1
for synthesis of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-
carbaldehyde 10, the key intermediate in the synthesis of
bicyclic heteroaryl substituted 6-alikylidene penem 4.
92.9% (potency); mp 33-38 °C; H NMR (300 MHz,
CDCl ) 2.75-2.83 (m, 2H), 2.90 (t, 2H, J ) 7.1 Hz), 4.43
3
(t, 2H, J ) 7.4 Hz); MS 127.1 (M + H). The product was
used directly in the next step.
Experimental Section:
Ethyl 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-2-car-
boxylate, 14, and Ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]-
pyrazole-3-carboxylate, 15. 3a,4,5,6-Tetrahydro-3-oxo-3H-
pyrrolo[1,2-c][1,2,3] oxadiazol-7-ium ylide, 13 (971 g, 7.70
mol, WAY-187725, made as in example 2) and 1,2-
diethoxyethane (DEE, 2.9 L) were charged to a multinecked,
General Methods. NMR spectra of the intermediates
were recorded on a Bruker 300 NMR spectrometer. Structure
elucidation for the target compound 10 was done on a Bruker
Avance DPX 400 NMR spectrometer equipped with a 5 mm
QNP 1H/13C/31P/19F Z-GRD probe. Spectra were refer-
enced by an internal standard.
1
2-L round-bottomed flask, equipped with a water-cooled
HPLC analysis of the intermediates and reaction monitor-
ing was carried out on an Agilent 1090 liquid chromatograph
equipped with a Phenomenex Prodigy ODS3 4.6 mm × 50
mm column. Standard method: 90:10 to 10:90 over 8 min
gradient of water/acetonitrile containing 0.02% TFA, flow
rate 1 mL/min.
condenser. The stirred solution was purged with nitrogen and
heated to 120-125 °C. Ethyl propiolate (971 g, 9.90 mol)
was added dropwise over a period of 3 h (carbon dioxide
evolution). The reaction was held at 120-125 °C for 5 h
until the conversion was >99% (<1% of residual 3a,4,5,6-
tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide
Thermal screening tests were performed on the unit made
by Hazard Evaluation Lan, Inc.
13 by GC-MS analysis). The mixture was then concentrated
to a residue in vacuo using a rotary evaporator with a bath
temperature up to 70 °C. About 1.5 kg of toluene was then
added to the residue, and the mixture was concentrated once
more. A dark oil was obtained (1218 g, 46.9% potency by
HPLC, 41% yield, corrected for potency, of ethyl 5,6-
dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, 14, from
crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]-
oxadiazol-7-ium ylide, 13). The individual esters were
isolated on a silica gel column, using hexanes/ethyl acetate,
(
2S)-1-Nitrosoproline 12. To a solution of L-proline (2.50
kg, 21.6 mol) and sodium nitrite (2.10 kg, 30.4 mol) in water
5.0 L) maintained at 0-10 °C was added concentrated
(
hydrochloric acid (2.53 L), and the resulting slurry was stirred
for 16 h at ambient temperature. The reaction mixture was
extracted with tert-butyl methyl ether (6 L + 2 × 3 L), and
the organic solution was concentrated using a rotary evapo-
rator with a bath temperature below 35 °C. Residual water
was removed by evaporation with 2.0 L of toluene. The
resulting (2S)-1-nitrosoproline (3.25 kg, 105%) was isolated
as a yellow solid and dried under vacuum at 25 °C, mp:
9
1
3
4
7
:1 to 1:1 gradient, detection by HPLC, 215 nm. Compound
1
4: mp 61-63 °C; H NMR (300 MHz, DMSO-d
H, J ) 7.1 Hz), 2.54 (m, 2H), 2.85 (t, 2H, J ) 7.4 Hz),
.13 (t, 2H, J ) 7.4 Hz), 4.23 (dd, 2H, J ) 7.4 Hz, J
.1 Hz), 6.465 (s, 1H). Compound 15: mp 40-42 °C; H
) 1.33 (t, 3H, J ) 7.3 Hz), 2.65 (m,
H), 3.08 (t, 2H, J ) 7.3 Hz), 4.16 (t, 2H, J ) 7.3 Hz), 4.27
dd, 2H, J ) 7.3 Hz, J ) 7.3 Hz), 7.899 (s, 1H).
Potassium 5,6-Dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-
6
) 1.26 (t,
7a
12
1
00-102 °C (lit. 106-107 °C, lit. 100-101 °C); HPLC
1
2
)
purity: 96.3% (215 nm, area %), and residual toluene: 4%.
The product, (2S)-1-nitrosoproline 12, was used directly,
without further purification, in the next step.
1
NMR (300 MHz, CDCl
2
(
3
3
a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]-
1
2
oxadiazol-7-ium Ylide 13. Trifluoroacetic anhydride (3.86
kg, 18.4 mol) was added slowly to a suspension of (2S)-1-
nitrosoproline 12 (1.75 kg, 12.2 mol from example 1) in
toluene (6 L) below 10 °C. The resulting dark-red solution
was stirred for 2 h at ambient temperature, and the reaction
was quenched by adding the dark-red solution to a stirred
mixture of potassium carbonate (2.70 kg, 19.6 mol), dichlo-
romethane (3.5 L), and water (2.0 L) below 25 °C. Following
complete addition and the subsequent separation of the upper
organic layer, the aqueous layer was extracted with dichlo-
romethane (3 × 3 L). The combined organic extracts were
concentrated in vacuo using a rotary evaporator with a bath
temperature not exceeding 35 °C. Residual water was
removed by evaporation with toluene (2 L) to afford the title
compound as a dark liquid, which solidified upon standing
carboxylate, 17. A freshly prepared solution of potassium
hydroxide (87.6% w/w pellets, 307.6 g, 4.80 mol) in 2B-3
ethanol (absolute, 1.86 L) was added over a period of 1 h to
a stirred solution of 1063.6 g [46.5% potency (HPLC), 2.744
mol] of the ester mixture, ethyl 5,6-dihydro-4H-pyrrolo[1,2-
b]pyrazole-2-carboxylate, 14, and ethyl 5,6-dihydro-4H-
pyrrolo[1,2-b]pyrazole-3-carboxylate, 15, in 2B ethanol
(absolute, 1.28 L) under a nitrogen atmosphere, while
maintaining the temperature in the range 15-22 °C. The
mixture was stirred for 4-7 h until ethyl 5,6-dihydro-4H-
pyrrolo[1,2-b]pyrazole-2-carboxylate, 14, was consumed, as
determined by HPLC. The slurry was filtered, and the filter
cake was washed with 2B ethanol (1.8-2.4 L, in portions).
The wet cake was dried under vacuum at 60-65 °C to
constant weight. Crude potassium 5,6-dihydro-4H-pyrrolo-
(917 g, 58% yield over two steps). The isolated product,
3
7
a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-
-ium ylide, 13, was 89.8% pure by HPLC (area %) and
[1,2-b]pyrazole-2-carboxylate, 17, 426.3 g, 81% (based on
the calculated quantity of 14) was obtained as a tan
(
10) Matur, R. V.; Ruppen, M. E. Process for the regioselective enzymatic
hydrolysis of mixtures of fused bicyclic pyrazolecarboxylate esters for use
in the preparation of penem-containing â-lactamase inhibitors. U.S. Pat.
Appl. Publ., U.S. Patent 4,229,324, 2004; Chem. Abstr. 2004, 142, 6525.
11) Lee, J. N.; Jeon, D. J.; Kim, Y. M.; Kim, K. M.; Song, J. H. Bull. Korean
Chem. Soc. 2000, 21(8), 761.
1
hygroscopic solid; H NMR (300 MHz, DMSO-d6, TFA)
2
.51-2.58 (m, 2H), 2.85 (t, 2H, J ) 7.3 Hz), 4.12 (t, 2H, J
) 7.3 Hz), 6.43 (s, 1H). The cake may optionally be
reslurried in 2B ethanol, if necessary, to remove impurities
(such as potassium 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-
(
(
12) Lijinsky, W.; Keffer, L.; Loo, J. Tetrahedron 1970, 5137.
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