The chemical development of the commercial route to sildenafil: A case history

Article abstract of DOI:10.1021/op9900683

This paper is a case history of the chemical development of sildenafil which covers various aspects of work in chemical development namely: route selection, scale-up issues, the development of an efficient synthesis with high throughput, process safety, and environmental issues. Interesting chemical points include improved methods of preparing pyrazolo[4,3-d]-pyrimidines and the unusual isolation of an intermediate as its double salt (10). The potential dangers of nitrating pyrazole-5-carboxylic acids which are activated to a decarboxylation reaction are discussed.

Full text of DOI:10.1021/op9900683

Organic Process Research & Development 2000, 4, 17−22
The Chemical Development of the Commercial Route to Sildenafil: A Case
History
David J. Dale, Peter J. Dunn,* Clare Golightly, Michael L. Hughes, Philip C. Levett, Andrew K. Pearce,
Patricia M. Searle, Gordon Ward, and Albert S. Wood
Department of Process Research and DeVelopment, Pfizer Central Research Laboratories,
Sandwich, Kent CT13 9NJ, United Kingdom
Scheme 1. Medicinal chemistry route to sildenafil
Abstract:
This paper is a case history of the chemical development of
sildenafil which covers various aspects of work in chemical
development namely: route selection, scale-up issues, the
development of an efficient synthesis with high throughput,
process safety, and environmental issues. Interesting chemical
points include improved methods of preparing pyrazolo[4,3-d]-
pyrimidines and the unusual isolation of an intermediate as its
double salt (10). The potential dangers of nitrating pyrazole-
5-carboxylic acids which are activated to a decarboxylation
reaction are discussed.
Introduction
Sildenafil is a selective inhibitor of phophodiesterase 5
(PDE5) and is the first agent with this mode of action for
the treatment of male erectile dysfunction (a disease more
commonly known as male impotence). This new drug was
approved for prescription use within the United States and
the European Union during 1998 and has become one of
the fastest-selling drugs of all time. Male erectile dysfunction
is a widespread condition which effects an estimated 30
million men and their partners in the United States.1
tions was perfectly serviceable for the synthesis of develop-
ment quantities. However, this route was suboptimal as a
commercial manufacturing route for the following reasons:
• The route is linear (nine linear steps).
• Potentially toxic materials [such as the sulphonyl
chloride (7)] are in the final bond-forming reaction. Multiple
recrystallisations of the final material were required to get
the usual high-quality material required by the pharmaceuti-
cal industry and to get these potentially toxic impurities to
appropriately low levels.
• The difficulties of scaling up chlorosulphonation reac-
tions are well-known in chemical development due to
competing hydrolysis during the increased quench times on
scale-up (and this was also noted for this project). Having
the chlorosulphonation late in the synthesis meant that these
yield losses occurred from a more expensive intermediate.
• Chlorosulphonating a late-stage, relatively high molec-
ular weight intermediate, leads to larger quench volumes and
hence increases both aqueous waste streams and the envi-
ronmental burden.
This first in class, oral drug works by inhibiting the
phosphodiesterase enzyme (PDE5) which is found in the
human corpus cavernosum. This enzyme regulates the level
of cyclic guanosine monophosphate (cGMP) by its conver-
sion to guanosine monophosphate (GMP). The inhibition of
PDE5 leads to higher levels of cGMP which in turn leads to
improved smooth muscle relaxation, increased blood flow,
and hence an improved erection.2 It is important to note that
sildenafil only assists the body’s natural processes and is
not an aphrodisiac.
The Medicinal Chemistry Route
The medicinal chemistry route3 is outlined in Scheme 1.
This route was used for the synthesis of early toxicity and
clinical batches and with the normal development modifica-
(1) NIH Consensus Development Panel on Impotence. Impotence. JAMA 1993,
270, 83-90.
10.1021/op9900683 CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/10/1999
Vol. 4, No. 1, 2000 / Organic Process Research & Development
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Scheme 2. Strategic commercial route selection
A key finding during the development of the medicinal
chemistry route, which impacted on the programme as a
whole, was the optimisation of the cyclisation reaction to
make the pyrimidinone (6). The medicinal chemistry method
was to cyclise compound 4 with an aqueous alcoholic
solution of sodium hydroxide and hydrogen peroxide.3 A
literature review of alternative cylisation methods revealed
that such reactions had previously only been performed in
moderate yield (30-70%).4 The main side product from the
medicinal chemistry reaction, in the presence or absence of
hydrogen peroxide, was the hydrolysis of the carboxamide
to give the acid (5). By conducting the cyclisation under
anhydrous conditions, KOtBu/tBuOH, the hydrolysis side
product was avoided, and the reaction proceeded in 100%
isolated yield with no impurities detected. This exceptionally
clean reaction led us to consider reordering the steps so that
the clean cyclisation was the final bond-forming reaction.
• Greater convergency.
• The clean cyclisation reaction is now at the end of the
synthesis in the final bond-forming step. The potentially toxic
materials now occur near the start of the synthesis.
• The scale-up and environmental issues associated with
the chlorosulphonation reaction are placed earlier in the
synthesis and are associated with a cheaper, lower molecular
weight material, hence minimising the problems.
Commercial Route Development
(a) Preparation of the Sulphonamide (8). The chloro-
sulphonation of 2-ethoxybenzoic acid was reasonably straight-
forward although it was essential to add thionyl chloride to
ensure the intermediate sulphonic acid was converted to the
sulphonyl chloride (9) (see Figure 1). The sulphonamide was
originally prepared and isolated as an unusual double salt
(10). This had two main disadvantages. First, it was found
that to get the double salt to crystallise, the in-going
sulphonyl chloride needed to be dry. The problems of drying
sulphonyl chlorides on a pilot plant scale are well-known,
and as expected, we obtained a lot of acidic, corrosive fumes
in our pilot plant ovens. The second problem was that the
double salt was very insoluble and was difficult to process
onwards using scaleable methods.
Both problems were solved when on treatment with water,
the double salt spontaneously dissociated to give a new
crystalline form of the free amino acid (8). This procedure
had been run many times before without crystallisation and
shows the importance of having a seed in crystallisation. In
our experience a seed is particularly important with zwitter-
ionic compounds such as (8).
Strategic Commercial Route Selection
A summary of the two routes is outlined in Scheme 2
below.
The flow diagrams in Scheme 2 clearly show that the
strategic advantages of the commercial route were as follows:
(2) Rajfer, J.; Aronson, W. J.; Bush, P. A.; Dorey, F. J.; Ignarro, L. J. Nitric
oxide as a mediator of relaxation of the corpus cavernosum in response to
nonadrenergic, noncholinergic neurotransmission. N. Eng. J. Med. 1992,
326, 90-4. Andersson, K.-E.; Wagner, G. Physiology of the penile erection.
Physiol. ReV. 1995, 75, 191-236. Burnett, A. L. The role of nitric oxide in
the physiology of an erection. Biol. Reprod. 1995, 52, 485-9. Boolell, M.;
Allen, M. J.; Ballard, S. A.; Gepi-Attee, S.; Muirhead, G. J.; Naylor, A.
M.; Osterloh, I. H.; Gingell, J. C. Sildenafil: an orally active type 5 GMP-
specific phosphodiesterase inhibitor of penile erection dysfunction. Int. J.
Impot. Res. 1996, 8, 47-52.
(3) Bell, A. S.; Brown, D.; Terrett, N. K. European Patent 0 463 756 A1, 1992.
(4) Hamilton, H. W.; Ortwine, D. F.; Worth, D. F.; Bristol, J. A. J. Med. Chem.
1987, 30, 91-96.
The process was quickly redesigned to take advantage of
this new finding. The water-wet sulphonyl chloride could
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Figure 3.
• The process was very simple, just mixing ethyl acetate
solutions of the imidazolide (11) and the amine (12) gave
the desired amide (13) which crystallised directly from the
reaction. The main by-product, imidazole, was very soluble
in ethyl acetate and remained in the mother liquors.
• The process was very robust. Ethyl acetate solutions/
suspensions of the amine, imidazolide or the acylation
mixture could be refluxed for several days without any
detriment to the quality of the isolated product.
Figure 1.
On scale-up into the full manufacturing plant some
problems were observed charging CDI (a sticky hygroscopic
reagent) through charging chutes. Additional in-process
controls had to be put in place to ensure a robust and
reproducible manufacturing process.
(c) Cyclisation Reaction. The final bond forming reaction
was performed by heating the amide (13) with 1.2 equiv of
potassium tert-butoxide at reflux for several hours (Figure
3). A simple high throughput isolation was devised, in which
the reaction was diluted with water and acidified with 4 M
hydrochloric acid to the isoelectric point (pH 7.5). Clinical
quality sildenafil was obtained directly from the reaction by
filtration, and hence our strategy of using the clean reaction
at the final step had been reduced to successful practice.
Process Safety
All reactions were evaluated in detail for exothermic
reactions and decompositions, and in our view, the nitration
reaction to give the pyrazole (2) posed the most significant
hazard and is worthy of further discussion. Initial differential
scanning calorimetry (DSC) screening5 showed no cause for
concern with the intermediate (1); however the nitropyrazole
(2) showed two exotherms. The first exotherm was detected
at 130 °C by DSC and evolved 16.2 kJ/mol and was
attributed to the decarboxylation reaction of the acid (2). This
is a well-known reaction which provides synthetic access to
3-nitropyrazoles which are unsubstituted in the 4-position.6
The second much larger exothermic event was detected at
295 °C by DSC and evolved 294 kJ/mol. It was calculated
that at normal chemical reaction concentrations (approx 6
L/kg) the energy in the first exothermic event was not
sufficiently large to raise the reaction temperature to a point
which could trigger the second decomposition under adiabatic
conditions. The nitropyrazole (2) was then examined further
using a Setaram C80 calorimeter and a Phi-Tec adiabatic
calorimeter, and these tests detected the two exotherms at
115 °C and 220 °C. The first exotherm was accompanied
by gas evolution and a corresponding pressure rise, and the
Figure 2.
be used directly in the sulphonamide reaction which was now
performed in water. On completion of the reaction, the
product was isolated by pH adjustment to the isoelectric point
and collection of the precipitated sulphonamide by filtration.
(b) Hydrogenation and Coupling Reaction. The stan-
nous chloride/hydrochloric acid reduction of (3) as used by
medicinal chemistry3 was replaced by a palladium-catalysed
hydrogenation reaction to give the amine (12) (see Figure
2). Activation of the carboxylic acid for the coupling reaction
was initially examined using either thionyl chloride or oxalyl
chloride to make the acid chloride. Eventually we decided
to use a slightly more expensive coupling agent, N,N′-
carbonyldiimidazole (CDI), which had the following advan-
tages and in our view outweighed the small additional cost:
• The nitro reduction, acid activation, and acylation
reactions could all be performed in ethyl acetate as solvent.
All three reactions could thus be telescoped into a single
step.
• The process step had a very low environmental impact.
There was no aqueous waste stream, and the use of ethyl
acetate as a single solvent allowed for easy solvent recovery.
(5) DSC performed at a scanning rate of 10 °C/min.
(6) Papesch V.; Dodson, R. M. J. Org. Chem. 1965, 30, 199.
Vol. 4, No. 1, 2000 / Organic Process Research & Development
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Figure 4. Comparison of organic waste from medicinal chemistry and commercial routes. The cyclisation solvent, tert-butyl alcohol,
ends up in the aqueous waste (for treatment) in both medicinal chemistry and commercial routes.
second exotherm rapidly became self-sustaining and violent,
causing large self-heats and pressure increases.
quench reaction. However, under these conditions the
potential adiabatic temperature rise was still 50-92 °C,
which we felt was still unacceptably close to the decomposi-
tion start point. Reducing the reaction temperature would
lower this potential rise but would increase the level of
accumulated reactants and in our opinion did not add to the
safety margin.
To introduce a greater margin of safety in traditional pilot
plant equipment and to avoid any consequences of a valve
jamming open, the decision was taken to only charge one-
third of the nitrating mixture to the header at any one time.
A HPLC analysis was then performed to ensure that the
appropriate degree of reaction completion had occurred
before charging the next portion of the nitrating acid mixture
to the header. Under these conditions the maximum adiabatic
temperature rise was calculated to be 21 °C. Obviously more
sophisticated engineering solutions8 would provide an even
greater margin of safety.
It was also discovered that in highly acidic media (i.e.,
the reaction mixture) the onset temperature for the start of
exothermic decarboxylation was reduced to around 100 °C,
and hence a process needed to be devised in which there
was no possibility of this reaction temperature being reached.
Hence, our major concerns in scaling up this reaction were
the following:
1. That if the decarboxylation reaction temperature was
reached, the large volume of carbon dioxide produced could
lead to excessive frothing or an unacceptable pressure
increase.
2. That uncontrolled reaction could lead to a catastrophic
runaway conditions.
The medicinal chemistry procedure involved adding solid
pyrazole (1) to a mixture of fuming nitric acid and oleum at
50 °C. This procedure involved the liberation of 249 kJ/mol
of heat, and it was calculated that under adiabatic conditions
this reaction (with a dilution of 6 L/kg) had the potential to
raise the temperature from 50 to 127 °C, well above the
decomposition reaction temperature.
It was decided to break the procedure down into three
parts in order to minimise the available energy. First, the
pyrazole (1) was dissolved in concentrated sulphuric acid,
eliminating 67 kJ/mol7 of energy from the reaction. Next,
the fuming nitric and concentrated sulphuric acids were
mixed, eliminating 44 kJ/mol7 from the reaction. We wanted
to run the reaction at around 6 L/kg so as to keep throughput
high and minimise the aqueous environmental waste in the
Environmental Assessment
The volume and the number and nature of solvents
required by the medicinal chemistry route and by the
commercial route to produce 1000 kg of drug substance are
compared strikingly in the pie-charts in Figure 4. In addition
the total aqueous volume was reduced by a factor of 5 by
switching to the commercial route.
A further advantage of the commercial route is that the
solvents are used as single organic solvents, which simplifies
solvent recovery.
(8) am Ende, D. J.; Clifford, P. J.; Northrup, D. L. Thermochim. Acta 1996,
289, 143-154.
(7) Energy based upon 1 mol of the intermedate (1).
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Conclusion
The commercial route described in this paper contains
all of the desired attributes required in chemical development,
namely:
dried in vacuo to give the title product (36.08 g, 90.6%). A
small reference sample of the purified product was obtained
by crystallisation from hexane/toluene: mp 115-116 °C.
Found C, 41.02; H, 3.27. C9H9ClO5S requires C, 40.84; H,
3.43%. H NMR (CDCl3) δ ) 1.64 (3H, t), 4.45 (2H, q),
7.26 (1H, d), 8.20 (1H, dd), 8.80 (1H, d).
1
• a safe, robust route
• a convergent synthesis
• a high yielding process [75.8% overall from pyrazole
(2) compared with the medicinal chemistry yield of 7.5%3]
• a high throughput in production plant
• an exceptionally low environmental impact.
2-Ethoxy-5-(4-methyl-1-piperazinesulphonyl)benzoic
Acid (Double Salt) (10). A solution of 5-chlorosulphonyl-
2-ethoxybenzoic acid (9) (50 g) in acetone (150 mL) was
added dropwise to a solution of triethylamine (28.9 mL) and
N-methylpiperazine (20.81 g) whilst keeping the temperature
below 20 °C. A white crystalline product formed during the
addition. After the mixture stirred for 1.5 h, the white solid
was collected by filtration, washed with acetone, and dried
in vacuo (78.97 g, 89.7%): mp 166-169 °C. Found C,
51.33; H, 8.14; N, 9.06; Cl, 8.02. C14H20N2O5S.C6H15N‚HCl
Experimental Section
Proton NMR data were recorded on a Varian Unity 300
spectrometer operating at 300 MHz. Microanalytical data
were performed by Exeter Analytical UK Ltd. Melting points
were determined on a Buchi melting point apparatus. The
experimental procedures below represent the reactions when
first discovered and may not be the final procedures selected
for scale-up into pilot plant trials.
1-Methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic
Acid (2). 1-Methyl-3-propyl-1H-pyrazole-5-carboxylic acid
(1)3 (1.59 kg, 9.45 mol) dissolved in concentrated sulphuric
acid (6.36L) was heated to 50 °C and treated with a mixture
of fuming nitric acid (90%, 0.55 L) dissolved in concentrated
sulphuric acid (1.35 L). The addition was made over at least
2 h keeping the reaction temperature between 50 and 55 °C.
On completion of the addition the reaction was stirred for 8
h at 50 °C, cooled to room temperature, and then carefully
added to cold water (34 L, 4 °C) over 1 h, keeping the
temperature below 25 °C. The precipitated title compound
was granulated for 2 h, collected by filtration, and then dried
in vacuo at 50 °C to give a pale yellow solid (1.93 kg,
96%): mp 125-127 °C (lit.3 124-127 °C). 1H NMR
(CDCl3) δ ) 1.05 (3H, t), 1.74 (2H, hextet), 2.91(2H, t),
4.20 (3H, s), 9.35 [1H, s(br)].
1-Methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxam-
ide (3). The carboxylic acid (2) (1 kg, 4.69mol) was slurried
in toluene (5 L) and a catalytic quantity of dimethylforma-
mide (37 mL) was added. The mixture was heated to 50 °C
and thionyl chloride (0.544 L, 7.5 mol) added over 10 min.
On completion of the addition the reaction was stirred and
heated for 55-60 °C for 6 h. The mixture was distilled under
vacuum (vessel temperature 55 to 65 °C) until 0.5 L of
solvent had been removed. The mixture was cooled to 20
°C and cold (5 °C) concentrated ammonia solution (6 L)
added over 100 min. The precipitated product was granulated,
collected by filtration, washed with water (2 × 2 L), and
dried at 50 °C to give an off white solid (0.92 kg, 92.3%):
mp 140-42 °C (lit.3 141-143 °C). 1H NMR (CDCl3) δ 1.02
(3H, t), 1.74 (2H, hextet), 2.90 (2H, t), 4.07 (3H, s), 6.13
[1H, s (br)], 7.52 [1H, s(br)].
5-Chlorosulphonyl-2-ethoxybenzoic Acid (9). Molten
2-ethoxybenzoic acid (25 g) was added to a mixture of
thionyl chloride (11 mL) and chlorosulphonic acid (41.3 mL)
whilst keeping the temperature below 25 °C. The resulting
mixture was stirred overnight at room temperature before
being quenched into a mixture of ice (270 g) and water (60
mL). An off-white precipitate formed which was stirred for
60 min, collected by filtration and washed with water and
1
requires C, 51.54; H, 7.79; N, 9.02; Cl, 7.61%. H NMR
[(CD3)2SO] δ ) 1.17 (9H, t), 1.32 (3H, t), 2.15 (3H, s), 2.47
[6H, s (br)], 2.86 [2H, s(br)], 3.02 (6H, q), 4.18 (2H, q),
7.32 (1H, d), 7.78 (1H, dd), 7.85 (1H, d).
2-Ethoxy-5-(4-methyl-1-piperazinesulphonyl)benzoic
Acid(8). Method 1. The double salt (10) (30 g) was stirred
in water (120 mL) to give an almost clear solution. Rapid
crystallisation occurred, and after 2 h the solid was collected
by filtration, washed with water, and dried in vacuo to give
1
a white solid (14.61 g, 69.1%). H NMR [(CD3)2SO] δ )
1.31 (3H, t), 2.12 (3H, s), 2.34 [4H, s (br)], 2.84 [4H, s (br)],
4.20 (2H, q), 7.32(1H, d), 7.80 (1H, dd), 7.86(1H, s).
A small reference sample was obtained by recrystallisation
from aqueous alcohol, mp 201 °C. Found C, 51.09; H, 6.16;
N, 8.43. C14H20N2O5S requires C, 51.21; H, 6.14; N, 8.53%.
2-Ethoxy-5-(4-methyl-1-piperazinesulphonyl)benzoic
Acid (8). Method 2. The sulphonyl chloride (9) (34.4 g)
(dried or used directly as a wet cake) was added to 124 mL
of water and the resulting suspension cooled to 10 °C.
N-methylpiperazine (33.6 mL) was added, keeping the
temperature below 20 °C. The resulting solution was cooled
to 10 °C. After 5 min the title compound started to crystallise.
The solid was collected after 2 h and washed with ice water,
and the resulting solid was dried in vacuo (36.7 g, 86%).
Part of this material (15 g) was purified by heating in
refluxing acetone for 1 h. The suspension was cooled to room
temperature, and the crystalline solid was collected by
filtration and dried in vacuo to give a white solid (11.7 g):
1
mp 198-199 °C. H NMR [(CD3)2SO] in agreement with
that reported above.
4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxam-
ide (12). The nitropyrazole3 (3) (237.7 g, 1.12 mol) was
suspended in ethyl acetate (2.02 L), and 47.5 g of 5%
palladium on carbon added. The resulting mixture was
hydrogenated at 50 °C and 50 psi for 4 h when the uptake
of hydrogen was complete. The reaction was cooled, and
the catalyst was filtered off and washed with ethyl acetate
to give an ethyl acetate solution of the title compound which
was used directly in the next step.
4-[2-Ethoxy-5-(4-methyl-1-piperazinylsulphonyl)ben-
zamido]-1-methyl-3-propyl-1H-pyrazole-5-carboxamide
(13). The benzoic acid (8) (408.6 g, 1.24 mol) was suspended
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in ethyl acetate (1.5 L). N,N′-Carbonyldiimidazole (210.8
g, 1.30 mol) was added and was washed into the vessel with
further ethyl acetate (1.36 L). The mixture was heated to 55
°C for 30 min and then for 2 h at reflux before being allowed
to cool to 27 °C. A solution of aminopyrazole (12) in ethyl
acetate (as prepared above, total solution weight 2.185 kg,
1.12 mol based upon an assumed 100% yield in the
hydrogenation) was added and the reaction stirred for 70 h
at room temperature. The title compound crystallised and
was collected by filtration and dried in a vacuum (425 g):
mp. 204-205.5 °C. The filtrates were concentrated to a low
volume, and a second crop of pure title compound (70 g)
was collected by filtration and dried in vacuo: yield as two
crops ) 90%. A small reference sample was obtained by
recrystallisation from methanol/water mp 206-208 °C.
Found C, 53.65; H, 6.54; N, 17.07. C22H32N6O5S requires
being cooled 62.5 mL of water was added and the resulting
solution filtered into a speck-free flask. A speck-free solution
of concentrated HCl (2.3 mL) in water (60 mL) was prepared
and added dropwise to the mixture over 2 h. The precipitated
product was granulated at pH 7 and 10 °C for a further hour.
The title compound was collected by filtration, washed with
water, and dried in vacuo to give a white solid, (10.70 g,
90.2%): mp 189-190 °C (lit.3 187-189 °C). Analysis of
the material by HPLC and quantitative TLC indicated that
clinical quality material had been obtained directly from the
reaction. Found C, 55.55; H, 6.34; N, 17.69. C22H30N6O4S
1
requires C, 55.68; H, 6.37; N, 17.71%. H NMR [(CD3)2-
SO] δ ) 0.94 (3H, t), 1.32 (3H, t), 1.73 (2H, hextet), 2.15
(3H, s), 2.35 [4H, s(br)], 2.76 (2H, t), 2.88 [4H, s(br)], 4.14
(3H, s), 4.18 (2H, q), 7.36 (1H, d), 7.80 (2H, m) 12.16 [1H,
s(br)].
1
C, 53.64; H, 6.55; N, 17.06%. H NMR (CDCl3) δ ) 0.96
(3H, t), 1.58 (3H, t), 1.66 (2H, m), 2.27 (3H, s), 2.43 (2H,
t), 3.05 [4H, s (br)], 4.05 (3H, s), 4.40 (2H, q), 5.61 [1H, s
(br)], 7.61 (1H, d), 7.65 [1H, s (br)], 7.90 (1H, dd), 8.62
(1H, d), 9.25 [1H, s(br)].
1-[4-Ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-
1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphoyl]-4-me-
thylpiperazine (Sildenafil). The pyrazolecarboxamide (13)
(12.32 g, 0.025 mol) was slurried in tert-butyl alcohol (61
mL) and potassium tert-butoxide (3.37 g) added. The
resulting mixture was heated at reflux for 8 h. On the mixture
Acknowledgment
The authors acknowledge many Pfizer colleagues for their
support in this project. In particular we would like to thank
Jon Beaman, Steve Belsey, Gina Coghlan, Jeff Duke, and
Darren Gore who provided the majority of the analytical
support.
Received for review August 3, 1999.
OP9900683
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