The process development of a scaleable route to the PDE5 inhibitor UK-357,903

Article abstract of DOI:10.1021/op0200468

A case history is outlined for the development of a scaleable route to the drug candidate UK-357,903. Despite the partial structural similarities to those of sildenafil (Viagra), the introduction of the central pyridine moiety within UK-357,903 had a significant impact on the commercial process. In particular, the triply activated 2-alkoxypyridyl moiety of UK-357,903 is much more susceptible to nucleophilic attack than the 2-ethoxyphenyl moiety of sildenafil, necessitating the development of new chemistry. Particular items of note are (i) the new six-step route to the advanced 2-ethoxy-5-(4-ethylpiperazinylsulfonyl)nicotinic acid intermediate and the subsequent telescoping to a two-pot process, (ii) the telescoping of the two steps from N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl)nicotin-amide to UK-357,903 to a single step, with the additional use of a hydroxide trapping agent to give an ambient pressure process yielding clinical quality product, and (iii) the introduction of process modifications to allow for the use of teratogenic 2-methoxyethanol, as both reagent and solvent, in the penultimate process step.

Full text of DOI:10.1021/op0200468

Organic Process Research & Development 2002, 6, 767−772
The Process Development of a Scaleable Route to the PDE5 Inhibitor
UK-357,903
David J. Dale, John Draper, Peter J. Dunn, Michael L. Hughes, Farhat Hussain, Philip C. Levett,* Gordon B. Ward, and
Albert S. Wood
Department of Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment Laboratories,
Sandwich, Kent CT13 9NJ, United Kingdom
Abstract:
A case history is outlined for the development of a scaleable
route to the drug candidate UK-357,903. Despite the partial
structural similarities to those of sildenafil (Viagra), the
introduction of the central pyridine moiety within UK-357,903
had a significant impact on the commercial process. In
particular, the triply activated 2-alkoxypyridyl moiety of UK-
357,903 is much more susceptible to nucleophilic attack than
the 2-ethoxyphenyl moiety of sildenafil, necessitating the de-
velopment of new chemistry. Particular items of note are (i)
the new six-step route to the advanced 2-ethoxy-5-(4-ethylpip-
erazinylsulfonyl)nicotinic acid intermediate and the subsequent
telescoping to a two-pot process, (ii) the telescoping of the two
steps from N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-
pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotin-
amide to UK-357,903 to a single step, with the additional use
of a hydroxide trapping agent to give an ambient pressure
process yielding clinical quality product, and (iii) the introduc-
tion of process modifications to allow for the use of teratogenic
2-methoxyethanol, as both reagent and solvent, in the penul-
timate process step.
Figure 1.
Scheme 1. Commercial route to sildenafil (7)
Introduction
UK-357,903 is a potent and selective phosphodiesterase
5 (PDE5) inhibitor which entered development for the
potential treatment of male erectile dysfunction (impotence).
It is thus of the same therapeutic class as sildenafil (7)
(Viagra). Although at first sight they appear structurally
similar (Figure 1), the introduction of the central pyridine
moiety within UK-357,903 (1) had a significant impact on
both the commercial process and the biological activity.
preparation of UK-357,903 (1), albeit with the necessary
introduction of a 2-methoxyethanol side chain as the final
step (Scheme 2). An analogous convergent approach seemed
appropriate for UK-357,903 (1), but a new synthesis of the
2-alkoxypyridyl moiety together with improvements in the
final two chemical steps was desirable.
Results and Discussion
(a) Preparation of the Nicotinic Acid (8). In the
sildenafil route the phenyl sulphonamide (4) was generated
via chlorosulphonylation of 2-ethoxybenzoic acid. A litera-
ture search for chemistry analogous with that of 2-alkoxy-
nicotinic acids proved fruitless, and the suggestion4 that the
more reactive 2-pyridone would not sulphonylate led to other
approaches being considered. Therefore Medicinal Chemistry
developed a novel route to sulphonamide (8), which served
Pfizer’s experience with the pyrazolopyrimidone class of
PDE5 inhibitors extends over a decade and during this
interim period, several synthetic approaches to this structural
class have been demonstrated.1,2 Following the commercial
route development of sildenafil (7) previously outlined in
this journal3 (see Scheme 1), our Medicinal Chemistry
colleagues used a closely analogous approach for the
(1) Bell, A. S.; Brown, D.; Terrett, N. K. Eur. Pat. 463756 B1, April 19, 1995.
(2) (a) Bunnage, M. E.; DeVries, K. M.; Harris, L. J.; Levett, P. C.; Mathias,
J. P.; Negri, J. T.; Street, S. D.; Wood, A. S. WO 01/27113, April 19, 2001.
(b) Dunn, P. J.; Levett, P. C. Eur. Pat. Appl. 994115 A2, April 19, 2000 (c)
DeVries, K. M.; Levett, P. C.; Negri, J. T.; Wood, A. S. Eur. Pat. Appl.
1092720 A2, April 18, 2001.
(3) Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce,
A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Process Res. DeV. 2000,
4, 17.
(4) Meislich, H. Pyridine and its Derivatives. In Heterocyclic Compounds;
Interscience Publishers: New York-London, 1962; Part Three, Chapter XII,
p 669.
10.1021/op0200468 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002
Vol. 6, No. 6, 2002 / Organic Process Research & Development
•
767

Scheme 2. Medicinal chemistry route to UK-357,903 (1)
Scheme 4. Chemical R&D route to nicotinic acid (8)
Scheme 3. Medicinal chemistry route to nicotinic acid (8)
option, since use of substoichiometric sulfur trioxide in
concentrated sulfuric acid failed to effect reaction completion.
Reaction calorimetry data showed the addition of the
2-hydroxynicotinic acid (15) to oleum at 40 °C generated
-60.1 kJ/mol based on nicotinic acid which could produce
an adiabatic temperature rise of 93 °C. Upon heating the
reaction mixture to 140 °C over 2 h to effect reaction
completion, calorimetry data showed further exothermic
activity both during the linear ramp, and after reaching the
final temperature (Total ∆Tad ) 53 °C). It was therefore
important to make sure the heat from the nicotinic acid
addition had dissipated before slow heating of the reaction
to ∼140 °C commenced to reduce this possible temperature
rise. Reaction calorimetry was also used to examine the
quench of the reaction at 55 °C with water which was added
over 1 h. This quench liberated -100 kJ/mol based on the
nicotinic acid, which was equivalent to an adiabatic tem-
perature rise of 88 °C (i.e., would cause boiling of the
reaction mixture). However, whilst it is not normal practice
to quench oleum reactions with water addition, this did allow
the reaction to be handled much more easily. Therefore,
provided adequate mixing (to avoid local boiling) is used
and the quench carefully controlled, the process was deemed
safe to run in this way.
To minimise the total number of steps, progression of
nicotinic acid (16) through to nicotinic acid (8) would ideally
have carried the 3-carboxyl functionality through unchanged.
This strategy was shown to be feasible (Scheme 5), with a
phosphorus pentachloride/heptane-mediated trichlorination of
16 to 20, followed by a selective hydrolysis of the unisolated
nicotinoyl chloride (20) back to the nicotinic acid (21),
occurring in up to 64% yield. Unfortunately this was a
particularly capricious reaction, with over-hydrolyzed sul-
fonic acid impurities being generated in up to 20%.
them well over the course of their discovery program
(Scheme 3). This route was then successfully used within
the Chemical R&D department for preparing the first 200
kg of sulfonamide (8).
However, this eight-step linear process utilised oleum
sulfonylation, bromination, diazotisation, chlorination, and
high-pressure carbonylation chemistry and yielded 8 in just
11% overall yield. Since there were a number of hazardous
reactions in this route and the high-temperature carbonylation
required specialised plant equipment, we were encouraged
to search for a new route.
Despite the discouraging literature claim,4 we decided to
investigate the sulfonylation of the inexpensive, agrochemical
intermediate, 2-hydroxynicotinic acid (Scheme 4), since we
believed success here could lead to a superior commercial
manufacturing process. Not surprisingly, we found that
sulfonylation of 2-hydroxynicotinic acid (15) did not occur
in concentrated sulphuric acid. In light of the harsher
conditions that were required to sulfonylate 2-aminopyridine
(as outlined above), we progressed to a successful reaction
with stoichiometric 30% oleum at 140 °C, yielding sulfonic
acid (16) in 90% yield. Catalytic oleum was not a viable
768
•
Vol. 6, No. 6, 2002 / Organic Process Research & Development

Scheme 5. Trichlorination approach to (21)
Scheme 6. Chemical R&D route to UK-357, 903 (1)
To compensate for this, a facile protecting-group strategy
was employed, whereby nicotinic acid (16) was first pro-
tected as the ethyl nicotinoate (17) in 74% yield over two
crops. To drive this condensation reaction to completion,
azeotropic removal of the generated water was required.
Interestingly, no additional acid catalysis was required for
this reaction, presumably due to the presence of the 5-sulfonic
acid functionality. A further process modification allowed
the telescoping of steps (15) to (17) in 90% yield by
quenching the oleum reaction directly into ethanol, although
controlling the simultaneous generation of diethyl sulfate
clearly had to be engineered into the process.
The dichlorination to the sulfonyl chloride (18) was
effected successfully in thionyl chloride with catalytic DMF
in quantitative yield (SAFETY NOTE: this generates the
known animal carcinogen dimethylcarbamoyl chloride).5
Subsequent formation of the sulfonamide (19), in the
presence of N-ethylpiperazine and triethylamine in ethyl
acetate, could also be achieved in quantitative yield once all
traces of thionyl chloride had been removed from the
previous step. The final introduction of the 2-ethoxy side
chain with ethanolic sodium ethoxide and subsequent ester
saponification to nicotinic acid (8) could then be effected in
a one pot process.
At this stage we had effectively telescoped the process
down to three isolation stages; (15) to (17), (17) to (19) and
(19) to (8), each being two synthetic transformations. The
final process, that has delivered multikilogam quantities of
nicotinic acid (8), further telescoped together the four
transformations (17) to (8) using a toluene solution without
intermediate isolation. Use of toluene as solvent in the
chlorination step, [(17) to (18)], allowed for facile azeotropic
removal of excess thionyl chloride, whilst also allowing the
thionyl chloride charge to be reduced from reaction solvent
to 5 equiv. The product sulfonyl chloride (18) was then taken
through to the sulfonamide-forming step as the toluene
solution, whereby the triethylamine hydrochloride generated
could be readily aqueous washed from the less dense toluene
layer rather then filtered, as had been the case previously.
The use of ethyl acetate as solvent was no longer required
and the water wet toluene solution of product (19) could be
readily azeotropically dried in the same vessel for the
subsequent water sensitive step. The sodium ethoxide medi-
ated introduction of the 2-ethoxy side chain could also be
effected in toluene with the subsequent ester saponification
utilising addition of aqueous sodium hydroxide. This two-
phase hydrolysis had the advantage of minimising generation
of the 2-pyridone impurity, with product isolation readily
achieved via extraction into the basic aqueous phase with
product crystallisation after pH adjustment to the isoelectric
point. This “four-into-one” step telescoped process generates
the nicotinic acid (8) in 54% yield (i.e., 51% from 2-hy-
droxynicotinic acid (15), compared to 11% for the Discovery
route), with the oVerall cost reduced to one-quarter compared
to the route starting from 2-aminopyridne.
(b) Preparation of Amide (10). As outlined in Scheme
2, the Medicinal Chemistry route utilised a hydroxybenzo-
triazole/1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hy-
drochloride (EDCI) coupling system with nicotinic acid (8)
and aminopyrazole (9)9 to generate amide (10) in ∼70%
yield. The moderate yield coupled with the knowledge that
EDCI was both a suspect sensitizer and expensive encour-
aged us to switch to the N,N-carbonyldiimidazole/ethyl
acetate approach (Scheme 6), as previously utilised in the
commercial route for the preparation of sildenafil. This
approach allowed crystallised product amide (10) to be
filtered directly from the reaction mixture in 91% yield, with
the imidazole byproduct remaining in the ethyl acetate
solution. The formation of the imidazolide generates carbon
dioxide and hence represents a potential overpressure hazard.
Safety work showed that the rate of gas evolution could be
controlled to acceptable levels by performing the CDI
addition at 25 °C and then heating the reaction in steps as
described in the Experimental Section. Off-gas measurement
data showed that when the reaction was heated at 1 °C/min
the maximum rate of off-gassing was 0.85 litre/min (per litre
of batch) occurring at ∼38 °C. To provide an adequate
margin for scale-up, it was a requirement to only use 50%
vessel fills and control the heat up rate to a maximum of 1
°C/min.
(c) Preparation of UK-357,903 (1). The two-step Me-
dicinal Chemistry process to convert amide 10 to UK-357,-
903 (1) by cyclisation and then displacement (Scheme 2)
(6) Salmi, E. J.; Leimu, R. Suom. Kemistil. 1947, 20B, 43. For abstract, see:
Chem. Abs. 1947, 41, 5370c.
(7) Urban, P. Bretherick’s Handbook of ReactiVe Chemical Hazards, 5th ed.;
Butterworth Heinemann: Woburn, MA, 1995; Vol. 2, p 193.
(8) Au, W.; Ahmed, E.; Chiechanwit, T.; Hsie, W.; Ma, H.; Moslen, T. Occup.
Hyg. 1996, 2, 177.
(9) For preparation of amino pyrazole (9), see ref 2c above, examples 1a to 1f,
inclusive.
(5) Levin, D. Org. Process Res. DeV. 1997, 1, 182.
Vol. 6, No. 6, 2002 / Organic Process Research & Development
•
769

product), giving an 80% yield in the pilot plant (compared
with 45% with KHMDS). For the displacement step 11 to
1, the use of potassium tert-butoxide in 2-methoxyethanol
again improved the yield to 97% (compared to 79% with
KHMDS), albeit now in the presence of an hydroxide-
trapping agent. These reactions should be charged and
conducted under nitrogen, since Bretherick7 highlights the
danger of metal alkoxides hydrolysing in moist air, whereby
the exotherm may ignite the solids.
Removing the need to run the cyclisation step at high
pressures (i.e., ethanol at 125 °C) conceptually seemed quite
straightforward, given that the medicinal chemists had
already demonstrated that a temperature of ∼125 °C was
required to effect cyclisation. As such, a range of higher-
boiling solvents was investigated, including hindered tertiary
alcohols (to prevent 2-ethoxy displacement). However in-
process HPLC assays revealed a maximum of 64% product
was achievable. The solution to this problem was particularly
satisfying. By telescoping together both the cyclisation and
displacement reactions, bisamide 10 could be converted
directly to UK-357,903 (1) using 2-methoxyethanol as both
the high-boiling solvent (for the cyclisation) and the reagent
(for the displacement) in the presence of potassium tert-
butoxide and ethyl pivalate. Unfortunately, filtration and
drying of the precipitated product after pH adjustment to the
isoelectric point was extremely slow (5 h and 4 days,
respectively). After laboratory evaluation we found that after
pH adjustment the product could be directly extracted into
warm methyl isobutyl ketone (MiBK) and then crystallised
at reduced volume to furnish a 78% yield of high,quality
UK-357,903 (1) which could be rapidly filtered and dried.
(d) The 2-Methoxyethanol Issue. The one downside of
this process was that 2-methoxyethanol is a teratogenic
solvent, with an OEL of 5 ppm.8 Hence, the process was
carefully designed to introduce a 2-methoxyethanol side
chain into our drug candidate, whilst safely controlling
2-methoxyethanol levels in the manufacturing plant, in the
waste streams, and in the final isolated UK-357,903 (1).
(1) Significant effort was put into finding a stoichiometric
2-methoxyethanol process that utilised an inert high-boiling
cosolvent. Dibutyl ether was our best option, but with just a
29% UK-357,903 yield (unisolated), this was clearly not
viable.
Figure 2.
was suboptimal as a commercial process for the following
reasons:
(1) The cyclisation of amide 10 to pyrimidone 11 gave a
35% combined level of the 2-pyridone impurities 22 and 23
(Figure 2). In contrast, the in-process reaction assay of the
analogous sildenafil cyclisation step showed >95% sildenafil
present (with very low levels of any impurities in the reaction
mixture), thus demonstrating the large difference in electro-
philicity between 2-ethoxypyridine and 2-ethoxybenzene
derivatives.
(2) Use of KHMDS as the base in alcoholic solvents for
both the cyclisation and displacement steps liberated sto-
ichiometric quantities of ammonia, which would require
process engineering to scrub. Furthermore, the liberated
ammonia reacted with the reactive 2-alkoxy substituent of
10, 11, and 1)to yield the analogous 2-aminopyridine
impurities.
(3) The cyclisation to pyrimidone 11 required the reaction
to be run in KHMDS/ethanol at 125 °C, thus necessitating
the use of a high-pressure reactor (∼60 psi).
We reasoned that the source of the 2-pyridone impurities
22 and 23 was the mole of potassium hydroxide generated
during the cyclisation of the bisamide 10 to the pyrimidone
11. We investigated a number of experimental approaches
to minimise the impact of potassium hydroxide. Several were
tried, but we surprisingly found that the best results were
obtained utilising an ester as a hydroxide-trapping reagent.
Initial efforts utilising ethyl acetate were very encouraging
with the impurities 22 and 23 reduced to a combined level
of ∼8% (from ∼35%). Further analysis of the isolated
product revealed the presence of the fused tetracyclic
impurity 24, presumably generated via acyl transfer from
ethyl acetate. To prevent formation of impurity 24, a
nonenolisable ester was used as a hydroxide-trapping agent.
Ethyl pivalate gave a further improvement, with no pivalated
impurities detected, and levels of the 2-pyridones 22 and 23
were reduced further to ∼6%, thus improving the isolated
yield.
(2) Introduction of the 2-methoxyethanol side chain earlier
in the process would have prevented 2-methoxyethanol
contamination of the isolated UK-357,903 (1), but the highly
labile nature of this side chain meant this could not be carried
through the synthetic sequence successfully. Literature
precedent demonstrates6 the facile leaving group potential
of the 2-methoxyethanol side chain, whereby the saponifica-
tion of a 2-methoxyethanol ester was shown to proceed at a
rate twice that of the ethoxy analoguespresumably due to
the neighbouring group participation of the â-methoxy
substituent.
Switching the base from KHMDS required the use of a
nonnucleophilic base to prevent undesired exchange at the
reactive 2-alkoxy site. For the cyclisation step, 10 to 11, this
could be best achieved with potassium ethoxide in ethanol
(since an ethoxy-for-ethoxy exchange would give the same
As a consequence we looked to engineering and process
optimisation within our current process to overcome the
2-methoxyethanol issues:
770
•
Vol. 6, No. 6, 2002 / Organic Process Research & Development

(1) Extensive vapour monitoring work was undertaken
using 3M passive diffusion monitors. Analysis by the
Institute of Occupational Medicine showed that at all stages
of the process within the pilot plant, levels were below the
MEL of 5 ppm except within 1 m of the chargehole during
the solids charging to reactors. Monitors within the operators’
airsuits always gave a “nondetected” reading.
screen was re-run with a wider range of counterions. This
ultimately resulted in the anhydrous p-toluenesulfonate salt
being selected, which could be reproducibly prepared in 98%
yield.
Conclusions
Despite the partial structural similarity between sildenafil
(7) and UK-357,903 (1), the scaleable route described in this
paper demonstrates the significant process variations required
to overcome the fundamental reactivity differences between
a 2-ethoxyphenyl and a 2-ethoxypyridyl derivative. The high
yielding, operationally streamlined, convergent route de-
scribed (36% yield from 2-hydroxynicotinic acid (15),
compared with the overall medicinal chemistry route yield
of 3.5% from 2-aminopyridine) allowed this new PDE5
inhibitor to be prepared on a multikilogram, large pilot-plant
scale.
(2) The process was optimised to ensure the 2-methoxy-
ethanol was contained within this single step and not
forwarded to the final salt-forming step. During the workup,
to separate the 2-methoxyethanol from the product it was
necessary to optimise the level of 2-methoxyethanol remain-
ing in the aqueous phase. Optimal results were achieved by
ensuring most of the ethanol (a byproduct from the displace-
ment component of the reaction) was azeotropically removed,
during the reaction, with several 2-methoxyethanol strip-and-
replace cycles. This minimised the effect of ethanol solu-
bilising the 2-methoxyethanol from the aqueous to the MiBK
phase after pH adjustment. This had the additional benefit
of driving the reaction further to completion, an added bonus
since the intermediate pyrimidone 11 was a difficult impurity
to purge. Furthermore. it was found that a MiBK strip (to 3
mL/g) followed by three aqueous washes of the MiBK phase
would lower the 2-methoxyethanol levels to a nondetectable
level within the isolated UK-357,903 (1). All waste streams
were subsequently incinerated.
(3) As a consequence of the optimisation work presented
above, our manufacturing division was prepared to run the
2-methoxyethanol process within a modified containment
facility.
(e) The Salt-Forming Step. Salt-selection work early in
the development cycle for UK-357,903 (1) identified the
benzenesulfonate monohydrate as the solid form of choice
over the anhydrous P255 form. Judicious process optimisa-
tion was then required to ensure dehydration to an anhydrous
benzene sulfonate salt did not occur:
(1) 8% water in MEK was optimal, allowing the speck-
freeing operation at 50 °C. Increasing the water level lowered
the yield, whilst reducing the water level to <5% water
yielded the anhydrous salt.
(2) Benzenesulfonic acid in 8% water wet MEK was
added to the solvated UK-357,903 (1) at 35 °C. An addition
temperature >50 °C yielded the anhydrous salt, as could a
concentration gradient if 8% wet MEK was not employed
in both the header tank and the main vessel.
(3) Drying the salt necessitated a temperature of around
40 °C, with full vacuum at high humidity (i.e., using a tray
of water in the bottom of the oven) to give the hydrated
benzene sulfonate in 87% yield. Unfortunately after many
successful batches, the process failed at 50 °C, producing
∼10% contamination with undesired anhydrous benzene-
sulfonate salt.
(4) A stability trial at 50 °C/20% RH also produced ∼5%
conversion to an anhydrous benzene sulfonate salt.
These two final results showed that we did not have
control of the process to guarantee generation of the besylate
monohydrate salt. Therefore, as we had lost confidence in
the processability and stability of this solid form, the salt
Experimental Section
Proton NMR data were recorded on a Varian Unity 300
spectrometer operating at 300 MHz. Melting points were
determined on a Buchi melting point apparatus and are
uncorrected.
2-Hydroxy-5-sulfonicotinic Acid (16). 2-Hydroxynico-
tinic acid (27 kg, 194.2 mol) was added portionwise to 30%
oleum (58.1 kg) at 50 °C over 1 h resulting in an exotherm
to 82°C. The reaction mixture was heated further to 140 °C.
After maintaining this temperature for 12 h the reactor
contents were cooled to 15 °C, quenched with water (25 L)
and filtered. The filter cake was then re-slurried with acetone
(33 kg) at room temperature, filtered, and dried to afford
the title compound (35.3 kg, 83%) as a white solid: mp 273
°C dec. (DMSO-d6) δ 7.93 (1H, d), 8.42 (1H, d). m/z
(Found: 220 [M + H]+, 100%. C6H6NO6S requires 220).
Ethyl 2-hydroxy-5-sulfonicotinoate (17). 2-Hydroxy-5-
sulfonicotinic acid (16) (500 g, 2.28 mol) was dissolved in
ethanol (2.5 L) with stirring and was heated to 80 °C. After
30 min, 0.5 L of solvent was distilled off and replaced with
fresh ethanol (0.5 L) and then reheated to 80 °C. After a
further 60 min 1.0 L of solvent was distilled off and then
replaced with fresh ethanol (1.0 L) and reheated to 80 °C.
After a further 60 min, 1.0 L of solvent was distilled off,
and the reaction was cooled to 22 °C and stirred for 16 h.
The precipitated product was filtered, washed with ethanol
(0.5 L), and dried at 50 °C under vacuum to afford the title
compound (416 g, 74%) as a white solid: mp 237 °C (dec).
(DMSO-d6) δ 1.25 (3H, t), 4.19 (2H, q), 7.66 (1H, d), 8.13
(1H, d). m/z (Found: 248 [M + H]+, 100%. C8H10NO6S
requires 248).
2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic Acid
(8): Telescoped Process in Toluene from (17). Ethyl
2-hydroxy-5-sulfonicotinoate (17) (441.5 g, 1.79 mol) was
dissolved in toluene (1.77 L); thionyl chloride (1.06 kg, 8.93
mol) and dimethylformamide (71.3 mL) were then added.
The stirred suspension was then heated to reflux for 3 h to
yield a yellow solution. Thionyl chloride (2.87 L) was
distilled with continual replacement with toluene (2.15 L).
The pale yellow solution was cooled to 10 °C, and a stirred
Vol. 6, No. 6, 2002 / Organic Process Research & Development
•
771

solution of N-ethylpiperazine (198.9 g, 1.66 mol) and
triethylamine (392.2 g, 3.88 mol) in toluene (700 mL) was
added dropwise over 90 min, keeping the reaction mixture
below 10 °C. The reaction was stirred at ambient temperature
for 18 h and washed with water (2 × 700 mL) and brine
(2 × 350 mL). The toluene phase was azeotropically dried
by distilling off 1750 mL, which was continuously replaced
by dry toluene (1750 mL). The remaining brown solution
was cooled to 10 °C, and sodium ethoxide (178.0 g) was
added portionwise, keeping the temperature below 10°C. The
reaction was stirred at 10 °C for 1 h and then warmed to
ambient temperature and stirred for 18 h. Sodium hydroxide
(34.9 g, 0.87mol) dissolved in water (1.5 L) was added to
the toluene mixture, and the two-phase mixture was vigor-
ously stirred for 18 h at 40 °C. Once cooled to ambient
temperature, the aqueous phase was separated off and
adjusted to pH 3 with concentrated hydrochloric acid. The
precipitated solid was granulated for 2 h with ice cooling
and then filtered, washed with water (300 mL), and dried in
vacuo at 50 °C to afford the title compound (338.4 g, 57.4%)
as an off-white solid: mp 206-207 °C. (CDCl3) δ 1.25 (3H,
t), 1.39 (3H, t), 2.82 (2H, q), 3.03 (4H, m), 3.25 (4H, m),
4.50 (2H, q), 8.25 (1H, d), 8.56 (1H, d). m/z (Found: 344
[M + H]+, 100%. C14H22N3O5S requires 344).
N-[3-Carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyra-
zol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotin-
amide (10). 2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)-
nicotinic acid (8) (0.875kg, 2.55mol) was dissolved in ethyl
acetate (7 L, 8 mL/g), and 2 mL/g was distilled off at
atmospheric pressure to ensure the reaction system was dry.
The slurry was cooled to room temperature under a nitrogen
atmosphere, and N,N′-carbonyldiimidazole (0.43 kg, 2.65
mol) was added in one portion. The slurry was heated at 35
°C for 30 min, at 45-50 °C for a further 30 min, and finally
at reflux for 1 h. On confirmation of complete imidazolide
formation the reaction was cooled to 45-50 °C under
nitrogen, and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyra-
zole-3-carboxamide (9)7 (0.59 kg, 2.42 mol) was charged in
one portion before returning to reflux; a further 1 mL/g was
distilled off at atmospheric pressure. The reaction was stirred
at reflux for 16 h and then cooled to 10-15 °C and
granulated for 1 h. The reaction slurry was filtered, washed
(ethyl acetate), and finally dried in vacuo at 50 °C to afford
the title compound (1.252 kg, 90.7%) as a white solid: mp
178-179 °C. (CDCl3) δ 1.04 (3H, t), 1.06 (3H, t), 1.59 (3H,
t), 2.40 (2H, q), 2.50 (4H, m), 2.90 (2H, q), 3.08 (4H, m),
4.78 (2H, q), 5.35 (1H, s), 5.48 (2H, s), 6.68 (1H, s), 6.92
(1H, d), 7.22 (1H, m), 7.65 (1H, m), 8.58 (1H, d), 8.64 (1H,
d), 8.83 (1H, d). m/z (Found: 571 [M + H]+, 100%.
C26H35N8O5S requires 571).
1-Ethyl-4-{5-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridyl-
methyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-6-(2-methoxy-
ethoxy)-3-pyridylsulfonyl}piperazine (1). N-[3-Carbamoyl-
5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-
ethyl-1-piperazinylsulfonyl)nicotinamide (10) (500 g, 0.876
mol) was added under nitrogen in one portion to 2-meth-
oxyethanol (2.5L, 5 mL/g), and the reaction was stirred at
ambient temperature for 10 min. The addition of potassium
tert-butoxide (236 g, 2.103 mol), added portionwise under
nitrogen over 10 min to the stirred reaction mixture, was
found to produce an exotherm (∆ ) 20-50 °C). The reaction
was stirred until a steady temperature was obtained, giving
a clear pale yellow solution. Ethyl pivalate (285 g, 2.19 mol)
was then washed in with 2-methoxyethanol (0.3 L). The
reaction mixture was heated to reflux temperature (115-
125 °C) and maintained at reflux temperature for 6 h,
removing the ethanol and tert-butyl alcohol byproducts by
distillation and replacing with 2-methoxyethanol. The re-
maining solvent is then reduced under vacuum distillation
to a volume of 2 mL/g. The viscous solution was stirred
and cooled to ambient temperature. Water (3 L) was added
to the viscous solution and stirred to produce a homogeneous
solution. Dilute aqueous hydrochloric acid was added to
adjust the pH of the reaction mixture from about pH ) 13
to 8, slowly over 1 h. MiBK (3 L) was added and the mixture
heated to 55 °C. The lower aqueous layer was separated off,
whilst the remaining organic layer was washed with warm
water (500 mL). The organic layer was removed and 1 L
distilled under vacuum. The remaining solution was cooled
to 50 °C, and the resulting precipitate, granulated at 50 °C
for 1 h, was filtered, washed with MiBK (1 L), and dried
under vacuum at 50 °C to afford the title compound (400.3
g, 78.4%) as a white solid: mp 157-158 °C. (CDCl3) δ
1.02 (3H, t), 1.30 (3H, t), 2.40 (2H, q), 2.55 (4H, m), 3.03
(2H, q), 3.12 (4H, m), 3.55 (3H, s), 3.85 (2H, m), 4.77 (2H,
m), 5.66 (2H, s), 7.10 (1H, d), 7.21 (1H, m), 7.63 (1H, m),
8.57 (1H, d), 8.62 (1H, d), 8.97 (1H, d). m/z (Found: 583
[M + H]+, 100%. C27H35N8O5S requires 583).
Acknowledgment
We acknowledge the advice and assistance of many Pfizer
colleagues throughout this development work. In particular
we thank Richard Storey for his assistance with the solid-
form work, Steven Galvin and Sandra Mullane for their
helpful suggestions around transfer to production, and
Wiebke Bahker, Rob Savage, Richard Shannon, Angela
Shaw, Zena Smith, and Geoff Walker for their analytical
support.
Received for review April 26, 2002.
OP0200468
772
•
Vol. 6, No. 6, 2002 / Organic Process Research & Development