A facile approach to the synthesis of 3-(6-Chloro-thiazolo[5,4-b]pyridin-2- ylmethoxy)-2,6-difluoro-benzamide (PC190723)

Article abstract of DOI:10.1055/s-0031-1290777

Practical synthesis of PC 190723, a bacterial cell division protein Ftsz inhibitor, has been achieved in a high overall yield of 45% in six steps from commercially available starting materials. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290777

LETTER
▌1039
lAetteFr acile Approach to the Synthesis of 3-(6-Chloro-thiazolo[5,4-b]pyridin-
2-ylmethoxy)-2,6-difluoro-benzamide (PC190723)
Synthesis of PC190723
Zi-Chun Ding,a Weicheng Zhou,a Xiang Ma*a,b
a
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry,
State Institute of Pharmaceutical Industry, 1111 North Zhongshan No.1 Rd, Shanghai 200437, P. R. of China
b
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, Hubei,
P. R. of China
Fax +86(27)83692750; E-mail: maxwellcn@yahoo.com
Received: 16.01.2012; Accepted after revision: 24.02.2012
able progress has been made recently in the field of anti-
bacterial small-molecule FtsZ inhibitors.3a,4 PC190723 (1;
Figure 1), a benzamide derivative with a thiazolo[5,4-
b]pyridine fragment, is one such synthetic compound that
is active on the GTPase of FtsZ.5 This compound was dis-
covered at Prolysis Inc, and operates through a new mech-
anism of action based on its interaction with FtsZ. It has
potent and selective in vitro bactericidal activity against
staphylococci, including methicillin- and multi-drug-
resistant aureus and was efficacious in an in vivo model of
infection, curing mice infected with a lethal dose of
S. aureus.5 There are a limited numbers of syntheses re-
ported for PC190723, including recent publications by
Haydon et al.5a and Sorto et al.6 The synthesis of
PC190723, which was initialized in medicinal chemistry
research on a small scale by Haydon et al., started from
expensive 2,6-difluoro-3-methoxybenzamide and used
benzyloxyacetyl chloride as a protection strategy. Subse-
quently, Sorto et al. reported a five-step synthesis of
PC190723 in a practical way by following a closely relat-
ed route. Due to its promising biological properties, our
group is interested in developing efficient syntheses of
PC190723 with the long-term goal of discovering new an-
tibiotic agents using PC190723 as a lead and understand-
ing the mechanism by which these compounds act on this
protein. We started the synthesis of PC190723 by exam-
ining the use of 6-chloro-2-(chloromethyl)thiazolo[5,4-
b]pyridine, the synthesis of which we reported recently,7
with the aim of developing a more versatile access to this
class of compounds. We herein report an efficient synthet-
ic route that is suitable for scaling up the production of
PC190723.
Abstract: Practical synthesis of PC 190723, a bacterial cell divi-
sion protein Ftsz inhibitor, has been achieved in a high overall yield
of 45% in six steps from commercially available starting materials.
Key words: antibacterial agents, cell division inhibitors, thiazo-
lo[5,4-b]pyridine, FtsZ
Antibiotic-resistant strains of pathogenic bacteria are in-
creasingly prevalent in hospitals and the community.1
Gram-positive infections caused by some antibiotic-resis-
tant pathogens, such as the multidrug-resistant strains of
Staphylococcus aureus in particular, are raising signifi-
cant medical, economic, and public health concerns
worldwide.2 New antibiotics are needed to combat these
bacterial pathogens, but progress in developing them are
on the decline. Although over the past decades, more than
100 new antibacterial agents have been developed, most
of these recently developed antimicrobial agents are new
members of established antibiotic classes rather than nov-
el drugs.1a There is therefore a great need to identify novel
antibiotic targets and discover new antibiotic classes that
will help to combat the rise of resistant pathogens.
Cl
N
S
O
F
N
F
NH2
O
PC190723, 1
Figure 1 Structure of PC 190723
The retrosynthetic analysis shown in Scheme 1 revealed
the synthetic strategy used for the preparation of
PC190723 (1), which involved the coupling reaction of
halomethyl substituted thiazolo[5,4-b]pyridine 2 and 2,6-
difluoro-3-hydroxybenzamide (3). The heterocycle 2 was
prepared from 2-bromo-5-chloropyridin-3-ylamine (4) in
a sequence of five steps. Benzamide 3 was readily synthe-
sized from 2,4-difluorophenol (5) by regioselective lithia-
tion and carboethoxylation followed by aminolysis. We
also considered the alternative possibility of synthesizing
3 from 2,6-difluorobenzoic acid (6) by a reaction se-
quence based on the retrosynthetic analysis depicted in
Scheme 1, involving the preparation and diazotization of
In this context, bacterial cytoskeleton and cell division
proteins, in particular FtsZ, have been recognized as un-
exploited and attractive targets in the search for new anti-
biotics with which to fight the widespread emergence of
pathogens resistant to current antibiotics.3 FtsZ is the key
protein of bacterial cell division and undergoes guanosine
5′-triphosphate (GTP) dependent polymerization to form
the Z ring at the mid-cell during cell division.3a Consider-
SYNLETT 204012, 237, 1039–1042
Advanced online publication: 05.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290777; Art ID: ST-2012-W0040-L
© Georg Thieme Verlag Stuttgart · New York

1040
Z.-C. Ding et al.
LETTER
NH2
F
O
Cl
F
N
S
HO
F
O
S
+
X
N
F
NH2
2a, X = Cl
2b, X = Br
2c, X = I
N
O
3
N
F
F
F
Cl
PC190723, 1
COOH
F
COOH
F
Cl
NH2
F
N
Br
OH
NH2
4
5
7
6
Scheme 1 Retrosynthetic route to PC190723 (1)
3-amino-2,6-difluoro-benzoic acid (7) to introduce the 3- However, after many unsuccessful attempts using Lawes-
hydroxy group on the phenyl ring.
son’s reagent, we solved the problem of dehalogenation
by changing the sulfurization reagent into the more com-
mon reagent phosphorus decasulfide (P4S10). Optimal
conditions were achieved when the sulfurization and ring
closure were conducted in a P4S10/toluene system at
110 °C for only 30 minutes. The shorter reaction time may
help minimize the formation of the unwanted dechlorinat-
ed byproducts and thus increase the yield. Compound 2a
was obtained in 83% yield with only a trace amount of de-
chlorinated byproduct being detected by TLC analysis.
However, under the same conditions, the sulfurization and
ring closure of 9 did not go well, with much larger
amounts of unwanted debrominated byproduct being
formed, and with only 22% yield of 2b. Bromide 2b was
also prepared through a halogen exchange from 2a in 51%
yield. The synthesis of iodide 2c required heating of com-
pound 2a with sodium iodide in acetone at room temper-
ature for 20 hours, which ensured almost complete
conversion while preventing decomposition of the prod-
uct (79% yield).
The synthesis commenced with the known intermediate 2-
bromo-5-chloropyridin-3-ylamine (4), which was pre-
pared from 2-amino-5-chloropyridine after nitration,8 di-
azotization–bromination8 and reduction,7 according to
previously described procedures7 (Scheme 2). The subse-
quent acylation of 4 with commercially available chloro-
acetyl chloride under the optimized conditions7 allowed
compound 8 to be efficiently prepared in 92% yield. In a
similar manner, bromide 9 was synthesized in 87% yield
by using bromoacetyl bromide as an acylation agent. Sub-
sequent sulfurization and ring closure of 8 and 9 suffered
some problems with dehalogenation byproduct formation
using Lawesson’s reagents either in toluene or p-xylene.
The formation of unwanted dechlorinated byproduct was
also observed when 2,5-dichloropyridin-3-ylamine was
used to prepare 2a under the same sulfurization conditions
reported in the previous publication.6 It was thought that
2-bromo-5-chloropyridin-3-ylamine derivative 8 may be-
have differently to the 2,5-dichloropyridin-3-ylamine re-
ported in the previous study on the ring closure process.
Cl
N
S
Cl
I
N
2c
N
NH2
acetone
KI
79%
H
N
Cl
Cl
N
P4S10
CH2ClCOCl, py
Cl
O
toluene, 110 °C,
83%
CH2Cl2, 0 °C
88%
S
Cl
N
N
Br
Cl
NH2
Br
2a
8
MeCN
51%
LiBr⋅H2O
Cl
N
H
Cl
N
P4S10
N
S
CH2BrCOBr, py
Br
O
toluene, 110 °C
22%
4
CH2Cl2, 0 °C
87%
N
Br
Br
N
2b
9
Scheme 2 Synthesis of 6-chloro-2-(chloromethyl)thiazolo[5,4-b]pyridine
Synlett 2012, 23, 1039–1042
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of PC190723
1041
OH
Pd/C, H2
NaNO2, H2SO4
concd HNO3
N
N
F
H2N
F
O2N
F
MeOH
94%
H2SO4
45%
concd H2SO4
85%
O
COOH
12
F
COOH
F
COOH
F
COOH
6
7
10
HO
F
F
COOH
11
Scheme 3 Attempted synthesis of 2,6-difluoro-3-hydroxybenzoic acid (11) from 2,6-difluorobenzoic acid (6)
We initially attempted the synthesis of 2,6-difluoro-3-hy- cyanoformate has attracted attention because it allows for
droxybenzoic acid (11) from inexpensive and readily one step formation of the ester of carboxylic acids, and as
available 2,6-difluorobenzoic acid (6), since the value of we proposed that it could be easily converted into amide
aniline as an efficient precursor of phenols is well recog- 16 during subsequent aminolysis. Unfortunately, amide
nized (Scheme 3). Nitration of 6 proceeded smoothly in 16 could not be prepared from the ester directly via ami-
concentrated HNO3/H2SO4 to obtain 10 in 85% yield. nolysis under a variety of conditions. The next step led, by
Subsequent reduction of 10 was performed in 94% yield efficient hydrolysis of the ester (94% yield), to acid 15.
with H2 over 10% Pd/C in methanol to give 7. Diazotiza- Activation of carboxylic acid using N,N′-carbonyldiimid-
tion of the latter to a diazonium ion seemed go very well, azole (CDI) successfully converted acid 15 into amide 16
however, subsequent displacement of the diazonium in 89% yield. Deprotection of 16 completed the synthesis
group by a hydroxy group upon heating in water was un- of 3 in 94% yield.
successful. Attempts were made to solve the problem by
reducing the reaction temperature and by using ethyl ester
or amide forms of 7 as a starting material for the diazoti-
zation. However, all attempts failed and the starting mate-
With fragments 2 and 3 in hand, we continued the synthe-
sis of target compound 1 according to the strategy de-
scribed in Scheme 5. Initial attempts to obtain 1 were
discouraging; the coupling reaction of 2a with 3 was very
rial was converted into 6-hydroxy-1-oxa-2,3-diazaindene-
sluggish. When Cs2CO3 was used as the base in acetoni-
7-carboxylic acid (12)9 via the diazonium intermediate.
trile, as suggested in a report by Sorto et al.,6 only approx-
imately 10% of product 1 was obtained after stirring for 3
h at 65 °C, with many other byproducts being formed. The
difficulties mainly arose from the moderate reactivity of
chloride 2a and its tendency to undergo dechlorination.
We therefore chose to include NaI as a catalyst for the al-
kylation, which eventually led to the desired coupling
Ultimately, we abandoned this route and instead chose to
use commercially available 2,4-difluoro-phenol (5) as the
starting material for the synthesis of fragment 3 (Scheme
4). Protection of phenol 5 as the methoxymethyl ether 13
was carried out over two hours in the presence of N,N-di-
isopropylethylamine (DIPEA) at 0 °C. The regioselective
lithiation of 13 was conveniently carried out with s-BuLi
product 1, albeit in a very modest isolated yield of 10%.
in anhydrous tetrahydrofuran (THF). The following phe-
The alkylation reaction was then conducted at room tem-
nyl ring carboethoxylation was furnished using ethyl cya-
perature. However, even reaction times of longer than 24
noformate to give compound 14. The use of ethyl
hours did not result in a better yield of 1. Alternatively, by
F
F
F
F
F
F
s-BuLi, –78 °C, 2 h
NCCOOEt, –40 °C, 1 h
MeOCH2Cl, (i-Pr)2NEt
NaOH
COOEt
CH2Cl2, 0 °C
89%
H2O–EtOH
94%
anhyd THF
82%
HO
MOMO
MOMO
5
13
14
F
F
F
CDI, CH2Cl2, 2 h, r.t.
6 M HCl
COOH
CONH2
CONH2
NH4OH, 3 h, r.t.
89%
MeOH
94%
MOMO
F
HO
F
MOMO
F
15
16
3
Scheme 4 Synthesis of 2,6-difluoro-3-hydroxybenzamide (3) from 2,4-difluorophenol (5)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1039–1042

1042
Z.-C. Ding et al.
LETTER
Cl
F
F
N
S
Cl
N
S
K2CO3
CONH2
O
F
N
+
DMF, r.t., 2 h
X
N
HO
F
NH2
O
2a, X = Cl
2b, X = Br
2c, X = I
PC190723, 1
3
Scheme 5 The synthesis of PC190723
(2) Spellberg, B.; Guidos, R.; Gilbert, D.; Bradley, J.; Boucher,
H. W.; Scheld, W. M.; Bartlett, J. G.; Edwards, J. Jr. Clin.
Infect. Dis. 2008, 46, 155.
(3) (a) Lock, R. L.; Harry, E. J. Nat. Rev. Drug Discovery 2008,
7, 324. (b) Vollmer, W. Appl. Microbiol. Biotechnol. 2006,
73, 37.
(4) (a) Mathew, B.; Srivastava, S.; Ross, L. J.; Suling, W. J.;
White, E. L.; Woolhiser, L. K.; Lenaerts, A. J.; Reynolds, R.
C. Bioorg. Med. Chem. 2011, 19, 7120. (b) Czaplewski, L.
G.; Collins, I.; Boyd, E. A.; Brown, D.; East, S. P.; Gardiner,
M.; Fletcher, R.; Haydon, D. J.; Henstock, V.; Ingram, P.;
Jones, C.; Noula, C.; Kennison, L.; Rockley, C.; Rose, V.;
Thomaides-Brears, H. B.; Ure, R.; Whittaker, M.; Stokes, N.
R. Bioorg. Med. Chem. Lett. 2009, 19, 524. (c) Margalit, D.
N.; Romberg, L.; Mets, R. B.; Hebert, A. M.; Mitchison, T.
J.; Kirschner, M. W.; RayChaudhuri, D. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 11821.
taking advantage of the higher reactivity of bromide 2b,
0.2 equivalent of NaI was used in the reaction with 3 in a
K2CO3/DMF system, which led to a marked improvement
in the efficiency of the reaction (36% yield). The improve-
ment prompted us to use 2c in the same reaction system,
which led to a further enhancement in the yield of 1 to
56%, although the preparation of 2c was more expensive
than those of 2a and 2b. Fortunately, in the course of the
optimization of the reaction conditions, we observed that
the yields improved when different base and solvent sys-
tems were used. By using K2CO3 as base in acetonitrile at
room temperature, the reaction of 2a and 3 catalyzed by
0.2 equivalent of NaI resulted in a marked improvement
in the efficiency of this reaction, and 1 was obtained in
79% yield.10
(5) (a) Haydon, D. J.; Bennett, J. M.; Brown, D.; Collins, I.;
Galbraith, G.; Lancett, P.; Macdonald, R.; Stokes, N. R.;
Chauhan, P. K.; Sutariya, J. K.; Nayal, N.; Srivastava, A.;
Beanland, J.; Hall, R.; Henstock, V.; Noula, C.; Rockley, C.;
Czaplewski, L. J. Med. Chem. 2010, 53, 3927. (b) Haydon,
D. J.; Stokes, N. R.; Ure, R.; Galbraith, G.; Bennett, J. M.;
Brown, D. R.; Baker, P. J.; Barynin, V. V.; Rice, D. W.;
Sedelnikova, S. E.; Heal, J. R.; Sheridan, J. M.; Aiwale, S.
T.; Chauhan, P. K.; Srivastava, A.; Taneja, A.; Collins, I.;
Errington, J.; Czaplewski, L. G. Science 2008, 321, 1673.
(6) Sorto, N. A.; Olmstead, M. M.; Shaw, J. T. J. Org. Chem.
2010, 75, 7946.
(7) Ding, Z.; Ma, X.; Zhou, W. Synth. Commun. 2012, DOI:
10.1080/00397911.2011.566408.
(8) Zhou, Z. L.; Navratil, J. M.; Cai, S. X.; Whittemore, E. R.;
Espitia, S. A.; Hawkinson, J. E.; Tran, M.; Woodward, R.
M.; Weber, E.; Keana, J. F. Bioorg. Med. Chem. 2001, 9,
2061.
(9) Analytical and spectral data: beige solid; mp 166–168 °C;
1H NMR (400 MHz, CDCl3): δ = 6.29 (d, J = 9.2 Hz, 1 H),
7.43 (d, J = 9.6 Hz, 1 H), 14.10 (s, 1 H), 15.00 (br s, 1 H);
MS (ESI): m/z = 203.04 [M + Na]+; HRMS (ESI): m/z [M+ +
Na]+ calcd for C7H4N2O4: 203.0069; found: 203.0070.
(10) Analytical and spectral data: yellow solid; mp 220–222 °C;
1H NMR (400 MHz, DMSO-d6): δ = 5.72 (s, 2 H), 7.10 (td,
J = 9.0, 2.0 Hz, 1 H), 7.41 (td, J = 9.2, 5.2 Hz, 1 H), 7.81 (br
s, 1 H), 8.10 (br s, 1 H), 8.65 (d, J = 2.4 Hz, 1 H), 8.72 (d,
J = 2.0 Hz, 1 H); MS (ESI): m/z = 378.04 [M + Na]+, 394.02
[M + K]+. 13C NMR (100 MHz, DMSO-d6): δ = 170.85,
161.12, 155.67, 152.83 (dd, J = 240.35, 6.3 Hz), 148.33 (dd,
J = 247.95, 9.6 Hz), 146.20, 145.95, 141.97 (dd, J = 11.2,
3.3 Hz), 129.92, 129.36, 117.16–116.71 (m), 111.32 (d, J =
4.2 Hz), 111.09 (d, J = 3.2 Hz), 69.29; 19F NMR (500 MHz,
DMSO-d6): δ = –122.78 (dd, J = 10.0, 5.0 Hz, 6-F), –133.55
(d, J = 10.0 Hz, 2-F); MS (ESI): m/z = 378.04 [M + Na]+,
394.02 [M + K]+; HRMS (ESI): m/z [M + Na]+ calcd for
C14H8ClF2N3O2S: 377.9892; found: 377.9895.
In summary, we have disclosed a short and efficient ap-
proach to a practical synthesis of PC190723 starting from
2,4-difluorophenol and 2-bromo-5-chloropyridin-3-yl-
amine. Reaction conditions were generally mild and only
a single protecting group was used during the process. We
believe that this is a general approach towards the synthe-
sis of this class of FtsZ inhibitors, which can be easily
used in the context of the formation of other analogues in
medicinal chemistry research. Although the synthesis of
PC1970223 requires metalation of an intermediate with s-
BuLi, it is easily scalable for the production of multigram
quantities. A major contrast between this approach and
the previously reported routes is the use of low-cost start-
ing materials, specifically avoiding 2,6-difluoro-3-
methoxybenzamide and benzyloxyacetyl chloride. Fur-
ther development and use of this methodology for the syn-
thesis of new inhibitors is in progress in our laboratory
and will be reported shortly.
Acknowledgment
This work was financially supported by The National Basic
Research Program (973 Program) (2010CB735601 and
2012CB724501).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
References and Notes
(1) (a) Fischbach, M. A.; Walsh, C. T. Science 2009, 325, 1089.
(b) Furtado, G. H.; Nicolau, D. P. Expert Opin. Ther. Pat.
2010, 20, 1273.
Synlett 2012, 23, 1039–1042
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