Development of a scaleable synthesis of a partial nicotinic acid receptor agonist

Article abstract of DOI:10.1021/op800290t

A practical and efficient synthesis of 1,4,5,6-tetrahydro-3-(1Htetrazol- 5-yl)cyclopenta[c]pyrazole, 1, is described. A new one-pot process has been developed, starting from the commercially available 1H-tetrazole-5-carboxylic acid-ethyl ester sodium salt which is reacted in a pseudo-Claisen condensation reaction with cyclopentanone, followed by the addition of hydrazine.

Full text of DOI:10.1021/op800290t

Organic Process Research & Development 2009, 13, 543–547
Development of a Scaleable Synthesis of a Partial Nicotinic Acid Receptor Agonist
Robert D. Wilson,*,† Ed Cleator,*,† Michael S. Ashwood,† Matthew M. Bio,† Karel M. J. Brands,† Antony J. Davies,†
Ulf-H. Dolling,‡ Khateeta M. Emerson,† Andrew D. Gibb,† David Hands,† Arlene E. McKeown,‡ Steven F. Oliver,†
Robert A. Reamer,‡ Faye J. Sheen,† Gavin W. Stewart,† and George X. Zhou‡
Department of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire
EN11 9BU, U.K., and Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, U.S.A.
Abstract:
pseudo-Claisen condensation reaction of cyclopentanone 2 with
diethyl oxalate 3 in the presence of KOtBu in DMF. The
resulting intermediate was then acidified prior to treatment with
hydrazine hydrochloride to afford the known ester 44 in 71%
yield. Ester 4 was then converted, under pressure, to amide 5
using methanolic ammonia in a sealed vessel at 95 °C. Benzyl
protection of 5 with benzyl bromide in aqueous THF using
sodium hydroxide was uneventful and afforded N-benzyl
protected primary amide 6 in a 98% yield. Dehydration of the
primary amide 6 with thionyl chloride in DMF gave the
corresponding nitrile, which underwent a zinc bromide-catalyzed
[3 + 2] cycloaddition at 120 °C when treated with sodium azide,
to afford tetrazole 7 in a 70% yield. Finally, benzyl deprotection
of tetrazole 7 was effected under standard transfer hydrogenation
conditions with formic acid employed as the hydrogen source.
It should be noted that that superstoichiometric amounts of
palladium black (1.55 equiv) were required to achieve complete
debenzylation and cleanly afford 1 in a 73% isolated yield.
A practical and efficient synthesis of 1,4,5,6-tetrahydro-3-(1H-
tetrazol-5-yl)cyclopenta[c]pyrazole, 1, is described. A new one-pot
process has been developed, starting from the commercially
available 1H-tetrazole-5-carboxylic acid-ethyl ester sodium salt
which is reacted in a pseudo-Claisen condensation reaction with
cyclopentanone, followed by the addition of hydrazine.
Introduction
1,4,5,6-Tetrahydro-3-(1H-tetrazol-5-yl)cyclopenta[c]pyra-
zole, 1, is found to be a partial nicotinic acid (niacin) receptor
(NAR) agonist that has been shown to suppress adipocyte
lipolysis1 both in Vitro and in ViVo. Due to these properties 1
was chosen as a development candidate for the potential
treatment for atherosclerosis.2 A scaleable synthetic route to this
drug candidate was therefore required to generate clinical
supplies of this material for support of toxicology and clinical
studies. Our aim was to initially exploit the medicinal chemistry
strategy for a rapid, first bulk delivery, whilst developing a new
shorter synthesis which could be employed for any subsequent,
larger deliveries as the compound progressed through the
development phases.
Modified Medicinal Chemistry Synthesis
Several reactions in the medicinal chemistry route were
highlighted as potential problems, and as such, we investigated
modifications to make this route more amenable to scale up
(Scheme 2). The development work focused on three key
challenges in the original route: the use of a high-pressure
aminolysis for the formation of amide 5, the use of sodium
azide at elevated temperature and the use of a protecting group
necessitating what appeared to be a difficult deprotection step.
The pseudo-Claisen condensation step was slightly modified
to allow more convenient scale-up. Thus, the reaction was run
in ethanol in the presence of potassium ethoxide and then
followed by condensation with aqueous hydrazine in the
presence of hydrochloric acid (1.2 equiv) rather than with
hydrazine hydrochloride. The new modifications allowed the
condensation reaction to be run at a higher concentration and
provided 44 in 88% isolated yield. The reaction temperature
was found to be important in both steps. For solubility reasons,
the initial condensation had to be performed at 30 °C, whilst
the hydrazine condensation step was best performed at tem-
peratures below -5 °C to avoid the generation of significant
colour in the product.
The First-Generation Synthesis
The original medicinal chemistry synthesis of 1 was achieved
in seven steps with an overall yield of 39% as outlined below,
(Scheme 1).3 The starting point for this sequence was the
* To whom correspondence should be addressed. E-mail: robert_wilson2@
merck.com.
† Merck Sharp and Dohme Research Laboratories, U.K.
‡ Merck Research Laboratories, U.S.A.
(1) Carballo-Jane, E.; Richman, J. G.; Cheng, K.; Cai, T. Q.; Taggart,
A. K. P.; Gaidarov, I.; Cameron, J. S.; Boatman, P. D.; Chen, R.;
Semple, G.; Connolly, D. T.; Hammond, M.; Wright, S. D.; Colletti,
S. L.; Tata, J. R.; Forrest, M. J.; Waters, M. G. Discovery and
Characterization of a partial agonist of niacotinic acid receptor
GPR109A. XVI International Symposium on Drugs Affecting Lipid
Metabolism, New York, N.Y., October 4-7, 2007.
(2) Tavintharan, S. Curr. Atheroscler. 2001, 3, 74–82.
(3) Semple, G.; Skinner, P. J.; Gharbaoui, T.; Shin, Y.-J.; Jung, J.-K.;
Cherrier, M. C.; Webb, P. J.; Tamura, S. Y.; Boatman, P. D.; Sage,
C. R.; Schrader, T. O.; Chen, R.; Colletti, S. L.; Tata, J. R.; Water,
M. G.; Cheng, K.; Taggart, A. K.; Cai, T.-Q.; Carballo-Jane, E.; Behan,
D. P.; Connolly, D. T.; Richman, J. G. J. Med. Chem. 2008, 51, 5101–
5108.
Next, our attention turned to addressing the amide formation
step. When the reaction was performed under the original
(4) Van Herk, T.; Brussee, J.; van den Nieuwendijk, A. M. C. H.; van
der Klein, P. A. M.; IJzerman, A. P.; Stannek, C.; Burmeister, A.;
Lorenzen, A. J. Med. Chem. 2003, 46, 3945–3951.
10.1021/op800290t CCC: $40.75  2009 American Chemical Society
Published on Web 03/16/2009
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543

Scheme 1
Scheme 2
conditions (reaction of ester 4 with methanolic ammonia in a
sealed vessel at 95 °C), vessel pressures in excess of 200 psi
were generated. This pressure was beyond our vessel capabili-
ties. Initially milder reaction conditions were screened, namely
treatment of ester 4 with aqueous ammonia (35% w/w) in THF
at room temperature. These conditions were found to be
unacceptable and led to a substantially lower yield of amide 5
(63-75% yield based on recovered starting material). In
addition the biphasic reaction was sluggish with incomplete
conversion observed even after prolonged aging (240 h at 20
°C). Alternatively switching the solvent to 2-propanol and
adding catalytic DMAP did increase the rate of the reaction;
however, this increase was still insufficient, and incomplete
conversion was observed after 96 h.
With the aminolysis performing poorly when milder condi-
tions were employed, an alternative approach to 5 was pursued.
The ester 4 was first hydrolyzed to the previously described
acid4 8. Saponification of 4 was achieved by treatment with
potassium hydroxide in methanol at 40 °C, and following a
pH adjustment with hydrochloric acid the desired acid 8 could
be isolated in 98% yield as a white crystalline solid (Scheme
2). It was anticipated that 8 could be activated towards amide
bond formation using standard methodology. However, a
number of the standard techniques to convert 8 to amide 5 (i.e.,
formation of the corresponding acid chloride, mixed anhydride
or using a carbodiimide-based coupling reagent) failed to
provide any product, this was thought to be due to a combination
of low solubility and apparent competitive reactivity of the
pyrazole moiety with the electrophiles. Ultimately a wider
screen of common coupling reagents identified 1,1-carbonyl-
diimidazole (CDI) as a potential activating agent for this
transformation.
When acid 8 was treated with (CDI) in THF, clean formation
of the imidazolide intermediate was achieved. Subsequently
warming the resulting slurry to 60 °C in the presence of aqueous
ammonia transformed the imidazolide to amide 5 which could
be isolated as a crystalline solid in 94% yield. Warming the
reaction mixture during CDI addition gave a steady and
controllable rate of carbon dioxide extrusion, thus eliminating
any potential risk of overpressurization. This scaleable alterna-
tive route to 5 adequately replaced the high-pressure aminolysis
conditions.
Changing to milder amide dehydration conditions also
proved critical in eliminating the need for benzyl protection of
the pyrazole from the original route. Thus, dehydration of 5
with trifluoroacetic anhydride (TFAA) and triethylamine in THF
yielded nitrile 9 as a crystalline solid in 86% yield. With the
protecting group no longer required, attention was turned
towards finding milder conditions for the tetrazole formation.
It was found that tetrazole 1 could be formed at an acceptable
rate and, more importantly, at a significantly lower temperature
when the conditions reported by Sharpless5,6 (NaN3/ZnBr2/IPA/
H2O), were employed. As a safety precaution the reaction was
run at 75 °C with slow addition of an aqueous sodium azide
solution. Under these conditions, the reaction was complete
within 10 h and provided 1 in 83% yield. Operational hazard
(5) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945–7950.
(6) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525–2527.
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Figure 2. Corresponding component spectra of hydrazoic acid
(HN3), propanol, and carbon dioxide for the reaction.
elevated temperatures;9 we therefore considered sodium salt 10a
as the reagent of choice.
Figure 1. Profiles of hydrazoic acid (HN3), propanol in the
headspace of the reaction at 65 °C in IPA and water.
The solvent screen identified that addition of a solution of
KOtBu (2 equiv) in DMF to a solution of sodium salt 10a and
cyclopentanone 2 (1.3 equiv) in DMF between -5 < T < 5 °C
gave optimum assay yields of salt 12 (50-60%). After
acidification of the crude reaction mixture with concen-
trated hydrochloric acid (2.5 equiv) the stream was treated
with 37% aqueous hydrazine (1 equiv) at 20 °C afford 1
in 48% assay yield. The formation of the hydroxy tetrazole
14 was typically observed as a byproduct in 4-5% yield.10
Thus, these conditions became the basis of our process
for the first bulk synthesis of 1.
evaluation of this chemistry showed no untoward exotherms;
however, analysis by ReactIR showed the presence of significant
amounts of hydrazoic acid (HN3) in the vapour phase (Figures
1 and 2). Hydrazoic acid is volatile, highly toxic, and potentially
explosive.5 No process modifications could be identified to
significantly reduced this risk, and therefore this azide reaction
was deemed too hazardous for scale-up.
The Second-Generation Synthesis
With the [3 + 2] cycloaddition reaction prohibiting the use
on scale of the modified medicinal chemistry route, we were
forced to adapt our second-generation synthesis for the provision
of all bulk material for development. The second-generation
approach relied on the ability to use tetrazole ester 10 as the
coupling partner in the pseudo-Claisen reaction. The incorpora-
tion of a preformed tetrazole moiety in a starting material was
obviously an attractive strategy for us as it obviated the use of
azide as well as furnishing a more streamlined approach to 1.
In addition the use of the commercially available tetrazole ester7
10 in pseudo-Claisen reactions with ketones has previously been
described.8 This suggested that a new and much shorter
synthesis of 1 might be possible by condensing cyclopentanone
first with 10 followed by a reaction of the resulting intermediate
11 with hydrazine to generate 1 directly (Scheme 3).
Hence, a screen of appropriate solvents and bases was
performed to identify optimal conditions for the condensation
of 2 with 10. The limited solubility of the sodium salt 10a in
most solvents necessitated the use of polar aprotic solvents,
whilst the high solubility of diketone 11 (and/or its correspond-
ing enol) in these solvents made any isolation difficult. We
therefore focused on developing a one-pot process, wherein
hydrazine was added directly to an acidified reaction mixture
of the intermediate 11 to form 1 directly. As the free acid, 10b
is known to be shock sensitive and thermally unstable at
In an effort to optimize the reaction further we examined
an inverse addition protocol in which 2 was added as a limiting
reagent to a solution of 10a in order to minimize the formation
of 13. Furthermore, it was found that the formation of 13 was
reversible under the reaction conditions.11 There were also
concerns about the stability of 10a in the reaction medium;
however, experimentation showed that, whilst the presence of
water was found to cause degradation of 10a, anhydrous
solutions were found to be stable and performed well in the
(9) Sodium salt 10a and its corresponding free acid 10b (prepared from
the sodium salt 10a by acidification and extraction into ethyl acetate)
were characterized by DSC and drop-weight testing. Free acid 10b
proved thermally unstable at elevated temperature (140 °C) and was
shock sensitive.
(10) The hydroxy tetrazole 14 is derived from the pseudo-Claisen conden-
sation reaction of the sodium salt 10a with the aldol product 13.
(11) Subjecting 13 to typical condensation reaction conditions with 10a
generates mainly 1, with <5% of 14 observed.
(7) Giles, R. G.; Lewis, N. J.; Oxley, P. W.; Quick, J. K. Tetrahedron
Lett. 1999, 40, 6093–6094.
(8) (a) Geen, G. R.; Giles, R. G.; Grinter, T. J.; Hayler, J. D.; Howie,
S. L. B.; Johnson, G.; Mann, I.; Novack, V. J.; Oxley, P. W.; Quick,
J. K.; Smith, N. Synth. Commun. 1997, 27, 1065–1073. (b) Hanson,
J. C.; Novack, V. J.; Ward, N. PCT Int. Appl. WO 9418178, 1994.
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Scheme 3
condensation reaction.12 Thus, under the optimal conditions,
cyclopentanonone 2 was slowly added to a dry mixture of 10a
(1.2 equiv) and KOtBu (1.5 equiv) in DMF at -5 °C. Using
these optimal conditions typically gave yields of the intermediate
11 in 88-96% yield, based on 2. For the pyrazole formation
step, it was found that quenching 12 with hydrochloric acid
(2.25 equiv) was necessary prior to charging an excess of the
35.5 wt % hydrazine in water (2.20 equiv). If the hydrazine
was undercharged (1.66 equiv), an orange reaction mixture with
a low assay yield of 1 (67%) was observed. Under these
conditions formation of hydrazone 15 was prevalent.13 If a
second charge of hydrazine (0.54 equiv) was added to this
mixture, all of hydrazone 15 could be turned over to 1. Under
these optimized conditions 1 could be obtained in 92-93%
overall assay yield, based on 2. Impurity 14 is typically detected
at <1% at the end of the reaction whilst 13 is not observed.
Finally a new convenient method to isolate the desired
product from the crude reaction mixture was developed. After
concentration of the mixture to a minimal volume Via a vacuum
distillation, a solvent switch to water and adjustment to pH 1
provided a slurry of 1 which could be simply isolated by
filtration in a 90% yield. Analysis of this product determined it
to be >99% pure.
1,4,5,6-Tetrahydro-3-(1H-tetrazol-5-yl)cyclopenta[c]pyra-
zole (1). Cyclopentanone (2, 3.36 kg; 40 mol) was added over
1 h to a solution of the 1H-tetrazole-5-carboxylic acid ethyl
ester sodium salt (10a, 7.87 kg; 48 mol) and potassium tert-
butoxide (6.74 kg; 60 mol) in DMF (75 L) between -2.5 and
-5 °C. The batch was aged at 0 °C for an hour. Hydrochloric
acid (9.88 L, 11 M) was added over 85 min, maintaining the
temperature below 6 °C. A 35.5 wt % solution of hydrazine in
water (8 L; 88.8 mol) was added over 35 min, maintaining the
temperature below 10 °C. The reaction mixture was then aged
for 18 h. HPLC analysis showed the assay yield of 1 was 92%.
The mixture was distilled under reduced pressure, removing
65 L of solvent. Water (25 L) was added, and further solvent
(31 L) was distilled off under reduced pressure. Water (125 L)
was added, and the mixture was aged overnight to crystallize.
Concentrated hydrochloric acid (11 M; 5.74 kg) was added to
pH 1. The mixture was then aged for 2 h at 20-25 °C. The
product was collected by filtration and washed with water (3
× 25 L), and dried in Vacuo at 45 °C for 72 h, to give 1,4,5,6-
tetrahydro-3-(1H-tetrazol-5-yl)cyclopenta[c]pyrazole (1, 6.33
kg) as a pale-yellow solid in 90% yield (>99% pure containing
<0.2% aldol impurity 14). 1H NMR (d6-DMSO): δ 2.73 (4H,
m); 2.52 (2H, m). 13C NMR (d6-DMSO): δ 153.0, 150.5, 130.3,
126.3, 30.9, 23.7, 23.4. IR (KBr) 2932 (s, br), 2862 (s), 2676
(s, br), 1617 (s), 1419 (m), 1304 (s), 1161 (m), 1128 (m), 1077
(m), 1011 (s), 988 (m), 893 (m), 819 (m, br), 758 (m) cm-1.
Anal. Calcd for C7H8N6: C, 47.72; H, 4.58: N, 47.70. Found:
C, 47.69; H, 4.59; N, 47.70.
1,4,5,6-Tetrahydro-cyclopenta[c]pyrazole-3-carboxylic Acid
Ethyl Ester (4). Potassium ethoxide (24.2 g; 288 mmol) was
dissolved in ethanol (100 mL). This solution was added over
10 min to a mixture of cyclopentanone (2, 25 mL; 283 mmol)
and diethyl oxalate (3, 39.2 mL; 288 mmol) in ethanol (125
mL). The mixture was heated to 29 °C, and held at this
temperature for 1.5 h. The mixture was then cooled to 3 °C.
Concentrated hydrochloric acid (28 mL; 12.2 M; 342 mmol)
was added over 5 min, maintaining the temperature less than
10 °C. The reaction mixture was cooled to 0 °C, and a 55%
solution of hydrazine hydrate (18.1 g; 311 mmol) was added
over 20 min, maintaining the temperature below 2 °C. The
reaction mixture was aged at this temperature for 1.5 h. The
mixture was warmed to 10 °C, and then distilled under reduced
pressure to remove 225 mL of solvent with simultaneous
addition of water (225 mL). To the resulting pale-yellow slurry
was charged a 5% solution of sodium bicarbonate (150 mL),
and the resulting mixture was aged at 25 °C for 40 min. The
slurry was then cooled to 10 °C and the product collected by
filtration, washed with cold water (40 mL), and dried in Vacuo
at 65 °C to give 1,4,5,6-tetrahydro-cyclopenta[c]pyrazole-3-
carboxylic acid ethyl ester (4, 45.0 g) as a off white solid (>99%
Conclusions
We have developed and demonstrated on scale a new one-
pot process for synthesis of the partial nicotinic acid receptor
agonist 1. The original discovery route required seven steps to
yield 1 with an overall yield of 39%. This more streamlined
approach provides a more practical and scaleable alternative
synthesis, whilst increasing the overall isolated yield for the
formation of 1 to 90%. The latter process also represents a viable
manufacturing route to 1, and successful demonstrations on 70-
kg scale have been undertaken without incident.
Experimental Section
All reactions were carried out under a positive pressure of
1
nitrogen. H NMR spectra were obtained at 400 MHz, in the
solvent indicated on a Bruker DPX 400 spectrometer. All purity
values were obtained by HPLC analysis at 210 and 235 nm.
The analysis for hydrazoic acid in the reaction headspace was
carried out using an FTIR analyzer (ReactIR4000) equipped
with an online gas cell (30 cc), connected to a 250 mL jacketed
resin kettle.
(12) It is important that the starting materials and the solvent are dry for
the condensation reaction. The variance in assay yield for the formation
of 1 appears to be directly attributable to water content with the highest
yields deriving from the lowest KF reactions.
(13) Structure of the hydrazone 15 was determined by single-crystal X-ray
diffraction analysis.
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pure) in 88% yield,. 1H NMR (CDCl3): δ 10.00 (1H, broad s);
4.36 (2H, q, J)7.2 Hz); 2.80 (4H, m); 2.48 (2H, m); 1.37 (3H,
t, J)7.2 Hz). 13C NMR (CDCl3): δ 160.8, 129.3, 60.8, 30.2,
24.4, 23.7, 14.3. IR (KBr) 2940 (s), 2863 (s), 1718 (s), 1524
(s), 1445 (s), 1388 (s), 1244 (s), 1113 (s), 1055 (s), 1023 (s),
873 (s), 846 (s), 785 (s) cm-1. HRMS (+EI): found 181.0977
(Calcd 181.0982). The NMR data was consistent with known
data of 4 in the literature.4
1,4,5,6-Tetrahydro-cyclopenta[c]pyrazole-3-carboxylic Acid
(8). 1,4,5,6-Tetrahydro-cyclopenta[c]pyrazole-3-carboxylic acid
ethyl ester (4, 10 g; 55.5 mmol) was slurried in methanol (50
mL), and then 4 M potassium hydroxide solution (31 mL; 122.1
mmol) was added. The mixture was heated to 43 °C and aged
at this temperature for 1.5 h. The mixture was cooled to 10 °C,
and 4 M hydrochloric acid (32 mL) was added over 5 min.
The product precipitated out of solution. The slurry was chilled
to 5 °C for 15 min. The product was collected by filtration,
washed with cold water (10 mL) and dried in Vacuo at 65 °C
to give 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic
acid (8, 8.31 g) as a white solid (>99.7% pure) in 98% yield.
1H NMR (d6-DMSO): δ 12.90 (1H, broad s); 2.64 (4H, m);
2.38 (2H, m). 13C NMR (d6-DMSO): δ 161.9, 128.7, 30.3, 24.2,
23.7. IR (KBr) 3252 (s, br), 2939 (s, br), 1704 (s), 1555 (s),
1469 (s), 1328 (s), 1304 (s), 1252 (s), 1205 (m), 1126 (s), 1060
(s), 785 (s), 711 (s) cm-1. HRMS (+EI): found 153.0664 (calcd
153.0663). The NMR data was consistent with known data of
8 in the literature.4
1671 (m), 1636 (s), 1597 (s), 1572 (s), 1492 (m), 1444 (m),
1295 (s), 1256 (s), 1132 (m), 1076 (s), 1042 (m), 839 (m), 771
(m), 645 (s) cm-1. HRMS (+EI): found 152.0824 (calcd
152.0826).
1,4,5,6-Tetrahydro-3-cyano-cyclopenta[c]pyrazole (9). A
suspension of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-car-
boxamide (5, 8 g; 52.9 mmol) in THF (40 mL) was cooled to
-10 °C. To the mixture was added triethylamine (11 mL),
followed by the slow addition of trifluoroacetic anhydride (15.7
mL) over 40 min whilst maintaining the temperature between
-10 and -5 °C. The reaction was aged for 3 h and then
quenched by the slow addition of saturated sodium bicarbonate
solution (200 mL) to the mixture, maintaining the temperature
below 0 °C. The THF was removed by distillation under
reduced pressure, to give a suspension. The product was
collected by filtration, washed with water (50 mL), and dried
in Vacuo to 50 °C to give 1,4,5,6-tetrahydro-3-cyano-cyclo-
penta[c]pyrazole (9, 6.4 g) as a white crystalline solid (>99.7%
pure) in 90% yield. 1H NMR (d6-DMSO): δ 13.50 (1H, broad
s); 2.68 (4H, m); 2.50 (2H, m). 13C NMR (d6-DMSO): δ 152.0,
131.0, 117.9, 115.5, 30.9, 23.6, 22.5. IR (KBr) 3264 (s), 2982
(m), 2961 (m), 2936 (m), 2242 (s), 1556 (s), 1515 (s), 1466
(m), 1446 (m), 1306 (m), 1297 (s), 1258 (s), 1210 (m), 1122
(s), 1053 (s), 824 (s), 611 (s) cm-1. HRMS (+EI): found
175.0984 (calcd 175.0979).
1,4,5,6-Tetrahydro-3-(1H-tetrazol-5-yl)cyclopenta[c]pyra-
zole (1). 1,4,5,6-Tetrahydro-3-cyano-cyclopenta[c]pyrazole (9,
2.6 g; 19.5 mmol), sodium azide (2.0 g; 30.8 mmol) and zinc
bromide (4.5 g, 20.0 mmol) were dissolved in a mixture of
propan-2-ol (90 mL) and water (35 mL). The solution was
stirred and heated at 75 °C for 7.5 h. A second charge of sodium
azide (0.3 g, 4.6 mmol) was added, and the mixture was heated
for a further 5 h and then cooled to 25 °C. The mixture was
acidified with 2 M hydrochloric acid (50 mL) to give a clear,
pale-yellow solution. The propan-2-ol was distilled under
reduced pressure and the resulting slurry diluted with water (100
mL). The product was collected by filtration, washed with water
(50 mL), and dried in Vacuo at 50 °C to give 1,4,5,6-tetrahydro-
3-(1H-tetrazol-5-yl)cyclopenta[c]pyrazole (1, 2.9 g) as a white
crystalline solid (>99.1% pure) in 85% yield.
1,4,5,6-Tetrahydro-cyclopenta[c]pyrazole-3-carboxam-
ide (5). A mixture of 1,4,5,6-Tetrahydro-cyclopenta[c]pyrazole-
3-carboxylic acid (8, 13 g; 85.5 mmol) and 1,1-carbonyldiim-
idazole (15.25 g; 94.1 mmol) in THF (195 mL) was heated to
60 °C over the course of an hour. The reaction initially became
a thick slurry, and the emission of carbon dioxide was observed.
At the end of this period a clear brown solution had formed.
The reaction was cooled down to 25 °C, and a 35% solution of
ammonium hydroxide (12.5 mL) was added in one portion. The
slurry was aged at 25 °C for 30 min and then cooled to 7 °C.
The product was collected by filtration, washed with chilled
(0 °C) THF (20 mL) and dried in Vacuo to give 1,4,5,6-
tetrahydro-cyclopenta[c]pyrazole-3-carboxamide (5, 12.18 g) as
1
a white solid (>99.7% pure) in 94% yield. H NMR (d6-
DMSO): δ 12.38 (1H, broad s); 6.78 (2H, broad s); 2.68 (4H,
m); 2.47 (2H, m). 13C NMR (d6-DMSO): δ 163.2, 126.4, 30.81,
24.0, 23.7. IR (KBr) 3362 (m), 3179 (s), 2929 (s), 2858 (s),
Received for review November 14, 2008.
OP800290T
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