Conclusion
In conclusion, a mild method of conducting Knorr
H, 3.36; Br, 26.63; N, 4.67. Found: C, 43.98; H, 3.31; Br,
6.65; N, 4.59.
-(4-Bromophenyl)-4-cyano-5-ethyl-1H-pyrrole-2-car-
boxylic Acid Ethyl Ester (13). Preparation of enolate 17:
Under a nitrogen atmosphere, potassium tert-butoxide (13.097
kg, 117.29 mol) was dissolved in THF (68.2 L) at 20 °C.
To the resulting mixture, a mixture of ethyl propionate 15
2
3
chemistry with â-ketonitriles was developed. This enabled
the preparation of pyrrole 1 in kilogram quantities and gave
access to AMPA potentiators for biological evaluation. In
addition, an analogue series of pyrroles was prepared varying
the steric bulk of the alkyl group on the â-ketonitrile Knorr
partner, which revealed a lack of tolerance for steric
encumberance. Last, an analogue series of pyrroles was
prepared with aromatic rings on the â-ketonitrile Knorr
partner.
(12.2 L, 106.63 mol) and acetonitrile 16 (6.68 L) was added
over 0.75 h at 18 to 21 °C and stirred for 1 h at this
temperature (NMR (10 µL of reaction mixture in 1 mL of
6
DMSO-d ) indicated no 15 remaining). Preparation of pyrrole
1
3: In a separate reactor under a nitrogen atmosphere,
R-isonitroso-â-ketoester 4 (12.8 kg, 42.65 mol) was dissolved
in EtOH (110 L) at 20 °C. The solution was cooled to 1 °C,
and zinc (6.429 kg, 98.01 mol) was added portionwise over
Experimental Section
Useful HPLC Method for Analyzing the Following
Reactions. Column: YMC Pack Pro C18, 250 mm × 4.5
mm, 3 µm. UV ) 218 nm. Oven temperature : 20 °C. Flow
0
.5 h. A solution of acetic acid (19.5 L), water (2.5 L), and
EtOH (11.5 L) was prepared. About 1 to 2% of the ethanolic
aqueous acetic acid solution was added to the mixture of 4
and zinc in EtOH at 0 °C to give a slight exotherm and
initiate the reduction. The rest of the ethanolic aqueous acetic
acid solution was added to the mixture of 4 and zinc in EtOH
over 1.5 h between -2 to 2 °C. The suspension was cooled
to -5 °C and stirred for 0.25 h (HPLC indicated 98.3%
conversion of 4). The potassium enolate 17 suspension was
added over 0.5 h to the zinc suspension at -9 to -2 °C.
The reaction was stirred at -4 °C for 3.0 h, warmed to 20
rate: 1 mL/min. Mobile phase: (A) 0.1% TFA in H
2 3
O/CH -
CN 9:1 v/v; (B) CH CN. Gradient: T ) 0 min 95% A 5%
3
B, T ) 10 min 50% A 50% B, T ) 18 min 5% A 95% B,
T ) 25 min 5% A 95% B. THF ) tetrahydrofuran, MTBE
)
methyl-tert-butyl ether.
3
-(4-Bromophenyl)-2-hydroxyimino-3-oxo-propionic
Acid Ethyl Ester (4). Step 1: Under a nitrogen atmosphere,
potassium tert-butoxide (18.13 kg, 161.66 mol) and THF
(
116 L) were combined, and diethyl carbonate (18 L, 154.31
mol) was added to the mixture between 15 and 21 °C over
.5 h. The resulting mixture was heated to 38 °C, and a THF
41 L) solution of 4-bromoacetophenone 5 (14.625 kg, 73.48
mol) was added over 0.5 h and stirred for an additional 3 h
HPLC indicated 99.29% conversion of the 4-bromoac-
°C over 10 h, and stirred at 20 °C for 3.0 h (HPLC indicated
0
(
a complete conversion of intermediate 20). The suspension
was filtered, and the filter cake washed with EtOH (6 L).
The mother liquor was distilled under reduced pressure at
(
5
5 °C to 28% of its original volume. IPA (66 L) was added
etophenone 5). Workup: The reaction mixture was cooled
to 0 °C and quenched by the addition of 50% aqueous acetic
acid (25 L) over 1 h. The resulting mixture was heated to
followed by water (128 L) at 35 to 38 °C and the resulting
suspension cooled to 10 °C over 6.0 h and stirred for 6.0 h.
The suspension was filtered and washed with water (51 L).
The filter cake was dried under a constant flow of nitrogen
for 48.0 h to afford pyrrole 13 (12.49 kg, 84% yield) as pale
yellow crystals (HPLC 99.73 area%). Mp 212.9-213.6 °C.
20 °C, and water (51 L) and MTBE (60 L) were added. After
phase separation, the aqueous phase was extracted with
MTBE (44 L), and the organic layers were combined. The
organic layers were washed with saturated Na
2 3
CO solution
-
1
IR (KBr) 3284, 2982, 2931, 2217, 1660, 1519, 1485 cm .
(
73 L) and with semisaturated brine (74 L). The organic
1
H NMR (500.0 MHz, DMSO-d
Hz), 1.26 (3H, t, J ) 7.6 Hz), 2.77 (2H, q, J ) 5.5 Hz),
.16 (2H, q, J ) 7.6 Hz), 7.41 (2H dd, J ) 6.6 Hz, J ) 1.6
Hz), 7.64 (2H, dd, J ) 6.6 Hz, J ) 1.6 Hz), 12.6 (bs, 1H).
6
) δ 1.14 (3H, t, J ) 5.5
solvent was reduced by distillation under reduced pressure
at 50 °C to 27% of the starting volume. THF (44 L) was
added, and the volume added was distilled. Step 2: To the
solution of â-ketoester 9 in THF, acetic acid (160 L) and
water (73 L) were added at 8 °C. To the resulting mixture,
4
1
3
C NMR (125.7 MHz, DMSO-d
2.4, 115.4, 117.9, 121.2, 130.6, 131.2, 131.4, 131.8, 146.9,
59.4. Anal. Calcd for C16 : C, 55.35; H, 4.35;
6
) δ 13.6, 13.9, 19.7, 60.1,
9
1
2
a solution of NaNO (6.35 kg, 92.00 mol) in water (30 L)
2 2
H15BrN O
was added at 6 to 9 °C over 1.5 h and stirred at about 9 °C
for 1.5 h (HPLC indicated 96.51% conversion of the
â-ketoester 9). Workup: At 4 to 7 °C, water (147 L) was
added over 0.5 h. The resulting suspension was filtered, and
the filter cake was washed with water (59 L) and heptane
Br, 23.01; N, 8.07. Found: C, 55.13; H, 4.37; Br, 2.55; N,
7
.84. Zinc analysis ) 544 ppm.
3-(4-Bromophenyl)-4-cyano-5-ethyl-1-methyl-1H-pyr-
role-2-carboxylic Acid Ethyl Ester (1). Under a nitrogen
atmosphere, pyrrole 13 (625 g, 1.80 mol) and acetone (6.25
L) were combined. The resulting mixture was heated to 30
(60 L). The filter cake was dried under a constant flow of
nitrogen for 13 h to afford R-isonitroso-â-ketoester 4 (18.73
kg, 85% yield) as a white powder. Mp 148.7-150.7 °C. IR
°C, and K CO
2
3
(powdered, 325 mesh, 497.6 g, 3.60 mol)
(
KBr) 3281, 3219, 3049, 2983, 2870, 1728, 1680, 1586, 1446
and D.I. H O (62.5 mL, 10 wt % based on 13) were added.
2
-
1 1
cm . H NMR (DMSO-d
6
, 500.0 MHz) δ 1.22 (3H, t, J )
MeI (510.98 g, 3.6 mol) was added to the above reaction
mixture over 12 min. The pot temperature rose to a high of
34.1 °C over the following 30 min and then began to drift
downward. The reaction was monitored by HPLC, with the
complete consumption of starting material noted after 3.5 h.
7
7
d
1
.1 Hz), 4.27 (2H, q, J ) 7.1 Hz), 7.75 (2H, d, J ) 8.8 Hz),
1
3
.83 (2H, d, J ) 8.8 Hz), 13.18 (s, 1H). C NMR (DMSO-
, 125.7 MHz) δ 14.3, 62.2, 129.6, 131.1, 133.1, 133.4,
48.4, 161.2, 191.1. Anal. Calcd for C11 : C, 44.02;
6
H10BrNO
4
Vol. 10, No. 5, 2006 / Organic Process Research & Development
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