 h
step 2
O
Me
Cl
12
O
O
1. H2SO4
70-80 °C
18 h
F
CO2H
F
CO2H
NH2
Cl
N
N
NH2
N
N
2. 30% NaOH
pH 6.0-6.5
step 3
+
O
OH
13 (6%)
Me
Cl
10 (64%)
Scheme 3
In summary, an improved, reproducible, and non-chromatographic process has been
developed for the large scale preparation of 7-[4-(2-amino-1-chloroethylidene)piperidin-1-
yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hy-
drochloride salt (11) in 19% yield in nine steps with excellent chemical purity (>99.0
HPLC area%).

1,6,7,8-Substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid
Experimental Section
155
Starting materials, reagents, and solvents were obtained from commercial suppliers and
were used without further purification. Melting points are uncorrected and were determined
1
on a Thomas Hoover capillary melting point apparatus. H-NMR spectra were recorded
at 300 MHz on a Bruker Avance-300 instrument and or 400 MHz on a Bruker Avance-
400 instrument. Mass spectra were obtained on an Agilent Series 180 LC/MS instrument
(positive/negative modes). The purity/impurity ratios of compounds 1–5 were determined
by HPLC method A with an Agilent Series 1100 system at UVmax = 210 and 254 nm,
ꢀR
using a Phenomenex Luna C18 (2) column (4.6 mm ID × 50 mm, 5.0 micron) at 35◦C
with flow rate of 1.0 mL/min and run time of 10.0 min. Solvents: A H2O + 0.05% TFA,
B CH3CN; Gradient: B 30% /0.0 min, B 40%/1.0 min, B 90%/4.0 min, B 90%/8.0 min, B
30%/10.0 min. The purity/impurity ratios of compounds 6–14 were determined by HPLC
method B with an Agilent Series 1100 system at UVmax = 210, 254, and 325 nm, using
ꢀR
a Phenomenex Luna C18 (2) column (4.6 mm ID × 50 mm, 5.0 micron) at 35◦C with
flow rate of 1.0 mL/min and run time of 10.0 min. Solvents: A H2O + 0.05% TFA, B
CH3CN; Gradient: B 20%/0.0 min, B 20%/1.0 min, B 90%/5.0 min, B 45%/8.0 min, B
20%/10.0 min. All reactions were conducted in a 4-neck round bottom flask equipped with
a thermocouple controller, a mechanical stirrer, a pressure-equalization dropping funnel, a
nitrogen inlet/outlet adapter, and/or a condenser whenever it was needed.
tert-Butyl 4-(1-Chloro-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (2a)
To a 5 L round bottom flask was added tert-butyl 4-oxopiperidine-1-carboxylate (1)
(230.0 g, 1.73 mol) and EtOH (3.0 L). Triethyl 2-chloro-2-phosphonoacetate (275.0 mL,
1.27 mol) was added followed by K2CO3 (375.0 g, 1.73 mol) and the resulting mixture was
stirred at 22◦C for 4 h. The progress of the reaction was monitored by HPLC and LC-MS.
Excess K2CO3 was removed by filtration and the filtrate was concentrated in vacuo to give
a viscous oil, which was diluted with EtOAc (1.0 L), washed with a saturated Na2CO3
solution (1.0 L × 3), and dried over Na2SO4. The solvent was concentrated at 50◦C under
house vacuum (∼160 mmHg) to afford 371.0 g (99% yield; 99 HPLC area%) of 2a as a
colorless viscous oil. 1H-NMR (CDCl3, 300 MHz): d 4.28 (q, 2 H, CH2), 3.43–3.57 (m, 4
H, 2 CH2), 2.84 (t, 2 H, 2 CH), 2.63 (t, 2 H, 2 CH), 1.48 (s, 9 H, 3 CH3), 1.35 (t, 3 H, CH3).
13C-NMR (CDCl3, 75.0MHz): δ 163.34, 154,67, 147.41, 117.81, 80.17, 61.59, 43.74 (2 C),
34.46, 31.97, 28.42 (3 C), 17.2. LC-MS: m/z 304 [MH+], 326 [M+Na]+, 629 [2M+Na]+.
Anal. Calcd for (C14H22ClNO4): C, 55.35; H, 7.30; Cl, 11.67; N, 4.61. Found: C, 55.31;
H, 7.40; Cl, 11.33; N, 4.36.
tert-Butyl 4-(1-Chloro-2-hydroxyethylidene)piperidine-1-carboxylate (3a)
To a 12 L round bottom flask charged with compound 2a (370.0 g, 1.29 mol) and THF
(4.0 L) and cooled to −78◦C, DIBALH (2.30 L, 2.90 mol; 1.5 M in toluene) was added
dropwise over a 2 h period while the temperature was maintained below −63◦C. After
the addition, the reaction mixture was stirred at −75◦C for 24 h, and then warmed to
10◦C and stirred for 2 h; the progress of the reaction was monitored by HPLC, TLC, and
LC-MS. Rochelle’s solution (4.0 L, 400 g/1 L) was added dropwise over 3 h; the mixture

156
Li et al.
was warmed to 20◦C and stirred for 24 h. After phase separation, the organic layer was
concentrated in vacuo to yield 244.0 g of crude material as a viscous oil, which was diluted
with EtOAc (1.0 L), washed with brine (1.0 L × 3), and dried over Na2SO4. The solvent
was concentrated at 50◦C under house vacuum (∼160 mmHg) to afford 186.0 g (62% yield;
98 HPLC area%) of compound 3a as a yellowish solid, mp. 66–69◦C. An additional 17.0
g (6% yield; 99 HPLC area%) of 3a was extracted using EtOAc from the aqueous layer.
1H-NMR (CDCl3, 300 MHz): δ 5.61 (s, 1 H, OH), 4.34 (s, 2 H, CH2), 3.39–3.51 (m, 4 H,
2 CH2), 2.37–2.54 (m, 4 H, 2 CH2), 1.48 (s, 9 H, 3 CH3). 13C-NMR (CDCl3, 75.0 MHz): δ
154.69, 134.40, 127.25, 79.89, 62.30, 43.75 (2C), 30.87, 29.86, 28.42 (3 C). LC-MS: m/z
262 [MH+], 284 [M+Na]+.
Anal. Calcd for C12H20ClNO3: C, 55.06; H, 7.70; Cl, 13.54; N, 5.35. Found: C, 55.04;
H, 7.78; Cl, 13.14; N, 5.08.
4-[1-Chloro-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)ethylidene]piperidine-1-carboxylic
Acid tert-Butyl Ester (4)
A 22-L round bottom flask was charged with 2-MeTHF (3.0 L), alcohol 3a (295.2 g,
1.13 mol), phthalimide (231.9 g, 1.58 mol), and triphenylphosphine (411.0 g, 1.58 mol)
and the mixture was stirred at 20◦C. The reaction mixture was cooled to −10◦C and
diisopropyl azodicarboxylate (309.0 mL, 1.58 mol) was added dropwise at a such rate that
the temperature remained below 10◦C. After the addition, the mixture was stirred at 20◦C
for 18 h and the progress of the reaction was monitored by HPLC and LC-MS. The reaction
mixture was quenched with deionized (D.I.) water (2 L) and then partitioned with EtOAc
(3 L). After phase separation, the organic layer was washed with 4 N HCl solution (2 L),
saturated NaHCO3 solution (2 L), and brine (2 L), and dried over MgSO4. The filtrate was
concentrated at 60◦C under house vacuum (∼ 120 mmHg) to afford a crude material, which
was crystallized from EtOAc/toluene (1/9, vol/vol) to yield 321.7 g of compound 4 (73%
yield, 98 HPLC area%) as a white solid, mp. 120–122◦C. 1H-NMR (CDCl3, 400 MHz): δ
7.89 (dd, 2 H, 2 ArCH), 7.74 (dd, 2 H, 2 ArCH), 4.56 (s, 2 H, CH2), 3.64–3.58 (m, 2 H, 2
CH), 3.50–3.41 (m, 2 H, 2 CH), 2.69–2.62 (m, 2 H, 2 CH), 2.55–2.45 (m, 2 H, 2 CH), 1.48
(s, 9 H, 3 CH3). 13C-NMR (CDCl3, 100.6 MHz): δ 154.74, 136.41, 134.28 (2 C), 131.97
(2 C), 123.56 (2 C), 121.50, 79.74, 44.8 (2 C), 39.97, 30.98, 30.40, 28.45 (3 C). LC-MS:
m/z 291 [(MH-100)+], 391 [MH+], 413 [M+Na]+, 803 [2M+Na]+.
Anal. Calcd for C20H23ClN2O4: C, 61.46; H, 5.93; Cl, 9.07; N, 7.17. Found: C, 61.13;
H, 6.01; Cl, 8.87; N, 7.01.
2-[2-Chloro-2-(piperidin-4-ylidene)ethyl]isoindoline-1,3-dione (5)
To a 12 L round bottom flask was charged with compound 4 (368.0 g, 0.942 mol) and
CH2Cl2 (3400 mL). The solution was stirred at 20◦C under nitrogen. TFA (435.3 mL,
5.649 mol) was added over a 10 min period. The mixture was warmed to 38◦C and stirred
for 3 h; the progress of the reaction was monitored by HPLC and LC-MS. The solvent was
removed at 40◦C under house vacuum (∼120 mmHg) and the resulting TFA salt (579.6 g;
86 HPLC area%) was dissolved in CH2Cl2 (3.0 L). The organic solution was washed with
10% Na2CO3 solution (2.0 L × 2), brine (2.0 L), dried over MgSO4, and then concentrated

1,6,7,8-Substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid
157
at 50◦C under house vacuum (∼160 mmHg) to afford 289.9 g (105% isolated yield, 90.0
HPLC area%) of free base 5 as an off-white solid, mp. 101–104◦C, after drying at 60◦C
under high vacuum (20 mmHg) for 20 h. 1H- NMR (CDCl3, 400 MHz): δ 7.88 (dd, 2 H,
2 ArCH), 7.75 (dd, 2 H, 2 ArCH), 4.62 (s, 2 H, CH2), 3.04 (m, 2 H, 2 CH), 2.92 (m, 2 H,
2 CH), 2.66 (m, 2 H, 2 CH), 2.48 (m, 2 H, 2 CH), 1.91–2.19 (br s, 1 H, NH). 13C-NMR
(CDCl3, 100.6 MHz): δ 167.72 (2 C), 136.40, 134.28 (2 C), 131,98 (2 C), 123.68 (2 C),
121.50, 45.6 (2 C), 39.92, 30.98, 30.46. LC-MS: m/z 291 [MH+], 313 [M+Na]+.
Anal. Calcd for C15H15ClN2O2: C, 61.97; H, 5.20; Cl, 12.19; N, 9.64. Found: C, 61.59;
H, 5.05; Cl, 12.58; N, 9.47.
[1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-quinoline-carboxylato-
κO3]difluoroboron (7)
To a 12 L round bottom flask was charged with 6 (250.0 g, 0.847 mol), anhydrous THF (3.0
L) and K2CO3 (129.6 g, 0.938 mol, ∼325 mesh). This suspension was stirred at 20◦C under
N2 for 5 min and BF3·Et2O (123.4 mL, 0.938 mol) was added over a 5 min period; the
mixture was heated to 66◦C and refluxed for 6 h. The progress of the reaction was monitored
by HPLC and LC-MS (when the reaction was incomplete, for example, 10% of starting acid
6 was determined to be present in the reaction mixture, a little more BF3·Et2O (20 mL, 0.158
mol) was added to the reaction, which drove the reaction to completion after refluxing an
additional 2 h). The reaction mixture was cooled to 20◦C and diluted with Et2O (5.0 L) and
stirred for 10 min (Et2O was replaced by t-butyl methyl ether (TBME) when production was
carried out on multi-kilogram scale). The solid was collected and washed with Et2O (100
mL × 2) and then dried at 50◦C under house vacuum (∼160 mmHg) for 20 h to afford 398.0
g (137% yield; 98.4 HPLC area%) of crude 7. This crude solid was suspended in MeCN
(4.0 L) and stirred at 20◦C for 20 min, the solid was filtered off and washed with MeCN
(100 mL). The filtration cake was re-suspended and stirred in MeCN three additional times
(2.0 L × 3, or until no more 6 could be detected by HPLC in the filtrate); the filtrates were
combined and concentrated at 50◦C under house vacuum (∼160 mmHg). The resulting
off-white crystalline solid was dried at 50◦C under house vacuum (∼160 mmHg) for 20
h to afford 282.6 g (97% yield; 99.6 HPLC area%) of pure 7, mp. 226–228◦C, lit.11 mp.
226–228◦C. HPLC (area%/retention time): 6, <0.5%/4.64 min; and 7, 99.5%/4.39 min.
1H-NMR (DMSO-d6, 400 MHz): δ 1.26–1.35 (m, 2 H, CH2), 1.36–1.41 (m, 2 H, CH2),
4.19 (s, 3 H, OCH3), 4.54 (m, 1 H, CH), 8.28 (dd, 1 ArCH), 9.21 (s, 1 H, ArCH). 13C-NMR
(DMSO-d6, 100.6 MHz): δ 170.21, 168.89, 159.29, 152.44, 150.38 (dd, 1JCF = 254.8 Hz,
2JCF = 12.88 Hz), 149.51 (dd, 1JCF = 257.13 Hz, 2JCF = 15.29 Hz), 141.78, 134.26, 119.20,
106.16, 63.72, 43.64, 8.71 (2 C). LC-MS: m/z 344 [MH+], 709 [2M+Na]+.
Anal. Calcd for C14H10BF4NO4: C, 49.02; H, 2.94; N, 4.08; B, 3.15; F, 22.15. Found:
C, 49.18; H, 2.86; N, 3.91; B, 3.36; F, 22.03.
7-{4-[1-Chloro-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylidene]piperidin-1-yl}-
1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid (9)
A 22 L round bottom flask was charged with difluoroborate ester 7 (300.0 g, 0.874 mol),
MeCN (8000 mL), and compound 5 (330.4 g, 1.136 mol). This suspension was stirred at
20◦C under N2 for 5 min, Et3N (731.0 mL, 5.244 mol) was added over a 10 min period,

158
Li et al.
and the mixture was heated to 80◦C and refluxed for 24 h; the progress of the reaction
was monitored by HPLC and LC-MS. The formation of intermediate 8 was confirmed
by LC-MS (MH+ = 614.2) as well as HPLC spiked with an authentic sample of 8. The
reaction mixture was cooled to 60◦C, EtOH (7000 mL) and Et3N (731.0 mL, 5.244 mol)
were added, and the mixture was heated to reflux at 72◦C for 2 h, and then cooled to 20◦C
and stirred for 18 h. The yellow solid was collected, washed with hexane (200 mL × 2), and
dried at 50◦C under house vacuum (∼160 mmHg) for 20 h to afford 229.8 g (47% yield;
92 HPLC area%) of crude compound 9, mp. 254–256◦C, which was used in the next step
without further purification. 1H-NMR (CF3CO2D, 400 MHz): δ 10.81 (s, 1 H, OH), 8.76 (s,
1 H, ArCH), 7.49 (d, 1 H, 1 ArCH), 7.18 (dd, 2 H, 2 ArCH), 7.08 (dd, 2 H, 2 ArCH), 4.02
(s, 2 H, CH2), 3.80–3.70 (m, 1 H, CH), 3.48–3.36 (m, 2 H, 2 CH), 3.31 (s, 3 H, OCH3),
3.28–3.18 (m, 2 H, 2 CH), 2.58–2.46 (m, 2 H, 2 CH), 2.40–2.29 (m, 2 H, 2 CH), 0.79–0.66
(m, 2 H, CH2), 0.53–0.39 (m, 2 H, CH2). 13C-NMR (CF3CO2D, 100.6 MHz): δ 172.41,
171.04 (2 C), 169.1, 156.61, 155.32 (d, 1JCF = 259.95 Hz), 154.03, 152.99, 145.75, 136.36
(2 C), 134.68, 130.77 (2 C), 124.04 (2 C), 121.74, 109.34, 105.05, 65.04, 54.70, 54.29,
42,85 (2 C), 39.84, 28.91, 28.37, 8.82 (2 C). LC-MS: m/z 566 [MH+], 588 [M+Na]+, 1153
[2M+Na]+.
Anal. Calcd for C29H25ClFN3O6·0.1 CH3CH2OH: C, 61.47; H, 4.52; Cl, 6.21; F, 3.33;
N, 7.36. Found: C, 61.64; H, 4.79; Cl, 6.11; F, 3.27; N, 7.48.
7-[4-(2-Amino-1-chloroethylidene)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-
4-oxo-1,4-dihydroquinoline-3-carboxylic Acid (10)
A 12 L round bottom flask was charged with compound 9 (224.0 g, 0.396 mol) and MeOH
(4.4 L). This suspension was stirred at 20◦C under nitrogen and H2NNH2 (101.4 mL,
3.166 mol) was added over a 5 min period. The yellowish suspension was heated to 65◦C
and refluxed for 1 h, and the progress of the reaction was monitored by HPLC and LC-MS.
The reaction was cooled to 60◦C and MeCN (3.3 L) was added. The mixture was heated
to reflux for 5 min (some phthalhydrazide precipitated during this period), and then was
cooled to 24◦C in a water bath. The off-white solid was collected and washed with MeCN
(200 mL × 2) and dried at 50◦C under house vacuum (∼160 mmHg) for 20 h to afford 69.6
g (108% yield; 98% of phthalhydrazide and ∼2% of 10, HPLC area%) of phthalhydrazide
as an off-white solid. The filtrate was concentrated at 60◦C to afford 198.5 g (115% yield;
89 HPLC area%) of crude compound 10 as a yellowish solid.
A 12 L round bottom flask was charged with crude 10 (198.5 g) and MeOH (4.4 L).
This suspension was heated to 65◦C and refluxed for 20 h. MeCN (3.5 L) was added at
65◦C and reflux was continued for 25 min; and then the solution was gradually cooled
to 0◦C and stirred for 30 min. The precipitated solid was collected, washed with MeCN
(200 mL × 2), and dried at 50◦C under high vacuum (∼4 mmHg) for 20 h to afford 138.0
g (80% yield; 99.4% of 10 and 0.35% of phthalhydrazide, HPLC area%) of free base 10
as a bright yellowish crystalline solid, mp. 186–188◦C. An additional 66.3 g of yellow
solid was obtained after concentration of the filtrate, which contained 58% of 10, 22% of
1
phthalhydrazide, along with 11% and 5% of two major uncharacterized impurities. H-
NMR of free base 10 (400 MHz, DMSO-d6) δ 10.9 (s, 1 H, OH), 8.69 (s, 1 H, ArCH), 7.64
(d, 1 H, ArCH), 4.18 (m, 1 H, CH), 3.75 (s, 3 H, OCH3), 3.48 (s, 2 H, NCH2), 3.46–3.20

1,6,7,8-Substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid
159
(m, 6 H, 2 CH2 + NH2), 2.64–2.52 (m, 2 H, CH2), 2.51–2.48 (m, 2 H, CH2), 1.18–1.08
(m, 2 H, CH2), 1.07–0.96 (m, 2 H, CH2). 13C-NMR (CF3CO2D, 100.6 MHz): δ 175.33,
1
164.67, 155.72 (d, JCF = 259.86 Hz), 149.32, 144.85, 138.24, 132.91, 129.71, 128.86,
119.69 105.41, 61.71, 49.99, 49.35, 47.43, 42,95, 39.54, 30.37, 29.09, 7.56 (2 C). LC-MS:
m/z 436 [MH+], 893 [2M+Na]+.
Anal. Calcd for C21H23ClFN3O4·0.1 CH3CN: C, 57.87; H, 5.34; Cl, 8.06; F, 4.32; N,
9.87. Found: C, 57.92; H, 5.28; Cl, 7.77; F, 4.16; N, 10.13.
7-[4-(2-Amino-1-chloroethylidene)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-
4-oxo-1,4-dihydroquinoline-3-carboxylic Acid Hydrochloride Salt (11)
A 12 L round bottom flask was charged with 10 (100.0 g, 0.229 mol) and EtOH (4.0 L)
and the suspension was stirred under N2 and cooled to 10◦C. A solution of HCl in Et2O
(1.0 M, 252.4 mL) was added over a 25 min period while the reaction temperature was
maintained between 8–10◦C. After the addition, the mixture was stirred at 10◦C for 5 min
and warmed to 20◦C and stirred for 20 min. Ethanol was removed in vacuo at 66◦C to
afford 134.6 g (98.4 HPLC area%) of the crude HCl salt 11 as a yellowish solid, which
was suspended in EtOH (2.5 L) in a 5-L RBF, heated to 76◦C and stirred for 5 min. EtOH
(50 ml × 10) was added to the suspension in 5 min intervals until a clear solution was
formed. The solution was cooled to 60◦C and seeded with pure HCl salt 11 (>99.6 HPLC
area%). The solution was gradually cooled to 0◦C over a 1 h period and stirred at 0◦C for
30 min. The solid was collected, washed with ice cold EtOH (100 mL × 2), and dried at
60◦C under high vacuum (∼ 4 mmHg) for 60 h (weekend). There was obtained 88.9 g
(82% yield; 99.9 HPLC area%) of pure HCl salt 11 as a slightly yellowish crystalline solid.
Recrystallization of the mother liquor solid (19.4 g, 18% yield; 97.7 HPLC area%) in EtOH
(388 mL) afforded an additional 8.6 g of HCl salt 11 (8% yield; 99.4 HPLC area%) also
as a yellowish crystalline solid, mp. 178–180◦C. 1H-NMR of pure HCl salt 11 (400 MHz,
CD3CO2D): δ 11.76–11.48 (br s, 3 H, OH + NH2), 9.02 (s, 1 H, 2 ArCH), 7.88 (d, 1 H, 2
ArCH), 4.28 (m, 1 H, CH), 4.25 3.48 (s, 2 H, NCH2), 3.86 (s, 3 H, OCH3), 3.48–3.63 (m,
4 H, 2 CH2), 2.46–2.78 (m, 4 H, 2 CH2), 1.31 (m, 2 H, CH2), 1.16 (m, 2 H, CH2). LC-MS:
m/z 436 [MH+], 869 [2M-H]+, 893 [2M+Na]+.
Anal. Calcd for C21H23N3O4ClF·1.0 HCl·0.2 CH3CH2OH·0.29 H2O: C, 52.81; H,
5.34; N, 8.63; Cl, 14.57; F, 3.90; % H2O, 1.06. Found: C, 52.78; H, 5.39; N, 8.34; Cl,
15.04; F, 3.75; % H2O, 1.06.
Cleavage of Phthalimide Intermediate 8 Using Inorganic Base and Acid
A 1 L round bottom flask was charged with 5 HCl salt (19.1 g, 58.37 mmol), difluoroborate
ester 7 (20.7 g, 60.34 mmol), DMF (72 mL), and Et3N (17.9 mL, 128.47 mmol). The
mixture was warmed to 35–40◦C and stirred for 4–5 h (a yellowish solid precipitated after
approximately 40 min). The suspension was cooled to 0–10◦C, diluted with EtOAc (112
mL) and stirred for 2 h. The solid was collected, and washed with methyl t-butyl methyl ether
(40 mL) to afford 35.8 g (77% of 8, HPLC area%) of intermediate 8 as a yellowish solid.
Intermediate 8 was suspended in MeCN (48 mL) and deionized H2O (100 mL), a
solution of 30% NaOH (41.6 mL, 312 mmol) was added and this mixture was gradually
heated to reflux at 78◦C which resulted in the distillation of about 11.0 g of liquid containing

160
Li et al.
t-butyl methyl ether and Et3N) and stirred for 3 h. The progress of the reaction was monitored
by HPLC and LC-MS, both of which indicated that compound 8 was completely converted
to 12 (LC-MS, MH+ = 584, M+Na+ = 606, M+2Na+ = 628). The reaction mixture
was cooled to 20◦C and MeCN (54 mL) was added, followed by the addition of 50%
aqueous solution of H2SO4 (16.6 mL) and then a 95–97% solution of H2SO4 (18.1 mL)
(pH 1.5–2.0). The mixture was heated to 78◦C again and stirred for 18 h. The progress of
the reaction was monitored by HPLC and LC-MS, both of which indicated that amide 12
was almost completely hydrolyzed to amine 10. The reaction mixture was cooled to 40◦C,
the mixture was diluted with deionized H2O (128 mL) and titrated with 30% NaOH (21.7
mL) to pH 6.0–6.5. The resulting suspension was stirred at 20◦C for 3 h, and the yellowish
solid was collected and washed with deionized water (50 mL) to give 25.5 g (64% yield;
92.8 HPLC area% of 10 and 6.4% of 8-demethylated 13 (MH+ = 422), HPLC area%) as
a beige-yellowish solid, mp. 181–186◦C.
References
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17. The hydrochloride salt of 5 was prepared by the treatment of compound 4 (10.0 g) with a solution
of 19% HCl in ethanol (100 mL) at 20◦C overnight. The resulting suspension was cooled to 0–5◦C
and the solid was collected. The filter cake was washed with cold ethanol (10 mL) and then dried
in a vacuum oven at 60◦C for 20 h to afford 7.3 g of 5·HCl as an off-white solid.

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