A Consolidated and Continuous Synthesis of Ciprofloxacin from a Vinylogous Cyclopropyl Amide

Article abstract of DOI:10.1021/acs.joc.8b03222

Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization's Essential Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory, and gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions, or purifications. The end-to-end process has a residence time of 4.7 min with a 15.8 g/h throughput at laboratory scale and an overall isolated yield of 83%.

Full text of DOI:10.1021/acs.joc.8b03222

Subscriber access provided by MIDWESTERN UNIVERSITY
Article
A Consolidated and Continuous Synthesis of
Ciprofloxacin from a Vinylogous Cyclopropyl Amide
N. Perrer Tosso, Bimbisar K. Desai, Eliseu De Oliveira, Juekun Wen, John Tomlin, and B. Frank Gupton
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03222 • Publication Date (Web): 20 Feb 2019
Downloaded from http://pubs.acs.org on February 21, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A Consolidated and Continuous Synthesis of Ciprofloxacin from a
Vinylogous Cyclopropyl Amide
†
†
†
†
†
N. Perrer Tosso , Bimbisar K. Desai , Eliseu De Oliveira , Juekun Wen , John Tomlin , and B. Frank
†
Gupton *
†Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University,
601 W. Main St. Richmond, VA 23220, USA.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Supporting Information
ABSTRACT: Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization’s Essential
Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory and
gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which
employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions or purifications. The end-
to end process has a residence time of 4.7 minutes with a 15.8 g/hr throughput at laboratory scale and an overall isolated yield of
83%.
INTRODUCTION
production of essential medicines as defined by the World
Health Organization (WHO). This approach involves utilizing
low-cost raw materials, developing high yielding convergent
chemical synthesis and novel manufacturing platforms.
this body of work, we report an improved continuous
Access to affordable medications continues to be one of the
most significant challenges in global health care management.
For many of these treatments, synthesis of the active
pharmaceutical ingredient (API) represents the most technically
demanding and financially important element in the preparation
of these materials. In many cases, the API cost accounts for up
to 60-75% of the total drug product cost. These API processes
often evolve from medicinal chemistry routes in an effort to
expedite commercialization of the drug product, thus providing
an opportunity to apply new and more cost effective synthetic
2
,8–10
In
preparation of ciprofloxacin (1).
Ciprofloxacin (1) is the most widely prescribed of the
fluoroquinolone class of antibiotics and is employed in the
treatment of urinary tract, respiratory tract and gastrointestinal
1–3
1
1–15
infections.
Since its discovery by Bayer AG nearly four
12
decades ago, limited advances has been made to the general
synthetic scheme for the preparation of this important
medication. One of the more efficient methods for the
preparation of ciprofloxacin (1) that has been published relies
on a multi-stage one pot batch synthesis with seven chemical
2,4–8
approaches for the preparation of these compounds.
Our research group has applied the principles of process
intensification to develop streamlined approaches to API
Scheme 1. Current synthetic route to ciprofloxacin
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 8
1
7–19
transformations (Scheme 1)
and an overall yield of 49%.
continuous
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Recently, Lin and coworkers reported
a
19
ciprofloxacin process with an overall yield of 60%. Both of
these processes employ a common synthetic strategy that
utilizes dimethylaminoacrylate (5) as a starting material.
Scheme 2. Our retrosynthetic strategy to ciprofloxacin
Figure 2. Major ciprofloxacin by-product
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
RESULTS AND DISCUSSION
The development of a viable synthetic route for the
vinylogous amide 3a represented the initial challenge towards
streamlining the API process. We elected to evaluate a range of
reaction conditions using the corresponding vinyl ether (7) and
cyclopropylamine as starting materials with the knowledge that
20–22
the poor electrophilic character of the ethyl ethoxyacrylate
may impede the conversion to 3a. Initial screening studies were
carried out with microwave heating under autogenous pressure
and a broad range of solvents. All experiments were conducted
in septum-sealed reaction vessels with the single-mode cavity
dedicated Biotage Initiator reactor. All reaction temperatures
were measured externally on the outside vessel wall by an IR
sensor, as permitted only by the conventional setup of the above
MW reactor. The results of these experiments are summarized
in Table 1. The reaction proceeded in ethanol albeit with only
35% conversion (Table 1, entry 1). The transformation failed to
proceed when poor microwave absorbing solvent such as
toluene and THF were used (Table 1, entry 3 and 4). The desired
product was obtained in good yields when the reactions were
We were able to take advantage of the ability of lithiated
secondary enamines to give the desired C-acylated product
19
(
Figure 1). In this application using LiHMDS as the base, a
high yielding chemoselective C-acylation product 10a (Scheme
) was exclusively produced and upon gradualwarming to room
2
o
temperature, gave the ring-closed precursor 6a in a 94% yield.
Furthermore, this approach precludes the formation of a key
microwave heated to 150 C in DMSO or DMF (Table1, entries
7 and 8).
side-product 4 that is produced when 5 (Scheme 1) is employed
18,19
as a starting material (Figure 2).
By consolidating this multi-
a
Table 1. Synthesis of vinylogous amides in microwave
step reaction sequence into a minimal number of high yielding
unit operations, the preparation and conversion of the quinolone
intermediate (6a) into the API can be readily applied to both
batch and continuous operations.
Time
o
b
Entry Solvent Temp ( C)
Conv. (%)
(
min)
90
30
30
30
60
30
60
60
1
2
3
4
5
6
7
8
EtOH
-
78
60
35
0
Figure 1. Competitive C-acylation and N-acylation
Toluene
THF
90
0
Herein we report an alternative, more convergent and
higher yielding approach for the synthesis of ciprofloxacin (1)
90
0
(Scheme 2) that relies on the early stage insertion of the
ACN
DMF
DMF
DMSO
140
150
150
150
38
87
cyclopropylamine moiety via a chemo-selective addition of the
corresponding vinylogous amide 3a, which was prepared from
a more affordable and cost-effective vinyl ether.
c
100 (96)
c
99 (96)
aReaction conditions: 7 (1.0 equiv.), cyclopropylamine (3.0 equiv.).
The aminations were carried out in a septum-sealed vial using the
b
Biotage Initiator Microwave Reactor. Conversions are determined
c
by HPLC. Isolated yield.
ACS Paragon Plus Environment

Page 3 of 8
The Journal of Organic Chemistry
The nucleophilic displacement was successfully reproduced
Scheme 3. Selective C-acylation vinylogous amide 3b-d.
1
2
3
4
5
6
7
8
9
when the reaction vessel was pressurized to 25 PSI with argon
o
and traditional thermal heating at 130 C to give 3a in a high
yield (96%). We also applied this methodology to various
substrates with the goal of producing corresponding vinylogous
amides. The method worked well with selected amines as
shown in Table 2.
a
Table 2. Synthesis of vinylogous amides in batch
a
Reaction conditions: 3b-d (1.0 equiv.), 9a (1.1 equiv.). LiHMDS
o
(
1.1 equiv.), -78 C to rt
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Previous reports suggest that 10a cyclizes in the presence
of an additional equivalent of strong bases (Table 4, entry 1-
1
7,19
4
).
When 10a was treated with LiHMDS, 6a was prepared
with a near quantitative yield (Table 4, entry 5). We additionally
sought to consolidate the acylation to 10a and the
intramolecular ring closing to 6a into a single step. By treating
a and 3a with a slight excess of LiHMDS we were able to
obtain the quinolone (6a) in a 94% isolated yield (Scheme 4).
b
Amines
R
3
Conv. (%)
Product (%)
c
8
a
cyclopropyl
propyl
100
96
3a (96)
9
8b
8c
3b (94)
3c (85)
3d (87)
benzyl
89
8
d
cyclohexyl
91
a
Table 4. Intramolecular ring closing to 6a
a
Reaction conditions: 7 (1.0 equiv.), amine (3.0 equiv.), DMSO.
o
All reactions were carried out at 130 C, at 25 PSI with argon.
b
c
Conversions are determined by HPLC. Isolated yield.
We then proceeded to react 3a with 2,4,5-trifluorobenzoyl
chloride. Previous attempts to achieve selective C-acylation
using n-BuLi as a base have been reported, yielding a mixture
19
of N-acylation and C-acylation in a ratio of 6:1 respectively .
Conv.
Temp
Entry
Base
DBU
Solvent
R
A screen of the bases confirmed the difficulty of the
chemoselective alkylation (Table 3, entry 1-4). However, in our
hands the desired alkylation was achieved when bulkier
lithiated non-nucleophilic bases were used (Table 3, entry 5 and
). A complete conversion with exclusively C-acylation was
achieved in the presence of LiHMDS with a 96% isolated yield
Table 3, entry 6). In addition, we were able to demonstrate the
selective C-acylation of the vinylogous amine when LiHMDS
was used when the R = propyl, benzyl and cyclohexyl in good
yield (Scheme 3).
o
b
(
C)
(
%)
98
98
96
1
2
3
4
5
90
DMSO
DMSO
DMSO
DMSO
Toluene
Et
Et
Et
H
2
K CO
3
90
90
90
rt
6
NaH
c
LiOH
98
(
c
LiHMDS
Et
98 (95 )
a
Reaction conditions: 10a (1.0 equiv.), base (1-4) (3 equiv.),
b
LiHMDS (1.1 equiv.). Conversions are determined by HPLC.
c
Isolated yield.
a
Table 3. C-acylation optimization
With the preparation of the quinolone (6a) optimized, we
set out to complete the synthesis of (1). The piperazine coupling
o
was carried out at 120 C in DMSO to give the ciprofloxacin
ester (12) with a 94% conversion. The ester was then
hydrolysed in the presence of NaOH, followed by a pH
adjustment to afford ciprofloxacin (1) (Scheme 4). With all
steps optimized, the process was telescoped into a one-pot
synthesis as shown in Scheme 4. The telescope batch synthesis
(Scheme 4) provided a final yield of 83% after crystallization,
which proposes to reduce the number of unit operations
compared to the existing batch process.
1
0a:11
ratio
o
b
Entry
Base
Et
Temp ( C)
Conv. (%)
1
2
3
4
5
6
7
3
N
90
rt
1:7
10.5
5
Pyridine
DBU
1:13
1:10
1:10
90
90
rt
6
Based on these findings, we envisioned a telescoped
continuous process over a three reactor platform with no
intermediate isolations, separations or purifications. Lin and co-
workers have previously reported a continuous method for the
preparation of 1 over five reactors with a total residence time of
DIPEA
LDA
6
>100:1
>100:1
1:60
83
c
LiHMDS
NaH
rt
100 (96%)
2
0
a
Reaction conditions: 3a (1.0 equiv.), 2,4,5-trifluorobenzoyl
chloride (1.2 equiv.), base (1.2 equiv.), toluene, Conversions
are determined by HPLC. Isolated yield. rt (room temperature).
b
c
ACS Paragon Plus Environment

The Journal of Organic Chemistry
with a residence time of 2.5 minutes to give a 96% conversion
Page 4 of 8
Scheme 4. Telescoped synthesis of 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
to 12. The hydrolysis of 12 was carried out in an additional 10
mL reactor coil (reactor III) with 1 M sodium hydroxide at 120
o
C followed by pH adjustment to give 1 in 83% isolated yield
and an overall throughput of 15.8 g/hr. A summary of the total
continuous synthesis of 1 is provided in Scheme 5.
CONCLUSION
In summary, we have developed an improved synthetic
route to ciprofloxacin employing a strategy based on the early
stage insertion of the cyclopropyl amine moiety via a
chemoselective addition of the corresponding vinylogous amide
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(3a). As a result, we were able to consolidate the acylation and
the S Ar into a single step, leading to an 83% overall yield of
N
the API. Furthermore, we successfully transitioned our
streamlined synthesis into a continuous process over only four
unit operations with a 4.7 min residence time and a 15.8 g/hr
throughput in our laboratory unit.
a
Reaction conditions: 3a (1.0 equiv.), 9a (1.1 equiv.). LiHMDS
o
o
(
2.2 equiv.), -78 C to rt, 2 h; piperazine (4 equiv.), H O, 90 C,
2
NaOH (4 equiv.).
EXPERIMENTAL SECTION
19
9
mins. Using this alternative streamlined synthetic approach,
General Information and Method. Experiments
involving moisture and/or air sensitive compounds were
performed under a positive pressure of argon in oven-dried
glassware equipped with a rubber septum inlet. Dried solvents
and liquids were transferred by oven-dried syringes or
hypodermic syringes cooled to ambient temperature. Reactions
mixtures were stirred in a round-bottom flask with Teflon-
coated magnetic stirring bars unless otherwise stated. Moisture
in non-volatile reagents/compounds was removed in high vacuo
by means of an oil pump and subsequent purging with argon.
Solvents were removed in vacuo under pressure and heated with
we carried out the acylation step by reaction of the lithiated 3a
with 9a over a 2 mL reactor coil. The direct conversion to the
quinolone (6a) was achieved in 1 min with a 92% yield in a 2
mL reactor coil (Scheme 5). However, the production of 6a
resulted in clogging when toluene was used as a solvent. By
substituting THF as the solvent, we were able to solubilize both
reactants and products to give a 95% isolated yield of 6a while
retaining a 1 min residence time.
Since we had previously found that the condensation of 6a
o
with piperazine required heating to 120 C, we preheated the
piperazine to this temperature in DMSO prior to mixing with
the output from reactor I which was preheated to 60 C. The
subsequent mixture was fed into a 10 mL reactor coil (reactor
o
water bath at 30-40 C using rotary evaporator with aspirator.
o
All experiments were monitored with High Performance Liquid
Chromatography (HPLC) analysis. UV detection was
monitored at 254 nm, 210 nm and 280 nm at the same time.
o
II). The reaction temperature was raised to 140 C, at 75 PSI
Scheme 5. Continuous synthesis of ciprofloxacin (1)
ACS Paragon Plus Environment

Page 5 of 8
The Journal of Organic Chemistry
1
3
HPLC samples were dissolved in HPLC grade acetonitrile
unless otherwise stated.
Columns for flash chromatography contained silica gel 200-300
mech. Columns were equilibrated using appropriate solvent
system.
2H); C{1H} NMR (150 MHz, CDCl
87.5, 83.1, 58.8, 14.5, 6.5. HRMS (ESI-Orbitrap) m/z: [M+H]
Calcd for C 156.0916; found 156.1002.
3
): δ 169.4, 152.1, 149.5,
+
1
2
3
4
5
6
7
8
9
8
H14NO
2
Synthesis of the amino acrylate (3a-d) from the vinyl ether
in batch (General Procedure A). To a solution of ethyl-3-
ethoxyacrylate (7) (5 g, 34.72 mmol) dissolved in DMSO (30
mL) in a 250-mL round-bottom pressure flask was added the
appropriate amine (8a-d) (3 equiv.). The vessel was pressurized
1
Instrumentation. Proton nuclear magnetic resonance ( H
13
NMR) and proton-decoupled carbon ( C{1H} NMR) (600 and
1
d
50 MHz, respectively) were recorded in CDCl
3
or in DMSO-
o
6
or otherwise stated on Bruker FT-NMR spectrometer. NMR
to 25 PSI under argon and heated to 130 C for 4-6 h. After
data were processed using MestReNova 10.0 software package.
Chemical shifts (δ) are reported in parts per million (ppm)
relative to TMS. In order to measure and assign the J19F-13C
coupling constants for compounds 6a, 10a, 10b, 10c, and 10d,
complete spectral assignments were obtained by detailed
cooling to room temperature, the reaction mixture was diluted
in dichloromethane (30 mL) and washed with water (2 x 10
mL), brine (10 mL) dried over sodium sulfate. The combined
organic layer was further purified by flash column
chromatography (5:1 Hex/EtOAc). The purity was determined
by HPLC.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
1
1
13
1
analysis of H 1D, C { H} 1-D, COSY, H- C HSQC, and H-
1
3
C HMBC experiments. The J19F-13C coupling constants were
1
3
1
measured from the C { H} 1-D spectra acquired using 32 k
data points defining the FID processed using 0.3 Hz line
broadening and zero filled to 256k to provide a reasonably fine
digital resolution of 0.14 Hz for 256k points spread over 240
ppm at 150 Hz/ppm.
Ethyl-3-(cyclopropylamino)acrylate (3a). Prepared following
the general procedure A from ethyl-3-ethoxyacrylate (7) (15 g,
104.16 mmol) and cyclopropylamine (8a) (17.81 g, 312.48
1
mmol) to give a yellow oil (15.5 g, 96%). H NMR (600 MHz,
CDCl , Mixture of (E/Z) Isomers (5:1); integrals represent the
3
The names of the products were generated using
PerkinElmer ChemBiodraw Ultra v.12.0.2 software package.
HPLC chromatograms were recorded on Agilent Technologies
1260 Infinity instrument with a Poroshell 120 EC-C18 column
major isomer): δ 7.44 (q, 1H), 5.06 (s, 1H) 5.01 (d, J = 12.8 Hz,
1H), 4.12 (q, J = 7.2, 2H), 2.39 (s, 1H), 1.25 (t, J = 7.2 Hz, 3H),
13
0.71 (q, 2H), 0.52 (m, 2H); C{1H} NMR (150 MHz, CDCl
3
):
δ 169.4, 152.1, 149.5, 87.5, 83.4, 58.8, 14.5, 6.5. HRMS (ESI-
+
(4.6 x 50 mm, 2.7 µm). High resolution mass spectra were
Orbitrap) m/z: [M+H] Calcd for C
8
H
14NO 156.0916; found
2
obtained through the Virginia Commonwealth University
Chemical and Proteomic Mass Spectrometry Core Facility
using an Orbitrap Velos mass spectrometer from Thermo
Electron Corporation. Microwave reactions were carried out in
Biotage Initiator. Continuous flow experiments were carried out
using the E-series flow reactor instrument purchased from
Vapourtec Ltd. PFA tubing (1/8” O.D. x 1/16” I.D.) was used
for all reactor coils in flow experiments.
156.1002.
Ethyl-3-(propylamino)acrylate (3b). Prepared following the
general procedure A from ethyl-3-ethoxyacrylate (7) (5 g, 34.72
mmol) and propylamine (8b) (6.15 g, 104.16 mmol) to give a
1
yellow oil (5.13 g, 94%). H NMR (600 MHz, CDCl
3
, Mixture
of (E/Z) Isomers (3.8:1); integrals represent the major isomer):
δ 7.78 (s, 1H), 6.57 (q, J = 7.0, 1H), 4.38 (d, J = 7.8 Hz, 1H),
4.07 (q, J = 7.0 Hz, 2H), 3.07 (q, J = 6.7 Hz, 2H), 1.52 (q, J =
13
Materials. All commercial reagents were purchased and
used without further purification. All reaction solvents used:
tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), toluene
7.1 Hz, 2H), 1.20 (t, J = 7.3 Hz, 3H), 0.89 (q, 3H); C{1H}
NMR (150 MHz, CDCl ): δ 171.0, 152.4, 81.3, 58.6, 50.4, 24.5,
14.6, 11.0. HRMS (ESI-Orbitrap) m/z: [M+H] Calcd for
158.1103; found 158.1160.
3
+
(PhMe) were taken from a “Grubbs‐style” solvent dispensing
C
8
H16NO
2
system purchased from Pure Process Technology. All other
anhydrous solvents used were purchased from Sigma-Aldrich
with Sure Seal. Analytical and preparative thin layer
chromatography (TLC) was performed using Analtech
Ethyl-3-(phenylamino)acrylate (3c). Prepared following the
general procedure A from ethyl-3-ethoxyacrylate (7) (5 g, 34.72
mmol) and benzylamine (8c) (11.15 g, 104.16 mmol). Further
TM
Uniplate Silica Gel GF (250 micron) precoated glass plates
purification with flash column chromatography (5:1:0.1
1
or Merck KGaA Silica Gel 60 F254. Spots were detected by 254
nm UV lamp.
Hex/EtOAc/Et
3
N) gave a yellow oil (6.05 g, 85%). H NMR
(600 MHz, CDCl
3
, Mixture of (E/Z) Isomers (3:1); integrals
represent the major isomer): δ 8.07 (s, 1H), 7.29 (m, 2H), 7.22
(m, 3H), 6.64 (q, J = 13.1 Hz, 8.2 Hz, 1H), 4.48 (d, J = 13.3 Hz,
1H,), 4.19 (d, J = 6.1 Hz, 2H), 4.08 (m, 2H), 1.2 (q, J = 7.2 Hz,
Experimental Procedures
Synthesis of Ethyl-3-(cyclopropylamino)acrylate (3a) in
microwave. To a solution of ethyl-3-ethoxyacrylate (7) (6.94
mmoles) was added cyclopropylamine (8a) (20.82 mmol) in 2
mL Biotage reaction vial. The mixture was diluted with 0.5 mL
of DMF and the septum-sealed reaction vial was irradiated by
1
3
3H); C{1H} NMR (150 MHz, CDCl
3
): δ 170.8, 152.1, 138.5,
128.7 (2C), 127.5, 127.1 (2C), 82.9, 58.7, 52.1, 14.5, 14.5.
+
HRMS (ESI-Orbitrap) m/z: [M+H] Calcd for C12
H
16NO
2
206.1103; found 206.1156.
o
microwave at 150 C for 1 h. The reaction was monitored by
HPLC. Upon completion of the reaction, the reaction mixture
was diluted with 10 mL of water and extracted with
dichloromethane (3 x 25 mL), washed with brine (10 mL) and
dried over sodium sulfate, filtered under gravity. The solvent
Ethyl-3-(cyclohexylamino)acrylate (3d). Prepared following
the general procedure A from ethyl-3-ethoxyacrylate (7) (5 g,
34.72 mmol) and cyclohexylamine (8d) (10.32 g, 104.16
mmol). Further purification with flash column chromatography
1
was removed under pressure to yield the product as a yellow oil
(5:1:0.1 Hex/EtOAc/Et
3
N) gave a white solid (5.97 g, 87%). H
1
(
1.03 g, 96%). H NMR (600 MHz, CDCl
3
, Mixture of (E/Z)
NMR (600 MHz, CDCl
3
, Mixture of (E/Z) Isomers (5:1);
Isomers (5:1); integrals represent the major isomer): δ 7.44 (q,
H), 5.06 (s, 1H) 5.01 (d, J = 13.0 Hz, 1H), 4.12 (q, 2H), 2.39
s, 1H), 1.25 (t, J = 7.2 Hz, 3H), 0.71 (quint, 2H), 0.52 (m,
integrals represent the major isomer): δ 7.89 (s, 1H), 6.74 (q,
1H) , 4.47 (d, 1H, J = 8.0 Hz), 4.14 (p, 2H), 3.05 (m, 1H), 1.92
(t, J = 6.0 Hz, 2H), 1.78 (m, 2H), 1.65 (t, J = 15.0 Hz , 2H), 1.32
1
(
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 8
1
3
1
(
q, 2H), 1.29 (t, J = 7.2 Hz , 3H), 1.21 (p, 2H); C{1H} NMR
(150 MHz, CDCl ): δ 170.9, 150.4, 81.2, 58.5, 56.7, 34.2 (2C),
25.3 (2C), 24.6, 14.6. HRMS (ESI-Orbitrap) m/z: [M+H] Calcd
198.1416; found 198.1469.
81%). H NMR (600 MHz, CDCl ) δ 11.24 (s, 1H), 8.24 (d, J =
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13.9 Hz, 1H), 7.40 (m, 4H), 7.30 (d, J = 7.5 Hz, 2H), 7.01 (d, J
= 8.7 Hz, 1H), 4.63 (d, J = 6.1 Hz, 2H), 4.01 (q, 2H), 1.01 (t, J
= 7.1 Hz, 3H); C{1H} NMR (150 MHz, CDCl
66.5, 161.3, 156.8 ( J19F-13C = 212.8 Hz), 142.8 ( J19F-13C = 6.0
Hz), 135.7, 130.8, 129.5 (2C), 128.8, 127.8 (2C), 125.6 ( J19F-
13C = 4 Hz), 121.4 ( J19F-13C = 18.9 Hz), 115.5 ( J19F-13C = 23.8
Hz), 101.1, 60.2, 58.3, 54.4, 14.2. The NMR data shows
evidence of one major and one minor isomer. The values for δ
3
+
1
3
for C11
H
20NO
2
3
) δ 191.3,
1
3
1
4
Synthesis of 10a-d (General Procedure B). A 1 M solution of
lithium bis(trimethylsilyl)amide was prepared by dissolving
lithium bis(trimethylsilyl)amide (8.4 g) in toluene in a 50 mL
volumetric flask under an argon atmosphere. The solution of
lithium bis(trimethylsilyl)amide (1.1 equiv.) was charged to an
oven dried three necked equipped with a stirring bar was
2
2
H
,
δ
C
, and J19F-13C are reported for the major isomer only. HRMS
(ESI-Orbitrap) m/z: [M+H] Calcd for
396.0491; found 396.0510.
+
C
19
H
2
17Cl FNO
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
charged under. The solution was cooled to -78 C and followed
by a slow addition of the acrylate (3) (1 equiv.). The resulting
bright yellow solution was stirred for 30 min followed by the
dropwise addition of 2,4,5-trifluorobenzoyl chloride (1.1
equiv.). The mixture was allowed to warm to room temperature
and stirred for 1h. After the completion of the reaction, the
Ethyl-3-(cyclohexylamino)-2-(2,4-dichloro-5-
fluorobenzoyl)acrylate (10d). Prepared following the general
procedure B from ethyl-3-(phenylamino)acrylate (3d) (5 g,
25.36 mmol), LiHMDS (27.9 mmol) and 2,4,5-trifluorobenzoyl
chloride (9a) (6.10 g, 27.9 mmol). Flash column
mixture was quenched with saturated aqueous NH
and diluted in 30 mL of dichloromethane. The organic layer was
washed with brine and dried over Na SO . The organic solvent
4
Cl (10 mL)
chromatography (5:1 Hex/EtOAc) gave a yellow solid (7.78 g,
1
2
4
79%). H NMR (600 MHz, CDCl
3
) δ 11.09 (s, 1H), 8.19 (d, J =
was removed under pressure. The resulting yellowish oil was
further purified by flash column chromatography (5:1
Hex/EtOAc) to afford the desired product.
14.3 Hz, 1H), 7.38 (d, J = 6.4 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H),
4.00 (q, 2H), 3.35 (br, 1H), 2.02 (m, 2H), 1.83 (m, 2H), 1.65 (m,
1H), 1.47 (q, 2H), 1.39 (q, 2H), 1.25 (m, 1H), 1.01 (t, J = 7.1
1
3
4
Hz, 3H); C{1H} NMR (150 MHz, CDCl
3
) δ 190.8 ( J19F-13C
=
1
3
Ethyl-3-(cyclopropylamino)-2-(2,4,5-trifluorobenzoyl) acrylate
(10a). Prepared following the general procedure B from Ethyl-
1.2 Hz), 166.7, 159.3, 156.9 ( J19F-13C = 249.6 Hz), 143.0 ( J19F-
13C = 5.9 Hz), 130.7, 125.6 ( J19F-13C = 3.7 Hz), 121.2 ( J19F-13C =
19.0 Hz), 115.4 ( J19F-13C = 23.5 Hz), 100.2, 60.0, 59.3, 33.8,
4
2
2
3
(
1
-(cyclopropylamino)acrylate (3a) (2 g, 12.9 mmol), LiHMDS
14.2 mmol) and 2,4,5-trifluorobenzoyl chloride (9a) (2.76 g,
4.19 mmol). Flash column chromatography (5:1 Hex/EtOAc)
25.2, 24.6, 14.2. The NMR data shows evidence of one major
and one minor isomer. The values for δ
H
, δ
C
, and J19F-13C are
1
gave a yellow oil (3.99 g, 96%). H NMR (600 MHz, CDCl
3
) δ
.12 (s,1H), 7.33 (q, 1H), 7.00 (q, 1H), 5.80 (d, J = 14.2 Hz,
H), 4.20 (q, 2H), 2.76 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.92
reported for the major isomer only. HRMS (ESI-Orbitrap) m/z:
+
8
1
[M+H] Calcd for C18
H
21Cl
2
FNO 388.0804; found 388.0816.
3
13
(br, 3H), 0.60 (br, 3H); C{1H} NMR (150 MHz, CDCl
3
4
) δ.
Synthesis of Ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylate (6a). An oven dried three
necked round bottom flask equipped with a stirring bar was
charged under argon with lithium bis(trimethylsilyl)amide in
1
2
167.4, 165.7, 154.4 ( J19F-13C = 250.9 Hz, J19F-13C = 9.8 Hz, J19F-
1
2
1
3
3C = 2.69 Hz), 152.3 ( J19F-13C = 257.1 Hz, J19F-13C = 26.2 Hz,
J
1
3
19F-13C = 13.0 Hz), 147.4 ( J19F-13C = 248.8 Hz, J19F-13C = 12.4
4
2
o
Hz, J19F-13C = 3.9 Hz), 142.0, 120.3, 118.4 ( J19F-13C = 20.8 Hz,
toluene (1 M) (70.54 mL, 70.54 mmol) and cooled to -78 C and
3
2
3
2
J
J
19F-13C = 4.7 Hz, J19F-13C = 1.6 Hz), 106.6 ( J19F-13C = 27.9 Hz,
followed by a slow addition of the acrylate (3a) (5 g, 32.2
mmol). The resulting bright yellow solution was stirred for 30
min followed by the dropwise addition of 2,4,5-
trifluorobenzoyl chloride (6.89 g, 35.48 mmol) over 10 min.
The mixture was allowed to slowly warm to room temperature
over an 1 h and stirred for an additional 1 h. After the
completion of the reaction, the mixture was quenched with
19F-13C = 21.2 Hz), 103.3, 60.6, 27.7, 14.6, 6.9, 4.5.
Ethyl-2-(2,4-dichloro-5-fluorobenzoyl)-3-
propylamino)acrylate (10b). Prepared following the general
(
procedure B from ethyl-3-(propylamino)acrylate (3b) (5 g, 31.8
mmol), LiHMDS (35 mmol) and 2,4,5-trifluorobenzoyl
chloride (9a) (7.96 g, 35 mmol). Flash column chromatography
saturated aqueous NH
dichloromethane. The organic layer was washed with brine and
dried over Na SO . The organic solvent was removed under
4
Cl (10 mL) and diluted in 60 mL of
1
(
5:1 Hex/EtOAc) gave a yellow solid (8.64 g, 78%). H NMR
(600 MHz, CDCl
3
) δ 11.04 (s, 1H), 8.14 (d, J = 14.1 Hz, 1H),
2
4
7.38 (d, J = 6.3 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 4.00 (q, 2H),
pressure. The resulting yellowish oil was further purified by
flash column chromatography (1.25:1 Hex/EtOAc) to afford a
yellow powder (8.9 g, 94%). All spectra collected and recorded
1
3
3
.43 (q, 2H), 1.73 (q, 2H), 1.01 (m, 6H); C{1H} NMR (150
1
MHz, CDCl
3
3
) δ 191.0, 166.7, 161.5, 156.9 ( J19F-13C = 250.1
Hz), 142.9 ( J19F-13C = 5.9 Hz), 130.8, 125.6 ( J19F-13C = 3.7 Hz),
21.3 ( J19F-13C = 19.3 Hz), 115.5 ( J19F-13C = 23.6 Hz), 100.5,
0.1, 52.5, 24.0, 14.2, 11.3. The NMR data shows evidence of
4
18,19 1
were in agreement with previously reported data.
(600 MHz, CDCl
4.39 (q, 2H), 3.45 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H), 1.37 (m,
H NMR
2
2
1
6
3
) δ 8.59 (s, 1H), 8.26 (dd, 1H), 7.73 (dd, 1H),
13
one major and two minor isomers/conformers. The values for
, δ , and J19F-13C are reported for the major isomer/conformer
only. HRMS (ESI-Orbitrap) m/z: [M+H] Calcd for
FNO 348.0491; found 348.0513.
2H), 1.16 (m, 2H); C{1H} NMR (150 MHz, CDCl ) δ 173.1
3
4
1
2
δ
H
C
( J19F-13C = 1.9 Hz), 165.7, 153.7 ( J19F-13C = 255.8 Hz, J19F-13C
+
1
2
= 14.8 Hz), 149.3, 149.0 ( J19F-13C = 251.2 Hz, J19F-13C = 13.5
Hz), 137.9 ( J19F-13C = 9.5 Hz. J19F-13C = 6.2 Hz), 126.1 ( J 19F-
3C = 4.9 Hz, J19F-13C = 2.3 Hz), 115.8 ( J19F-13C = 18.8 Hz, J19F-
13C = 2.2 Hz), 111.3, 105.8 ( J19F-13C = 22.7 Hz), 61.5, 35.1, 14.7,
3
4
3
C
15
H
17Cl
2
3
4
2
4
1
2
Ethyl-3-(benzylamino)-2-(2,4-dichloro-5-
fluorobenzoyl)acrylate (10c). Prepared following the general
procedure B from ethyl-3-(phenylamino)acrylate (3c) (5 g, 24.4
mmol), LiHMDS (26.8 mmol) and 2,4,5-trifluorobenzoyl
chloride (9a) (6.10 g, 26.8 mmol). Flash column
chromatography (5:1 Hex/EtOAc) gave a white solid (7.83 g,
8.6 (2C).
Synthesis of ciprofloxacin (1). An oven dried three necked
round bottom flask equipped with a stirring bar was charged
under argon with lithium bis(trimethylsilyl)amide in toluene (1
ACS Paragon Plus Environment

Page 7 of 8
The Journal of Organic Chemistry
o
M) (70.54 mL, 70.54 mmol) and toluene and cooled to -78 C
and followed by a slow addition of the acrylate (3a) (5 g, 32.2
mmol). The resulting bright yellow solution was stirred for 30
min followed by the dropwise addition of 2,4,5-
trifluorobenzoyl chloride (6.89 g, 35.48 mmol) over 10 min.
The mixture was allowed to slowly warm to room temperature
over an 1h and stirred for an additional 1 h. Upon completion
of the reaction, the reaction mixture was diluted with DMSO
MHz, DMSO-d )  8.66 (s, 1H), 7.90 (d, J = 12 Hz, 1H), 7.55
6
1
2
3
4
5
6
7
8
9
(d, J = 12 Hz, 1H), 3.86 (m, 1H), 3.25 (t, J = 12 Hz, 4H), 2.92
13
(t, J = 12 Hz, 4H), 1.34 (q, 2H), 1.20 (q, 2H). C{1H} NMR
(
150 MHz, DMSO-d )  176.6, 166.4, 152.6, 148.3, 146.2,
6
139.7, 118.7, 111.4, 111.2, 107.1, 106.5, 51.2, 45.8 (2C), 36.3,
8.0 (2C).
ASSOCIATED CONTENT
Supporting Information
Copies of 1H, 13C{1H} NMR spectra
(
30 mL) followed by the addition of piperazine (11 g, 128
o
mmol) and the mixture was heated to 120 C over 2 h. After
complete consumption of 6a, the temperature was lowered to
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
9
0 C and the reaction mixture was charged with NaOH (2.6 g,
ACKNOWLEDGEMENTS
65 mmol). The reaction mixture was stirred over 1 h, cooled to
room temperature, diluted with 30 mL of water followed by
addition of 4 N HCl to adjust the pH to 7. Ciprofloxacin was
This work was supported by The Defense Advanced Research
Projects Agency (DARPA) (W911NF-16-2-0023).
The authors are thankful to Dr. Raymond N. Dominey and Dr.
Jeffrey H. Simpson for their valuable contributions. We would
like to thank Caleb Kong for his suggestions that have enhanced
the quality of this publication. We would like to thank Evan
Crawford for his assistance.
o
allowed to gradually precipitate in a 4 C fridge. The solid was
filtered, washed three with water and dried to afford (8.84 g,
8
3%) of yellow solid. All spectra collected and recorded were
18,19 1
in agreement with previously reported data.
H NMR (600
MHz, DMSO-d
6
)  8.66 (s, 1H), 7.90 (d, J = 13.4 Hz, 1H), 7.55
(
(
(
d, J = 7.5 Hz, 1H), 3.86 (m, 1H), 3.25 (t, J = 5.0 Hz, 4H), 2.92
AUTHOR INFORMATION
Corresponding Author
13
t, J = 5.0 Hz, 4H), 1.34 (q, 2H), 1.20 (q, 2H). C{1H} NMR
150 MHz, DMSO-d )  176.6, 166.4, 152.6, 148.3, 146.2,
39.7, 118.7, 111.4, 111.2, 107.1, 106.5, 51.2, 45.8 (2C), 36.3,
.03 (2C).
6
*
Email: bfgupton@vcu.edu
1
8
REFERENCES
(1) Pinheiro, E.; Vasan, A.; Yong, J.; Lee, E.; Marc, J.; Perriens, J.
Synthesis of ciprofloxacin in flow. Solutions A-B were
prepared in oven-dried 50 mL screw cap volumetric flasks
under an argon atmosphere. Without any precautions, solution
C were prepared in a 100 mL volumetric flask. Back pressure
was regulated with a back-pressure regulator (BPR). Mixing
was done by combining two streams into a tee (IDEX Health &
Science P-712).
Examining the Production Costs of Antiretroviral Drugs. AIDS 2006, No.
20, 1745–1752.
(2) Ott, D.; Kralisch, D.; Denčić, I.; Hessel, V.; Laribi, Y.; Perrichon, P. D.;
Berguerand, C.; Kiwi-Minsker, L.; Loeb, P. Life Cycle Analysis within
Pharmaceutical Process Optimization and Intensification: Case Study of
Active Pharmaceutical Ingredient Production. ChemSusChem 2014, 7 (12),
3
521–3533.
(3) Bumpas, J.; Betsch, E. "Exploratory Study on Active Pharmaceutical
The sequence was run on two Vapourtec E-series units with
each Vapourtec E series flow reactor equipment consisting of
two peristaltic pumps for reagents and solvents delivery. The
Vapourtec using were equipped with one 2 mL and two 10 mL
PFA reactors (1/8” O.D. x 1/16” I.D.) that was utilized in the
flow chemistry experiments. All reactors were primed with
anhydrous THF before each experiment. Reactor II was pre-
heated to 140 °C and Reactor II was pre-heated to 120 °C. The
Vapourtec Pump A was used to pump the stock of 2,4,5-
trifluorobenzoyl chloride (0.66 M) and Vapourtec Pump B was
used to pump the stock of the acrylate (8a) and LiHMDS
mixture in THF (0.6 M). Solutions A and B were mixed at a T-
piece (M1) (IDEX Health and Science, P-726) and pumped
through Reactor I (1/8” O.D. x 1/16” I.D., 2 mL) and streamed
Ingredient Manufacturing for Essential Medicines." 2009.
(4) Verghese, J.; Kong, C. J.; Rivalti, D.; Yu, E. C.; Krack, R.; Alcázar, J.;
Manley, J. B.; McQuade, D. T.; Ahmad, S.; Belecki, K.; Gupton, F. B.
Increasing Global Access to the High-Volume HIV Drug Nevirapine
through Process Intensification. Green Chem. 2017, 19 (13), 2986–2991.
(5) Dach, R.; Song, J. J.; Roschangar, F.; Samstag, W.; Senanayake, C. H.
The Eight Criteria Defining a Good Chemical Manufacturing Process. Org.
Process Res. Dev. 2012, 16 (0), 1697–1706.
(6) Goldbach, M.; Danieli, E.; Perlo, J.; Kaptein, B.; Litvinov, V. M.;
Blümich, B.; Casanova, F.; Duchateau, A. L. L. Preparation of Grignard
Reagents from Magnesium Metal under Continuous Flow Conditions and
On-Line Monitoring by NMR Spectroscopy. Tetrahedron Lett. 2016, 57
(1), 122–125.
(7) Chemical Process Research and Development in the 21st Century:
Challenges, Strategies, and Solutions from a Pharmaceutical Industry
Perspective. Acc. Chem. Res. 2009, 42 (5), 671–680.
(8) Caron, S.; Thomson, N. M. Pharmaceutical Process Chemistry:
Evolution of a Contemporary Data-Rich Laboratory Environment. J. Org.
Chem. 2015, 80 (6), 2943–2958.
(9) Yu, E.; Mangunuru, H. P. R.; Telang, N. S.; Kong, C. J.; Verghese, J.;
Gilliland, S. E.; Ahmad, S.; Dominey, R. N.; Gupton, B. F. High-Yielding
Continuous-Flow Synthesis of Antimalarial Drug Hydroxychloroquine.
Beilstein J. Org. Chem. 2018, 14, 583–592.
(10) Korwar, S.; Amir, S.; Tosso, P. N.; Desai, B. K.; Kong, C. J.; Fadnis,
S.; Telang, N. S.; Ahmad, S.; Roper, T. D.; Gupton, B. F. The Application
of a Continuous Grignard Reaction in the Preparation of Fluconazole.
European J. Org. Chem. 2017, 2017 (44), 6495–6498.
o
into a continuous stir tank reactor heated at 60 C. The heated
mixture was then pumped out through pump C meeting a
preheated solution of piperazine (1.2 M) in DMSO preheated
o
(
120 C) at a second T-piece (M2). The collective flow mixture
was allowed to pump into Reactor II (1/8” O.D. x 1/16” I.D., 10
mL). The output from Reactor II was connected to a third T-
piece (M3) meeting a solution of 1.0 M of NaOH. The collective
flow mixture was allowed to pump in Reactor III (1/8” O.D. x
1/16” I.D., 10 mL). A 75 PSI back pressure regulator (BPR)
(11) Kong, C. J.; Fisher, D.; Desai, B. K.; Yang, Y.; Ahmad, S.; Belecki,
K.; Gupton, B. F. High Throughput Photo-Oxidations in a Packed Bed
Reactor System. Bioorg. Med. Chem. 2017.
(IDEX Health and Science, P-785) was connected after Reactor
III. After approximately three total system residence times, the
output flow from Reactor III was collected for 10 min (80 mL).
The output was allowed to cool to room temperature was
(12) Emmerson, A. M. The Quinolones: Decades of Development and Use.
J. Antimicrob. Chemother. 2003, 51 (90001), 13–20.
(13) Mitscher, L. A. Bacterial Topoisomerase Inhibitors: Quinolone and
Pyridone Antibacterial Agents. Chem. Rev. 2005, 105 (2), 559–592.
followed by the addition of 4 N HCl to adjust the pH to 7.
o
Ciprofloxacin was allowed to gradually precipitate in a 4
C
(14) Aldred, K. J.; Kerns, R. J.; Osheroff, N. Mechanism of Quinolone
fridge. The solid was filtered, washed three with water and dried
1
Action and Resistance. Biochemistry 2014, 53 (10), 1565–1574.
(15) Linder, J. A.; Huang, E. S.; Steinman, M. A.; Gonzales, R.; Stafford,
to afford 4.7 g (83% overall) of yellow solid. H NMR (600
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 8
R. S. Fluoroquinolone Prescribing in the United States: 1995 to 2002. Am.
J. Med. 2005, 118 (3), 259–268.
(20) Bartoli, G.; Cimarelli, C.; Dalpozzo, R.; Palmieri, G. A Versatile Route
toꢀ-Enamino Esters by Acylation of Lithium Enamines with Diethyl
Carbonate or Benzyl Chloroformate. Tetrahedron 1995, 51 (31), 8613–
8622.
(21) Lavrard, H.; Larini, P.; Popowycz, F. Superacidic Cyclization of
Activated Anthranilonitriles into 2-Unsubstituted-4-Aminoquinolines. Org.
Lett. 2017, 19 (16), 4203–4206.
(22) Girling, P. R.; Batsanov, A. S.; Shen, H. C.; Whiting, A. A
Multicomponent Formal [1+2+1+2]-Cycloaddition for the Synthesis of
Dihydropyridines. Chem. Commun. 2012, 48 (40), 4893–4895.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(16) Andriole, V. T. The Quinolonesꢀ: Past , Present , and Future. 2005, 41
(Suppl 2), 113–119.
(17) Grohe, K.; Heitzer, H. Cycloaracylation of Enamines. I. Synthesis of
4-Quinolone-3-Carboxylic Acids. Liebigs Ann. Chem. 1987, No. 1, 29–37.
(18) Schwalbe, T.; Kadzimirsz, D.; Jas, G. Synthesis of a Library of
Ciprofloxacin Analogues by Means of Sequential Organic Synthesis in
Microreactors. QSAR Comb. Sci. 2005, 24 (6), 758–768.
(19) Lin, H.; Dai, C.; Jamison, T. F.; Jensen, K. F. A Rapid Total Synthesis
of Ciprofloxacin Hydrochloride in Continuous Flow. Angew. Chemie - Int.
Ed. 2017, 8870–8873.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment