Process improvements in the production of a novel non-xanthine adenosine A1 receptor antagonist. A "one-pot" horner-emmons isomerization reaction

Article abstract of DOI:10.1021/op990066i

Pilot plant scale synthesis of 2-[3-(2-phenylpyrazolo[l,5-a]-pyridin-3-yl-l(6H)-pyridazin-6-one)-l-cyclohexen- l-yl] acetic acid (FR166124) is described. The process involved efficient isomerization of regioisomers produced in a Horner-Emmons reaction and employed ester exchange and hydrolysis with NaOH in MeOH. Challenges encountered in the final purification stage to afford high quality drug substance in pure crystalline form are also described. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a straightforward, practical, and cost-effective synthesis of FR166124. These methods were successfully scaled up in a pilot plant to give bulk drug suitable for pharmacological and toxicological evaluation.

Full text of DOI:10.1021/op990066i

Organic Process Research & Development 1999, 3, 394−399
Process Improvements in the Production of a Novel Non-Xanthine Adenosine A
1
Receptor Antagonist. A “ One-Pot” Horner-Emmons Isomerization Reaction
Atsuhiko Zanka,*,† Norihumi Itoh,† and Satoru Kuroda‡
Technological DeVelopment Laboratories, Fujisawa Pharmaceutical Co. Ltd., 2-1-6 Kashima, Yodogawa-ku,
Osaka, 532-8514, Japan, and Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd.,
2-1-6 Kashima, Yodogawa-ku, Osaka, 532-8514, Japan
Abstract:
Pilot plant scale synthesis of 2-[3-(2-phenylpyrazolo[1,5-a]-
pyridin-3-yl-1(6H)-pyridazin-6-one)-1-cyclohexen-1-yl] acetic
acid (FR166124) is described. The process involved efficient
isomerization of regioisomers produced in a Horner-Emmons
reaction and employed ester exchange and hydrolysis with
NaOH in MeOH. Challenges encountered in the final purifica-
tion stage to afford high quality drug substance in pure
crystalline form are also described. Process improvements and
optimization of each step permitted elimination of column
chromatography, resulting in a straightforward, practical, and
cost-effective synthesis of FR166124. These methods were
successfully scaled up in a pilot plant to give bulk drug suitable
for pharmacological and toxicological evaluation.
Figure 1. Structure of adenosine A1 receptor antagonists.
temperature conditions in a Swern oxidation step, (2) using
excess amounts of NaH in a Horner-Emmons reaction, (3)
column chromatographic separation of 6d from the isomer
6b, (4) selective preparation of 2d in the desired crystalline
form (B-form). This paper describes findings during endeav-
ours that resulted in a reliable and rugged process suitable
for a large scale synthesis.
Introduction
In previous papers,1 we described a pilot scale synthesis
of the selective adenosine Al receptor antagonist, FK838 (1)
(3-[2-phenylpyrazolo[1,5-a]pyridin-3-yl]-1(6H)-pyridazine-
6-one butyric acid, Figure 1). This drug has characteristic
features related to both diuretic and anti-hypertensive effects.2
Whilst the development project of 1 was progressing, intense
efforts centered on searching for new types of pyrazolo[1,5-
a]pyridine adenosine Al receptor antagonist, led to the
discovery of FR166124 (2d) as a more potent and versatile
second-generation candidate.3 To support later-stage pre-
clinical development we were charged with efficient prepara-
tion of 2d on a large scale.
Results and Discussion
Pyridazone (3) was prepared from 4-phenyl-3-butyn-2-
one and pyridine N-imine by the methods described in our
previous paper.1b Ketone (5a) was obtained on a laboratory
scale by alkylation of 3 with cyclohexene oxide in a mixture
of toluene and water under reflux for 16 h, followed by
oxidation. However, the long reaction for the alkylation time
was an important issue for a large-scale synthesis. During
further investigations it was found that the reaction rate was
significantly affected by solvent volume, regardless of the
presence of a phase-transfer catalyst. Thus, the reaction was
complete in 6 h when solvent volumes were reduced by half.
At the end of the reaction, water was added to a reaction
mixture to dissolve a precipitated trace amount of sodium
salt of unreacted pyridazone (3) in the aqueous layer, and
the mixture cooled to 0 °C. The major by-product 4b
remained dissolved in the organic layer (Scheme 2). Thus,
these impurities were cleanly removed in mother liquor (3
in the aqueous layer and 4b in the organic layer) by filtration,
leading to alcohol (4a) in excellent quality. For the subse-
quent oxidation step, ketone (5a) was effectively prepared
by Swern oxidation on a laboratory scale, but very low-
temperature conditions (∼ -60 °C) were not acceptable for
a pilot plant synthesis. As an alternative and improved
oxidation system, we examined the Parikh-Doering reac-
Recently, Kuroda et al. reported a novel synthesis of 2d
using a sequential Horner-Emmons/isomerization reaction
(Scheme 1).4 Whilst efficient enough to afford the material
in sufficient quantities for early preclinical evaluation, the
reported methods had a number of limitations that became
apparent only when conducting the process on a large scale.
Significant scale-up issues were as follows: (1) low-
† Technological Development Laboratories, Fujisawa Pharmaceutical Co. Ltd.
‡ Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co.
Ltd.
(1) (a) Zanka, A. Org. Process Res. DeV. 1998, 2, 60. (b) Zanka, A.; Hashimoto,
N.; Uematsu, R.; Okamoto, T. Org. Process Res. DeV. 1998, 2, 320.
(2) (a) Horiai, H.; Kohno, Y.; Minoura, H.; Takeda, M.; Nakano, K.; Hanaoka,
K.; Kusunoki, T.; Otsuka, M.; Shimomura, K. Can. J. Physiol. Pharmacol.
1994, 72, P17.3.9. (b) Takeda, M.; Kohno, Y.; Esumi, K.; Horiai, H.;
Ohtsuka, M.; Shimomura, K.; Imai, M. Jpn. J. Pharmacol. 1994, 64, O-376.
(3) Kuroda, S.; Akahane, A.; Itani, H.; Nishimura, S.; Durkin, K.; Kinoshita,
T.; Tenda, Y.; Sakane, K. Bioorg. Med. Chem. Lett. 1999, 9, 1979.
(4) Kuroda, S.; Akahane, A.; Itani, H.; Nishimura, S.; Durkin, K.; Kinoshita,
T.; Nakanishi, I.; Sakane, K. Tetrahedron 1999, 55, 10351.
394
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10.1021/op990066i CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry
Published on Web 10/13/1999

Scheme 1. Laboratory scale route to 2da
Scheme 2. Synthetic route to 5a
a Reagents and conditions: (1) cyclohexene oxide, NaOH/PhMe-H2O, PTC;
(2) Swern oxidation; (3) (EtO)2POCH2CO2 Bu, NaH/toluene; (4) TFA/CH2Cl2.
nates, followed by isomerization to 6d were investigated.
First, we examined triethyl phosphonoacetate since this
reagent is inexpensive and readily available in large quanti-
ties; however, the reaction furnished a mixture of hydrolyzed
materials (2a-d, Scheme 3).
t
tion.5 Reaction proceeded smoothly, although two minor by-
products were obtained which were presumed to be sul-
fonated material (5b) and methylthiomethyl ether (MTM
ether, 5c). Further studies indicated that formation of 5b was
influenced by reaction temperature and the molar ratio of
pyridine:SO3 and Et3N. Whilst formation of 5c was controlled
in the presence of excess Et3N, a large excess led to a
reduction in reaction activity. Thus, the optimized reaction
conditions were identified as pyridine:SO3 complex (2 molar
equiv) and Et3N (4 molar equiv) at 3-8 °C in CH2Cl2 as
solvent. Other methods such as Ac2O-DMSO6 produced
significant amounts of 5c.
On the other hand, Kuroda et al. reported an efficient
synthesis of 6d applying tert-butyl diethylphosphonoacetate.
The mechanism of isomerization was clarified in the report,
and the authors emphasized that the excess use of both tert-
butyl diethylphosphonoacetate and NaH as a base in toluene
was crucial for efficient isomerization.4 Despite these
discoveries, there still existed obstacles which had to be
removed before a fully efficient chemical process was
realized. For example, the long reaction time (24 h) was
problematic, and furthermore, gummy by-products were
present in the reaction mixture, which contained unreacted
sodium hydride. After consideration of the pyrophoric
hazards associated with sodium hydride, the base employed
was changed. First, a mixture of granulated sodium hydroxide
and powdered potassium carbonate was examined as an
With an efficient preparation of the ketone (5a) in hand
and the material available in large quantities, subsequent
Horner-Emmons reaction of the ketone (5a) with phospho-
(5) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
(6) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416.
Vol. 3, No. 6, 1999 / Organic Process Research & Development
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395

Scheme 3. Horner-Emmons reaction of 5a
Table 2. Regioselective isomerization and hydrolysis of
6a-da
a In the presence of 3 equiv of NaOH at 55 °C. b Ratio determined by HPLC.
c ‘Scale-down experiment’. d Pilot plant scale synthesis.
Scheme 4. Isomerization and hydrolysis of a mixture of 6b
and 6d to FR166124, 2d
Table 1. Horner-Emmons reaction of ketone (5a) and
tert-butyl diethylphosphonoacetatea
product ratiob
temp time
entry base (equiv) solvent (°C) (h) 5a 2c 6a 6b 6c 6d
1
2
NaH (1.5)
NaOH (2.0), DMSO
K2CO3 (2.0)
NaOH (2.0), DME
K2CO3 (2.0)
NaOH (2.5), DME
K2CO3 (2.5)
NaOH (2.5), DME
K2CO3 (2.5)
NaOH (4.0), DME
K2CO3 (4.0)
NaOH (4.0), DME
K2CO3 (4.0)
toluene 25
24
2
0
0
0
0
20 18
0
9
62
76
was selectively obtained (entry 5). These unexpected results
indicated that the presence of excess molar amounts of
granulated NaOH and powdered K2CO3 are crucial for the
isomerization. Whilst using an excess amount of base
enhanced the isomerization rate (entry 3, 4, 6), a very large
excess increased the saponified materials (2a-d, entry 6,
7). Thus, optimized reaction conditions were identified as
in entry 5. Small amounts of hydrolyzed by-products (2a-
d) were not of serious concern since they were cleanly
removed in the extraction.
Next, we investigated a practical purification of 6d. On a
scale of less than 100 g, 6d was separated from the mixture
using column chromatography, however, the required amount
of silica gel was large and thus precluded implementation
of this approach on a large scale. Despite further efforts with
a goal of selective “one-pot” preparation of 6d, the ratio of
6b and 6d was not influenced to any significant degree by
changing reaction conditions. Control experiments showed
that isolated 6b afforded an approximately 1:8 mixture of
6b and 6d with trace amounts of 6c when exposed to the
reaction conditions. These results indicated that 6b and 6d
might be in an equilibrium state (Scheme 3).
50
25
25
25
25
25
25
25
25
7
8
3
4
5
6
7
2
2
5
2
5
5
8
8
0
0
0
0
0
0
0
0
0
3
47 15
33 13
0
0
1
0
0
1
1
2
38
50
81
63
78
58
78
78
6
0
12
15 15
11
25 15
8
10
1
1
8d NaOH (2.5), DME
K2CO3 (2.5)
9d NaOH (2.5), DME
K2CO3 (2.5)
3
6
3
12
8
10e NaOH (2.5), DME
K2CO3 (2.5)
9
a 1.5 equiv of tert-butyl diethylphosphonoacetate. b Product ratio was deter-
mined by quantitative HPLC using authentic samples.4 c A mixture of 2a, 2b,
2c, and 2d. d ‘Scale-down experiment’. e Pilot plant scale synthesis.
alternative base. Interestingly, whilst the reaction conducted
in DMSO as solvent afforded a mixture of four kinds of
isomers (6a-d, Table 1, entry 2), 6c was not present in DME
as solvent (entry 3). Furthermore, after optimization of the
amount of base and reaction time, a mixture of 6b and 6d
396
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Chart 1. X-ray powder diffraction analysis of A-form 2d
During further studies, it was found that the esters (6a-
d) were completely hydrolyzed to acids (2a-d) under
elevated temperature conditions (55 °C) in the presence of
excess granulated NaOH (3 equiv), as shown in Table 2.
Furthermore, when the reaction was conducted in MeOH as
solvent, 2d was selectively obtained (entry 2). To understand
the mechanism of this unexpected isomerization, 6b and a
mixture of 6b and 6d were exposed to MeONa in MeOH to
afford a mixture of 25% of 2d and 75% of the precursor
methyl ester of 2d in both cases. Control experiments
indicated that no isomerization occurred when exposing
hydrolyzed materials (2b or a mixture of 2b and 2d) to these
conditions. Thus, isomerization presumably occurs after ester
moiety exchange from tert-butyl to methyl, followed by
hydrolysis to give selectively 2d (Scheme 4).
Although a practical and efficient preparative method of
2d was established, this process is promising only when the
isomerization is much faster than hydrolysis of the precursor
esters. Therefore, we had to investigate the reproducibility
for a proposed pilot plant scale trial. In effect, reactions can
be influenced by impeller shape or agitation speed, and poor
stirring efficacy of pilot plant vessels sometimes leads to
unexpected results. These results are sometimes effectively
foreseen by a “scale-down experiment” which is conducted
using the same shape equipment as in the pilot plant under
conditions where power consumption per unit volume is
constant.7 As shown in Table 1, the scale-down experiment
indicated that small amounts of isomer 6a may remain
unisomerised when the reaction was conducted in a pilot
plant (Table 1, entry 8, 9). However, this was not a serious
concern, since this reaction system proved to be highly
successful for direct and selective preparation of 2d, even
from a mixture of 6a, 6b, and 6d (Table 2, entry 3, 4).
Final purification of crude 2d required significant elabora-
tion to realize suitable quality material. As shown in Chart
1 and Chart 2, two kinds of crystalline forms of 2d [A-form
(metastable form), B-form (stable form)] were possible, and
pure and selective preparation of B-form crystals was
required.
During early investigations, it was found that B-form 2d
was selectively precipitated from a high content (>66%) of
ethanol in water; however, this method involved considerable
loss in the mother liquor (Table 3, entry 4), and with a large
amount of 2b (0.75%) or residual ethanol (0.5%) in the
purified 2d (entry 3, 4). On the other hand, 2d was more
efficiently purified by recrystallization from 50% ethanol in
water; however, the obtained material was a mixture of A-
and B-forms (entry 1, 2). In general, crystalline form is
effectively controlled in many cases by addition of a seed
possessing the desired crystalline form;8 however, the
required amount for selective precipitation of the B-form of
2d was large and prevented implementation on a large scale.
Extensive studies provided the following practical solution
to these problems. Crude 2d was dissolved in the presence
of NaOH in a mixture of ethanol and purified water. The
resulting solution was filtered to remove solid impurities,
and the solution was acidified with hydrochloric acid (to give
an ethanol concentration of 66%), leading to selective
crystallization of 2d in the desired form (B). The resulting
slurry was heated to reflux and then cooled and further
diluted with ethanol and water to adjust the conditions to
that for entry 2 (50% ethanol in water), allowing efficient
and selective removal of isomer 2b in the mother liquor. At
this stage, B-form 2d, which had precipitated in the previous
step, acted as a seed, and avoided crystallization of the
A-form 2d. To improve filtration, the mixture was again
refluxed, followed by cooling to 23-27 °C over 1 h and
then to 0 °C. The precipitate was collected and dried under
reduced pressure to afford pure B-form material in high
chemical purity, suitable for pharmacological and toxicologi-
cal evaluation.
(8) Nagata, S. MIXING principles and applications; Wiley: New York, 1975
p 1-83.
(7) Sudo, S.; Sato, K.; Harano, Y. J. Chem. Eng. Japan 1991, 24, 237.
Vol. 3, No. 6, 1999 / Organic Process Research & Development
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397

Chart 2. X-ray powder diffraction analysis of B-form 2d
AC200P (1H, 200 MHz). Chemical shifts were given in parts
per million, and tetramethylsilane was used as the internal
standard. Mass spectra were measured on a Hitachi model
M-80 mass spectrometer using EI for ionization. Elemental
analyses were carried out on a Perkin-Elmer 2400 CHN
Elemental Analyzer. HPLC analyses were performed using
a YMC GEL ODS 120 Å S-5 column and an acetonitrile/
water or methanol/water mobile phase and detection at 254
nm. Purity of each obtained product was determined by
comparison with purified authentic samples using quantitative
HPLC. Melting points were measured on a Thomas-Hoover
apparatus and are uncorrected. X-ray powder diffraction
analyses were performed using a Philips MPD 1880 X-ray
Powder Diffraction System.
Table 3. Recrystallization of crude 2d from aqueous
ethanola
residual
EtOH
(%)
solvent
(mL)
yield
(%)
2b
crystalline
form(s)c
entry
(%)b
1
2
3
4
50% EtOH
(50)
50% EtOH
(200)
66% EtOH
(75)
80% EtOH
(125)
97.0
91.0
89.4
64.4
0.62
0.24
0.75
0.19
0.1
0.1
0.2
0.5
a mixture
of A and B
a mixture
of A and B
B
B
a Crude 2d (mixture of A- and B-forms) was contaminated with 1.1% of 2b
recrystallization was conducted on a 5 g scale of crude 2d. b Quantity of 2b
contaminated in purified 2d was determined by quantitative HPLC. c Crystalline
form was determined by X-ray analysis.
3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl-1(6H)-pyridazin-
6-one)-1-cyclohexan-2-ol (4a). To a solution of pyridazone
(3) (34.0 kg, 118 mol) and NaOH (4.72 kg, 118 mol) in a
mixture of water (170 L) and toluene (170 L) was added
cyclohexene oxide (34.7 kg, 354 mol). After completion of
the addition, the resulting mixture was refluxed for 6 h and
then cooled to 76 °C. To this solution was added water (170
L) and cooled to 0 °C. The precipitate was filtered off,
washed with water (68 L) and toluene (68 L), and dried under
reduced pressure to afford 4a (37.6 kg, 83% yield) of 95%
Conclusions
In this paper we have described process development of
the novel non-xanthine adenosine Al receptor antagonist
FR166124, 2d. Horner-Emmons reaction using tert-butyl
diethylphosphonoacetate, followed by ester moiety exchange
and hydrolysis in the presence of granulated NaOH in MeOH
as solvent, resulted in a successful selective isomerization.
The drug substance of pure crystalline form and high
chemical purity was obtained in excellent yield by controlling
the recrystallization conditions. Process improvement efforts
for each step, focusing on safe and optimized reaction
conditions resulted in a chromatography-free, inexpensive,
and practical synthesis of 2d applicable to a pilot plant scale.
1
chemical purity as a yellowish solid: mp 226-228 °C; H
NMR (200 MHz, CDCl3) δ 1.32-1.62 (m, 3H), 1.59 (d, 3H,
J ) 12.2 Hz), 2.21 (d, 1H, J ) 12.1 Hz), 2.67 (d, 1H, J )
6.9 Hz), 3.97 (t, 1H, J ) 4.0 Hz), 4.94 (td, 1H, J ) 10.8,
4.3 Hz), 6.78 (d, 1H, J ) 9.6 Hz), 6.90 (td, 1H, J ) 6.9, 1.3
Hz), 7.02 (d, 1H, J ) 9.6 Hz), 7.44 (t, 1H, J ) 3.7 Hz),
7.56-7.63 (m, 2H), 7.94 (d, 1H, J ) 8.9 Hz), 8.53 (d, 1H,
J ) 6.9 Hz); IR (KBr) 2928, 2854, 1652, 1631, 1586, 1522
cm-1; MS (EI) m/z 387 (M + H)+, 369, 289. Anal. Calcd
for C23H22N4O2: C, 71.48; H, 5.74; N,14.50. Found: C,
71.12; H, 5.75; N,14.37.
Experimental Section
General Procedures. Pure grade tert-butyl diethylphospho-
noacetate is available from Jyohoku Chemical Co. Cyclo-
hexene oxide was from Toray Industries, Inc. Pyridine sulfur
trioxide complex was from Saeurefabrik Schweizerhall Co.
All other chemicals were obtained from the usual commercial
suppliers. IR spectra were recorded on a HORIBA FT-210
spectrometer. NMR spectra were measured on a Brucker
3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl-1(6H)-pyridazin-
6-one)-1-cyclohexan-2-one (5a). To a solution of the alcohol
(4a) (37.6 kg, 97.3 mol) and Et3N (39.5 kg, 390 mol) in a
398
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Vol. 3, No. 6, 1999 / Organic Process Research & Development

mixture of CH2Cl2 (188L) and DMSO (376 L) was added
pyridine sulfur trioxide complex (31.0 kg, 195 mol) at 3-8
°C, and stirring was continued at ambient temperature for 4
h. Methylene chloride (752 L) and water (942 L) were added
to an extraction vessel, and to this mixture was added the
reaction mixture. The separated organic layer was concen-
trated to ∼376 L under reduced pressure. To this residual
organic solution was added ethanol (376 L) and then re-
concentrated to ∼376 L under reduced pressure. To obtain
5a in high quality and facilitate the filtration, the precipitate
was dissolved at 82 °C and the solution cooled to 50 °C
followed by addition of purified 5a (38g). After the
precipitation of 5a, stirring was continued at ambient
temperature for 30 min and cooled to 0 °C for 2 h. The
precipitated 5a was filtered off, washed with cooled (<10
°C) ethanol (76 L), and dried under reduced pressure to
afford 5a (29.0 kg, 78% yield) of 99% chemical purity as a
1.8-2.0 with 18% hydrochloric acid (∼21 L). The organic
layer was separated and washed with saturated sodium
bicarbonate in purified water (135 L). The separated organic
layer was concentrated to ∼150 L under reduced pressure,
followed by addition of ethyl acetate (180 L) and then
concentrated again to ∼150 L. To obtain 2d in high quality,
the precipitate was dissolved by refluxing and then cooled
to 0 °C. After the precipitation of 2d, stirring was continued
at ambient temperature for over 1 h. The precipitated 2d was
filtered off, washed with cooled (<10 °C) ethyl acetate (30
L), and dried under reduced pressure to afford crude 2d (12.7
kg, 79% yield) of 98% chemical purity as a white solid. The
crude 2d (12.7 kg, 29.8 mol) was added to a solution of
NaOH (1.25 kg, 31.3 mol) in a mixture of purified water
(58 L) and ethanol (130 L) and purified by passing through
a 0.6 µm filter. The filtrate was adjusted to pH ) 3.9-4.2
by 30% hydrochloric acid (∼6.5 L) at 25 °C. This mixture
was then heated to reflux for 30 min. During this procedure
the precipitate was dissolved at 65 °C and again precipitated
at ∼80 °C. The mixture was then cooled to 65 °C, followed
by addition of purified water (195 L) and ethanol (130 L) at
ambient temperature, and then refluxed for 30 min. The slurry
was stirred at 25 °C for 1 h and cooled to 0 °C. Stirring was
continued at ambient temperature overnight, and the pre-
cipitate was filtered off, washed with cooled (<10 °C)
ethanol (13 L) and purified water (13 L), and dried under
reduced pressure to afford purified 2d (12.2 kg, 96% yield)
of 99% chemical purity as a white solid: mp 147-148 °C;
1H NMR (200 MHz, CDCl3) δ 1.85-1.92 (m, 4H), 2.32-
2.52 (m, 4H), 2.92 (d, 1H, J ) 14.4 Hz), 3.14 (d, 1H, J )
14.1 Hz), 6.90 (d, 1H, J ) 9.7 Hz), 6.92 (t, 1H, J ) 7.0
Hz), 7.13 (d, 1H, J ) 9.7 Hz), 7.35 (td, 1H, J ) 6.8, 1.0
Hz), 7.47 (t, 3H, J ) 2.9 Hz), 7.55-7.60 (m, 2H), 7.93 (dd,
1H, J ) 7.8, 1.1 Hz), 8.26 (dd, 1H, J ) 6.9, 1.0 Hz); IR
(KBr) 2938, 1725, 1634, 1580, 1532, 1495 cm-1; MS (EI)
m/z 427 (M + H)+, 409, 361, 289. Anal. Calcd for
C25H22N4O3: C, 70.41; H,5.20; N, 13.14. Found: C, 70.57;
H, 5.27; N, 13.11.
1
yellowish solid: mp 182-183 °C; H NMR (200 MHz,
CDCl3) δ 1.72-2.26 (m, 4H), 2.34-2.70 (m, 4H), 5.79 (dd,
1H, J ) 11.7, 7.0 Hz), 6.79 (d, 1H, J ) 9.7 Hz), 6.91 (td,
1H, J ) 6.2, 1.4 Hz), 7.04 (d, 1H, J ) 9.7 Hz), 7.28 (td,
1H, J ) 6.3, 1.5 Hz), 7.43-7.47 (m, 3H), 7.61-7.66 (m,
2H), 7.88 (dd, 1H, J ) 7.8, 1.1 Hz), 8.52 (dd, 1H, J ) 6.0,
0.9 Hz); IR (KBr) 1714, 1661, 1632, 1588, 1527 cm-1; MS
(EI) m/z 385 (M + H)+, 355, 289, 236. Anal. Calcd for
C23H20N4O3: C,71.86; H,5.24; N,14.57. Found C,71.90; H,
5.27; N,14.53.
2-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl-1(6H)-py-
ridazin-6-one)-1-cyclohexen-1-yl] Acetic Acid (FR166124,
2d). To a mixture of tert-butyl diethylphosphonoacetate (14.8
kg, 58.7 mol), fine granulated NaOH (3.90 kg, 97.5 mol),
potassium carbonate (13.5 kg, 97.5 mol) in DME (113 L)
was added 5a (15.0 kg, 39.0 mol) at 15 °C. The reaction
was continued for 5 h at 15-20 °C. The reaction mixture
cooled to 10 °C, and to the reaction mixture was added
methylene chloride (113 L) and purified water (150 L) at
<20 °C. The organic layers were separated and washed with
purified water (75 L) and brine (75 L) and concentrated to
∼30 L. To this solution was added MeOH (60 L) and then
concentrated to ∼30L under reduced pressure. In another
vessel, NaOH (4.68 kg, 117 mol) was dissolved in MeOH
(45 L), and to this solution was added dropwise the previous
solution maintaining the temperature below 45 °C. After
stirring at 55 °C for 8 h, the reaction mixture was cooled to
25 °C, followed by addition of purified water (300 L) and
n-heptane (75 L). To the separated aqueous layer was added
methylene chloride (300 L), followed by adjusting to pH )
Acknowledgment
We especially thank Dr. David Barrett, Medicinal Chem-
istry Research Laboratories, Fujisawa Pharmaceutical Co.
Ltd., for his interest and ongoing advice in this work.
Received for review July 15, 1999.
OP990066I
Vol. 3, No. 6, 1999 / Organic Process Research & Development
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