A Rapid Total Synthesis of Ciprofloxacin Hydrochloride in Continuous Flow

Article abstract of DOI:10.1002/anie.201703812

Within a total residence time of 9 min, the sodium salt of ciprofloxacin was prepared from simple building blocks via a linear sequence of six chemical reactions in five flow reactors. Sequential offline acidifications and filtrations afforded ciprofloxacin and ciprofloxacin hydrochloride. The overall yield of the eight-step sequence was 60 %. No separation of intermediates was required throughout the synthesis when a single acylation reaction was applied to remove the main byproduct, dimethylamine.

Full text of DOI:10.1002/anie.201703812

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: A Rapid Total Synthesis of Ciprofloxacin Hydrochloride in
Continuous Flow
Authors: Hongkun Lin, Chunhui Dai, Timothy F. Jamison, and Klavs F.
Jensen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703812
Angew. Chem. 10.1002/ange.201703812
Link to VoR: http://dx.doi.org/10.1002/anie.201703812
http://dx.doi.org/10.1002/ange.201703812

Angewandte Chemie International Edition
10.1002/anie.201703812
COMMUNICATION
A Rapid Total Synthesis of Ciprofloxacin Hydrochloride in
Continuous Flow
Hongkun Lin,[a] Chunhui Dai,[b] Timothy F. Jamison*[b] and Klavs F. Jensen*[a]
Abstract: Within a total residence time of 9 min, the sodium salt of
ciprofloxacin was prepared from simple building blocks via a linear
sequence of six chemical reactions in five flow reactors. Sequential
offline acidifications and filtrations afforded ciprofloxacin and
ciprofloxacin hydrochloride. The overall yield of the eight-step
sequence was 60 %. No separation of intermediates was required
throughout the synthesis when a single acylation reaction was applied
to remove the main byproduct, dimethylamine.
increasing the overall yield to 57 % but with > 100 h reaction
time.[10]
O
N
O
O
N
O
O
O
F
F
F
F
OH
OEt
OEt
N
N
N
H
2
N
HN
Cl
ciprofloxacin hydrochloride
2
3
1
Low solubility
Low solubility
Continuous flow synthesis has emerged as an efficient
technique in synthetic chemistry. The rapid mixing as well as
enhanced heat and mass transfer in flow reactors allow better
control of reaction selectivity.[1] An elegant example is the
selective reduction of esters to aldehydes.[ Extremely rapid
lithiation reactions also showcase the unprecedented control of
reactions in microreactors.[ In addition, flow reaction technology
enables much safer operation under conditions of high
temperature and high pressure.[
O
F
O
O
O
O
O
F
F
F
NH
2
5
F
F
Cl
OEt
OEt
NMe
OEt
NH

F
NMe
7
2
F
6
2
7
F
8
4
2]
Scheme 1. Retrosynthesis of ciprofloxacin hydrochloride.
3]
1d,4]
Taking advantage of flow chemistry, we are aiming to
increase the synthetic efficiency of ciprofloxacin. Our synthetic
plan is shown in Scheme 1. Acylation of commercially available
acyl chloride 8 with vinylogous carbamate 7 would afford 6.
Several elegant examples of multistep synthesis have been
performed in flow reactors,[5] but efficient telescoping of reactions
[
5c,5f-
still remains a challenge owing to needs for solvent switches,
h,6a]
[5c,5f-h]
and necessity of workup[5a,5g-h]
mismatch of flow rates,
.
Ciprofloxacin hydrochloride
1
would be generated after
Herein, we report a total synthesis of ciprofloxacin in continuous
flow, in which six reactions are telescoped in five reactors
sequentially without any separation or isolation of intermediates.
To the best of our knowledge, this is the longest linear sequence
of reactions telescoped in flow to date, without holding the
displacement with cyclopropylamine 5, two regioselective S Ar
reactions, hydrolysis of ester and acidification.
N
We started with screening solvents and bases for the
acylation of vinylogous carbamate 7 with 8. Although 6 was
obtained in good yields with a handful of bases and solvents in
batch, in the context of continuous flow synthesis, the requirement
to avoid generation of any precipitates needed to be satisfied.
Three combinations of solvent/base were identified,
acetonitrile/N,N-diisopropylethylamine (DIEA), chloroform/DIEA
and chloroform/triethylamine (See supporting information for
details of screening).[ Considering that the U.S. Food and Drug
[
7]
reaction stream.
Ciprofloxacin is on the World Health Organization List of
Essential Medicines.[8] It belongs to the family of fluoro-quinolone
antibiotics and is used to treat a number of types of bacterial
infections. Bayer AG developed and patented a seven-step
synthesis in the 1980s, with an overall yield of 49 % and > 24 h of
reaction time.[ Later, a similar sequence of reactions were
performed on resin supported analog of 6 (Scheme 1), slightly
11]
9]
Administration (FDA) imposes a concentration limit of 60 ppm of
chloroform and 410 ppm of acetonitrile,[
12]
we selected the
combination of acetonitrile/DIEA. At 180 °C and 175 psi, 98 % of
was generated with a residence time of 1.5 min. Addition of
6
cyclopropylamine to the crude stream of 6 furnished exchange
product 4 in 96 % isolated yield (Scheme 2).
[
[
a]
b]
Dr. H. Lin and Prof. K. F. Jensen
Department of Chemical Engineering
Massachusetts Institute of Technology
NH
2
5
77 Massachusetts Ave, Cambridge, Massachusetts, 02139, United
DIEA
80 °C, 1.5 min
O
F
O
O
F
O
O
F
O
1
25 °C, 1 min
States
F
F
F
F
F
F
Cl

OEt
OEt
NMe
OEt
NH
E-mail: kfjensen@mit.edu
Dr. C. Dai and Prof. T. F. Jamison
Department of Chemistry
Massachusetts Institute of Technology
NMe
2
2
7
8
7
6
4
98 %
96 %
7
7 Massachusetts Ave, Cambridge, Massachusetts, 02139, United
Scheme 2. Preparation of 4 in flow reactors. 1.0 equiv. of 7, 1.2 equiv. of 8, 1.15
equiv. of DIEA, 1.25 equiv. of 5. See supporting information for details.
States
E-mail: tfj@mit.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201703812
COMMUNICATION
(
a) Stepwise synthesis of 131st generation
Meanwhile, we also investigated various batch reaction
conditions for the direct acylation of 9, which was prepared by
addition of 5 to 10 quantitatively either in batch or in flow.[ When
O
O
O
N
O
O
N
O
DBU, DMSO
piperazine, DMSO
150 °C, 6.7 min
F
F
150 °C, 1.7 min
F
F
F
OEt
NH
OEt
OEt
13]
F
N
HN
9
was treated with weak bases, we obtained a mixture of C-
4
3
2
acylation (4’) and N-acylation (11) products. Under our best
conditions, the ratio of 4’:11 was 6:1.[14] Moreover, the reaction
was much slower than acylation of 7, reflecting significant
difference in the nucleophilicity of both substrates (Scheme 3a).
O
N
O
O
N
O
NaOH
0 °C, 0.9 min
8
F
HCl
F
ONa
OH
N
N
HN
HN
12
1
3
n
ciprofloxacin
In contrast, when 9 was deprotonated with strong base BuLi,
8
6 %
(
b) One-pot synthesis of 22nd generation
followed by acylation with 8, cyclization product 3’’ immediately
precipitated along with a small amount of 4’ (Scheme 3b). We did
not optimize this set of conditions in flow, considering both the
intolerance of flow reactors with rapid precipitation of 3’’ and the
higher cost of 10 than 7.[15]
O
N
O
DBU, piperazine
DMSO/MeCN
180 °C, 4.3 min
F
O
O
O
N
O
OEt
F
F
F
OEt
NH
OEt
2
Me N
F
N
HN
3'
4
2
5
8 % before acetyl chloride treatment
0 % after acetyl chloride treatment
8
2 % in batch and flow
(a) Acylation of 9 with weak bases
O
8, Bu
N
O
O
1
,4-dioxane
3
2
CO Me
1
50 °C, 1 min
OMe 10 mol % PPh
3
F
F
Scheme 4. Stepwise and one-pot synthesis of 2 in flow. Reaction conditions:
(a) 1.0 equiv. of 4 (0.15 M in DMSO, 2.8 mL/min), 2.0 equiv. of DBU (neat, 118.0
μL/min), 150 °C, 1.7 min; 3.0 equiv. of piperazine (0.8 M in DMSO, 1.58 mL/min),
O
OMe
O
NH
2


F
F
OMe
NH
F
NH
N
1
,4-dioxane, rt
5
10
6:1 4':11
F
9
4'
11
quantitative
2
150 °C, 6.7 min; 4.0 equiv. of NaOH (2 M in H O, 0.84 mL/min); Adjusting pH to
(
b) Acylation of 9 with strong bases
7 with HCl offline; 86 % isolated yield. (b) 82 % isolated yield. See supporting
information for details.
O
O
O
O
N
O
1
)
n
BuLi
F
F
F
OMe
NH
OMe

OMe
2) 8
,4-dioxane
F
NH
F
1
9
4'
3'', precipitated
to DBU and piperazine, 2 was obtained with 82 % yield in batch.
After some optimization (Table 1), almost identical batch yield was
observed when crude 4 after acetyl chloride treatment was used.
Scheme 3. Alternative unoptimized methods for preparation of 4’. Conditions
for preparation of 9 in a continuous flow reactor: 1.0 equiv. of 5 (2.0 M in 1,4-
dioxane, 222.0 μL/min), 1.0 equiv. of 10 (2.0 M in 1,4-dioxane, 222.0 μL/min),
1
The one-pot reaction was monitored by H NMR. 4 was first
150 °C, 1 min, 200 psi back pressure.
deprotonated to form one anionic species followed by cyclization
and piperazine substitution sequentially. We were then able to
telescope the five reactions to afford 2 in 82 % overall yield in flow
under optimized conditions (Schemes 4b and 5).
We continued our flow synthesis with the acylation-exchange
method. In agreement with Schwalbe’s report,[
11]
competitive
substitution by HNMe
2
to form 3’ (Scheme 4),[ lowered the yield
16]
of desired cyclization product 3 to 24 %. Different from Schwalbe
and coworkers who removed HNMe by evaporation, which would
otherwise result in discontinuous operation, we employed a rapid
acylation reaction for the removal of HNMe to ensure continuous
Table 1. Optimization of one-pot cyclization–S
N
Ar reaction of crude 4 in
batch.[
a]
2
Entry
DBU
equiv.)
Piperazine
(equiv.)
Yield of 3 (%)[b]
Yield of 2 (%)[b]
2
(
operation. Simply by mixing the crude reaction mixture of 4 after
exchange with acetyl chloride and DIEA at ambient temperature
for a residence time of 1 min, HNMe was completely converted
2
to N,N-dimethylacetamide (DMA), which did not interfere
cyclization under the reaction conditions (Schemes 4 and 5).
Now the stage is set for cyclization. It is noteworthy that the
solubility of 2 and 3 is low in a variety of polar aprotic solvents
1
2
3
1.5
3
1.2
1.2
2.5
49
28
53
16
59
11
1.5
4
5
3.0
3.0
2.5
3.0
17
-
67
81
N
suitable for S Ar reactions at ambient temperature (e.g. solubility
of 3 < 0.016 M in DMSO), possibly due to π-π stacking
interactions, therefore either higher temperature or high dilution is
required for continuous flow synthesis to prevent clogging of
reactors. As we observed that it took 1-2 min for the crystals of
[
a] Reactions were run at 180 °C in sealed vessels for 5 min. [b] 1H NMR
yields. 1,3,5-Trimethoxybenzene was used as standard.
2
/3 to nucleate when cooling from a hot solution, we insulated
related connections to prevent clogging. Initially we tried stepwise
cyclization and S Ar reaction and found a residence time of 1.7
N
Mixing the stream of 2 with a stream of 1.0 M aqueous NaOH
for a residence time of 0.9 min afforded the sodium carboxylate
2. Adjusting the pH of the solution to 7 with aqueous HCl offline
enabled precipitation of crude ciprofloxacin 13 in 75 % yield. It
was then dissolved in a minimal volume of aqueous HCl to form
hydrochloride salt of ciprofloxacin 1, which was crystallized by
additon of acetone (Scheme 5).
min was sufficient for the rapid intramolecular cyclization. Mixing
the stream of 3 with a stream of piperazine afforded 2 after a
reaction of 6.7 min. Hydrolysis and acidification afforded
ciprofloxacin 13 in 86 % yield. Inspired by the formation of side
product 3’, we envisioned that one-pot cyclization and piperazine
substitution may be feasible. Indeed, when pure 4 was subjected
1
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201703812
COMMUNICATION
Reactor I
80 °C
= 1.5 min
Reactor II
25 °C
O
O
O
O
O
1
Keywords: aromatic substitution • ciprofloxacin • continuous
flow • multicomponent reactions • multistep synthesis
t
1
F
F
OEt
NMe
t
2
= 1 min
F
F
OEt
OEt
NMe
F
NH
2
F
6
2
7
4
DIEA
98 %
HNMe
2
[
1]
(a) J. Yoshida, Y. Takahashi, A. Nagaki, Chem. Commun. 2013, 49,
9896-9904. (b) D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675-680.
(c) I. R. Baxendale, S. V. Ley, A. C. Mansfield, C. D. Smith, Angew. Chem.
Int. Ed. 2009, 48, 4017-4021; Angew. Chem. 2009, 121, 4077-4081. (d)
S. Suga, M. Okajima, K. Fujiwara, J. Yoshida, J. Am. Chem. Soc. 2001,
123, 7941-7942. (e) H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem.
Int. Ed. 2007, 46, 5704-5708; Angew. Chem. 2007, 119, 5806-5810. (f)
B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan, D. T. McQuade,
Chem. Rev. 2007, 107, 2300-2318.
O
F
NH
2
O
F
F
Cl
5
DIEA
Cl
Reactor III
25 °C
t = 1 min
3
8
Reactor V
0 °C
= 0.9 min
Reactor IV
180 °C
t
4
O
F
O
8
O
N
O
F
F
t
5
F
= 4.3 min
OEt
NH
OEt
175 psi BPR
N
2
4
HN
8
2 %
96 %
DMA
NaOH
DBU
HN
[2]
D. Webb, T. F. Jamison, Org. Lett. 2012, 14, 568-571.
[
3]
(a) H. Kim, K.-I. Min, K. Inoue, D. J. Im, D.-P. Kim, J. Yoshida, Science
NH
2016, 352, 691-694. (b) A. Nagaki, Y. Takahashi, J. Yoshida, Angew.
O
N
O
O
N
O
O
O
Chem. Int. Ed. 2016, 55, 5327-5331; Angew. Chem. 2016, 128, 5413-
5417. (c) A. Nagaki, D. Ichinari, J. Yoshida, J. Am. Chem. Soc. 2014,
136, 12245-12248. (d) Y. Tomida, A. Nagaki, J. Yoshida, J. Am. Chem.
Soc. 2011, 133, 3744-3747.
offline HCl aq
to pH 7
offline HCl aq
to pH < 3
F
F
F
ONa
OH
OH
N
N
acetone
N
N
HN
HN
H
2
N
12
Cl
1
3
1
ciprofloxacin
5 %
ciprofloxacin hydrochloride
60 %
[
4]
(a) C. Wiles, P. Watts, in Micro Reaction Technology in Organic
Synthesis, CRC Press, Boca Raton, FL, USA, 2011, pp. 1-36. (b) D.
Barrow, S. Taylor, A. Morgan, L. Giles, in Microreactors in Organic
Chemistry and Catalysis, Second Edition (Ed.: T. Wirth), Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim, Germany, 2013, pp. 1-33. (c) B.
Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54,
7
Scheme 5. Flow scheme of continuous total synthesis of ciprofloxacin. 1.0 equiv.
of 7, 1.2 equiv. of 8, 1.15 equiv. of DIEA, 1.25 equiv. of 5, 1.15 equiv. of DIEA,
.2 equiv. of acetyl chloride, 3.5 equiv. of DBU, 3.5 equiv. of piperazine, 6.0
equiv. of NaOH. See supporting information for details. DBU
Diazabicyclo[5.4.0]undec-7-ene.
[
17]
1
= 1,8-
6
688-6728; Angew. Chem. 2015, 127, 6788-6832.
(a) D. R. Snead, T. F. Jamison, Angew. Chem. Int. Ed. 2015, 54, 983-
87; Angew. Chem. 2015, 127, 997-1001. (b) T. Tsubogo, H. Oyamada,
[
5]
9
S. Kobayashi, Nature 2015, 520, 329-332. (c) S. Newton, C. F. Carter,
C. M. Pearson, L. de C. Alves, H. Lange, P. Thansandote, S. V. Ley,
Angew. Chem. Int. Ed. 2014, 53, 4915-4920; Angew. Chem. 2014, 126,
In summary, we have developed a rapid total synthesis of
ciprofloxacin in continuous flow. The total residence time is 9
minutes, compared to over 24 hours in patented synthesis[
9,14]
and
5
015-5020. (d) J. Hartwig, S. Ceylan, L. Kupracz, L. Coutable, A.
Kirschning, Angew. Chem. Int. Ed. 2013, 52, 9813-9817; Angew. Chem.
013, 125, 9995-9999. (e) P. R. D. Murray, D. L. Browne, J. C. Pastre,
polymer supported synthesis[10]. The 60 % overall yield is
comparable to batch[14] and semi-batch syntheses[11]. To the best
of our knowledge, it is the longest linear sequence of reactions
telescoped in continuous flow to date without interrupting the flow
by any workup requirements. Through meticulous selection of
reaction conditions, only one inline workup step is required for the
six-step sequence of reactions, in complement to modular flow
synthesis.[5c,18] The key to continuous operation is (1) inline
acylation of byproduct dimethylamine and (2) keeping the crude
solution of 2 warm before entering Reactor V to avoid solid
formation, due to its low solubility. Isolation of pure ciprofloxacin
involves simple pH adjustment, filtration and washing. This
synthesis enables significant reduction of reaction time and waste
production.
2
C. Butters, D. Guthrie, S. V. Ley, Org. Process Res. Dev. 2013, 17, 1192-
1208. (f) M. Brasholtz, J. M. Macdonald, S. Saubern, J. H. Ryan, A. B.
Holmes, Chem. Eur. J. 2010, 16, 11471-11480. (g) E. Riva, A. Rencurosi,
S. Gagliardi, D. Passarella, M. Martinelli, Chem. Eur. J. 2011, 17, 6221-
6226. (h) B. Ahmed-Omer, A. J. Sanderson, Org. Biomol. Chem. 2011,
9, 3854-3862. (i) A. Adamo, R. L. Beingessner, M. Behnam, J. Chen, T.
F. Jamison, K. F. Jensen, J.-C. M. Monbaliu, A. S. Myerson, E. M.
Revalor, D. R. Snead, T. Stelzer, N. Weeranoppanant, S. Y. Wong, P.
Zhang, Science 2016, 352, 61-67. (j) L. Kupracz, A. Kirschning, Adv.
Synth. Catal. 2013, 355, 3375-3380. (k) J. Hartwig, A. Kirschning, Chem.
Eur. J. 2016, 22, 3044-3052.
[6]
(a) L. Peeva, J. Da Silver Burgal, Z. Heckenast, F. Brazy, F. Cazenave,
A. Livingston, Angew. Chem. Int. Ed. 2016, 55, 13576-13579; Angew.
Chem. 2016, 128, 13774-13777. For an example of employing an
additive to circumvent solvent switch, see (b) J. C. Yang, D. Niu, B. P.
Karsten, F. Lima, S. L. Buchwald, Angew. Chem. Int. Ed. 2016, 55, 2531-
2535; Angew. Chem. Int. Ed. 2016, 128, 2577-2581.
Acknowledgements
[
[
7]
8]
For a longer sequence of operations with holding tanks, see R. J. Ingham,
C. Battilocchio, D. E. Fitzpatrick, E. Sliwinski, J. M. Hawkins, S. V. Ley,
Angew. Chem. Int. Ed. 2015, 54, 144-148; Angew. Chem. 2015, 127,
We are grateful to Professor Kai Wang of Tsinghua University, Dr.
Jisong Zhang, Dr. Guohua Liang, Dr. Nopphon Weeranoppanant
for technical support and helpful discussions. We thank Dr.
Marcus O'Mahony and Dr. Naomi Briggs for solubility data of
ciprofloxacin 13 and ciprofloxacin hydrochloride salt 1. We also
thank Dr. Bruce Adams in the Department of Chemistry
Instrumentation Facility (DCIF) at MIT for NMR assistance. This
work was supported by Defense Advanced Research Projects
Agency (DARPA) (N666001-11-C-4005).
146-150.
“19th WHO Model List of Essential Medicines (April 2015)”, can be found
under
http://www.who.int/medicines/publications/essentialmedicines/EML2015
_8-May-15.pdf
[9]
J. J. Li, D. S. Johnson, D. R. Sliskovic, B. D. Roth, in Contemporary Drug
Synthesis, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2004, pp. 75-87.
[
10] (a) A. A. MacDonald, S. H. DeWitt, E. M. Hogan, R. Ramage,
Tetrahedron Lett. 1996, 37, 4815-4818. (b) A. M. Hay, S. Hobbs-Dewitt,
A. A. MacDonald, R. Ramage, Tetrahedron Lett. 1998, 39, 8721-8724.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201703812
COMMUNICATION
(
c) A. M. Hay, S. Hobbs-Dewitt, A. A. MacDonald, R. Ramage, Synthesis
999, 1979-1985.
11] T. Schwalbe, D. Kadzimirsz, G. Jas, QSAR Comb. Sci. 2005, 24, 758-
68.
12] “Guidance for Industry Q3C Tables and List, 2012 Revision 2”, can be
1
[
[
7
found
under
https://www.fda.gov/downloads/Drugs/Guidances/ucm073395.pdf
[
13] (a) F. Dubar, G. Anquetin, B. Pradines, D. Dive, J. Khalife, C. Biot, J.
Med. Chem. 2009, 52, 7954-7957. (b) C.-H. Park, J. Lee, H. Y. Jung, M.
J. Kim, S. H. Lim, H. T. Yeo, E. C. Choi, E. J. Yoon, K. W. Kim, J. H. Cha,
S.-H. Kim, D.-J. Chang, D.-Y. Kwon, F. Li, Y.-G. Suh, Bioorg. Med. Chem.
2007, 15, 6517-6526.
[
[
14] K. Grohe, H. Heitzer, Leibigs Ann. Chem. 1987, 29-37.
15] For comparison, 10 and 7 are provided by Alfa Aesar at $5.85/gram and
$
2.20/gram, respectively.
16] Based on basicity, HNMe
presumably protonated by DIEA•HCl present in the mixture. HNMe
[
2
, a byproduct in the exchange reaction, is
is
•HCl by DBU under cyclization
2
released via neutralization of HNMe
conditions.
2
[
[
17] Although the yield of 6 was unchanged with excess of 7, it is critical to
use excess of 8 to ensure complete conversion of 7, otherwise unreacted
7
would exchange with piperazine to form 3’ in Reactor IV.
18] D. Ghislieri, K. Gilmore, P. H. Seeberger, Angew. Chem. Int. Ed. 2015,
4, 678-682; Angew. Chem. 2015, 127, 688-692.
5
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201703812
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Rapid assembly of five building blocks
to make ciprofloxacin was achieved in
nine minutes in flow. A total of six
reactions took place in five reactors to
afford ciprofloxacin sodium salt.
Simple offline pH adjustment, filtration
and crystallization afforded
ciprofloxacin hydrochloride crystal.
H. Lin, C. Dai, T. F. Jamison*, K. F.
Jensen*
Page No. – Page No.
A Rapid Total Synthesis of
Ciprofloxacin Hydrochloride in
Continuous Flow
This article is protected by copyright. All rights reserved.