The use of environmental metrics to evaluate green chemistry improvements to the synthesis of (S,S)-reboxetine succinate

Article abstract of DOI:10.1039/c1gc15921f

The Pfizer Green Chemistry metrics program is described and exemplified with a case history involving the synthesis of (S,S)-reboxetine succinate. The initial route used a classical resolution approach and generated high levels of waste. This route was replaced by an enantiospecific synthesis which used Sharpless epoxidation chemistry, an enzymatic process to selectively protect a primary alcohol and a new efficient method of chiral morpholine construction as key steps. These improvements reduced the levels of waste produced by the synthesis by more than 90%. Detailed metrics starting from a common starting material (trans-cinnamyl alcohol) for all routes of synthesis are presented.

Full text of DOI:10.1039/c1gc15921f

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PAPER
The use of environmental metrics to evaluate green chemistry improvements
to the synthesis of (S,S)-reboxetine succinate
Georges Assaf, Graham Checksfield, Doug Critcher, Peter J. Dunn, Stuart Field, Laurence J. Harris,*†
Roger M. Howard, Gemma Scotney, Adam Scott, Suju Mathew, Geoffrey M. H. Walker† and
Alexander Wilder
Received 28th July 2011, Accepted 16th September 2011
DOI: 10.1039/c1gc15921f
The Pfizer Green Chemistry metrics program is described and exemplified with a case history
involving the synthesis of (S,S)-reboxetine succinate. The initial route used a classical resolution
approach and generated high levels of waste. This route was replaced by an enantiospecific
synthesis which used Sharpless epoxidation chemistry, an enzymatic process to selectively protect
a primary alcohol and a new efficient method of chiral morpholine construction as key steps.
These improvements reduced the levels of waste produced by the synthesis by more than 90%.
Detailed metrics starting from a common starting material (trans-cinnamyl alcohol) for all routes
of synthesis are presented.
and analysis of Green Chemistry metrics. The synthesis of ( )-
Introduction
reboxetine mesylate is shown in Scheme 1 and its conversion to
( )-Reboxetine mesylate 1 is a selective norepinephrine uptake
(S,S)-reboxetine succinate shown in Scheme 2.
(NRI) inhibitor1 which is marketed as the racemate, under the
trade name EdronaxTM, for the treatment of depression, in
more than 60 countries. The (S,S)-enantiomer is significantly
more active than the racemate in a number of studies2 and
has undergone clinical evaluation as the succinate salt 2 for a
number of indications in the pain therapeutic area. The chemical
development program for (S,S)-reboxetine succinate was very
much influenced by the unusual history of the compound. Phar-
macia had manufactured 15 000 kg of ( )-reboxetine mesylate
or late stage intermediates, such as 3 in readiness for a US
approval of EdronaxTM. When this approval did not occur it
Pharmacia intended to commercialise this synthesis based on
was clear that only a small proportion of the stock would be
a very fast development program and a desire to use up the
required to support the other markets and the remainder was
existing stocks and in late 2003 the chemistry was successfully
“written off” and made available to the research organisation.
transferred to a manufacturing site. Following the takeover of
Not surprisingly the large stock pile of material was initially used
Pharmacia by Pfizer, the program was reassessed both from
as a starting point for the synthesis of (S,S)-reboxetine succinate,
the single enantiomer which was being developed for new
a clinical and chemistry point of view and this led to an
evaluation of new routes and processes. From a Green Chemistry
indications in the pain area. The development work was being
perspective the chemistry outlined in Schemes 1 and 2 had a
carried out at a time when the discipline of Green Chemistry was
becoming more established in the pharmaceutical industry.3 As
such, in this article we focus on the environmental (and cost)
number of disadvantages:
∑ The use of a late stage resolution meant that by definition
more than half of the materials used to prepare ( )-reboxetine
improvements that were achieved through process development
were wasted.
and synthetic route design coupled with rigorous measurement
∑ The isolation of the mesylate salt (Scheme 1) and breaking
that salt back to reboxetine free base (Scheme 2) was clearly
historical and produced large quantities of unnecessary chemical
waste.
∑ Differentiation of the two hydroxyl groups in compound
4 required a protection and deprotection strategy which was
Chemical Research and Development, PharmaTherapeutics
Pharmaceutical Sciences, Pfizer Worldwide Research and Development,
Sandwich Laboratories, Ramsgate Road, Sandwich, Kent, CT13 9NJ
† Analytical development
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Scheme 1 The synthesis of ( )-reboxetine mesylate,4 the Active Pharmaceutical Ingredient (API) for EdronaxTM
.
Scheme 2 The conversion of ( )-reboxetine mesylate to (S,S)-reboxetine succinate.
sub-optimal, as the initial TMS protection was poorly selective
for the primary alcohol.
and the mass of solid waste generated. In the early days there
was a tendency to collect metrics on projects that showed a
story of success but in 2006 the company moved to a position
of capturing metrics for all of its development compounds. In
2008 reduction goals were set for the first time (for example a
20% reduction in organic solvent use across the development
portfolio by 2012). To help achieve these goals a number of
strategies were put in place.
∑ The avoidance of late stage resolutions – An analysis of the
portfolio showed that having just one late stage resolution in
the portfolio (classical, chromatographic or biocatalytic) would
mean that the reduction target would not be met.
∑ Chloroacetyl chloride was used as a two carbon fragment to
build up the morpholine ring, however this produced interme-
diate 5 at the wrong oxidation level so necessitating a reduction
reaction with a strong metal hydride reagent (VitrideTM).
∑ Dichloromethane was used as a solvent in the processes to
break both the mesylate and mandelate salts (Scheme 2).
∑ In total more than 1098 kg of solvent, 77 kg of reagents
and 770 kg of water was used to convert the ( )-diol 4 into
(S,S)-reboxetine succinate.
∑ To increase the number of genuine telescoped steps, where
the solvent for one reaction is also used for the next reaction,
with little or no additional processing.
∑ To increase the number of reactions carried out in water
(especially reactions catalysed by enzymes).
∑ To run reactions with low heats of reaction in more concen-
trated solution or suspension after detailed discussion with the
process safety laboratory. Process chemists in pharmaceutical
Green Chemistry metrics program
Pfizer started to collect Green Chemistry metrics more than a
decade ago5–7 and by 2004 had identified and agreed a global set
of metrics to be collected at all of its research sites. This global
set of metrics included organic solvent use, reagent use, water
use, overall percentage yield, number of synthetic steps, number
of catalytic steps, number of isolations, number of solvents used
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Scheme 3 The Pfizer early resolution route to (S,S)-reboxetine succinate.
and fine chemical companies routinely obtain heat of reaction
data for safety reasons before scale up, but this data is not always
used to help with efficient process design.
resolution step much earlier in the synthesis. We also envisaged
being able to make improvements to the metal hydride reduction
step to reduce both the reagent stoichiometry and the amount of
solid waste generated by the work-up procedure. We also wanted
to improve on the conversion and in situ quality generated in the
ring closure reaction to avoid the need for carbon treatments that
purged significant process related impurities and color generated
in the Pharmacia EdronaxTM process.
Scheme 3 shows how this early resolution strategy was
successfully implemented at pilot scale.
Key features of this new process that made a significant
contribution to the overall reduction in the amount of materials
used to prepare the API were:
∑ To introduce more efficient intermediate isolations (e.g. by
direct isolation processes).8
∑ To use technologies to reduce solvent usage (e.g. using solu-
bility data from automated solubility measurements in process
design, using centrifugal extraction when appropriate and if
solvent replacement (striping one solvent and replacing with
another) is required to use the Pfizer distillation optimisation
tool.9
∑ Engage the manufacturing group early in solvent recovery
plans especially for expensive solvents with a high life cycle
impact such as THF and 2-MeTHF.
In general these strategies were successful and the goal of
reducing solvent use by 20% across the development portfolio
was achieved two years early. For (S,S)-reboxetine succinate, the
waste levels produced via the EdronaxTM route (Schemes 1 and
2) were more than 20 times the 2012 target, so there was much
work to be done.
∑ The ( )-amino alcohol 3 was resolved in the first step using
a “non-classical” resolution process to establish the absolute
stereochemistry.
∑ The ( )-mesylate salt was no longer generated or isolated as
a process intermediate and this simplified the overall synthesis in
terms of number of steps and hence reduced waste generation.
∑ The N-acylation/cyclisation sequence to generate 8 was
improved significantly. The use of tert-butanol/tert-butoxide for
the ring closing step allowed the chemistry to be run safely in a
semi-batch process. Having more control over the addition rate
minimised the heat generated and gave a superior in situ impurity
profile (>97% vs. 65%) meaning that activated carbon treat-
ment was no longer required to purge process related impuri-
ties.
∑ In the reduction of 8, VitrideTM (MW = 202.16) was replaced
by the more atom economical lithium aluminium hydride (LAH,
MW = 37.95) and the stoichiometry was reduced from 5 to 1
molar equivalents. This resulted in a >95% reduction in the
mass of reducing agent charged to the vessel when carrying out
this reaction.
Improving the throughput and minimising the
environmental impact of the Edronax process
One of the obvious issues with using ( )-reboxetine mesylate
1 as an isolated intermediate en-route to (S,S)-reboxetine was
that the end game of the synthesis became very protracted. All of
the carbon framework of the API was established after the metal
hydride reduction step but this still required mesylate salt forma-
tion, resolution, recrystallisation (to upgrade the mandelate salt
enantiomeric excess) and finally counter ion exchange to afford
the succinate salt of (S,S)-reboxetine. This inefficiency (overall
yield 17.8% from 3) could be improved upon by moving the
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Scheme 4 The Pfizer asymmetric synthesis for (S,S)-reboxetine intended for commercialisation.
∑ The work-up of the reduction reaction was improved by
implementing an aqueous triethanolamine quench followed by
an aqueous NaOH extraction of the complexed aluminium salts,
which completely eliminated solid waste from the process. As
an additional benefit, the reduction in molar equivalents of
metal hydride reagent reduced the energy evolved by the quench,
making it much safer to scale-up.
In the resolution step the chiral acid used, (S)-camphanic
acid forms an insoluble salt with the undesired enantiomer.
After filtration, the resultant toluene solution of the desired
camphanate salt 6 was then used to make an insoluble benzoate
salt which upgrades in chiral purity from 80% e.e. to 99% e.e.
upon isolation. A classical resolution would have crystallised
the desired enantiomer and this could be achieved by using (R)-
camphanic acid but due to its much higher cost and limited
availability on scale the non-classical process was preferred. A
great feature of this resolution process was the use of a single
organic solvent (toluene) all the way through the process, which
made it operationally simple but also made full recovery of this
solvent a viable option. On laboratory scale we also identified
that the (S)-camphanic acid could be recycled and reused as the
resolving agent in subsequent batches.
bond forming chemistry were required to take the project
to the next level of environmental performance and further
reduce the API $/kg cost. The team focussed on; establishing
the absolute stereochemistry of the molecule via asymmetric
synthesis, the protecting group strategy and the construction of
the morpholine ring without the need to adjust the oxidation
state. We envisaged using the common cinnamyl alcohol as the
starting point of the synthetic sequence as it was known to
be a good substrate for the Sharpless asymmetric epoxidation
reaction (SAE)10 and the subsequent ring opening of the epoxide
with 2-ethoxyphenol (to generate 9) had been demonstrated in
earlier work by the Pharmacia team.11 Scheme 4 shows the
route that was developed and intended for use in commercial
manufacturing.
Once the key chiral diol intermediate 9 had been secured
we turned our attention to the protecting group strategy. The
EdronaxTM process utilised trimethylsilyl (TMS) protection at
-20 ◦C to selectively protect the primary alcohol which was
followed by mesylation of the secondary alcohol, acidic cleavage
of the O-TMS bond and then base-induced epoxidation under
phase transfer conditions, (Scheme 1). The major issues with
this chemistry are related to TMS protection step which required
cryogenic reaction conditions. In addition TMS migration to the
secondary alcohol led to a loss of selectivity and generation of
impurities in the downstream steps. In addition it was ◦found that
the chiral diol 9 was much higher melting (by some 28 C)4,11 and
much less soluble than the racemic diol 4, and this necessitated
the whole sequence was run in a chlorinated solvent (DCM).11
To address these issues we evaluated alternative protecting
groups. An initial investigation of chemical methods (e.g. acyl
chlorides) lacked the required selectivity, however enzymatic
methods proved to be successful in selectively acylating the
primary alcohol at 30 ◦C using iso-propenyl acetate as the acyl
source to deliver protected intermediate 10. A nice advantage
of this approach was that the by-product is acetone. Activation
of the secondary alcohol then afforded the mesylate 11 which
The overall yield at pilot plant scale for this route was 24.6%
from 3 (versus 17.8% for the late resolution process) and all
chlorinated solvents were removed from the manufacturing
process that was used to generate clinical (phase 3) quality
API. Although this represented a significant improvement this
route was still limited by the absolute stereochemistry being
established by a resolution step that has a maximum theoretical
yield of 50%.
A step change in efficiency; changes to the bond
forming chemistry
Although good progress had been made with the introduction
of the early resolution route it was felt that changes in the
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was subjected to a one pot, base mediated acetate cleavage and
subsequent ring closure to generate the chiral epoxide 12.
The major innovative feature of the chemistry depicted in
Scheme 4 was a redesign of the morpholine ring construction.
From the EdronaxTM process we knew that the epoxide 12
would undergo ring opening at its terminus with ammonia.
We hoped to exploit this reactivity towards amines in a ring
opening reaction with a bifunctional reagent; that would deliver
the two carbon atoms required to complete the skeleton of the
API but also embed a leaving group into the molecule to set up
a system that would undergo a ring closure reaction to generate
the morpholine.
is supported by the observed 55% reduction in input materials
required to run the early resolution process at pilot scale.
However by switching to the commercial route that installs the
absolute stereochemistry by a catalytic asymmetric reaction,
requires fewer intermediate isolations and avoids the lactam
reduction step then order of magnitude reductions in the total
amount of materials used to make a kilogram of product were
realised. The process that was intended for commercialisation
generates more than 90% less waste than the original Pharmacia
process, with an almost five-fold increase in overall yield.
Key experimental procedures13
The commercial process (Scheme 4) utilises a low toxicity
bi-functional reagent, 2-aminoethyl hydrogensulfate 13 (tested
AMES negative) that cleanly opens the epoxide 12 in the
presence of DBU to generate zwitterion 14, which was insoluble
in the toluene/ethanol reaction solvents. The product of this
reaction could be filtered and dried to afford an intermediate of
very high purity. Finally we found that by careful selection of the
reaction conditions (base, solvent, temperature) the zwitterion
14 would cyclise to (S,S)-reboxetine free base via a highly
selective and high yielding intramolecular reaction.12
With the bond forming chemistry established the environmen-
tal performance was optimised by designing all the reactions
into an efficient manufacturing process; telescoping most of
the transformations, minimising solvent volumes, optimising
reagent stoichiometries and isolating only two intermediates (9
and 14).
General
Ethanol refers to ethanol denatured with 3% cyclohexane. The
diol 9 was prepared by the method of Henegar.11 NMR spectra
were obtained on a Joel ECS 400 spectrometer operating at
400 MHz for proton and 100 MHz for carbon. The number of
hydrogens attached to each carbon was assigned using a HSQC
experiment. Reactions were monitored using reversed phase
HPLC (Fortis C18, 3 mM particle size column, buffer; 10mMol
NH4OAc at pH 6.8). The mass spectrum of the zwitterion 14
was recorded on a Waters Micromass ZQ Mass Spectrometer.
Optical rotation of the final product 2 was measured on a
Perkin Elmer 341 polarimeter. For (S,S)-reboxetine succinate
2 the assay was determined by reversed phase HPLC using
a Phenomenex Luna C8(2) 150 ¥ 4.6 mm 5 mm column,
MPA = 0.02 M KH2PO4 @ pH 6.8 (0.5 M KOH) and MPB =
acetonitrile. Chiral purity was determined by HPLC using
a Diacel chiracel OJ 250 ¥ 4.6 mm column, eluting with
heptane/ethanol/diethylamine (1500/500/1).
Green Chemistry metrics for (S,S)-reboxetine
succinate
Preparation of acetate 10
Throughout the design and development of the (S,S)-reboxetine
commercial route the team regularly (at least annually) collected
a set of metrics and analysed these for opportunities to improve
the environmental performance of the API manufacturing
process. We used an in-house metrics tool for data collection
to model the effect of individual process changes on the
performance of the overall process and our ability to achieve
or exceed the goals that we had established at a portfolio level.
A comparison of the three routes described in this paper is
presented in Table 1. As the key raw material to all routes is
trans-cinnamyl alcohol then this data provides a like for like
comparison of waste generated by the three different routes.
This data clearly shows that significant reductions in the
amount of process waste can be achieved by reordering steps
and eliminating redundant unit operations and isolations. This
Toluene (5.0 L) and iso-propenyl acetate (694.43 g, 6.94 mol)
were charged to a 25 L fixed rig reactor followed by the diol 9
(1.0 kg, 3.47 moles). The reaction mixture was agitated at 100
rpm and heated to an internal temperature of 30 ◦C. Novozymes
CaL B (20.0 g) was added and the mixture was agitated for 17 h
after which time the acylation was complete by HPLC analysis.
The enzyme was removed by filtration and the filtrate progressed
to the next step.
Preparation of the mesylate 11
To a stirred solution of 10 from the previous step, triethylamine
(596.6 g, 5.90 mol) was added in one portion at 20 ◦C. A solution
of methanesulfonyl chloride (536.3 g, 4.68 mol) in toluene (1.0 L)
Table 1 A comparison of the key Green Chemistry metrics for the 3 routes
Solvent (L
kg-1 API)
Aqueous (L
kg-1 API)
Reagent (kg
kg-1 API)
Number of inter-
mediate isolations
Overall yield
7.3%
Pharmacia Edronax process starting from trans-cinnamyl
alcohol (Scheme 1 & 2)
Pfizer early resolution process starting from trans-cinnamyl
alcohol (Scheme 3)
1237
657
79
854
272
61
112
64
6
4
2
10.1%
Pfizer process for commercialization starting from
trans-cinnamyl alcohol (Scheme 4)
Input material reduction relative to initial Edronax process
13
35.0%
94%
93%
88%
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was added dropwise over 120 min. The reaction mixture was
stirred for a further 60 min after which time analysis by HPLC
showed that the reaction was complete.
Hydrochloric acid (1 M, 3.0 L, 3.0 mol) was added in one
portion. The biphasic mixture was agitated at 100 rpm for 30 min
then allowed to separate for 10 min. The phases were separated
and the organic (toluene) phase of the mesylate 11 progressed
directly to the next step.
(1H, m, Ph–H), 7.34 (2H, m, Ph–H), 7.42 (2H, m, Ph–H) ppm:
13C NMR [100 MHz, [CD3)2SO] d = 15.3 (CH3), 47.7 (CH2),
49.6 (CH2), 61.8 (CH2), 64.6 (CH2), 69.4 (CH), 82.7 (CH), 114.8
(CH), 118.1 (CH), 121.2 (CH), 122.8 (CH), 127.9 (CH), 128.4
(CH), 128.7 (CH), 138.0 (C), 147.6 (C), 149.9 (C) ppm. MS
(positive ion) m/z = 412 (100%, M +1), 332 [50%, (M-SO3) + 1].
Conversion of the zwitterion 14 to (S,S)-reboxetine succinate 2
Preparation of epoxide 12
To a 25 L fixed rig reactor was introduced tetrahydrofuran
(7.14 L) and ethanol (210 ml) followed by the zwitterion 14
(1.05 kg, 2.55 moles). The resulting slurry was stirred at 18 ◦C.
Sodium hydroxide (317.69 g, 7.66 mol) was added in one portion.
On completion of the addition, the temperature was increased
to reflux (65 C) by setting the jacket temperature to 80 C. A
stir rate of 100 rpm was used. The reaction was monitored by
HPLC until completion (approximately 3 h).
The reaction mixture was cooled to room temperature then
treated with water (5.25 L) and left to stir for 16 h at room
temperature. Cyclohexane (4.20 L; 3.28 kg) was added to
improve the phase separation. The biphasic mixture was stirred
for 1 h after which time the phases were separated.
The organic layer was washed with water (2.20 L). This water
wash was analysed before proceeding [ensuring that the pH >
12.0 and that conductivity (to assess removal of inorganics) to
be within 1–2 mS cm-1, actual s = 1.63mS cm-1].
A solution of sodium hydroxide (1.44 kg, 36 mol) in water
(3.0 L) and methyltributylammonium chloride (81.79 g, 346.8
mmol) was added to toluene solution of the mesylate 11 from
the previous step. The resulting mixture was agitated at 100 rpm
for 3.5 h after which time analysis by HPLC showed the reaction
was complete.
The phases were separated, the bottom phase discarded. A
thin dark layer was present between the organic (top) and
aqueous (bottom) layers and this material was mainly residue
from the phase transfer catalyst. To remove the phase transfer
catalyst from the vessel, an extra water wash (2.0 L) was applied.
The biphasic mixture was agitated at 100 rpm for 15 min then the
phases were allowed to separate. The lower aqueous phase was
separated and the upper organic phase (containing the epoxide
12) was held at 0 ◦C before proceeding to next step.
◦
◦
Preparation of the zwitterion 14
The organic layer was distilled at atmospheric pressure under
Dean–Stark conditions to decrease the water level to 0.2%
(Karl-Fischer analysis). The organic phase was concentrated
by distillation under atmospheric pressure to approximately 2.0
L (2.0 L/kg of total volume). The concentrate was treated with
ethanol (5.10 L) and distilled at atmospheric pressure to remove
most of the THF. The operation was repeated until no THF was
detected by NMR (typically two strip and replace cycles were
required to achieve the target).
After removing the THF, ethanol (4.94 L) was charged to
the reaction vessel giving a total volume of 7.0 L/kg input
zwitterion 14. A suitable crystallisation process with respect
to seeding point occurs between 5.5 and 6.5 L/kg. Succinic
acid (301.3 g, 2.55 mol) was added as solid to the reactor and
the resulting mixture heated to reflux to ensure full dissolution.
Approximately 1.0 L of solvent was removed in the recirculation
loop lowering the concentration to the desired range. The
temperature was lowered to 65–66 ◦C (internal) and seeded with
2 (5.51 g, 12.76 mmol). The seeds were allowed to grow over a
period of 3 h at 65–66 ◦C. The mixture cooled at a rate of 0.5 ◦C
per minute to reach 0 ◦C (internal temperature) and granulated
at 0 ◦C overnight for 16 h.
Epoxide 12 (937.5 g, 3.47mol) was diluted with toluene (5.0 L)
and charged to an addition funnel. 2-Aminoethyl hydrogensul-
fate 13 (1.22 kg, 8.67 mol) was slurried in a mixture of toluene
(2.0 L) and ethanol (2.0 L). 1,8-Diazabicyclo[5.4.0]undec-7-ene
(1.29 L, 8.6 mol) was added in one portion and the contents
were heated to 65 ◦C and agitated for 60 min. The solution
of the epoxide 12 in toluene was added to the activated amine
mixture over 1 h and the mixture stirred at 70 ◦C. Two hours after
the end of the addition, the reaction was finished and worked
up. The reaction mixture was cooled to room temperature and
treated with an aqueous solution of sodium hydroxide (416.1
g, 10.4 mol) in water (8.0 L). The resulting biphasic mixture
was stirred at room temperature for 2 h. Stirring was stopped
and the phases allowed to separate. The organic layer was
discarded and the aqueous layer recharged to the reactor. The
aqueous layer was treated with 1.0 M HCl to adjust the pH
value to 5.1–5.2 (the isoelectric point of the zwitterion 14). The
zwitterion crystallised during the pH adjustment, was isolated
by filtration and washed with water (1.225 kg, 86% from diol
9). The zwitterion 14 was purified by reslurrying in ethanol (6.1
L) at 50 ◦C for 2 h, followed by cooling to 25 ◦C and isolation
1
by filtration (1.06 kg, 74% from diol 9). H NMR (400 MHz,
The reaction product was isolated by filtration. The reactor
was washed with cold ethanol (2.10 L) and this solvent was also
used to wash the filter cake. Another charge of ethanol (2.10 L)
CD3OD) d = 1.43 (3H, t, J = 7.1 Hz, CH3CH2O), 3.10 (1H, dd J =
12.6, 3.4 Hz, –CHOHCH2NH2-), 3.18 (1H, dd, J = 12.6, 9.8 Hz,
◦
-
–CHOHCH2NH2-), 3.32 (2H, m, –H2NCH2CH2OSO3 ), 4.10
at room temperature (~20 C) was also used to wash the filter
(1H, dq, J = 11.8, 7.1, CH3CH2OAr), 4.11 (1H, dq, J = 11.8, 7.1,
CH3CH2OAr), 4.21 (2H, m, –H2NCH2CH2OSO3 ), 4.26 [1H,
ddd, J = 9.8, 5.3, 3.4 Hz, Ph(CHOAr)CHOH–], 5.14 [1H, d,
J = 5.3 Hz, Ph(CHOAr)–], 6.68 (1H, ddd, J = 8.1, 7.3, 1.6 Hz,
Ar–H), 6.74 (1H, dd, J = 8.1, 1.6 Hz, Ar–H), 6.84 (1H, ddd, J =
8.1, 7.3, 1.6, Ar–H), 6.93 (1H, dd, J = 8.1, 1.6 Hz, Ar–H), 7.28
cake.
-
The wet solid (0.912 kg) was dried for 24 h under 350 mbars at
50 ◦C to give (S,S)-reboxetine succinate 2 (897.0 g; 81.5% yield)
as a white solid. HPLC assay 72.2% as is, 99.5% salt corrected,
no impurities detected above 0.05%. Chiral purity determined
by HPLC > 99.9% e.e., [a]3D2.4 +18.37 (c 0.37, EtOH). 1H NMR
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data (400 MHz, CDCl3) was in agreement with that reported in
the literature.11
7 G. P. Taber, D. M. Pfisterer and J. C. Colberg, Org. Process Res. Dev.,
2004, 8, 385–388.
8 N. G. Anderson, Org. Process Res. Dev., 2004, 8, 260–265.
9 The Pfizer distillation optimisation tool predicts the most solvent
sparing conditions for the scale up of a stripping and replacement
operation. The tool is set against a backdrop of green solvent
selection. This predictive tool is available on-line to all Pfizer chemists
and chemical engineers and its use can lead to significant reductions
in solvent use. A discussion of the tool was given by D. J. Am Ende,
13th Annual Green Chemistry & Engineering Conference, June 23–
25, 2009.
10 R. M. Hanson and K. B. Sharpless, J. Org. Chem., 1986, 51,
1922–1925; Y. R. M. Hanson, J. M. Klunder, S. Y. Ko, H.
Masamune and K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765–
570.
Acknowledgements
We thank Stewart Hayes, Wilfried Hoffman, Alan Pettman and
Rob Walton for their help and contributions to this project.
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