Selective hydrolysis of methanesulfonate esters

Article abstract of DOI:10.1021/op700226s

The pH dependence of the hydrolysis of 4-{2-[(methylsulfonyl)oxy]ethyI} phenyl methanesulfonate, 1, and two carboxylate esters, ethyl 2(S)-ethoxy-3-(4-hydroxyphenyl)propionate, 2 and (2S)-2-ethoxy-3-[4-(2-{4- [(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]propanoate, 3, has been studied with a view to the selective removal of any remaining 1, following coupling with 2 to generate 3 in water at 95 °C (Scheme 1). It is shown that reduction of pH from that of the reaction conditions (pH ≈ 10) to pH 7-8 has little effect on the hydrolysis of 1, which is dominated by the water rate over this pH range, but reduces the rate of hydrolysis of the carboxylate ester group by 3 orders of magnitude (pH 7). This very strong quantitative difference in the response of the two types of ester group to pH change allows complete removal of 1 at low pH without measurable loss to the product ester, 3. The conclusions should be generally applicable to the removal of potentially genotoxic alkyl esters of methane sulfonic acid in the presence of carboxylic esters and other base-sensitive groups.

Full text of DOI:10.1021/op700226s

Organic Process Research & Development 2008, 12, 213–217
Selective Hydrolysis of Methanesulfonate Esters
Lai Chun Chan,* Brian G. Cox, and Rhona S. Sinclair*,†
AstraZeneca PR&D, Silk Road Industrial Park, Charter Way, Macclesfield, Cheshire SK10 2NA, U.K.
Abstract:
Scheme 1. Formation of ester 3
The pH dependence of the hydrolysis of 4-{2-[(methylsul-
fonyl)oxy]ethyl}phenyl methanesulfonate, 1, and two carboxylate
esters, ethyl 2(S)-ethoxy-3-(4-hydroxyphenyl)propionate, 2 and
(2S)-2-ethoxy-3-[4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxy)phe-
nyl]propanoate, 3, has been studied with a view to the selective
removal of any remaining 1, following coupling with 2 to
generate 3 in water at 95 °C (Scheme 1). It is shown that
reduction of pH from that of the reaction conditions (pH ≈
1
0) to pH 7–8 has little effect on the hydrolysis of 1, which is
dominated by the water rate over this pH range, but reduces
the rate of hydrolysis of the carboxylate ester group by 3 orders
of magnitude (pH 7). This very strong quantitative difference
in the response of the two types of ester group to pH change
allows complete removal of 1 at low pH without measurable
loss to the product ester, 3. The conclusions should be generally
applicable to the removal of potentially genotoxic alkyl esters
of methane sulfonic acid in the presence of carboxylic esters
and other base-sensitive groups.
optimisation of the levels and mode of addition of carbonate
base, thereby enabling a reduction in the excess of the
dimesylate, 1. However, the very low final levels of 1 required
for product specification meant that in spite of this, it was not
possible to avoid a subsequent prolonged hydrolysis, with its
potential for yield losses. We therefore, wished to explore
conditions under which it might be possible to achieve a more
selective hydrolysis of 1 in the presence of the carboxylate ester
Introduction
The synthesis of the ester 3, (2S)-2-ethoxy-3-[4-(2-{4-
[(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]propanoate, from
3, recognising also that the selective hydrolysis of base-sensitive
dimesylate 1, 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl meth-
anesulfonate, and ethyl 2(S)-ethoxy-3-(4-hydroxyphenyl)pro-
pionate (EEHP), 2, proceeds very efficiently in a biphasic
mixture with aqueous sodium carbonate at reflux (ca. 100 °C)
for about 4–5 h, in the presence of a phase-transfer catalyst,
PEG-400, Scheme 1.
group is an issue of general importance.
The rate law for hydrolysis of a substrate, S, under basic
conditions at fixed pH has the form shown in eqs 1 and 2.
d[S]
dt
-
) k [S]
(1)
(2)
e
In order to maximise the efficiency of the reaction with
respect to EEHP, 2, usage, the reaction is typically run with an
excess of dimesylate 1, (up to 1.6 mol eq). It was necessary,
however, to reduce the level 1 at the end of this stage to <0.03
area % by HPLC in order to meet later-stage product specifica-
tions for this potentially genotoxic mesylate ester. Thus,
although typically the coupling reaction itself is complete in
about 4–5 h, an additional 3–4 h at reflux is required to degrade
any excess 1. During this prolonged heating period the ester
group of the product, 3, although partially protected by its low
water solubility, is also susceptible to hydrolysis. Losses may
be significant on extended heating; complete hydrolysis of the
product under reaction conditions occurs after about 16 h. One
important development target was the minimisation of the
competing hydrolysis of EEHP, 2, during coupling, through
where
-
k ) k + k [OH ]
e
o
OH
e o
In eqs 1 and 2, k is the observed first-order rate constant, k
the rate constant for the uncatalysed (water) rate, and kOH the
rate constant for the hydroxide reaction. In an important paper,
1
King and co-workers pointed out that the relative values of k
o
and kOH are very substrate dependent, and introduced the
concept of pH , the pH at which the water and hydroxide rates
are equal (i.e., k
i
-
o
i
) kOH[OH ] at pH). In particular, it is
noticeable that hydrolyses of methanesulfonate and carboxylate
esters have very different pH dependences. The hydrolysis of
simple methansulfonate esters, such as ethyl methanesulfonate,
*
To whom correspondence should be addressed, lai.chan@astrazeneca.com;
rhona.sinclair2@astrazeneca.com.
†
Present address: Astrazeneca PR&D Charnwood, Bakewell Road, Lough-
(1) King, I. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.; Klassen, D.F. J Am.
Chem. Soc. 1992, 114, 3028.
borough, Leicestershire LE11 5RH, UK.
1
0.1021/op700226s CCC: $40.75

2008 American Chemical Society
Vol. 12, No. 2, 2008 / Organic Process Research & Development
•
213
Published on Web 02/16/2008

Scheme 2. Rates of hydrolysis investigated
Figure 1. Reaction profile for hydrolysis of dimesylate 1, at
pH 6: ( (black) observed concentration of product, 4; ( (pink)
-
4 -1
calculated concentration, eqs 3 and 4: k
e
) 5.35 × 10
o
s ; S ,
)
0.12 M. The arrow denotes the point at which the system
becomes homogeneous.
Table 1. Hydrolysis of dimesylate 1, in aqueous solution at
9
5 °C
pH
.0
is dominated by the water rate until high pH values (pH
i
≈
-
a
4
/s-1
[OH ]/M
10 k
e
o
S /M
12). Carboxylate ester hydrolysis on the other hand typically
-7
6
6.8 × 10
6.8 × 10
5.3
5.4
7.3
5
0.12
0.11
0.11
-5
shows low water rates but very high rate constants for acid-
and base-catalysed reactions; typically, the hydrolysis rates
depend directly on the hydroxide concentration from pH ≈ 5
8.0
8
0
6.8 × 10-
3
b
1
0.0
a
) 6.76 × 10-13
2
4
b
K
w
M
(pKw ) 12.17) at 95 °C.
Relatively slow (ke ) 5.5
-
5
-1
2,3
× 10
s
) hydrolysis of the aryl mesylate group of 1 and 4 is also observed at
onwards. The two processes are, therefore, in principle
separable, and lower pH values should strongly favour meth-
anesulfonate hydrolysis relative to carboxylate hydrolysis.
In view of the above, the hydrolysis rates for 1-3 (Scheme
pH ) 10.
d[4]
dt
)
ke[1]
(4)
2), at different pH values were investigated as part of process
optimisation for this system.
By fitting the observed reaction profile to a combination of
Under strongly basic conditions, there is also the possibility
that hydrolysis of the arylsulfonate ester group in 4 would give
the corresponding phenol.
eqs 3 and 4, it was possible to determine k and S simulta-
e
o
neously. Figure 1 shows such a profile for reaction at pH 6,
with an initial [1] ) 0.27 M. The calculated curve (pink) has
e o
been obtained from eqs 3 and 4 with values for k and S of:
-4
-1
k
e
) 5.35 × 10 s ; S
o
) 0.12 M.
Results
It may be seen from Figure 1 that there is an initial linear
increase in the product alcohol formation until the mixture
becomes homogeneous at [1] ) 0.12 M ([4] ) 0.15 M), beyond
which there is an exponential change in concentration with time.
Table 1 lists the observed rate constants and solubility at
the different pH values.
Dimesylate 1. The hydrolysis of dimesylate, 1, was inves-
tigated at 95 °C at pH 6, 8, and 10. The temperature of 95 °C
was chosen to allow a conveniently high reaction rate, without
the complications arising from sampling at reflux. Reaction
concentrations (Scheme 1, with initial concentrations c ) 0.3
M) are such that 1 is only partially miscible with water; it forms
a second phase at the beginning of the reaction, but as the
amount of 1, is reduced the system becomes homogeneous part-
way through the hydrolysis. There are, thus, two kinetic regimes
during the hydrolysis, as follows:
It is clear from the results in Table 1, which show no change
in k
e
between pH 6 and pH 8, and a modest increase at pH 10,
, eq 2) is dominant until around pH 10,
that the water rate (k
o
when the hydroxide reaction begins to become important (see
Discussion below). Analysing the rate constant at pH 10 in terms
-
4
-1
-
-3
of eq 2, using k
(
o
) 5.4 × 10
s
and [OH ] ) 6.8 × 10
M
-2
-1 -1
Table 1), gives kOH ) 2.8 × 10
M
s
at 95 °C. These k
o
(
i) An initial two-phase reaction in which the aqueous
concentration of 1 remains constant at its solubility, S , with
a zero-order rate law for the formation of product alcohol,
and kOH values may be used to estimate the pH at which the
rates of the water and hydroxide rates are equal, pH : k
o
i
o
)
-
-
-2
k
OH[OH] at [OH ] ) 2 × 10 M, i.e., pH
i
) 10.5 at 95 °C.
≈ 12.5 for simple
4
-(2-hydroxyethyl)phenyl methanesulfonate, 4, eq 3.
This is somewhat lower than the value of pH
i
1
alkyl methanesulfonates at 25 °C. This difference, however,
d[4]
dt
is mainly a reflection of the temperature dependence of K
w
,
)
keSo
(3)
as pK decreases from 14.00 at 25 °C to 12.17 at 95 °C.
w
(
ii) A homogeneous reaction, that occurs once the total
(2) Bamford, C. H.; Ester Formation and Hydrolysis and Related Reactions;
Tipper, C. F. H., Eds.; Chemical Kinetics, Vol. 10; Elsevier: Amster-
dam, 1972.
o
amount of 1 is reduced such that [1] e S , with a first-
order rate law, eq 4.
(3) Robertson, R. E. Prog. Phys. Org. Chem. 1967, 4, 213.
2
14
•
Vol. 12, No. 2, 2008 / Organic Process Research & Development

Table 2. Hydrolysis of EEHP, 2, in aqueous solution at 95 °C
ionisation of
%
-
a
5
/s-1
pH
[OH ]/M
10 k
5.68
69.2
>311
e
phenolic group
5
4
8
.0
6.8 × 10-
2.0
18.9
68
-
9
1
.0
6.8 × 10
b
-3
0.0
6.8 × 10
a
) 6.76 × 10 M2 (pK
-13
) 12.17) at 95 °C.4 Reaction limited by rate of
b
K
w
w
dissolution of 2 and instrument response time.
Hence for a given pH at 95 °C the hydroxide concentration
is almost 2 orders of magnitude higher than at the
-
Figure 2. pH Dependence of the hydrolysis of dimesylate (1)
and EEHP (2) at 95 °C.
corresponding pH at 25 °C; indeed the [OH ] at which k
o
-
2
)
k
OH for this ester at 95 °C (2 × 10 M) is very similar
-
2
1
to that for ethyl methanesulfonate at 25 °C (3 × 10 M).
value as that for the ester group in EEHP, 2, i.e., k
e
) 6.9 ×
-4
-1
EEHP, 2. The kinetics of this reaction showed simple first-
order behaviour, eq 5, for the rate of formation of the acid,
ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid, 5, as
expected, because 2 is soluble as a phenol/phenolate mixture
at reaction concentrations.
10 s : this corresponds to a solubility of 3 in water at 95
-4
°C, of S ) 1.5 × 10 M. At pH 9, the above rate shows that
o
complete reaction would require ca. 250 h.
The reaction at pH 10 was significantly faster than at pH 9
(hydroxide consumption and HPLC analysis), as expected. The
reaction was, however, difficult to analyse quantitatively without
further assumptions because of some accompanying hydrolysis
of the aryl sulfonate group of the (soluble) product, 6, which is
manifested as accelerating hydroxide consumption as the
reaction proceeds. The hydrolysis of aryl sulfonate esters has
d[5]
dt
)
ke[2]
(5)
The reaction was studied at pH values 8, 9, and 10, and the
results are listed in Table 2. Also included in Table 2 is the %
ionisation of the phenolic group, determined from the total
5,6
been previously shown to be base catalysed.
-
hydroxide uptake (mol OH consumed/mol 2 ) 1 + fraction
Discussion
of phenolic group of 2/5 ionised).
The present kinetic data are limited, but the implications for
process development are clear. The conclusions that the rate of
hydrolysis of the carboxylic ester group of 2 and 3 in the range
studied is directly proportional to the hydroxide concentration,
whereas that of the alkyl mesylate ester of 1 is independent of
pH below pH ≈ 10 at 95 °C are consistent with expectations
based on simple carboxylate and methylsulfonate ester hydroly-
sis. Furthermore, the contrasting behaviour of the carboxylate
ester of 2 and the alkylsulfonate ester of 1, illustrated in Figure 2,
point immediately to a solution to the issue of selective removal
of 1 in the presence of product ester, 3, namely the use of near-
neutral pH conditions.
In this case, as expected, the rate constants for hydrolysis
of the ester group increase strongly with pH. At pH 10 the rate
-3
-1
constant would be expected to be around 6 × 10
s
(half-
life ≈ 2 min), based on extrapolation from values at pH 8 and
pH 9, but under these conditions the reaction is partially limited
by the rate of dissolution of 2. The percentage ionisation at the
different pH values may also be determined from the total
amount of hydroxide consumed during reaction, and the
observed values (Table 2) correspond to pK
a
) 9.6 ( 0.1 for
the phenolic groups of ethyl ester 2, and its hydrolysis product,
5, assuming these to be closely similar.
Thus, for example, at pH 7 the rate constant for hydrolysis
of the sulfonate ester of 1 is 100 times that of the carboxylate
ester, 2, whereas it is 10 times lower at pH 10. The product
ester, 3, should similarly show a 1000-fold rate reduction relative
to 1 as the pH is reduced from 10 to 7. The product is also
further protected by its low solubility, as under reaction
conditions only 0.2% is soluble at reaction end.
Ester, 3. The pH-rate profile for ester 3 in homogeneous
solution should be very similar to that of 2. The very low water
solubility of 3, however, means that at higher levels of 3 the
resulting two-phase system will hydrolyse much more slowly
due its low availability in the aqueous phase. Reactions were
studied at pH ) 9 and 10. At pH 9 the observed reaction, as
measured by hydroxide uptake and HPLC analysis, shows a
zero-order rate of product (2S)-2-ethoxy-3-[4-(2-{4-[(methylsul-
fonyl)oxy]phenyl}ethoxy)phenyl] propanoic acid, 6), formation,
2 3
The pH of the reaction mixture (4 mol Na CO /mol 1),
Scheme 1, varies between 10.5 at the start of reaction and 9.5
at the end of the hold period. The above results suggest that
losses of 3 during removal of any remaining 1 from the reaction
mixture could be reduced to a negligible value by neutralising
the reaction mixture to around pH 7 for the hold period once
-7
-1
eq 6, with k
S
e o
) 1.04 × 10 M s at 95 °C.
d[6]
dt
)
keSo
(6)
(
4) Harned, H. S.; Robinson, R. A. Trans. Farad. Soc. 1940, 36, 973.
It is therefore not possible to determine separately k
e
and
(5) Farrar, C. R.; Williams, A. J. Am. Chem. Soc., 1977, 99, 1912 and
references therein.
the solubility S
can, however, estimate S
o
directly from the kinetic measurements. We
if we assume that k has the same
(
6) Laleh, A.; Ranson, R.; Tillett, J. G., J. Chem. Soc., 1980, 610 and
o
e
references therein.
Vol. 12, No. 2, 2008 / Organic Process Research & Development
•
215

the coupling is complete. It was found that under such
conditions, hydrolysis of remaining 1 to alcohol 4 proceeds at
a rate similar to that observed in mixtures held under normal
reaction conditions obtained at the end of the coupling process,
but no observable loss of 3 occurred even after an additional
hold time of 16 h.
°C to remove any residual methanesulfonyl chloride. The
product was isolated by filtration and dried in vacuo at
40 °C. The yield of dimesylate (1) was 18.2 g (85%).
1
H NMR (CDCl , 500 MHz, 300 K) δ 7.30-7.18 (m, 4H),
3
4.41 (t, J ) 6.7 Hz, 2H), 3.14 (s, 3H), 3.07 (t, J ) 6.7 Hz, 2H),
13
2.90 (s, 3H); C (NMR (CDCl
36.3, 131.0 (2C), 122.7 (2C), 70.0, 37.9 (2C), 35.4.
MS (ES) m/z 317 (M + Na), 312 (M + NH
M + H).
3
, 125 MHz, 300 K) δ 148.6,
1
+), 295
4
Conclusion
(
The pH dependence of the base hydrolysis of alkyl car-
boxylate and methanesulfonate esters shows strong quantitative
differences. The former react very slowly at low pH (5–6), but
Ethyl 2(S)Ethoxy-3-(4-hydroxyphenyl)propanoate (EEHP),
2
. was supplied by Lonza AG, Switzerland, or was prepared
7
as previously described.
the rate increases directly as the hydroxide concentration
-
Preparation of Ethyl (2S)-2-Ethoxy-3-[4-(2-{4-[(methylsul-
fonyl)oxy]phenyl}ethoxy)phenyl]propanoate, 3. Concentrated
hydrochloric acid (37%w/w, 1.75 mL, 0.37 mol equiv) was
added to a mixture of 6 (35 g, 1.0 mol equiv) in ethanol (350
mL, 10.0 rel vol) at ambient temperature. The mixture was then
heated to reflux and distilled under atmospheric pressure to
effect the reaction. After 150 mL of solvent had been collected,
the reaction mixture was analysed by TLC (60: 40 EtOAc/
isohexane) for the presence of starting material 6. TLC analysis
indicated no starting material was left. The mixture was then
cooled to room temperature and concentrated under reduced
increases (rate constant (eq 4), k
e
∝ [OH ]). The latter are
characterised by high, uncatalysed (water) rates, but relatively
lower kOH values; the result is a constant rate of hydrolysis up
to around pH 12 at 25 °C (pH 10 at 95 °C), above which the
-
rate increases with [OH ]. We have shown that this difference
can be successfully exploited to enable selective hydrolysis of
an alkyl methanesulfonate impurity in the presence of a
carboxylic ester-containing product. The conclusions should be
generally applicable to the removal of (potentially genotoxic)
alkyl esters of methane sulfonic acid in the presence of
carboxylic esters and indeed other base-sensitive groups.
vacuum to give a pale-yellow/colourless oil (36.1 g, 96.6%).
1
H NMR (CDCl , 500 MHz, 300 K) δ 7.33 (d, J ) 8.6 Hz,
3
Experimental Section
2H), 7.22 (d, J ) 8.6 Hz, 2H), 7.14 (d, J ) 8.6 Hz, 2H), 6.80
(
d, J ) 8.6 Hz, 2H), 4.20-4.09 (m, 4H), 3.96 (dd, J ) 6.0 Hz,
.2 Hz, 1H), 3.63-3.55 (m, 1H), 3.39-3.30 (m, 1H), 3.11 (s,
Materials. Inorganic chemicals and the phase-transfer
catalyst, PEG-400, were high-purity commercial reagents used
without further purification.
1
3
7
H), 3.08 (t, J ) 6.6 Hz, 2H), 2.99-2.89 (m, 2H), 1.22 (t, J )
13
.0 Hz, 3H), 1.16 (t, J ) 7.0 Hz, 3H); C NMR (CDCl
3
, 125
HPLC analyses were carried out using Agilent Symmetry
MHz, 300 K) δ 172.5, 157.4, 147.9, 138.0, 130.6 (2C), 130.4
2C), 129.5, 121.9 (2C), 114.3 (2C), 80.4, 68.2, 66.2, 60.8, 38.4,
C8 column (3.9 mm × 150 mm) with 45/55 (v/v) CH
3
CN/50
(
3
mM sodium phosphate buffer and 70/30 (v/v) CH CN/ 50 mM
3
7.3, 35.1, 15.1, 14.2.
MS (ES) m/z 454 (M + NH
sodium phosphate buffer as the mobile phases (1.0 mL/min)
and detection at 220 nm wavelength.
Preparation of 4-{2-[(Methylsulfonyl)oxy]ethyl}phenyl
Methanesulfonate, 1. Methanesulfonyl chloride (12.88 mL,
+), 437 (M + H).
4
1
4
-(2-Hydroxyethyl)phenyl methanesulfonate, 4. H NMR
CDCl , 500 MHz, 300 K): δ 7.30-7.18 (m, 4H), 3.88-3.80
m, 2H), 3.12 (s, 3H), 2.86 (t, J ) 6.6 Hz, 2H), 1.74-1.68 (br
(
(
3
1
67 mmols, 2.30 mol equiv) was added slowly over 2-2.5
13
s, OH); C NMR (CDCl
3
, 125 MHz, 300 K) δ 147.8, 138.3,
h to a cooled (-20 °C) solution of 2-(4-hydroxy-
phenyl)ethanol (10.0 g, 72.4 mmols, 1.0 mol equiv) and
triethylamine (23.2 mL, 167 mmols, 2.3 mol equiv) in
iso-butyl methyl ketone (MIBK) (87.0 mL, 8.7 rel vol),
keeping the reaction temperature below 20 °C. The
mixture was heated to 25 °C and held at 25 °C for 1 h to
complete the reaction. The mixture was then warmed to
1
30.6 (2C), 122.0 (2C), 63.3, 38.5, 37.3.
+
MS (ES) m/z 234 (M + NH
4
).
Kinetic Measurements. The hydrolysis of dimesylate, 1,
EEHP, 2, and ester, 3, were carried out in a 500-mL jacketed
vessel, using HEL Autolab software to control and record the
temperature, the pH of the experiment, and the volume of
hydroxide consumed as the reactions proceeded. The vessel was
equipped with a retreat-curve agitator, thermocouple, water
condenser, and Frisolyt pH probe. The reaction temperature was
maintained at 95 °C. Samples were also removed periodically
for HPLC analysis to confirm species identity as reactions
proceeded.
3
5 °C and filtered to remove the triethylamine hydrochlo-
ride. The filter cake was washed with MIBK (50.0 mL,
.0 rel vol). The combined filtrates were washed twice
5
with water (2 × 20.0 mL, 2.0 rel vol) at 35 °C. The MIBK
solution was then concentrated under reduced vacuum to
a total volume 60 mL (6.0 rel vol). The solution was
cooled to 20 °C and seeded with dimesylate (1) (0.06 g,
Hydrolysis of Dimesylate, 1. In a typical procedure, water
(280 mL) and PEG-400 (1.24 mL, 0.2 mol equiv) were charged
0
.2 mmol, 0.003 mol equiv). The solution was held at 20
into a 500-mL jacketed vessel. The mixture was stirred at 350
rpm and was heated to 95 °C. To adjust the pH of the contents
to 10, 1 M NaOH was then added via solenoid pump.
Dimesylate (1) (8.21 g, 0.0279 mol, 1.0 mol equiv) was then
°
C for 1 h to effect nucleation and then cooled over 2 h
to 5 °C for the crystallisation. Isooctane (25.0 mL, 2.5
rel vol) was then added slowly over 1 h, keeping the
reaction temperature below 20 °C. The slurry was then
cooled to 5 °C, and the solids were filtered. The solid
was then slurried in ethanol (30.0 mL, 3.0 rel vol) at 20
(
7) Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Process Res. DeV
2004, 8, 838.
2
16
•
Vol. 12, No. 2, 2008 / Organic Process Research & Development

added in three aliquots over 10 min, keeping the reaction
temperature at 95 °C and the pH at 10. The mixture was held
at 95 °C and at pH 10, and the volume of hydroxide consumed
was recorded until the reaction had stopped, i.e. no more NaOH
was taken up.
Hydrolysis of Ethyl Ester (2). 2[6.65 g (0.0279 mol)] was
charged, and the hydrolysis was studied at pH 10, 9, and 8.
Hydrolysis of Ethyl Ester (3). In 10 mL of xylene was
dissolved 10.9 g (0.023 mol) of (3). The ester solution was then
added to the water at 95 °C at pH 10, over 5 min. The hydrolysis
of 3 was studied at pH 10 and 9.
any inorganics. Water (70 mL, 3.5 rel vol) was added to the
filtrates, and the mixture was extracted with EtOAc (3 × 60
mL, 3 × 3.0 rel vol) at 35 °C. The aqueous phase was then
concentrated to 4.0 rel vol by vacuum distillation. Acetic acid
(83.9 g, 1.398 mols, 16.65 mol equiv) and acid 6 seeds (0.1 g,
0.25 mmol, 0.003 mol equiv) were added to the mixture at 27
°C. The mixture was stirred at 27 °C for 1 h. An aqueous
2 4
solution of CH SO (3.6 mL, 0.068 mol, 0.8 mol equiv in water
(92 mL, 4.6 rel vol)) was then added over 2 h, keeping the
temperature of the contents at 27 °C. The slurry was cooled to
-10 °C over 7 h and held at -10 °C for 2 h. The slurry was
then filtered, washed with water (3 × 60 mL, 3 × 3.0 rel vol),
and dried under vacuum at 40 °C to give product 6 (24.2 g,
70%).
Typical Manufacturing Process for (2S)-2-Ethoxy-3-
[
4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxyphenyl]pro-
panoic Acid, 6. Dimesylate, 1, (39.53 g, 0.134 mol, 1.6 mol
equiv), EEHP, 2 (20.0 g, 0.084 mol, 1.0 mol equiv), water (144
mL, 7.2 rel vol), sodium bicarbonate (35.59 g, 0.336 mol, 4.0
mol equiv), and polyethyene glycol (PEG 400) (6.71 g, 0.017
mol, 0.2 mol equiv) were heated to reflux (∼102 °C) in a 500-
mL jacketed vessel with vigorous stirring. The biphasic was
held at reflux for 7 h. The mixture was cooled to 95 °C and the
aqueous phase separated. The organic phase was cooled <55
This reaction has also been carried out on 256 mol scale on
plant.
Acknowledgment
We thank Lisselotte B. Johansson (who sadly passed away
in 2007) for help with analytical data.
°
C, and acetone (54 mL, 2.7 rel vol) was added. The mixture
was cooled to 25 °C, aqueous solution of LiOH·xH O (4.6 g,
.109 mol, 1.3 mol equiv in water (80 mL, 4.0 rel vol)) was
Supporting Information Available
H, C NMR and LC/MS spectra in pdf format for
compounds 1, 3, and 4. This information is available free of
1
13
2
0
added, and the mixture was stirred at 25 °C for 2 h. EtOAc (10
charge via the Internet at http://pubs.acs.org.
mL, 0.5 rel vol), was added, and the mixture was stirred at 25
°
4
C for another 45 min. The solution was then concentrated to
.5 rel vol by vacuum distillation. EtOAc (120 mL, 6.0 rel vol)
was added, and the mixture was screened at 35 °C to remove
Received for review October 9, 2007.
OP700226S
Vol. 12, No. 2, 2008 / Organic Process Research & Development
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