Practical synthesis of FR195752, the side chain of Micafungin, utilizing a regioselective conversion of diaryl-β-diketone to 3,5-diarylisoxazole

Article abstract of DOI:10.1021/op0497862

The practical synthesis of FR195752, the side chain of Micafungin, was established utilizing a highly regioselective conversion of diaryl-β- diketone to 3,5-diarylisoxazole via the corresponding β-keto enamine intermediate whose disfavored regioisomer could be recycled efficiently after its hydrolysis. In addition, the related substance of FR195752 could be strictly controlled by the purification of its intermediate.

Full text of DOI:10.1021/op0497862

Organic Process Research & Development 2005, 9, 179−184
Practical Synthesis of FR195752, the Side Chain of Micafungin, Utilizing a
Regioselective Conversion of Diaryl-â-diketone to 3,5-Diarylisoxazole
Atsushi Ohigashi,* Atsushi Kanda, Hiroyuki Tsuboi, and Norio Hashimoto*
Chemical DeVelopment Laboratories, Fujisawa Pharmaceutical Co. Ltd. 2-1-6,
Kashima, Yodogawa-ku, Osaka, 532-8514, Japan
Abstract:
(4) no reproducibility in biphasic chlorination reaction of
aldoxime intermediate, (5) low yield through the whole
process (50%).
The practical synthesis of FR195752, the side chain of Micaf-
ungin, was established utilizing a highly regioselective conver-
sion of diaryl-â-diketone to 3,5-diarylisoxazole via the corre-
sponding â-keto enamine intermediate whose disfavored
regioisomer could be recycled efficiently after its hydrolysis.
In addition, the related substance of FR195752 could be strictly
controlled by the purification of its intermediate.
Especially, possible contamination of drug substance with
pollutive metals is a serious concern for pharmaceutical
industries. These issues urged us to develop not only a more
environmentally friendly but also a cost-effective synthesis
for industrial scale production. The details of which are
described herein. Here, we disclose a new, practical, and
environmentally friendly synthesis of 1, utilizing a regio-
selective conversion of diaryl-â-diketone 6a to 3,5-diaryl-
isoxazole 4a via the corresponding â-keto enamine inter-
mediate 10a (Scheme 3).
Introduction
Micafungin (Funguard) 3 launched by Fujisawa Pharma-
ceutical Co. in 2002 has shown its significant activities for
the treatment of systemic Candidiasis and Aspergillosis
1
without any concerns of side effects, while satisfying unmet
Results and Discussion
medical needs and making a contribution to the treatment
of invasive fungal infections. Micafungin is a new class of
lipopeptide compounds synthesized by the acylation of the
fermentative product 2 with FR195752, 1-[[4-[5-(4-pentyl-
Synthetic Strategy of Asymmetric Isoxazole 4a. To
eliminate the problems mentioned above, we started to build
up a new strategy involving a regioselective synthetic method
for the isoxazole moiety. There were two other well-known
methods for synthesis of isoxazoles. The first one involved
the oxidation of 4,5-dihydroxyisoxazole resulting from the
intramolecular cyclization of R,â-unsaturated oximes, and
second was the oximation of â-diketones followed by a
cyclization process. The former method has been often used
for a regioselective synthesis of isoxazoles; however the
oxyphenyl)isoxazol-3-yl]benzoyl]-1-H-benzotriazole(1)(Scheme
2
1
). The original synthesis of 1 employed by medicinal
2
chemists involved 1,3-dipolar cycloaddition of hydroximoyl
chloride to phenylacetylene derivative which was one of the
well-known methods of preparing asymmetric 3,5-diaryl-
3
isoxazole (Scheme 2). However, phenylacetylene derivatives
5
are usually unavailable, so it is generally prepared by utilizing
usage of pollutive metals such as palladium complex, lead-
4
6
7
a cross coupling reaction such as the Sonogashira reaction
(IV) acetate, and tetrakis(pyridine)cobalt(II)dichromate is
unavoidable. In addition, we noticed that the application of
this method to the synthesis of 1 required an expensive
starting material, methyl 4-acetylbenzoate. In the latter
method, on the other hand, there is no need to use metals
and the easy access to the starting materials for the
under the pollutive metal catalyzed conditions. As a conse-
quence, the original synthesis involved several problems to
be overcome from the viewpoints of industrial manufactur-
ing: (1) the use of pollutive metals, PdCl
2) cytotoxicity of some acetylene intermediates, (3) the use
of an expensive starting material, methyl 4-formylbenzoate,
2 3 2
(PPh ) -CuCl,
(
8
asymmetric â-diketones (6a). However, this method is
usually used for the synthesis of symmetric diarylisoxazoles,
because the oximation of asymmetric â-diketones might
produce two isomeric diarylisoxazoles whose separation was
deemed to be difficult. For example, Bandiera and co-
workers reported that 1-(4-nitrophenyl)-3-(4-methoxyphen-
yl)-1,3-propanedione (6b) reacted with hydroxylamine hy-
*
Authorstowhomcorrespondenceshouldbeaddressed.E-mail: atusi_oohigasi@
po.fujisawa.co.jp; norio_hashimoto@po.fujisawa.co.jp.
(
1) (a) Tawara, S.; Ikeda, F.; Maki K.; Morishita Y.; Otomo, K.; Teratani, N.;
Goto, T.; Tomishima, M.; Ohki, H.; Yamada, A.; Kawabata, K.; Takasugi,
H.; Sakane, K.; Tanaka H.; Matsumoto, F.; Kuwahara, S. Antimicrob. Agents
Chemother. 2000, 44, 57-62. (b) Ikeda F.; Wakai Y.; Matsumoto, S.; Maki
K.; Watabe E.: Tawara, S.; Goto, T.; Watanabe Y.; Matsumoto, F.;
Kuwahara, S. Antimicrob. Agents Chemother. 2000, 44, 614-618. (c)
Matsumoto, S.; Wakai Y.; Nakai T.; Hatano, K.; Ushitani T.; Ikeda F.;
Tawara, S.; Goto, T.; Matsumoto, F.; Kuwahara, S. Antimicrob. Agents
Chemother. 2000, 44, 619-621. (d) Hatano, K.; Morishita, Y.; Nakai, T.;
Ikeda, F. J. Antibiot. 2002, 55, 219-222.
9
drochloride to give a mixture of the corresponding two
(5) Maeda, K.; Hosokawa, T.; Murahashi, S.; Moritani, I. Tetrahedron Lett.
1973, 14, 5075-5076.
(6) Sharma, J. C.; Roginder, S.; Berger, D. D.; Kale, A. V. Indian J. Chem.
1986, 25B, 437.
(7) Wei, X.; Fang, J.; Hu, Y.; Hu, H. Synthesis 1992, 1205-1206.
(8) Gr u¨ nanger, P.; Vitafinzi, P. Isoxazoles, Part I, The Chemistry of Heterocyclic
Compounds; Wiley-Interscience: New York, 1991; Vol. 49, pp 129-149.
(9) Bandiera, T.; Gr u¨ nanger, P.; Albini, F. M. J. Heterocycl. Chem. 1992, 29,
1423-1428.
(
2) Tomishima, M.; Ohki H.; Yamada A.; Takasugi H.; Maki K.; Tawara S.;
Tanaka, H. J. Antibiot. 1999, 52, 674-676.
(
3) (a) Campbell, M. M.; Cosford, N. D. P.; Rae, D. R.; Sainsbury, M. J. Chem.
Soc., Perkin Trans. 1 1991, 765-770. (b) Moriya, O.; Urata, Y.; Endo, T.
J. Chem. Soc., Chem. Commun. 1991, 26, 17-18.
(
4) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467-
4
470.
1
0.1021/op0497862 CCC: $30.25 © 2005 American Chemical Society
Vol. 9, No. 2, 2005 / Organic Process Research & Development
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179
Published on Web 02/11/2005

Scheme 1. Synthesis of Micafungin
Scheme 2. Original synthesis of 1
Scheme 3. Regioselective conversion of diaryl-â-diketone to 3,5-diarylisoxazole via the corresponding â-keto enamine
Scheme 4. Regioselective conversion of asymmetric diaryl-â-diketone to isoxazole
isomeric isoxazoles with moderate regioselectivity (77:23)
Scheme 4), and no method was reported to separate these
phenone, 1-bromopentane, and dimethyl terephthalate (DMT)
(Scheme 5).
(
isomers from the mixture. As they reported, an electron-
withdrawing substituent like the nitro group increased the
reactivity of the nearest ketones to afford a major isomer.
On the basis of these experimental results and information,
we decided to utilize a 1,3-asymmetric diaryl-â-diketone 6a.
Thus, compound 1 could be broken into three commercially
available and inexpensive fragments, 4-hydroxyaceto-
Synthesis of Diaryl-â-diketone 6a. We began with the
alkylation of 4-hydroxyacetophenone with 1-bromopentane
(Scheme 6). The oily product 7 was obtained quantitatively
and used without any purification for the next aldol
condensation to afford diaryl-â-diketone 6a. The aldol
condensation was optimized with 1.6 equiv of cheap DMT
in the presence of t-BuOK, and then 6a was isolated in 88%
180
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Vol. 9, No. 2, 2005 / Organic Process Research & Development

Scheme 5. Retrosynthesis of 1
Scheme 6. Synthesis of 6a
Table 1. Aldol condensation of 7 to â-diketone 6aa
10
ditions, 6a was best converted into 4a in 74% isolated yield,
including 11% of its isomer (4b). However, this process had
to be abandoned because it proved to be impossible to obtain
pure 4a from the mixture of two isomers with any practical
purification methods. During the research of regioselective
activation of 6a, we discovered that â-diketone 6a readily
isolated
DMT
base
yield
(%)
impurity 8
entry (equiv) (equiv) conditions
(%)
1
2
3
4
1.3
1.3
1.6
2.5
MeONa 40-45 °C
1.5) 24 h
t-BuOK 20-25 °C
1.5) 3 h
t-BuOK 20-25 °C
1.5) 3 h
t-BuOK 20-25 °C
1.5) 3 h
74
75
88
82
1.8
2.6
0.8
0.6
(
reacted with AcONH
1a, which could be isolated as a stable crystalline form
Scheme 7). This offered a great possibility that isomerically
4
to give a mixture of enamine 10a and
(
1
(
(
pure â-keto enamine 10a would activate a regioselective
oximation followed by a spontaneous intramolecular cy-
clization to afford the asymmetric isoxazole 4a. To realize
this methodology, a regioselective enamination of â-diketone
(
a
DMF was used as the solvent in all entries, and no DMT was observed in
each 6a.
6
a became the most important matter.
Various primary amines with alkyl or aryl substituents
yield including 0.8% of impurity 8 by the crystallization in
MeOH to get rid of the residual DMT (Table 1, entry 3).
Increasing the equivalent of DMT by more than 1.6 was not
effective in eliminating 8 (Table 1, entry 4). In addition,
neither changing the kind of solvent nor diluting the reaction
solution was satisfactory with low yield.
This diacylated compound 8 also was converted into
impurity 9 in the next step, which resulted in one of the major
related compounds in the final product 1, as mentioned later.
Regioselective Conversion of Diaryl-â-diketone 6a to
Isoxazole 4a. After considering the conversion of diaryl-â-
diketone 6a to isoxazole 4a with hydroxylamine hydrochlo-
ride, we envisaged that the desired regioselectivity would
be recognized by the synergistic effect of the electron-
were examined for a regioselective enamination of 6a (Table
). As shown in entries 1 and 2, only ammonium salts gave
2
the satisfactory results with moderate regioselectivity. Other
amines except for ammonium salts made the reaction slow
and did not show any regioselectivity (entries 3-7). Acetic
or formic acid might activate the more electron-withdrawing
ketone of 6a. In the workup and following an isolation study,
fortunately the crystallization treated with the AcOEt/n-
heptane (1/5) solvent system afforded an almost sole isomer
1
0a in 70% yield due to the difference of the solubility of
each isomer. As around 2.5% of 11a was included in the
isolated 10a, it was still unsatisfactory for use in the next
cyclization step. Accordingly, crude 10a was recrystallized
successfully with AcOEt/n-heptane (1/5) to give a high
quality of 10a in 86% isolated yield (Scheme 7). As an end
2
withdrawing substituent (-CO Me) and electron-donating
(10) Conducted with hydroxylamine hydrochloride (5 equiv) in N-methyl-2-
substituent (-O(CH CH ). Under optimized reaction con-
2
)
4
3
pyrrolidone at 60 °C for 30 h.
Vol. 9, No. 2, 2005 / Organic Process Research & Development
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181

Scheme 7. Regioselective conversion of diaryl-â-diketone 6a to 3,5-diarylisoxazole 4a via the corresponding â-keto enamine
intermediate 10a and its recovery system
Table 2. Regioselective enamination of 6a to 10a-f with various aminesa
isolated
yield
(%)
reaction selectivity
time
(h)
conversion
(%)
entry
amine
R
10
11
1
2
3
4
5
6
7
HCO
AcONH
2
NH
4
4
4.5
4.5
24
24
74
3.5
73
96
94
NR
NR
41
NR
36
H
H
83
82
17
18
70b
c
HCO
HCO
2
H/n-BuNH
H/t-BuNH
NH
2
n-Bu
t-Bu
MeO(CH
EtO
c
2
2
MeO(CH
EtONH
BzNH
2
)
2
2
2
)
2
50
50
50
50
c
2
2
Bz
a
Amine (5 equiv), DMF at 100 °C were used in all entries. b Including 2.5% of isomer 11a. c Not reacted.
result, the specification of 10a in terms of 11a was
determined to be not more than 0.2%. In the next step with
hydroxylamine hydrochloride, â-keto enamine 10a was
highly regioselectively converted into 3,5-diarylisoxazole
acid/MeOH solution to give 6a of high quality in 90% yield
(Scheme 7).
Synthesis of 1 and Removal of 9. Thus, an isomerically
pure 3,5-diarylisoxazole 4a was converted into 1 by the
hydrolysis of methyl ester with aqueous sodium hydroxide,
followed by esterification with 1-hydroxybenzotriazole (HOBt)/
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochlo-
ride (WSC‚HCl) in 100% and 95% yield, respectively. At
this stage, another issue on the quality of 1 emerged as a
new related substance 9 derived from impurity 8 was
identified at a level of 2%, and this highly insoluble related
substance caused not only a deterioration of the quality of 1
but also a difficulty of cleaning facilities used for the
coupling reaction of 1 and 2, the critical step of 3. Thus we
had to remove 9 from 1 before the critical steps.
4a free of its isomer 4b. The enamine exchange followed
by spontaneous cyclization reaction prior to oximation of
â-keto enamine 10a proceeded smoothly in 96% isolated
yield.
Although â-diketone 6a was successfully converted into
0a of high quality in 60% isolated yield after the recrys-
1
tallization, the combined mother liquor still contained as
much as 30% of 10a and 11a based on 6a. To recycle the
enamines 10a and 11a in the mother liquor, it was concen-
trated under reduced pressure and the resulting residue was
easily hydrolyzed by treatment with aqueous hydrochloric
182
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Vol. 9, No. 2, 2005 / Organic Process Research & Development

Table 3. Solubility data for 9, 5b, and 5c
Packard 1100LC/MSD mass spectrometer using EI for
ionization. Elemental analyses were carried out on a Perkin-
Elmer CHN elemental analyzer.
solubility (µg/mL)a
substrate
acetone
AcOEt
DMF
MeOH
THF
Methyl 4-{3-Oxo-3-[4-(pentyloxy)phenyl]propanoyl}-
benzoate (6a). 4-Hydroxyacetophenone (35.0 kg), DMF (175
L), 1-pentylbromide (42.7 kg), and potassium carbonate (42.6
kg) were combined in a reaction vessel. The mixture was
stirred at 65-70 °C for 4 h, and then water (525 L) and
n-heptane (280 L) were added to the reaction mixture at
below 30 °C. The organic layer was separated and washed
with aqueous sodium hydroxide solution (sodium hydroxide
9
20
2
1
40
8
1
60
50
60
3
600
330
250
140
7
5
5
b
c
a
All solubility data were measured at room temperature.
3
.4 kg in water 168 L), following aqueous hydrochloric acid
solution (35% hydrochloric acid 7 L and water 168 L), water
175 L), and aqueous sodium chloride solution (sodium
(
chloride 35.0 kg in water 175 L) successively. The organic
layer was treated with anhydrous magnesium sulfate (7.0 kg).
The mixture was filtered, and magnesium sulfate cake was
washed with n-heptane. The combined organic filtrates were
concentrated under vacuum to remove n-heptane. To the
concentrated oily residue DMF (840 L), dimethyl tereph-
thalate (79.9 kg), and potassium tert-butoxide (43.3 kg) were
added at 20-25 °C and stirred at the same temperature for
4 h. The mixture was diluted with methanol (2135 L) at 20-
30 °C and then quenched and crystallized by slow addition
of aqueous hydrochloric acid solution (35% hydrochloric acid
53 L and water 53 L) at 5-15 °C. The mixture was filtered,
washed with methanol (280 L), and water (280 L). The wet
crystal was dried under vacuum at 40-60 °C to give 83.3
kg of 6a (88% yield).
Figure 1. Solubility of 9, 5b, and 5c in THF.
To eliminate the contamination of 9 from 1, we examined
what stage of the manufacturing process of 1 is most
effective. As 9 has a symmetric and nonionizable structure,
we expected a solubility difference in the alkaline salts of
5a. Table 3 shows the preliminary solvent screening for the
discrimination of 9 from 5b and 5c. We have found that the
combination of THF and potassium salt 5c shows the best
selectivity.
Furthermore, the solubility of 9 in THF is highly depend-
ent on the temperature, and at 40 °C, its solubility increased
three times compared to the room temperature solubility
whilst the solubility of 5c remained the same (Figure 1).
Thus, we chose insoluble 5c as the intermediate for the
esterification step and then conducted the reslurry washing
in THF at 40 °C effectively. As a result, the quality of 1
prepared via potassium salt 5c met its specification, free of
both regioisomer and 9.
1H NMR (200 MHz, CDCl
3
-d, δ) 0.96 (3H, t, J ) 6.5),
1
(
.35-1.51 (4H, m), 1.76-1.86 (2H, m), 3.96 (3H, s), 4.04
2H, t, J ) 6.5 Hz), 4.60 (0.05H, s, keto CH ), 6.82 (0.95H,
s, enol CH), 6.97 (2H, dd, J ) 8.5, 2.0 Hz), 7.97 (2H, dd, J
7.0, 2.0 Hz), 8.02 (2H, dd, J ) 6.5, 2.0 Hz), 8.14 (2H,
2
)
dd, J ) 7.5, 2.0 Hz), 16.89 (0.9H, s, enol OH)(6a exists as
its keto-enol tautomer.); IR (ATR) 2955, 2926, 1719, 1605,
-
1
+
1
586, 1281, 1107 cm ; MS (EI) m/z 391 [M + Na] . Anal.
Conclusions
24 5
Calcd for C22H O : C, 71.72; H, 6.57. Found: C, 71.84;
Compound 1 was thus manufactured in 60% overall yield
from 4-hydroxyacetophenone including the recovery of 6a.
The present method is advantageous over the original
methods from the viewpoints of a large scale manufacturing;
we obtained the following advantages: (1) elimination of
troublesome metals and impurities, (2) improvement of
overall yield and cost-efficiency, (3) efficient use of dis-
favored regioisomer, utilizing a regioselective conversion of
diaryl-â-diketone 6a to 3,5-diarylisoxazole 4a via the cor-
responding â-keto enamine 10a. This process could be
successfully applied for industrial scale manufacturing (50
kg scale).
H, 6.42.
Methyl 4-{1-Amino-3-[4-(pentyloxyphenyl)-3-oxo-1-
propenyl}benzoate (Crude 10a). Compound 6a (83.3 kg),
DMF (417 L), and ammonium formate (71.3 kg) were
combined in a reaction vessel, and the mixture was stirred
at 100-105 °C for 4 h. Ethyl acetate (2083 L) and water
(2083 L) were added to the mixture at 20-30 °C, and then
the organic layer was separated and washed with aqueous
sodium chloride solution (sodium chloride 208 kg in water
2
083 L) and another aqueous sodium chloride solution
(sodium chloride 417 kg in water 2084 L) successively. The
organic layer was concentrated to about 417 L under vacuum.
The resultant solution was heated to 50-55 °C, and then
n-heptane (2083 L) was added dropwise for 1-1.5 h for
crystallization. The slurry was cooled to 20-25 °C and
stirred for 1 h. The mixture was filtered and washed with
the mixture of ethyl acetate (70 L) and n-heptane (350 L).
The wet crystal was dried under vacuum at 40-60 °C to
give 58.2 kg of crude 10a (70% yield).
Experimental Section
Solvents and reagents were obtained from commercial
1
sources and were used without any purification. H NMR
spectra were obtained on a Brucker Biospin DPX200 using
tetramethylsilane as internal standard. IR spectra were
recorded on a Horiba FT-720 Fourier transform infrared
spectrometer. Mass spectra were recorded on a Hewlett-
Vol. 9, No. 2, 2005 / Organic Process Research & Development
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183

Purification of 10a. Crude 10a (58.2 kg) and ethyl acetate
1H NMR (200 MHz, DMSO-d
, δ) 0.91 (3H, t, J ) 7.0
6
(
291 L) were combined in a reaction vessel. The mixture
Hz), 1.27-1.48 (4H, m), 1.61-1.82 (2H, m), 4.05 (2H, t, J
) 6.5 Hz), 7.12 (2H, d, J ) 9.0 Hz), 7.54 (1H, s), 7.85 (2H,
d, J ) 9.0 Hz), 8.03 (2H, d, J ) 9.0 Hz), 8.10 (2H, d, J )
was stirred at 50-70 °C to dissolve, and then n-heptane
1455 L) was added at 50-55 °C for 1-1.5 h for crystal-
(
-
1
lization. The mixture was cooled to 20-30 °C and stirred
for 1 h. The mixture was filtered and washed with the mixture
of ethyl acetate (58 L) and n-heptane (290 L). The wet crystal
was dried under vacuum at 40-60 °C to give 50.1 kg of
8.5 Hz); IR (ATR) 2938, 2867, 1677, 1613, 1248 cm ; MS
+
(EI) m/z 352 [M + 1] . Anal. Calcd for C21
H
21NO
4
: C,
71.78; H, 6.02; N, 3.99. Found: C, 71.72; H, 6.04; N, 3.96.
1-[[4-[5-(4-Pentyloxyphenyl)isoxazol-3-yl]benzoyl]-1-H-
benzotriazole (1). Compound 5a (42.7 kg), THF (427 L),
DMF (342 L), and HOBt (23.0 kg) were combined in a
reaction vessel and then WSC‚HCL (39.6 kg) was added
and stirred for 4 h at 20-30 °C. The mixture was cooled,
and ethyl acetate (1708 L) was added and then water (427
L) was added at 0-25 °C followed by stirring for 1 h at
2-7 °C. The mixture was filtered and washed with aceto-
nitrile (68 L). The wet crystal was dried under vacuum at
1
0a (86% yield).
1H NMR (200 MHz, CDCl
3
-d, δ) 0.94 (3H, t, J ) 7.2),
1
.34-1.52 (4H, m), 1.74-1.83 (2H, m), 3.95 (3H, s), 4.01
(2H, t, J ) 6.5 Hz), 6.12 (1H, bs), 6.97 (2H, dd, J ) 8.0,
2
8
2
.0 Hz), 7.70 (2H, dd, J ) 8.5, 2.0 Hz), 7.93 (2H, dd, J )
.5, 2.0 Hz), 8.12 (2H, dd, J ) 8.5, 2.0 Hz); IR (ATR) 3420,
-
1
952, 2929, 1715, 1706, 1594, 1528, 1492, 1278 cm ; MS
+
(EI) m/z 390 [M + Na] . Anal. Calcd for C22
4
H25NO : C,
7
1.91; H, 6.86; N, 3.81. Found: C, 71.91; H, 7.01; N, 3.84.
Methyl 4-{5-[4-(Pentyloxy)phenyl]-3-isoxazolyl}benzoate
40-45 °C to give 54.1 kg of 1 (95% yield).
1
3
H NMR (200 MHz, CDCl -d, δ) 0.95 (3H, t, J ) 7.0
(
4a). Compound 10a (50.1 kg), DMF (401 L), and hy-
Hz), 1.32-1.54 (4H, m), 1.76-1.90 (2H, m), 4.03 (2H, t, J
) 6.5 Hz), 6.81 (1H, s), 7.01 (2H, dd, J ) 9.0, 2.5 Hz),
7.42-7.62 (3H, m), 7.79 (2H, dd, J ) 9.0, 2.5 Hz), 8.11
(2H, d, J ) 8.5 Hz), 8.12 (1H, dd, J ) 8.0, 1.0 Hz), 8.39
droxylamine hydrochloride (18.9 kg) were combined in a
reaction vessel, and the mixture was stirred at 60-65 °C
for 4 h. The mixture was cooled to 20-40 °C, and
acetonitrile (501 L) was added at this temperature for 30
min and then water (501 L) for 30 min for crystallization.
The resulting precipitate was cooled to 20-25 °C then
filtered and washed with aqueous acetonitrile solution
-1
(2H, d, J ) 8.5 Hz); IR (ATR) 3116, 2948, 1773, 1251 cm ;
+
MS (EI) m/z 469 [M + 1] . Anal. Calcd for C27
24 4 4
H N O :
C, 69.22; H, 5.16; N, 11.96. Found: C, 68.90; H, 5.44; N,
11.78.
(
acetonitrile 125 L and water 125 L). The wet cake was dried
Recovery of 6a. The combined filtrates both of crude 10a
step and its purification step were concentrated under
vacuum. To the resulting residue, methanol (833 L) and 35%
(w/v) hydrochloric acid (83 L) were added. The mixture was
stirred at 60-65 °C for 3 h, then cooled at 20-25 °C,
filtered, and washed with methanol (350 L). The wet crystal
was dried under vacuum at 40-60 °C to give 6a (27% yield
under vacuum at 40-60 °C to give 47.8 kg of 4a (96%
yield).
1H NMR (200 MHz, CDCl
-d, δ) 0.95 (3H, t, J ) 6.5
Hz), 1.35-1.53 (4H, m), 1.76-1.86 (2H, m), 3.95 (3H, s),
.02 (2H, t, J ) 6.5 Hz), 6.74 (1H, s), 6.99 (2H, d, J ) 8.5
3
4
Hz), 7.77 (2H, dd, J ) 8.5, 2.0 Hz), 7.93 (2H, d, J ) 8.5
Hz), 8.15 (2H, d, J ) 8.5 Hz); IR (ATR) 2961, 2944, 1716,
based on the starting material 4-hydroxyacetophenone).
-
1
+
1
1
612, 1278, 1107 cm ; MS (EI) m/z 388 [M + Na] . Anal.
Calcd for C22 : C, 72.31; H, 6.34; N, 3.83. Found:
C, 72.39; H, 6.41; N, 3.87.
-{5-[4-(Pentyloxy)phenyl]-3-isoxazolyl}benzoic Acid
5a). Compound 4a (47.8 kg), THF (478 L), methanol (72
3
H NMR (200 MHz, CDCl -d, δ) 0.95 (3H, t, J ) 7.0),
H23NO
4
1.35-1.51 (4H, m), 1.76-1.86 (2H, m), 3.96 (3H, s), 4.04
(2H, t, J ) 6.5 Hz), 4.60 (0.05H, s, keto CH ), 6.82 (0.95H,
2
4
s, enol CH), 6.97 (2H, dd, J ) 9.0, 2.0 Hz), 7.98 (2H, dd, J
) 7.0, 2.0 Hz), 8.02 (2H, dd, J ) 6.5, 2.0 Hz), 8.14 (2H,
dd, J ) 8.5, 2.0 Hz), 16.89 (0.9H, s, enol OH) (6a exists as
its keto-enol tautomer); IR (ATR) 2956, 2927, 1718, 1605,
(
L), and aqueous potassium hydroxide solution (potassium
hydroxide 11.6 kg in water 72 L) were combined in reaction
vessel. The suspension solution was stirred at 50-60 °C for
-
1
+
1586, 1281, 1107 cm ; MS (EI) m/z 391 [M + Na] . Anal.
2
h, and THF (956 L) was added at this temperature. The
24 5
Calcd for C22H O : C, 71.72; H, 6.57. Found: C, 71.74;
mixture was cooled to 40-45 °C and then filtered and
washed with THF (478 L) to give a wet cake (crude 5c).
The obtained wet cake and THF (956 L) were charged into
a reaction vessel. The mixture was stirred at 50-60 °C for
H, 6.64
Acknowledgment
We would like to thank Mr. Goto of Chemical Develop-
ment Laboratories for helpful discussions and documentation.
20 min and cooled to 40-45 °C. The mixture was filtered
and washed with THF (478 L) to give a wet cake (5c) and
eliminate compound 9. The obtained wet cake, water (382
L), and THF (382 L) were charged into a reaction vessel.
The aqueous hydrochloric acid solution (35% hydrochloric
acid 20.1 L and water 219 L) and water (478 L) were added
to the mixture at 40-55 °C for crystallization. And then,
the mixture was cooled at 25-35 °C, filtered, and washed
with water (378 L) and then acetone (239 L). The wet crystal
was dried under vacuum at 40-60 °C to give 42.7 kg of 5a
Note Added after ASAP Publication: In the version
published on the Internet February 11, 2005, the asterisk and
e-mail address for one of the authors were not present. The
final version published February 15, 2005, and the print
version are correct.
Received for review November 26, 2004.
OP0497862
(93% yield).
184
•
Vol. 9, No. 2, 2005 / Organic Process Research & Development