Sorto et al.
JOCNote
SCHEME 5. (A) Final Alkylation To Produce 1; (B) Improved
Alkylation Yield from Conversion of Chloride 2 to Iodide 20
3-Ethoxymethoxy-2,6-difluorobenzoic Acid (11). Compound
9 (3.93 g, 20.9 mmol) was dissolved in dry THF (80 mL), and
n-BuLi (10 mL, 25.0 mmol, 2.5 M in hexanes) was added
dropwise at -78 °C. After stirring at -78 °C for 2 h, the mixture
was poured onto freshly crushed CO
2
followed by the addition
. The mixture was
of another layer of freshly crushed CO
2
allowed to warm to room temperature overnight. Water was
added to the mixture (50 mL) and extracted with EtOAc. The
aqueous layer was acidified to pH 1 and extracted immediately
with CH
Na SO . The solvent was evaporated in vacuo, yielding a white
2 2
Cl . The organic layers were combined and dried over
2
4
1
solid (4.51 g, 93%): mp 153-154 °C; H NMR (400 MHz,
CDCl ) δ 7.37 (m, 1H), 6.91 (dd, J = 10.1, 8.3 Hz, 1H), 5.25 (s,
H), 3.80 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); C NMR
3
1
3
2
(
100 MHz, CDCl ) δ 166.4, 155.5 (dd, J = 253.5, 4.4 Hz), 151.9
3
(
dd, J = 260.0, 5.9 Hz), 142.2 (dd, J = 11.0, 3.7 Hz), 122.2 (dd,
J = 9.9, 3.2 Hz), 111.6 (dd, J = 23.1, 4.4 Hz), 110.5 (dd, J =
-
1
;
1
R 0.340 in 50% EtOAc/hexanes ; HRMS (ESI) m/z calcd for
7.7, 14.5 Hz), 95.1, 65.0, 15.1; IR (neat) 3536, 3476, 1671 cm
f
-
C
10
H
3
10
F
2
O
4
(M - H) 231.0469, found 231.0479.
-Ethoxymethoxy-2,6-difluoro-benzamide (12). Compound
1 (1.20 g, 5.18 mmol) was dissolved in 50 mL of dry CH Cl
1
2
2
followed by the addition of (i-Pr) NEt (0.976 mL, 5.70 mmol).
2
Ethyl chloroformate (0.600 mL, 6.30 mmol) was added at 0 °C.
After 1.5 h at 0 °C, 6 mL of 12 M NH OH was added and stirred
4
for an additional 30 min. The reaction was monitored by TLC.
After 3 h, the solvent was evaporated in vacuo, and then 1 M HCl
(30 mL) was added to the mixture and extracted 2ꢀ with ethyl
acetate. The organic layers were combined, washed with brine,
and concentrated. The crude mixture was purified by flash
chromatography (40% to 70% EtOAc/hexanes). The solvent
1
process. Characterization data for 1/PC190723 ( H NMR,
13
19
C NMR, F NMR, HRMS, IR) was consistent with pub-
lished structure of PC190723.
In summary, we have demonstrated a practical synthesis
of PC190723 in a longest linear sequence of five steps from
was evaporated in vacuo yielding a white solid (1.13 g, 94%): mp
1
2,4-difluorophenol using a single protecting group. Although
87.4-87.5 °C; H NMR (400 MHz, CDCl ) δ 7.27 (td, J = 9.4, 5.3,
3
the synthesis requires metalation of an intermediate with n-BuLi,
it is easily scaleable for the production of multigram quantities.
A principle contrast between the previously reported route and
ours is the use of low-cost starting materials, specifically
avoiding 2,6-difluoro-3-methoxy-benzamide and benzyloxya-
cetyl chloride. Access to this potent inhibitor of bacterial cell
1H), 6.98 - 6.80 (m, 1H), 6.33 (brs, 1H), 6.06 (brs, 1H), 5.23 (s, 2H),
3.78 (q, J = 7.1, 2H), 1.23 (t, J = 7.1, 3H); C NMR (75 MHz,
13
CDCl
3
) δ 162.7, 154.2 (dd, J = 247.3, 5.2), 150.5 (dd, J = 253.9,
.2), 142.0 (dd, J = 11.1, 3.4), 120.3 (d, J = 9.3), 114.4-113.8 (m),
11.3 (dd, J = 23.5, 3.6), 94.9, 64.9, 15.1; IR (neat) 3381, 3198, 1656
7
1
-
1
cm ;R
f
0.409 in 60% EtOAC/hexanes; HRMS (ESI) m/zcalcd for
(M þ H) 232.0785, found 232.0765.
þ
1
8
C
10
H
11
F
2
NO
3
division will enable detailed studies of this essential process
and pave the way for the development of new inhibitors that
might serve as medicinal leads.
2
,6-Difluoro-3-hydroxy-benzamide (4). The EOM-protected
amide 12 (0.875 g, 3.78 mmol) was dissolved in a 50:50 mixture
of 6 M HCl and MeOH (30 mL total volume). The reaction was
monitored by TLC. After ∼2 h, the solvent was evaporated in
1
Experimental Section
vacuo yielding an amorphous white solid (0.622 g, 95%): H
NMR (400 MHz, DMSO-d) δ 9.96 (brs, 1H), 8.09 (brs, 1H), 7.79
1
-Ethoxymethoxy-2,4-difluorobenzene (9). 2,4-Difluorophe-
nol (0.999 g, 7.68 mmol) was dissolved in 10 mL of dry CH Cl .
(
13
(
brs, 1H), 6.93 (m, 2H); C NMR (75 MHz, DMSO-d) δ 162.5,
2
2
151.3 (dd, J = 238.6, 6.3), 147.6 (dd, J = 245.2, 8.6), 142.1 (d,
J = 14.9), 118.1 (dd, J = 9.0, 3.6), 117.1 (dd, J = 24.6, 20.7),
2
i-Pr) NEt (1.58 mL, 9.22 mmol) was added, and the mixture
was cooled to 0 °C. This was followed by the addition of
chloromethyl ethyl ether (9.86 mL, 9.26 mmol). After 2 h of
stirring at room temperature, 3 M NaOH (20 mL) was added
-1
1
0
C
11.6 (dd, J = 22.8, 3.4); IR (neat) 3433, 3371, 1687 cm ; Rf
.185 in 50% EtOAc/hexanes; HRMS (ESI) m/z calcd for
þ
1
7
5
H F
2
NO
2
(M þ H) 174.0366, found 174.0354. H NMR
and extracted 2ꢀ with CH
2
Cl . The organic layers were com-
bined and 1 M HCl was added (20 mL) and extracted 2ꢀ with
2
10
spectrum was in accordance with the literature.
-Chloro-N-(2,5-dichloro-pyridin-3-yl)-acetamide (7). 3-Amino-
,5-dichloropyridine 8 (1.02 g, 6.25 mmol) was dissolved
in dry CH Cl
(50 mL). The mixture was cooled to 0 °C, and
chloroacetyl chloride (0.75 mL, 9.43 mmol) was added drop-
wise. This was followed by the addition of (i-Pr) NEt (1.6 mL,
.35 mmol). The reaction was monitored by TLC. After 3 h, the
2
CH Cl . The organic layers were combined and washed with
2
2
2
brine and dried over K CO . The solvent was evaporated in
2
3
1
2
2
vacuo yielding a colorless oil (1.32 g, 91%): H NMR (300 MHz,
CDCl ) δ 7.16 (td, J = 9.1, 5,4 Hz, 1H), 6.90-6.71 (m, 2H), 5.19
s, 2H), 3.76 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H);
NMR (75 MHz, CDCl ) δ 157.4 (dd, J = 242.7, 10.5 Hz), 153.2
dd, J = 248.8, 12.1 Hz), 141.7 (dd, J = 10.9, 3.6 Hz), 119.1 (dd,
J = 9.4, 2.6 Hz), 110.6 (dd, J = 22.5, 3.9 Hz), 104.8 (dd, J =
6.8, 22.6 Hz), 95.0, 64.8, 14.9; R 0.851 in 30% EtOAc/hexanes;
3
1
3
2
(
C
9
3
solvent was evaporated in vacuo, and the crude mixture was
purified by flash chromatography (30% to 50% EtOAc/
(
hexanes) yielding an off-white solid (1.44 g, 96%): mp 121-
2
1
f
1
2
22 °C; H NMR (300 MHz, CDCl
.4, 1H), 8.14 (d, J = 2.4, 1H), 4.26 (s, 2H); C NMR (75 MHz,
3
) δ 8.94 (s, 1H), 8.82 (d, J =
HRMS (ESI) m/z calcd for C
found 187.0579.
9
H
10
2
F O
2
(M - H)- 187.0574,
13
CDCl
neat) 3366, 2946, 1682 cm ; R
3
) δ 164.7, 143.3, 137.9, 131.6, 131.4, 128.1, 42.7; IR
-1
(
HRMS (ESI) m/z calcd for C
found 238.9512.
f
0.833 in 50% EtOAc/hexanes;
N
H
5
Cl
3
2
O (M þ H)þ 238.9545,
(18) Research quantities of this compound are available on request.
Please contact J.T.S. by email (shaw@chem.ucdavis.edu).
7
7
948 J. Org. Chem. Vol. 75, No. 22, 2010