Application of the Sch?pf method to optimization of the synthesis of 3-[2-(p-N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid: Simultaneous reduction of three functional groups to maximize yield and throughput

Article abstract of DOI:10.1021/op000206k

Application of the Sch?pf method to development of a high yield condensation process to prepare a labile β-(p-nitrophenyl)-α,β-unsaturated ketone system, along with development of a procedure for simultaneous hydrogenation/hydrogenolysis of olefin, benzyl

Full text of DOI:10.1021/op000206k

Organic Process Research & Development 2000, 4, 596−600
Application of the Scho¨pf Method to Optimization of the Synthesis of
3-[2-(p-N-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic Acid:
Simultaneous Reduction of Three Functional Groups to Maximize Yield and
Throughput
Carl F. Deering, Brian K. Huckabee, Sechoing Lin, Ken T. Porter, Craig A. Rossman, and James Wemple*
Chemical DeVelopment Department, Pfizer Global Research and DeVelopment, 188 Howard AVenue,
Holland, Michigan 49424, U.S.A.
Abstract:
The starting point for the formation of 1 would appear to
be a 4-methyl-1-(para-substituted-phenyl)-3-pentanone de-
rivative in which the para substituent may be either a
protected (e.g. acylated) amino function or a nitro group.
As we shall see below, the nitro group has an advantage
over an acylated amino function, particularly when trying
to carry out the carbanion chemistry to generate the tertiary
alcohol group in 1. Various types of 4-methyl-1-(para-
substituted-phenyl)-3-pentanone derivatives were considered
as targets including 1-hydroxy-4-methyl-1-(p-nitrophenyl)-
pentan-3-one (4) and 4-methyl-1-(p-nitrophenyl)-1-penten-
3-one (9). The latter compound has been prepared previously
using a rather expensive arsonium Wittig approach4 or
alternatively, from methyl isopropyl ketone and p-nitro-
benzaldehyde in low overall yield (34%) using a two-step
process involving initial base-induced aldol condensation to
form â-hydroxyketone 4 followed by acid-induced elimina-
tion to give 9 which then required column chromatography
for purification.5
One would expect that a condensation reaction between
p-nitrobenzaldehyde and methyl isopropyl ketone would be
straightforward. However, low yields were encountered when
we tried to carry out this reaction under a variety of
conditions.6 Typically, under basic conditions, the reaction
would turn black. Complex mixtures were invariably ob-
tained. The solution to this problem became apparent from
work reported by Grayson and Tuite7 who applied the
Scho¨pf8 method to preparation of certain â-hydroxy ketones
including a compound, 1-hydroxy-1-(p-nitrophenyl)pentan-
3-one, that was structurally closely related to the â-hy-
droxyketone 4 that we required. They found that 1-hydroxy-
1-(p-nitrophenyl)pentan-3-one could be obtained in good
yield from p-nitrobenzaldehyde and â-ketovaleric acid using
pyridine as catalyst. The isobutyrylacetic acid (3) required
Application of the Scho1pf method to development of a high yield
condensation process to prepare a labile â-(p-nitrophenyl)-r,â-
unsaturated ketone system, along with development of a
procedure for simultaneous hydrogenation/hydrogenolysis of
olefin, benzyl ester, and nitro groups, allows the construction
of an inexpensive route to 3-[2-(p-N-acetylaminophenyl)ethyl]-
3-hydroxy-4-methylpentanoic acid, a key intermediate in the
preparation of CI-1029 and related HIV protease inhibitors.
3-Arylthio-4-hydroxy-5,6-dihydropyrones such as CI-
1029 are members of a new class of HIV protease inhibitors
which are nonpeptidic, competitive, reversible inhibitors of
the protease enzyme.1,2 The 3-arylthio-4-hydroxy-5,6-dihy-
dropyrones enjoy low cross resistance relative to currently
marketed peptidomimetic protease inhibitors.1 Key synthetic
intermediates required for the preparation of CI-1029 and
related members in this class are the 3-[2-(p-N-protected
aminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acids (1).2,3
To find a scaleable, cost-effective method for CI-1029, we
have developed a high-yield, high-throughput process for 1a
(R ) acetyl) which uses inexpensive, readily available raw
materials and standard production equipment.
(3) Boyer, F. E.; Domagala, J. M.; Ellsworth, E. L.; Gajda, C. A.; Hagen, S.
E.; Hamilton, H. W.; Lunney, E. A.; Markoski, L. J.; VaraPrasad, J. V.
N.; Tait, B. D. U.S. Patent 5,834,506, 1998.
(1) Tummino, P. J.; Vara Prasad, J. V. N.; Ferguson, D.; Nouhan, C.; Graham,
N.; Domagala, J. M.; Ellsworth, E.; Gajda, C.; Hagen, S. E.; Lunney, E.
A.; Para, K. S.; Tait, B. D.; Pavlovsky, A.; Erickson, J. W.; Gracheck, S.;
McQuade, T. J.; Hupe, D. J. Bioorg. Med. Chem. 1996, 4, 1401.
(2) Hagen, S. E.; Vara Prasad, J. V. N.; Boyer, F. E.; Domagala, J. M.;
Ellsworth, E. L.; Gajda, C.; Hamilton, H. W.; Markoski, L. J.; Steinbaugh,
B. A.; Tait, B. D.; Lunney, E. A.; Tummino, P. J.; Ferguson, D.; Hupe,
D.; Nouhan, C.; Gracheck, S. J.; Saunders: J. M.; VanderRoest, S. J. Med.
Chem. 1997, 40, 3707.
(4) Huang, Y.-Z.; Shi, L.-L.; Li, S.-W. Synthesis 1988, 975.
(5) Barker, S. D.; Norris, R. K. Aust. J. Chem. 1983, 36, 527.
(6) (a) Sinisterra, J. V.; Garcia-Raso, A.; Cabello, J. A.; Marinas, J. M. Synthesis
1984, 502. (b) Noyce, D. S.; Pryor, W. A. J. Am. Chem. Soc. 1955, 77,
1397. (c) Van Arnum, S. D.; Ramig, K.; Stepsus, N. A.; Yong, D.; Outten,
R. A. Tetrahedron Lett. 1996, 8659. (d) Chuitt, C.; Corriu, R. J. P.; Reye,
C. Synthesis 1983, 294.
(7) Grayson D. H.; Tuite. M. R. J. J. Chem. Soc., Perkin Trans. I 1986, 2137.
(8) Scho¨pf, C.; Thierfelder, K. Justus Liebigs Ann. Chem. 1935, 518, 127.
596
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Vol. 4, No. 6, 2000 / Organic Process Research & Development
10.1021/op000206k CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 10/21/2000

Scheme 1
in our case is unstable, readily undergoing decarboxylation
at room temperature. Isobutyrylacetic acid was generated in
situ by saponification of inexpensive9 methyl isobutyryl
acetate (2), followed by acidification with HCl at low
temperature (<10 °C). The â-keto acid was then used directly
in the next step reacting with p-nitrobenzaldehyde to give 4
in high yield. By stopping at 4, we avoid generation of the
labile â-(p-nitrophenyl)-R,â-unsaturated ketone system under
the strongly basic conditions normally required to bring about
the direct condensation of p-nitrobenzaldehyde with methyl
isopropyl ketone.
With an inexpensive source of 4 now available, we
investigated hydrogenation of this system with the hope of
achieving simultaneous reduction of both the nitro and benzyl
alcohol functions. The yield in this reduction proved
mediocre at best due to over reduction of the ketone to
produce, as by-product, 1-(p-aminophenyl)-4-methyl-3-pen-
tanol. Hydrogenation conditions were varied, but without
success in avoiding this side reaction. Further study showed
that reduction of the ketone function could be largely avoided
by first converting the benzylic alcohol group to its acetate
derivative, 1-acetoxy-4-methyl-1-(p-nitrophenyl)pentan-3-one
(5), using acetic anhydride and pyridine as base. For economy
purposes, to complete the acetylation, we used the same
pyridine employed in the initial Scho¨pf condensation reac-
tion. Reduction of 5 then proceeded smoothly using 20%
palladium hydroxide on carbon to produce 1-(p-amino-
phenyl)-4-methylpentan-3-one (6) in high yield. The latter
was not isolated but treated directly with acetic anhydride
to give the corresponding acetamide derivative, 1-(p-N-
acetylaminophenyl)-4-methylpentan-3-one (7). The prepara-
tion of 7 in four steps from p-nitrobenzaldehyde went
sufficiently well to allow us to avoid isolation/purification
of 7. Crude 7 was typically better than 90 area % pure by
HPLC analysis in both lab and pilot plant runs. The latter
was used directly in the next step in a reaction carried out
with excess lithium enolate of benzyl acetate generated in
situ from lithium diisopropylamide and benzyl acetate. The
resulting tertiary alcohol, 3-[2-(p-N-acetylaminophenyl)-
ethyl]-3-hydroxy-4-methylpentanoic acid benzyl ester (8) was
also not purified, but instead converted directly into the
desired final product, 1a, by hydrogenolysis over 20%
palladium hydroxide catalyst. Overall yields of 65-70%
were obtained for the seven-step process (Scheme 1).
This initial method for 1a was run several times on pilot
scale and proved effective in preparation of toxicology and
phase I clinical supplies. However, one step in the procedure
suffered from poor throughput. In particular the benzyl
acetate lithium enolate addition reaction with 1-(p-N-acetyl-
aminophenyl)-4-methylpentan-3-one (7) required more than
3 equiv of the enolate anion for optimum yield. The product
of this addition reaction was a bis anion in which the tertiary
alcohol function as well as the acetamide group were both
ionized. This bis anion had poor solubility in THF and excess
solvent was required to maintain agitation.
To address the throughput problem, we considered strate-
gies which would allow us to complete the enolate anion
addition procedure in the presence of an amino protecting
group that did not contain an acidic proton. The acetamide
as well as other well-known acylated derivatives such as
BOC- or Z-protected amines were not expected to work well
for the purpose of optimizing throughput. Bis acylated
aminessfor example, phthalimide derivativesswere likely
to be too labile in the presence of the strong benzyl acetate
enolate anion nucleophile. This led us to consider the nitro
group as a protected amine function for the purpose of
completing this enolate anion addition step under high
throughput conditions. We were not initially encouraged to
try this due to our extensive experience with black, complex
reaction mixtures whenever we placed a â-(p-nitrophenyl)-
R,â-unsaturated ketone system in a strongly basic reaction
medium. We considered that we may possibly avoid this
decomposition process if we take advantage of the fact that
enolate carbanion additions to ketones can be carried out at
very low temperatures, for example, -70 to -80 °C. The
black, polymeric mixtures that we encountered with â-(p-
nitrophenyl)-R,â-unsaturated ketone intermediates in the
presence of strong base, were all seen at relatively high
temperature (0-25 °C) or conditions which are typical of
most Knoevenagel and Claisen Schmidt condensation
reactions. Thus, we tried the addition of the benzyl acetate
enolate anion to (E)-4-methyl-1-(p-nitrophenyl)-1-penten-3-
one (9) at -60 to -75 °C in THF. Although we did observe
the black color, the reaction was clean and produced a high
yield of the desired addition product, 3-hydroxy-3-isopropyl-
5-(p-nitrophenyl)-4-pentenoic acid benzyl ester (10). The
dark color was reduced by a subsequent carbon treat-
ment.
In addition to helping throughput, this procedure also
allowed us to combine the two hydrogenation reactions in
our first method. Thus, with 20% palladium hydroxide on
carbon as catalyst, we could reduce three functional groups
in 10 in one step. This reduction chemistry proceeded cleanly,
in high yield and with good throughput. In the development
(9) Several suppliers are available including Wacker Chemicals, Burghausen,
Germany, and UBE Industries Inc., Tokyo, Japan.
Vol. 4, No. 6, 2000 / Organic Process Research & Development
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597

Scheme 2
variable wavelength UV detector set at 254 nm. A 4.6 mm
× 25 cm 5µ C18 (YMC-AQ) column was used with mobile
phases consisting of A: CH3CN and B: 0.2% aqueous acetic
acid in a gradient mode at a flow rate of 1.0 mL/min.
3-[2-(p-N-Acetylaminophenyl)ethyl]-3-hydroxy-4-
methylpentanoic Acid (1a); High-Throughput Process.
Methyl isobutyryl acetate (80.0 kg), methyl tert-butyl ether
(20 L) and water (120 L) were charged to a still under an
inert atmosphere, and the mixture was stirred and cooled to
18 °C. Sodium hydroxide (120 kg of a 50% aqueous solution)
was added over 80 min while maintaining the temperature
between 15 and 23 °C. The mixture was stirred overnight at
24-26 °C and then cooled to 0 °C. Hydrochloric acid (148
kg of a 37% aqueous solution) was added while maintaining
the temperature below 5 °C to adjust the pH to 0.1. After
settling the aqueous layer was separated and treated with
sodium chloride (6 kg) and extracted with methyl tert-butyl
ether (10 L). The combined organic layers were added to a
mixture of p-nitrobenzaldehyde (52.0 kg, 344 mmol) and
pyridine (102 kg) over 45 min while maintaining the
temperature between -2 and -5 °C. The resulting mixture
was stirred over the weekend at -2 to 1 °C and then warmed
to 32-38 °C where it was held for 5 h. Toluene (60 L) was
charged to the mixture which was then cooled to 15 °C and
extracted with a solution of sodium carbonate (6 kg) in water
(60 L) followed by a solution of sodium chloride (24 kg) in
water (60 L). The remaining organic layer was dried over
sodium carbonate (20 kg). After filtration to remove the
sodium carbonate, the carbonate was washed with toluene
(120 L) and the wash combined with the filtrate to provide
a solution of 1-hydroxy-4-methyl-1-(p-nitrophenyl)pentan-
3-one (4) in toluene, pyridine, and methyl tert-butyl ether.
This was cooled to -2 °C and acetic anhydride (68.0 kg)
added over 30 min while maintaining the temperature
between 0 and -2 °C. The resulting mixture was stirred
overnight while maintaining the temperature between 1 and
-2 °C, thus providing a solution of 1-acetoxy-4-methyl-1-
(p-nitrophenyl)pentan-3-one (5) in toluene, methyl tert-butyl
ether, and pyridine. This was heated to 85-87 °C where it
was held for 6 h. After cooling to 9 °C, water (80 L) was
added with stirring. After settling, the aqueous layer was
separated and the organic layer extracted with a solution 37%
hydrochloric acid (78 kg) in water (150 L) while including
a 10 L toluene rinse to aid in transfer of the organic solution
of the product. The latter was treated with 37% hydrochloric
acid (26 kg), water (110 L), ADP carbon (4 kg), Supercel
Hyflo (12 kg), and toluene (20 L). After stirring the mixture
was filtered and the residue rinsed with toluene (60 L). The
combined filtrate and rinse were allowed to settle, and the
aqueous layer was separated from the organic layer. The
latter was extracted with water (50 L). The water extracts
were discarded, and the organic solution was concentrated
under vacuum to remove solvent. This provides (E)-4-
methyl-1-(p-nitrophenyl)-1-penten-3-one (9) as a solid. The
9 was dissolved in tetrahydrofuran (140 L). A solution of
the lithium enolate anion of benzyl acetate was prepared
starting with 43.0 kg diisopropylamine in 180 L THF
followed by treatment of this solution with 30.8 kg 10 M
of an efficient synthesis of the drug encainide,10 a different
mix of three functional groups, including a nitro group, were
also reduced together successfully. The reduction product,
11, was not isolated but instead treated directly with acetic
anhydride to give the desired final product, 1a. The required
intermediate 9 is readily available by warming 5 with the
weak base, pyridine. Again for economy, the same pyridine
is used that was employed for the initial Scho¨pf reaction to
make 4. In pilot plant runs the HPLC purity of crude 9 was
typically better than 97 area %, and yields of 9 from
p-nitrobenzaldehyde were estimated to be better than 90%.
The overall yield for the seven-step process to produce 1a
from p-nitrobenzaldehyde was again in the 65-70% range,
producing material which had HPLC purity in excess of 99
area % (Scheme 2).
The only significant impurity found in the process is that
formed in the acetylation reaction to produce 11 from 10.
In this conversion we found 10-20% 3-acetoxy-3-[2-(p-
acetylaminophenyl)ethyl]-4-methylpentanoic acid (12) result-
ing from over acetylation of 11, probably via the mixed
anhydride of 12 with acetic acid. The structure of this
impurity was confirmed by independent synthesis. However,
12 could be converted back to 1a prior to isolation by heating
under basic conditions for several hours at 60-75 °C.
In summary, we have developed an economical, high
throughput method for preparation of 3-[2-(p-N-acetyl-
aminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (1a)
in seven combined steps. The method provides product in
high purity and is suitable for use in manufacture of the
protease inhibitor, CI-1029.
Experimental Section
Melting points were obtained using a Bu¨chi B-545 melting
point apparatus. H NMR spectra were recorded in CDCl3
or DMSO-d6 at 200 MHz on a Varian XL 200 NMR
spectrometer. Chemical shifts are reported downfield in ppm
from an internal tetramethylsilane standard. Analytical high-
performance liquid chromatography (HPLC) was carried out
using a Hitachi model L-6200 pump, a Hitachi model L-7400
1
(10) Dillon, J. L.; Spector, R. H.; Madding, G. D.; Wire, M. E. J. Heterocycl.
Chem. 1993, 30, 707.
598
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1
n-butyllithium in hexanes at -25 to -58 °C followed by
addition of 57.6 kg benzyl acetate to the resulting solution
of lithiun diisopropylamide at -59 to -65 °C. The solution
of 10 in THF was added to this benzyl acetate enolate anion
solution over 2.5 h while maintaining the temperature
between -60 to -64 °C. The mixture was stirred another
20 min at -60 to -64 °C and acetic acid (38 kg) was added
while maintaining the temperature between -55 to -64 °C.
Methanol (120 L) was added, and the mixture was stirred
and warmed to 28 °C. Agitation was stopped, and salts were
allowed to settle to the bottom of the still. The supernatant
was transferred into a second reactor containing ADP carbon
(6 kg) and Supercel Hyflo (5 kg). The remaining salts were
treated with water (400 L) and toluene (60 L). The aqueous
layer was separated and discarded. The upper toluene layer
was combined with the supernatant, ADP carbon, and
Supercel in the second reactor and the resulting mixture
stirred at 20-30 °C for 30 min. This mixture was then
concentrated under vacuum to a volume of 520-540 L. The
mixture was filtered and the residue washed with a mixture
of THF (60 L) and methanol (60 L). The combined filtrates
containing 3-hydroxy-3-isopropyl-5-(p-nitrophenyl)-4-pen-
tenoic acid benzyl ester (10) in methanol-THF solvent were
hydrogenated over 11 kg 20% palladium hydroxide catalyst,
50% water wet, at 28-38 °C and 50 psi hydrogen. The
hydrogenation mixture was filtered to remove catalyst and
the catalyst washed with methanol (80 L) and this combined
with the whole to give a solution of 3-[2-(p-aminophenyl)-
ethyl]-3-hydroxy-4-methylpentanoic acid (11) in THF and
methanol. The latter was cooled to 4 °C and acetic anhydride
(50.0 kg) added over 35 min while maintaining the temper-
ature below 13 °C. The resulting solution was stirred 40 min
at 13-15 °C and then concentrated under vacuum to remove
solvent and the residue treated with toluene (40 L), methyl
tert-butyl ether (20 L) and water (300 L). Sodium hydroxide
50% aqueous solution (64 kg) was added to adjust the pH
to 12.5 while maintaining the temperature below 22 °C. The
resulting mixture was heated to 60-72 °C where it was held
overnight. The mixture was cooled to 25 °C, and the layers
were separated, and the organic layer was extracted with
water (40 L). The organic layer was discarded and the water
extract combined with the aqueous product solution. The
combined aqueous layers were treated with ethyl acetate (180
L), and 37% hydrochloric acid (109 kg) was added to bring
the pH to 2.7 while maintaining the temperature below
15 °C. The aqueous layer was separated and extracted with
ethyl acetate (140 L) and the aqueous solution discarded.
The combined ethyl acetate extracts were washed twice with
a solution of 6 kg 37% hydrochloric acid in 60 L water
followed by 60 L water and then concentrated under vacuum
to a volume of 100-140 L. Toluene (160 L) was charged to
the still and the vacuum distillation continued to reduce the
volume again to 100-140 L. Ethyl acetate (60 L) was added
to the mixture, which was stirred and cooled to 4 °C and
filtered. The solid was washed with ethyl acetate (80 kg
and 60 kg) and vacuum-dried at 40 °C until the LOD was
less than 0.5%. This provides 64.9 kg (221 mol, 64.3%)
of 3-[2-(p-N-acetylaminophenyl)ethyl]-3-hydroxy-4-methyl-
pentanoic acid (1a): mp 157-160 °C; H NMR (DMSO-
d6) δ 0.86 (d, 6H), 1,6-1.9 (m, 3H), 1.99 (s, 3H), 2.3-2.6
(m, 5H), 7.07 (d, 2H), 7.44 (d, 2H), 9.81 (s, 1H); HPLC:
99.6 area %; ROI 0.10%. A second crop was isolated from
the mother liquors: 4.9 kg (17 mol, 4.9%); mp 147-148
°C; HPLC 95.5 area %. An analytical sample was prepared
by recrystallization from ethyl acetate. Anal. Calcd for
C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.72,
H, 7.92; N, 4.65.
1-Hydroxy-4-methyl-1-(p-nitrophenyl)pentan-3-one (4).
A portion of the 1-hydroxy-4-methyl-1-(p-nitrophenyl)-
pentan-3-one (4) solution in toluene, pyridine, and methyl
tert-butyl ether was concentrated to a solid. This was
recrystallized from toluene and heptane: mp 64-65 °C; 1H
NMR (DMSO-d6) δ 0.93, 0.98 (d,d, 6H), 2.45-2.95 (m, 3H),
5.11 (m, 1H), 5.62 (d, 1H), 7.62 (d, 2H), 8.17 (d, 2H); HPLC
99.2 area %. Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37;
N, 5.90. Found: C, 60.67, H, 6.20; N, 5.76.
1-Acetoxy-4-methyl-1-(p-nitrophenyl)pentan-3-one (5).
A portion of the 1-acetoxy-4-methyl-1-(p-nitrophenyl)pentan-
3-one (5) solution in toluene and methyl tert-butyl ether was
concentrated to an oil. On standing, crystals were formed.
A portion was recrystallized from toluene and heptane: mp
54-55 °C; 1H NMR (CDCl3) δ 1.04,1.11 (d,d, 6H); 2.07 (s,
3H), 2.57 (h, 1H), 2.86 (ABX, 1H), 3.19 (ABX, 1H), 6.25
(ABX, 1H), 7.54 (d, 2H), 8.21 (d, 2H); HPLC 99.6 area %.
Anal. Calcd for C14H17NO5: C, 60.21; H, 6.14; N, 5.02.
Found: C, 60.32, H, 5.95; N, 4.97.
1-(p-N-Acetylaminophenyl)-4-methylpentan-3-one (7).
Crude 1-(p-N-acetylaminophenyl)-4-methylpentan-3-one (7)
was recrystallized from ether followed by recrystalliation
from ether and heptane: mp 76-77 °C; 1H NMR (DMSO-
d6) δ 0.93 (d, 6H), 1.98 (s, 3H), 2.45-2.8 (m, 5H), 7.07 (d,
2H), 7.42 (d, 2H), 9.80 (s, 1H); HPLC 97.2 area %.
3-Hydroxy-3-isopropyl-5-(p-nitrophenyl)-4-pentenoic
Acid Benzyl Ester (10). A small portion of the crude
3-hydroxy-3-isopropyl-5-(p-nitrophenyl)-4-pentenoic acid ben-
zyl ester (10) obtained form the above sequence was
partitioned between toluene and water. The toluene solution
was extracted with water and concentrated to an oil that
solidified on standing. The solid was recrystallized from
toluene and heptane: mp 57-58 °C; HPLC: 99.0 area %;
1H NMR (DMSO-d6) δ 0.85 (d,d, 6H), 1.85 (h, 1H), 2.68
(AB, 2H), 4.91 (s, 1H), 5.01 (s, 2H), 6.66 (s, 2H), 7.25 (s,
5H), 7.60 (d, 2H), 8.14 (d, 2H). Anal. Calcd for C21H23-
NO5: C, 68.28, H, 6.28; N, 3.79. Found: C, 68.16, H, 6.15;
N, 3.70.
3-Acetoxy-3-[2-(p-N-acetylaminophenyl)ethyl]-4-meth-
ylpentanoic Acid (12). 3-[2-(p-Acetylaminophenyl)ethyl]-
3-hydroxy-4-methylpentanoic acid (1a) (5.87 g) and sodium
acetate (0.18 g) were added to THF (35 mL), and the mixture
was treated with acetic anhydride (2.25 g) and stirred at rt.
After a few minutes the mixture became thick, and more
THF (15 mL) was added to facilitate stirring. Stirring was
continued overnight to give a solution. Ethyl acetate (25 mL)
and water (10 mL) were added and the layers separated. The
organic layer was extracted with water (10 mL) and
concentrated to about 25 mL, and additional water was
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separated. The organic layer was treated with ethyl acetate
(50 mL) and toluene (25 mL) and concentrated to about 30
mL. Standing gave crystals which were collected and
vacuum-dried to give 4.5 g of 3-acetoxy-3-[2-(p-N-acetyl-
aminophenyl)ethyl]-4-methylpentanoic acid (12): mp 112-
1.99 (s,s, 6H), 2.0-2.6 (m, 7H), 7.06 (d, 2H), 7.43 (d, 2H),
9.83 (s, 1H); MS (DCI, isobutane) 336 (M + 1).
Received for review April 5, 2000.
OP000206K
1
114 °C; H NMR (DMSO-d6) δ 0.90, 0.92 (d,d, 6H), 1.95,
600
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Vol. 4, No. 6, 2000 / Organic Process Research & Development