Development of a scalable synthetic process for DG-051B, a first-in-class inhibitior of LTA4H

Article abstract of DOI:10.1021/op900231j

DG-051B is a first-in-class small molecule inhibitor of leukotriene A4 hydrolase (LTA4H), currently in Phase II clinical development for the prevention of heart attack. Process optimization led from a linear seven-step synthetic procedure to a convergent

Full text of DOI:10.1021/op900231j

Organic Process Research & Development 2009, 13, 1177–1184
Development of a Scalable Synthetic Process for DG-051B, A First-in-Class Inhibitior
of LTA4H
Livia A. Enache,* Isaac Kennedy, David W. Sullins, Wei Chen, Dragan Ristic, Glenn L. Stahl, Sergey Dzekhtser,
Robert A. Erickson, Changren Yan, Frank W. Muellner, Michael D. Krohn, Jennifer Winger, Vincent Sandanayaka,
Jasbir Singh, David E. Zembower, and Alex S. Kiselyov
deCODE Chemistry, Inc., 2501 DaVey Road, Woodridge, Illinois 60517, U.S.A.
Abstract:
central role of LTA4H in other diseases6 including inflammatory
bowel disease (IBD),7 rheumatoid arthritis,8 and inflammatory
lung conditions including asthma9 has been confirmed by
numerous research groups.
DG-051B is a first-in-class small molecule inhibitor of leukotriene
A4 hydrolase (LTA4H), currently in Phase II clinical development
for the prevention of heart attack. Process optimization led from
a linear seven-step synthetic procedure to a convergent four-step
manufacturing sequence that has been used to manufacture at 100-
kg scale. The entire process can be telescoped due to high
conversion reactions, low impurity levels, efficient separations, and
a very effective final purification. Two key aspects of the process
are: (a) bypassing the isolation of a reactive electrophile by using
its aqueous-washed reaction mixture directly into a coupling
reaction with a phenoxide nucleophile and (b) modulating the
properties of the final product solutions for optimal extraction,
purification, and crystallization.
In our structure-based approach to the identification of
nonpeptidic LTA4H inhibitors, we iteratively used fragment-
based crystallography and medicinal chemistry to arrive at the
optimized clinical candidate designated as DG-051.10,11 This
compound featured good potency against the enzyme combined
with good aqueous solubility, high oral bioavailability and
efficacy featuring significant reduction of LTB4 as a biomarker.
Our agent DG-051 is currently undergoing a phase II clinical
evaluation for the treatment of myocardial infarction and stroke.
In this contribution, we summarize our efforts to both develop
and demonstrate a process-scale chemical synthesis of DG-051
suitable for the human clinical trials. Our starting point was
the medicinal chemistry procedure.11 Scaling up this protocol
presented a number of drawbacks including the formation of
several byproducts (up to ∼30% of the total conversion, for
certain steps), several chromatographic purifications, and low
overall yield (∼10%) of the targeted molecule. Our development
goals were to simplify and streamline the process, increase
overall yield, reduce materials and processing costs, and meet
regulatory guidelines.
Introduction
Myocardial infarction (MI) is the leading cause of death in
the industrialized world. Despite widespread use of drugs to
treat dyslipidemia, hypertension, and diabetes as risk factors
for MI and stroke, morbidity and mortality from cardiovascular
(CV) disease remain unacceptably high. Our recent studies using
human population genetics pinpointed the leukotriene (LT)
pathway1,2 as a major risk factor for MI and stroke.3 We further
narrowed our focus on leukotriene A4 hydrolase (LTA4H) as
a key pathway enzyme responsible for the increased production
of leukotriene B4 (LTB4) in atherosclerotic plaque.4,5 The
Results and Discussion
tert-Butyl (2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-
pyrrolidine-1-carboxylate, 6 (Scheme 1), was identified as a key
intermediate in all our approaches to DG-051. The presence of
the electron-withdrawing group (EWG) (Boc) on the pyrrolidine
nitrogen of 6 was beneficial in yielding the targeted bis-ether
core in high yields and purity. Attempts to use respective N-(4-
butyryl) derivatives as direct precursors to DG-051 for the
coupling reaction with phenoxide consistently led to the
* Author for correspondence. E-mail: enache.livia1@gmail.com.
(1) Helgadottir, A.; Manolescu, A.; Thorleifsson, G.; Jonsdottir, H.;
Thorsteinsdottir, U.; Samani, N. J.; Gretarsdottir, S.; Johannsson, H.;
Gudmundsson, G.; Grant, S. F. A.; Sveinbjornsdottir, S.; Valdimarsson,
E. M.; Matthiasson, S. E.; Gudmundsdottir, O.; Gurney, M.; Sainz,
J.; Thorhallsdottir, M.; Andresdottir, M.; Frigge, M. L.; Gudnason,
V.; Kong, A.; Topol, E. J.; Thorgeirsson, G.; Gulcher, J. R.;
Hakonarson, H.; Stefansson, K. Nat. Genet. 2004, 36, 233.
(2) Helgadottir, A.; Manolescu, A.; Helgason, A.; Thorleifsson, G.;
Thorsteinsdottir, U.; Gudbjartsson, D. F.; Gretarsdottir, S.; Magnusson,
K. P.; Gudmundsson, G.; Hicks, A.; Jonsson, T.; Grant, S. F. A.; Sainz,
J.; O’Brien, S. J.; Sveinbjornsdottir, S.; Valdimarsson, E. M.;
Matthiasson, S. E.; Levey, A. I.; Abramson, J. L.; Reilly, M.;
Vaccarino, V.; Wolfe, M.; Gudnason, V.; Quyyumi, A. A.; Topol,
E. J.; Rader, D. J.; Thorgeirsson, G.; Gulcher, J. R.; Hakonarson, H.;
Kong, A.; Stefansson, K. Nat. Genet. 2006, 38, 68.
(6) Werz, O.; Steinhilber, D. Pharmacol. Ther. 2006, 112, 701.
(7) Sharon, P.; Stenson, W. F. Gastroenterology 1984, 86, 453.
(8) Tsuji, F.; Oki, K.; Fujisawa, K.; Okahara, A.; Horiuchi, M.; Mita, S.
Life Sci. 1999, 64, PL 51.
(9) Holloway, J. W.; Barton, S. J.; Holgate, S. T.; Rose-Zerilli, M. J.;
Sayers, I. Allergy 2008, 63, 1046.
(10) Davies, D. R.; Mamat, B.; Magnusson, O. T.; Christensen, J.;
Haraldsson, M. H.; Mishra, R.; Pease, B.; Hansen, E.; Singh, J.;
Zembower, D.; Kim, H.; Kiselyov, A. S.; Burgin, A. B.; Gurney, M. E.;
Stewart, L. J. J. Med. Chem. 2009, 52, 4694.
(3) Meng, C. Q. Curr. Top. Med. Chem. 2006, 6, 93.
(4) Cipollone, F.; Mezzetti, A.; Fazia, M. L.; Cuccurullo, C.; Iezzi, A.;
Ucchino, S.; Spigonardo, F.; Bucci, M.; Cuccurullo, F.; Prescott, S. M.;
Stafforini, D. M. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1665.
(5) Qiu, H.; Gabrielsen, A.; Agardh, H. E.; Wan, M.; Wetterholm, A.;
Wong, C. H.; Hedin, U.; Swedenborg, J.; Hansson, G. K.; Samuelsson,
B.; Paulsson-Berne, G.; Haeggstro¨m, J. Z. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 8161.
(11) Sandanayaka, V.; Mamat, B.; Mishra, R. K.; Winger, J.; Krohn, M.;
Zhao, L.-M.; Keyvan, M.; Enache, L.; Sullins, D.; Onua, E.; Zhang,
J.; Halldorsdottir, G.; Sigthorsdottir, H.; Thorlaksdottir, A.; Sigthors-
son, G.; Thorsteinnsdottir, M.; Davies, D. R.; Stewart, L.; Zembower,
D. E.; Andresson, T.; Kiselyov, A. S.; Singh, J.; Gurney, M. E. J. Med.
Chem. 2009. Manuscript submitted.
10.1021/op900231j CCC: $40.75  2009 American Chemical Society
Published on Web 11/02/2009
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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Scheme 1. Sequential synthetic route to intermediate 6
increased formation of side products (mainly N-alkylated
piperidine analogues), potentially via intramolecular nucleophilic
attack of the nitrogen at the carbon bearing the OTs leaving
group, followed by rearrangement. A formal study of all the
side products and their mechanism of formation has not been
conducted.
scheme featuring the reaction of the preformed diaryl ether
building block 1213 with tosylate 2 (Scheme 2). This develop-
ment work resulted in substantial modifications to the prepara-
tive techniques.
In following this path, our preferred approach to 4-(4-
chlorophenoxy)phenol 12 was the Ullmann-type coupling of
4-bromochlorobenzene (9) and 4-methoxyphenol (10) in 1,4-
dioxane mediated by Cs2CO3 and catalytic CuI. Yields of the
intermediate diaryl ether 1114 were typically around 90%.
Addition of a Cu-complexing cocatalyst such as N,N-dimeth-
ylglycine15 resulted in both a better conversion rate and more
manageable temperature control (100 °C) of this step. Depro-
tection of 11 to 12 was accomplished with TMSI formed in
situ from the cheaper NaI and TMSCl. Phenol 12 was isolated
in 65-85% yields (over two steps) and 98-99% purity16 after
recrystallization from heptane. This two-step synthesis was
successfully validated on a 100-kg scale as we designated 12
to be a key starting material in manufacturing DG-051. Our
attempts to access 12 in a one-pot procedure Via either coupling
of 4-chlorophenol and 4-iodophenol or diazotization of 4-(4-
chlorophenoxy)aniline were unsuccessful. These one-pot ap-
proaches, while achieving reasonable chemical conversion
(∼70%) for the synthetic method screening stage, did not lend
themselves to easy isolation of 12 with high enough recovery
and purity.
For the O-alkylation of phenol 12 with tosylate 2, conditions
similar to those developed for the reaction of 2 with 3 (DMF
as the solvent and KOtBu as the phenol deprotonating base)
still provided the best yields (consistently above 80%) and
shortest reaction times at a reasonable temperature (6-16 h at
45-60 °C). The reaction proceeded cleanly in the presence of
a relatively small excess of 12 (1.05-1.15 equiv) and corre-
sponding KOtBu. Tosylate 2 was completely consumed, and
the excess of 12 was easily removed during the aqueous workup
by alkaline washes.
First-Generation Approach to Compound 6. We initially
focused on the synthesis of compound 6 following the three-
step sequence illustrated in Scheme 1. According to this
approach, prolinol 1 was tosylated using p-toluenesulfonyl
chloride (TsCl) in the presence of triethylamine (TEA) and a
catalytic amount of 4-dimethylaminopyridine (DMAP) in
dichloromethane (DCM). The reaction in DCM was notably
faster (4-8 h at ambient) than in other solvents.12 The yields
were consistently high and reproducible (96-99%). Intermedi-
ate 2,10 when stored refrigerated and used within 1-2 weeks
of preparation, required no further purification. In later applica-
tions, DMAP could be easily replaced by trimethylamine
hydrochloride (TMA ·HCl), thus reducing materials costs.
Displacement of the tosylate group in 2 by the phenoxide
generated from 4-iodophenol (3) with potassium tert-butoxide
(KOtBu) in DMF yielded ether intermediate 4. Other solvents,
such as THF or 1,4-dioxane, were respectively ruled out due
to increased reaction time or stirrability issues. NaOH or KOH
as the base also resulted in increased reaction time, as well as
more impurities. We used an Ullmann-type protocol to couple
4 with 4-chlorophenol (5) in the presence of CuI and Cs2CO3.
Unfortunately, this step afforded 6 only in moderate yields
(48-71%). In following this route, we also noticed significant
formation of impurities as exemplified by structures 7 and 8 in
Figure 1. Attempts to purify 6 by chromatography failed, but
trituration techniques did afford analytically pure material;
however, the recovery was <50%. Overall, this route was
cumbersome and poorly utilized the expensive building
block, 1.
Second-Generation Approach to Compound 6. In order
to address the observed issues associated with the harsh
conditions of the Ullmann reaction, we selected a convergent
One of the most important achievements of our process
development was telescoping the two-step synthesis of inter-
mediate 6 from 1. The tosylate formation and isolation from
(12) Other solvents examined included: EtOAc, tetrahydrofuran (THF), 1,4-
dioxane, tert-butyl methyl ether (MTBE), and 1-methyl-2-pyrrolidinone
(NMP).
(13) Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63.
(14) Tulp, M. T. M.; Hutzinger, O. Biomed. Mass Spectrom. 1978, 224.
(15) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
Figure 1. The two major impurities from the Ullmann reaction
in Scheme 1.
(16) All chemical purity values are provided as area % by HPLC.
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Scheme 2. Concerted synthetic route to intermediate 6
Scheme 3. Original route to DG-051 from intermediate 6
DCM was a high-yielding procedure, but intermediate 2 needed
to be stored under refrigeration and only for a limited time (1-2
weeks). The purity of 2 ranged from 99% (on 100-g scale) to
slightly over 92% (on 5-kg scale) due to some instability during
concentration, which would have posed a problem on a
manufacturing scale (100 kg and above).
synthetic protocol. In addition, both manufacturing time and
overall processing costs were greatly reduced.
Synthesis of DG-051 from Intermediate 6. From inter-
mediate 6, the completion of the synthesis appeared to be
straightforward: deprotection of the pyrrolidine nitrogen, N-
alkylation, saponification, salt formation, and isolation (Scheme
3).
A desirable modification was to combine both tosylation and
coupling in a single manufacturing step, thus bypassing any
concerns regarding isolation and storage of tosylate 2. To that
effect, intermediate 2 needed to be prepared in a solution that
could be directly mixed with the phenoxide generated from 12.
We ruled out solvents such as DCM, DMF, THF, 1,4-dioxane,
MTBE, NMP, or EtOAc due either to compatibility concerns
in any of the combined steps or to stirrability issues and
increased reaction time. We eventually solved the problem by
developing a new, multisolvent system. Specifically, we carried
out the tosylation in a 1:1 (v/v) mixture of toluene and
acetonitrile, which after 3 h was worked up (neither toluene
nor acetonitrile alone had been completely satisfactory in the
combined procedure). The resulting solution of 2 reproducibly
carried less than 1% water and could be reacted directly with
the phenoxide of 12 that had been preformed in DMF.
Intermediate 6 was readily isolated after aqueous quench and
heptane extraction. Isolated crude yields of 6 were typically in
the 85-90% range over the two-stage reaction step, at ∼97%
purity. The purity of intermediate 6 could be improved to 99.8%
by trituration with heptane, but crude 6 could be used in the
next step without any further manipulation. By eliminating the
issues connected with the potential for tosylate decomposition,
we significantly increased the feasibility and scalability of the
We have used two procedures to deprotect intermediate 6
to yield the free pyrrolidine nucleophile 13. A 4 M HCl/1,4-
dioxane solution proved to be the reagent of choice for the
removal of Boc-protecting group on gram to ∼6 kg scale;
however, on the manufacturing scale (∼90 kg), it was more
feasible to perform the reaction in ethyl acetate saturated with
gaseous HCl. In both cases, the reaction proceeded cleanly, and
intermediate 13 was consistently isolated after a simple aqueous
workup in close to quantitative yields while purity routinely
exceeded 98%.
The introduction of the four-carbon side-chain was per-
formed Via the nucleophilic attack of commercially available
alkyl 4-bromobutyrates. Application of 4-bromobutyric acid
resulted in slow reaction and, after overnight reaction at 50 °C,
a 22% conversion to DG-051 and 36% of an unidentified
byproduct. Whereas methyl 4-bromobutyrate had been used in
our medicinal chemistry preparations of the targeted molecule,11
we chose the cheaper ethyl 4-bromobutyrate as an electrophile
for development. For our small-scale needs, we ran the reaction
with very good yield in DMF, utilizing 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) as the base. At later stages of manufacturing
protocol development, we resorted to a more scalable procedure,
utilizing K2CO3 in acetonitrile. Under these conditions, the
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Scheme 4. Preparation of DG-051 salts from the corresponding ethyl ester without isolation of the intermediate zwitterion
reaction was completed in 8-16 h with 1.1-1.2 equiv ethyl
4-bromobutyrate and 2.0-2.5 equiv of K2CO3. Following
workup, the resulting crude ester 14 could be used in the next
step without further purification.
problem was addressed by developing a recrystallization solvent
system capable of efficiently excluding all impurities, without
the need for a pH 9.5 prewash. At early stages of this particular
development operation, we found that we could isolate DG-
051 of higher than 99% purity by simply concentrating the crude
DG-051 sodium salt at the end of the saponification step,
generating and extracting the HCl salt from salified aqueous
medium, and performing a final recrystallization of DG-051
from MTBE, MEK, or MEK/MTBE mixtures. MEK as a single
solvent afforded low recovery of the targeted molecule, while
MTBE, whether used alone or in combination with MEK,
proved difficult to remove from the final product which led to
increased drying time. Once we developed the adjusted MEK/
MIBK mixtures for the extraction of DG-051 from aqueous
media (Vide supra), we experimented with similar modifications
of MEK/MIBK ratios as crystallization solvents. We success-
fully isolated DG-051 in good yield (70-85%) by crystallizing
the product from 7:1 to 12:1 (v/v) MIBK/MEK mixtures to
furnish DG-051 in high purity (g99%, 100% ee) on up to 1.3
kg scale.
Eventually, the hydrochloride form of DG-051 proved not
to be an optimal choice for advanced development, due mainly
to its hygroscopicity, multiple polymorphs, and low melting
point (96-103 °C). A salt screen resulted in the selection of
the p-toluenesulfonate (tosylate) salt, DG-051B, as a better
candidate for development. DG-051B is not hygroscopic, has
a higher melting point (115-116 °C), and has a single known
polymorphic form.
From the preparative point of view, working with the tosylate
form resulted in further simplification of the isolation/purifica-
tion procedure, since its extraction from aqueous solution by
MEK/MIBK mixtures required only a moderate excess of
p-toluenesulfonic acid (p-TsOH, 2-4 equiv) and no additional
NaCl.
Another major focus of the development work addressed
both saponification and acidification steps. During the course
of our studies, we discovered that both zwitterion 15 and the
corresponding salts are easily soluble in water, leading to
considerable losses of the final product. Multiple extractions
of aqueous solutions of 15 with organic solvents did not address
this issue adequately. The saponification itself could be easily
carried out in ∼ 2:1 (v/v) ethanol/water in the presence of 2-2.5
equiv NaOH (other alkalis were also effective) in 4-6 h.
Initially, this apparently simple chemistry approach had two
distinct operational steps, namely: (a) saponification reaction
with the isolation of the zwitterion 15 and (b) formation,
isolation, and purification of the respective salt (in that case,
the hydrochloride form) (Scheme 3). At the end of the
saponification reaction, the alkaline reaction mixture was
concentrated and worked up (including a wash with MTBE or
MTBE/heptanes of pH 9.5 aqueous solution); eventually the
pH of the aqueous layer was adjusted to 6.0-6.3, corresponding
to the estimated range of the DG-051 isoelectric point (con-
firmed experimentally to be 6.185). Water was completely
removed in Vacuo to afford the zwitterion as the solid reaction
residue. Redissolution in organic solvent(s), filtration to clarify,
dilution with diethyl ether, acidification with 2 M HCl in diethyl
ether, filtration, rinse with diethyl ether, and drying produced
crystalline DG-051. This was consistently of high purity (better
than 99% on up to 100 g scale); however, the method was
extremely laborious. Multiple operations, lengthy concentrations
from aqueous solutions, and the use of diethyl ether would pose
problems for transferring this protocol to a multikilogram scale.
In amending the described procedure to a large-scale
preparation of 15, we achieved a major breakthrough by
extracting DG-051 from acidic (pH 2) aqueous solutions whose
ionic strength had been increased by addition of NaCl. Namely,
we were able to efficiently extract DG-051 in THF and
especially 2-butanone (MEK) but to also solve problems with
drying, we added the structurally related but more hydrophobic
4-methyl-2-pentanone (MIBK) (very effective at the level of
5-10% v/v in MEK). In addition, MIBK facilitated azeotropic
removal of water from the organic extract prior to the final
crystallization. DG-051 generation in aqueous medium, its direct
extraction into an organic solvent and ability to work with
aqueous HCl (vs ether solutions thereof) allowed us to scale
up the process (Scheme 4).
Finally, the purification of DG-051B by crystallization from
MIBK/MEK mixtures proved to be a very effective procedure
for the removal of practically all major impurities generated in
the process. Also, the newly developed process was simple,
high-yielding, and resulted in only small amounts of byproduct.
As a result, the entire synthesis of DG-051B from prolinol 1
could be telescoped. The reaction intermediates needed neither
individual purification nor isolation and were transferred to the
progressive steps Via solvent swaps. The current process
(Scheme 5) has been applied to produce up to 88 kg of DG-
051B, which was isolated in 52-66% overall yield, 100% ee,
and >99% purity. A similar procedure was used to prepare the
high-purity (>99%, 100% ee) (R)-enantiomer of DG-051B.
The operation of washing at pH 9.5 was effective in
removing most organic impurities into the MTBE or MTBE/
heptane layer and contributed to the eventual isolation of a very
pure final product. Unfortunately, it was also lengthy and
cumbersome due to the frequent formation of emulsions. This
Conclusions
In conclusion, we have developed scalable and commercially
viable processes for the preparation of a clinical phase II
leukotriene A4 hydrolase (LTA4H) inhibitor DG-051 and its
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Scheme 5. Final optimized four-step route to DG-051B
tosylate salt DG-051B. The process furnished up to 66% yield
of either targeted molecule over four manufacturing steps (six
chemical transformation steps) that did not require intermediate
isolation or purification. The final products were isolated as
analytically and chemically pure optical isomers that success-
fully met regulatory requirements. The key to achieving process
development goals was our careful consideration of the specific
chemical and physical properties of our substrates, intermediates,
and products in order to evolve general synthetic procedures
into product-specific ones, at maximized conversion and isola-
tion/purification rates. Key discoveries that allowed us to
streamline the scale-up include: (i) a streamlined route and
specific synthetic procedures that afforded both the intermediate
6 and the target products in high yields and purity, (ii) a specific
solvent mixture that allowed for the telescoped preparation of
a reactive tosylate electrophile and its coupling with a phenoxide
nucleophile, (iii) an optimized extraction protocol that allowed
us to generate and extract DG-051 and DG-051B directly from
solutions of increased ionic strength, and (iv) an efficient final
crystallization procedure that, together with the high-yielding
and clean individual steps, allowed us to forego intermediate
purifications.
APCI-MS and ESI-MS were recorded with an Agilent 1100
LC/MS system in either positive or negative ionization mode.
IR spectra were recorded neat on a Nexus 470 FT-IR system
and are reported in cm-1. Melting points were measured on
first isolated material using a TA Instruments digital scanning
calorimeter. Elemental analysis data are reported in wt %.
Pilot-PlantProcedure.4-{(2S)-2-[4-(4-Chlorophenoxy)phen-
oxymethyl]pyrrolidin-1-yl}butyric Acid p-Toluenesulfonate (DG-
051B) from Prolinol 1 by Telescoped Procedure, with No
Intermediate Isolation. To a solution of prolinol 1 (58.0 kg,
288.2 mol) and trimethylamine hydrochloride (2.7 kg, 28.3 mol)
in 166 L of 1:1 (v/v) mixture of acetonitrile and toluene was
added triethylamine (62.1 kg, 613.7 mol) at 20-30 °C. The
mixture was cooled to 15 °C, a solution of TsCl (65.9 kg, 345.7
mol) in 144 L of 1:1 (v/v) mixture of acetonitrile and toluene
was added, and the resulting mixture was stirred 2 h at ambient
temperature. The reaction was quenched by addition of water
(290.9 L) at 20-25 °C. The organic layer containing intermedi-
ate 2 was washed with 25% aqueous NaCl solution (2 × 293
L). In a separate vessel, 4-(4-chlorophenoxy)phenol 12 (70.2
kg, 318.1 mol) was dissolved in DMF (423.0 L). A solution of
15% KOtBu in tert-butanol (299.9 kg, 400.9 mol) was added
at 20-25 °C. After 30 min, to the resulting potassium 4-(4-
chlorophenoxy)phenoxide solution was added the solution of
2 previously prepared, at 20-22 °C. The resulting reaction
mixture was heated to 55-63 °C over 6 h, then held at that
temperature for 27 h, cooled to 22 °C, quenched by addition of
water (76.4 L), diluted with more water (695 L) and heptanes
(772 L), and allowed to separate. The organic layer was washed
sequentially with 1 M citric acid (1 × 826 L), 0.5 N sodium
hydroxide (2 × 786 L), and water (771 L), after which the bulk
of the solvents was removed by vacuum distillation, and the
remaining solvents were exchanged to EtOAc by repeated (3×)
vacuum concentration from EtOAc. The amount of dissolved
crude 6 was determined by concentration of a small aliquot to
be 89.4 kg, and to the EtOAc solution was added the necessary
EtOAc to adjust the concentration to 21 wt %. Through this
solution, kept at 15-20 °C, was bubbled gaseous HCl (40.3
Experimental Section
General Experimental. HPLC chemical purity analysis of
products and intermediates was performed using an Agilent
1100 liquid chromatograph equipped with a Zorbax SB-CN 4.6
mm × 250 mm column. Standard method: 85:15 to 15:85 over
45 min gradient of water-acetonitrile containing 2.5% H3PO4,
flow rate 1.0 mL/min. The retention time for DG-051 is 14.5
min, while the relative retention times (RRT) for the key
intermediates are respectively 1.86 for 6, 0.96 for 13, and 1.18
for 14. HPLC chiral purity determination was done on a
Chiralpak AD-H 4.6 mm × 250 mm column eluted isocratically
with a mixture of 80:20:0.1 hexane/IPA/ethane sulfonic acid,
flow rate 1.0 mL/min. DG-051 elutes at 12-13 min, while its
enantiomer at 15-16 min. 1H NMR and 13C NMR spectra were
recorded on Varian Oxford 400 and 500 MHz spectrometers.
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kg, 1105.3 mol) over 4.4 h. Water (558 L) was added, the
mixture was stirred 30 min, and the layers were allowed to
separate. The aqueous layer was extracted with EtOAc (193
L). The combined organic extracts were washed with 50%
aqueous K2CO3 (480 kg), after which the bulk of the EtOAc
was removed by vacuum distillation, and the remaining EtOAc
was exchanged to acetonitrile by repeated (3×) vacuum
concentration from acetonitrile. The amount of dissolved crude
13 was determined by concentration of a small aliquot to be
63.7 kg, and to the acetonitrile solution was added the necessary
acetonitrile to adjust the concentration to 17.4 wt %. To the
resulting solution were added ethyl 4-bromobutyrate (47.5 kg,
243.5 mol) and K2CO3 (67.5 kg, 488.4 mol). The mixture was
stirred at 50-58 °C for 10.8 h, cooled to 25 °C, stirred for 30
min with water (398 L), and the layers were allowed to separate.
The organic layer was vacuum distilled to remove most of the
acetonitrile, after which the remaining acetonitrile was ex-
changed to ethanol by repeated (3×) vacuum concentration from
ethanol. The amount of dissolved crude 14 was determined by
concentration of a small aliquot to be 94.7 kg, and to the ethanol
solution was added the necessary ethanol to adjust the concen-
tration to 18.7 wt %. The resulting mixture was stirred with a
solution of aqueous 10.5% NaOH (198.9 kg solution, 522.1
mol) for 6 h at 21-25 °C, after which it was concentrated to
39% of the original volume to remove most of the ethanol,
diluted with 214 L water, and partially concentrated again, then
diluted with 183 L water. The aqueous solution was stirred with
p-TsOH·H2O (159.4 kg, 838.0 mol) for 30 min at 20 °C, then
extracted repeatedly with MIBK/MEK mixtures (1 × (3:1, v/v),
578 L; 1 × (1:1, v/v), 288 L; 8 × (1:2, v/v), 285 L each). The
combined organic extracts were washed with water (2 × 264
L), vacuum concentrated to remove the bulk of MEK, then
concentrated again from MIBK (438 L) until the resulting
suspension in MIBK contained 19.2 wt % DG-051B. The slurry
was cooled to 25 °C, and the solid product was isolated by
filtration, rinsed with MIBK (428 L; 396 L), and dried 23 h at
50 ( 5 °C to afford 71 kg (43.8%) DG-051B of 99.9% purity.
More DG-051B (17 kg; 99.5% purity) could be isolated from
the aqueous mother liquors that remained after the MIBK/MEK
extractions (further diluted with 1 vol water) by one more
extraction with 3:1 (v/v) MIBK/MEK, thus achieving a
cumulated yield of 54.3%.
Advanced Laboratory Procedures. tert-Butyl (2S)-2-
[(p-toluenesulfonyloxy)methyl]pyrrolidine-1-carboxylate (2). A
solution of Boc-(S)-(-)-2-pyrrolidinemethanol (1) (1.43 kg, 7.10
mol) and DMAP (86.40 g, 0.71 mol) in DCM (11 L) was cooled
to 5 °C. TsCl (1.49 kg, 7.81 mol) was added in portions over
20 min at 0-5 °C. The resulting mixture was allowed to warm
up to ambient temperature over 18 h, after which it was
quenched with 6 L water. The organic layer was separated,
washed with 6 L water, 4 × 5 L 0.3 M aqueous HCl, 2 × 6 L
water, and 4 L brine, after which it was dried over anhyd
Na2SO4, filtered, and concentrated in Vacuo to afford the desired
intermediate 2 (2.42 kg, 96%). The purity (96.3%) was suitable
for the material to be used in the following step without further
purification. This material could be stored at 2-8 °C, under
inert atmosphere, for 2 weeks; 1H NMR (500 MHz, CDCl3) δ
1.36 and 1.41 (two singlets without baseline separation, 9 H),
1.75-2.05 (m, 4 H), 2.44 (s, 3 H), 3.23-3.40 (m, 2 H),
3.85-4.20 (m, 3 H), 7.35 (m, 2 H), 7.78 (d, 2 H, J ) 8.0 Hz).
13C NMR (500 MHz, CDCl3; 2 rotamers) δ 21.57, 22.79 and
23.77, 27.58 and 28.48, 28.30, 46.42 and 46.88, 55.50, 69.93,
79.53 and 79.86, 127.80, 129.83, 132.92, 144.66 and 144.86,
153.97 and 154.36.
4-(4-Chlorophenoxy)phenol (12). To a solution of 4-bro-
mochlorobenzene (9) (4.89 kg, 25.50 mol) and 4-methoxyphe-
nol (10) (4.87 kg, 39.20 mol) in 1,4-dioxane (34.8 L) under
nitrogen were added Cs2CO3 (17.10 kg, 52.50 mol), N,N-
dimethylglycine hydrochloride (1.07 kg, 7.70 mol) and CuI
(0.49 kg, 2.60 mol). The resulting suspension was heated to
110 ( 5 °C. Vigorous bubbling occurred at around 104 °C for
about 40 min, after which TLC (silica gel; hexane/EtOAc 3:1,
v/v) indicated consumption of 9. After 60 min more at 105 (
5 °C the reaction mixture was allowed to cool to ambient
temperature over 18 h. MTBE (30 L) followed by water (30
L) were added. The aqueous layer was extracted with MTBE
(10 L). The combined organic layers were washed with water
(12 L), 10% aqueous NaOH (2 × 15 L), and brine (15 L), dried
over anhyd Na2SO4 and concentrated to crude 4-(4-chlorophe-
noxy)anisole 11 (5.24 kg, 88.4% crude yield) as an oil that
solidified upon standing and could be used as such in the next
step. 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3 H), 6.86 (d, 2
H, J ) 9.2 Hz), 6.88 (d, 2 H, J ) 9.2 Hz), 6.96 (d, 2 H, J )
9.2 Hz), 7.24 (d, 2 H, J ) 9.2 Hz).
Acetonitrile (22 L) and NaI (16.54 kg, 110.4 mol) were
charged to a different vessel and chlorotrimethylsilane (11.99
kg, 110.4 mol) was added over 40 min and stirred for 30 min
after which crude 11 (5.18 kg) dissolved in acetonitrile (8 L)
was added in one portion. The mixture was stirred for 20 min,
brought to reflux, held 16 h, and then cooled to 23 °C over 2 h.
Water (20 L) was added over 40 min to the reaction mixture
and stirring continued for 40 min. Isopropyl acetate (IPAC, 25
L) was added and the aqueous layer was extracted with IPAC
(7 L). The combined organic layers were washed with water
(10 L), 10% aqueous Na2S2O3 (3 × 10 L) and brine (10 L),
dried over anhyd Na2SO4, filtered, and concentrated to afford
crude phenol 12 (4.80 kg). This material was recrystallized from
heptane (4 L) to afford intermediate 12 of 98.3% purity (3.80
kg, 68.3% yield over two steps). 1H NMR (500 MHz, CDCl3)
δ 4.96 (br s, 1 H), 6.83 (d, 2 H, J ) 9.0 Hz), 6.88 (d, 2 H, J )
1H NMR (500 MHz, DMSO-d6) δ 1.83 (m, 1 H), 1.86-1.98
(m, 2 H), 2.03 (m, 1 H), 2.24 (m, 1 H), 2.28 (s, 3H), 2.37 (t, 2
H, J ) 7.0 Hz), 3.12-3.24 (m, 2 H), 3.48 (m, 1 H), 3.64 (m,
1 H), 3.94 (m, 1 H), 4.19 (m, 1 H), 4.30 (dd, 2 H, J ) 11.0 Hz,
3.5 Hz), 6.94 (d, 2 H, J ) 9.0 Hz), 7.05 (s, 4 H), 7.11 (d, 2 H,
J ) 8.0 Hz), 7.40 (d, 2 H, J ) 9.0 Hz), 7.51 (d, 2 H, J ) 8.0
Hz), 9.54 (br s, 1H), 12.30 (br s, 1 H). 13C NMR (500 MHz,
DMSO-d6) δ 20.61, 20.74, 22.32, 26.18, 30.44, 39.75, 54.35,
66.19, 66.79, 116.03, 118.97, 120.78, 125.46, 126.41, 128.11,
129.71, 137.84, 145.31, 149.71, 154.17, 156.81, 173.51. IR
2986, 1721, 1504, 1484, 1221, 1151, 1120, 1033, 1009, 824,
814, 681, 565. MS (APCI+) m/z 390.2 M+ + 1. Mp 115.5 °C.
Anal. Calcd for C28H32ClNO7S: C, 59.83; H, 5.74; Cl, 6.31; N,
2.49; S, 5.70. Found: C, 60.03; H, 5.81; Cl, 6.07; N, 2.41; S,
5.90.
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9.0 Hz), 6.92 (d, 2 H, J ) 9.0 Hz), 7.25 (d, 2 H, J ) 9.0 Hz).
13C NMR (500 MHz, CDCl3) δ 116.44, 118.80, 120.97, 127.45,
129.55, 149.95, 151.86, 157.04. IR 3440, 1501, 1481, 1450,
1208, 1188, 1097, 826. Mp 84.8 °C. A small portion of this
material was further purified by a second recrystallization for
elemental analysis. Anal. Calcd for C12H9ClO2: C, 65.32; H,
4.11; Cl, 16.07. Found: C, 65.26; H, 4.02; Cl, 15.92.
(2S)-2-{[4-(4-Chlorophenoxy)phenoxy]methyl}pyrrolidine
(13). To a solution of intermediate 6 (5.84 kg, 14.46 mol) in
1,4-dioxane (27 L) was added 4 M HCl/1,4-dioxane (18 L) over
35 min. The reaction mixture was stirred 16 h at ambient
temperature, degassed by bubbling nitrogen, and concentrated
in Vacuo. The residue (4.99 kg) was dissolved in water (29 L)
and washed with MTBE (3 × 22 L). K2CO3 (2.1 kg, 15.19
mol) was added to bring the pH to 10. The resulting mixture
was stirred for 3 h and allowed to separate. The aqueous layer
was extracted with IPAC (2 × 20 L). The combined organic
layers were washed with brine (40 L), dried over anhyd Na2SO4
(6.40 kg), filtered, and concentrated in Vacuo to afford inter-
mediate 13 as a thick oil that solidified upon standing (4.37
tert-Butyl (2S)-2-{[4-(4-Chlorophenoxy)phenoxy]methyl}-
pyrrolidine-1-carboxylate (6). Method A. From Isolated Tosy-
late 2 and Phenol 12. To a solution of phenol 12 (4.29 kg,
19.43 mol) in DMF (55 L) was added KOtBu (2.36 kg, 21.03
mol) and the resulting mixture was stirred at ambient temper-
ature for 1 h. Tosylate 2 (6.22 kg, 17.50 mol) dissolved in 12
L DMF was added and the reaction mixture was heated to 55
( 5 °C for 18 h. The reaction mixture was diluted with heptane
(50 L) and water (31 L) at 30 ( 5 °C. The aqueous layer was
extracted with heptane (50 L) at 30 ( 5 °C. The combined
organic layers were washed with 5% aqueous NaOH (2 × 31
L), water (31 L) and brine (31 L) at 30 ( 5 °C. Concentration
in Vacuo afforded 6.58 kg of off-white solids that were
suspended in heptane (20 L), stirred at ambient temperature
16 h, cooled to 5 ( 5 °C for 2 h, and filtered. The solids were
washed with heptane (2 × 3 L) and dried in Vacuo at 40 °C for
17 h to afford 99.7% pure intermediate 6 (5.84 kg, 82.7%).
Method B. From Prolinol 1 and Phenol 12, without
Isolation of 2. To a solution of prolinol 1 (140.00 g, 0.70 mol),
TEA (140.70 g, 1.39 mol) and DMAP (8.40 g, 0.07 mol) in
acetonitrile (350 mL) and toluene (350 mL) was added TsCl
(145.60 g, 0.76 mol) in two equal portions, 10 min apart, at 5
( 5 °C. The resulting mixture was stirred 3 h at 25 °C and
quenched with water (700 mL). The organic layer was washed
with brine (2 × 700 mL). In a separate flask, KOtBu (93.80 g,
0.84 mol) was added to a solution of 12 (168.70 g, 0.76 mol)
in DMF (1855 mL). The solution containing tosylate 2 was
transferred into the DMF reaction mixture. The resulting mixture
was stirred at 60 ( 3 °C for 20 h, cooled to ambient, quenched
with water (1850 mL), and extracted with heptane (1850 mL).
The organic extract was washed with 0.5 N HCl (1850 mL),
0.5 N NaOH (2 × 1850 mL) and water (1850 mL). Concentra-
tion in Vacuo of the heptane layer afforded crude 6 (235.15 g,
83.7% crude yield, 93.5% purity) of which 227.15 g were
recrystallized17 from heptane (570 mL) to afford 166.68 g
intermediate 6 (99.2% purity, 62% yield over two steps and
purification).
1
kg, 99.5%; 99.1% purity). H NMR (500 MHz, CDCl3) δ
1.53-1.61 (m, 1 H), 1.73-1.90 (m, 2 H), 1.90-2.00 (m, 1 H),
2.58 (br s, 1 H), 2.93-3.08 (m, 2 H), 3.53 (ddd, 1 H, J ) 14.0,
6.8, 5.2 Hz), 3.86 (dd, 1 H, J ) 9.2, 6.8 Hz), 3.92 (dd, 1 H, J
) 9.2, 5.2 Hz), 6.86 (d, 2 H, J ) 8.8 Hz), 6.89 (d, 2 H, J ) 9.2
Hz), 6.94 (d, 2 H, J ) 9.2 Hz), 7.24 (d, 2 H, J ) 8.8 Hz). 13
C
NMR (500 MHz, CDCl3) δ 25.27, 27.97, 46.55, 57.31, 71.76,
115.63, 118.74, 120.75, 127.32, 129.50, 149.82, 155.53, 157.16.
IR 2928, 1505, 1484, 1226, 1090, 826, 815. MS (APCI+) m/z
304.0 M+ + 1. Mp 52.7 °C. Anal. Calcd for C17H18Cl-
NO2 ·0.1H2O: C, 66.82; H, 6.00; Cl, 11.60; N, 4.58. Found: C,
66.72; H, 5.88; Cl, 11.50; N, 4.70.
Ethyl 4-{(2S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyr-
rolidin-1-yl}butyrate (14). To a mixture of pyrrolidine 13 (4.36
kg, 14.38 mol) and anhyd acetonitrile (27 L) were added K2CO3
(4.00 kg, 28.96 mol) and ethyl 4-bromobutyrate (3.11 kg, 15.97
mol). The reaction mixture was stirred at 55 ( 5 °C for 18 h.
TLC (silica gel; 6:2:1 EtOAc/heptane/TEA) indicated that about
10-15% of 13 was still present. More K2CO3 (1.59 kg, 11.51
mol) and ethyl-4-bromobutyrate (1.12 kg, 5.75 mol) were added,
and stirring continued at 55 ( 5 °C. After a total of 68 h at 55
( 5 °C, the reaction was complete.18 The mixture was cooled
to 29 °C, and water (27 L) was added. The organic phase was
concentrated in Vacuo to afford crude intermediate 14 of 93.0%
purity (7.30 kg, 121.4%; contained unreacted ethyl 4-bromobu-
1
tyrate) that could be used as such in the next step. H NMR
(500 MHz, CDCl3) δ 1.24 (t, 3 H, J ) 7.0 Hz), 1.66-1.75 (m,
1 H), 1.75-1.87 (m, 4 H), 1.95-2.04 (m, 1 H), 2.22-2.47 (m,
4 H), 2.82-2.92 (m, 2 H), 3.16 (m, 1 H), 3.76 (dd, 1 H, J )
9.0, 6.8 Hz), 3.90 (dd, 1 H, J ) 9.0, 5.0 Hz), 4. Eleven (q, 2 H,
J ) 7.0 Hz), 6.86 (d, 2 H, J ) 8.5 Hz), 6.88 (d, 2 H, J ) 9.0
Hz), 6.94 (d, 2 H, J ) 9.0 Hz), 7.24 (d, 2 H, J ) 8.5 Hz). 13
C
1H NMR (500 MHz, CDCl3) δ 1.47 (s, 9 H), 1.80-2.10
(m, 4 H), 3.30-3.50 (m, 2 H), 3.73-3.95 (m, 1 H), 4.03-4.20
(m, 2 H), 6.86 (d, 2 H, J ) 9.2 Hz), 6.88-6.97 (m, 4 H), 7.24
(d, 2 H, J ) 9.2 Hz). 13C NMR (500 MHz, CDCl3; 2 rotamers)
22.69 and 23.66, 27.88 and 28.60, 28.38, 46.44 and 46.80, 55.75
and 55.86, 68.26 and 68.76, 79.12 and 79.48, 115.57, 118.56,
120.64, 127.10, 129.34, 149.53 and 149.74, 154.24 and 154.50,
155.23 and 155.31, 157.06. IR 2973, 2931, 2872, 1695, 1504,
1486, 1392, 1237, 1162, 1090, 828. MS (ES+) m/z 404.5 M+
+ 1, 304.0 (base peak) M+ + 1 - COOtBu. Mp 75.7 °C. Anal.
Calcd for C22H26ClNO4: C, 65.42; H, 6.49; Cl, 8.78; N, 3.47.
Found: C, 65.39; H, 6.49; Cl, 8.82; N, 3.52.
NMR (500 MHz, CDCl3) δ 14.18, 23.19, 24.17, 28.60, 32.15,
54.24, 54.83, 60.13, 62.86, 71.92, 115.53, 118.65, 120.71,
127.23, 129.44, 149.65, 155.59, 157.17, 173.54. IR 2959, 2928,
1732, 1503, 1484, 1223, 826. A small portion of this material
was further purified chromatographically (silica gel; EtOAc
stepwise gradient in hexane, 10% increments from 10% to 50%)
for elemental analysis. Anal. Calcd for C23H28ClNO4 ·0.2H2O:
(18) Pilot reactions of this procedure were complete in less than 16 h. In
this particular scale-up, using 2.0 equiv of potassium carbonate with
1.1 equiv of ethyl 4-bromobutyrate did not result in complete reaction
after 24 h reaction time. In later installments, starting the reaction
with 2.3-2.5 equiv of finely powdered potassium carbonate and 1.1-
1.2 equiv of ethyl 4-bromobutyrate resulted in complete conversion
within 10-16 h at 52-55 °C.
(17) Crude 6 can be used in the next step without further purification.
Vol. 13, No. 6, 2009 / Organic Process Research & Development
•
1183

C, 65.53; H, 6.79; Cl, 8.41; N, 3.32. Found: C, 65.41; H, 6.50;
Cl, 8.79; N, 3.54.
1404, 1220, 1086, 1056, 824. MS (APCI+) m/z 390.2 M+ +
1. Mp 103.9 °C. Anal. Calcd for C21H25Cl2NO4: C, 59.16; H,
5.91; Cl, 16.63; N, 3.29. Found: C, 58.86; H, 6.08; Cl, 16.93;
N, 3.47.
4-{(2S)-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidin-
1-yl}butyric Acid Hydrochloride (DG-051). A mixture of crude
ester 14 (1193.00 g of crude material containing some residual
ethyl 4-bromobutyrate and maximum 860.96 g (2.06 mol) of
14), EtOH (3.5 L), NaOH (165.00 g, 4.12 mol), and water (2.0
L) was stirred at ambient temperature for 21 h, after which it
was concentrated in Vacuo and dissolved in water (5.0 L). The
aqueous solution was acidified (pH 1) using concd HCl (550
mL), at 15-30 °C. NaCl (500.00 g) was added, and the mixture
was extracted twice with MEK (3 L, then 1 L). To the combined
organic extracts was added 4-methyl-2-pentanone (MIBK, 1
L), and the resulting mixture was concentrated in Vacuo. The
solid residue was stirred with MEK (4 L) at 50 ( 3 °C for 3 h.
The resulting mixture was filtered through Celite. The Celite
cake was rinsed with MEK (2 × 150 mL), and the combined
MEK filtrate was stirred for 20 h at ambient temperature. A
suspension formed that was cooled to 5 °C, diluted with MIBK
(6 L), and stirred 3 h at 5 °C. The precipitated solids were
isolated by filtration, rinsed on filter with cold (5 °C) MIBK (2
× 250 mL), and dried to afford 626.00 g (71.3%) DG-051 of
99.4% purity.
4-{(2S)-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidin-
1-yl}butyric Acid p-Toluenesulfonate (DG-051B). To a solution
of crude ester 14 (7.30 kg crude containing some residual ethyl
4-bromobutyrate and maximum 6.00 kg (14.37 mol) of 14) in
EtOH (30 L) was added a solution of NaOH (1.44 kg, 36.08
mol) in water (17.2 L) and the resulting mixture was stirred at
ambient temperature for 16 h (the reaction was complete after
5 h). The mixture was concentrated in Vacuo to 11.90 kg of
residue that was dissolved in water (52 L) at 30 ( 5 °C. The
resulting solution was cooled to 20 °C, then p-TsOH·H2O
(10.97 kg, 57.67 mol) was added in two portions (6.87 and
4.10 kg) at 15-25 °C, and stirring was continued at ambient
temperature for 1 h. The resulting suspension was extracted
with 3:1 (v/v) MIBK/MEK (1 × 44 L, 1 × 15 L). The
combined organic layers were washed with water (2 × 16 L).
The organic extract was concentrated in Vacuo to 21.50 kg
suspension that was heated with MIBK (36 L) at 50 °C for 30
min. The mixture was allowed to cool to ambient temperature
over 18 h. The precipitated solids were isolated by filtration,
washed on filter with MIBK (3 × 8 L), suction dried, and then
dried to afford 6.85 kg (84.8%) of DG-051B of 99.9% purity.
1H NMR (500 MHz, DMSO-d6) δ 1.81 (m, 1 H), 1.86-2.10
(m, 4 H), 2.25 (m, 1 H), 2.40 (m, 1 H), 3.06-3.24 (m, 2 H),
3.53 (m, 1 H), 3.65 (m, 1 H), 3.89 (m, 1 H), 4.32 (dd, 1 H, J
) 10.5, 3.8 Hz), 4.50 (m, 1 H), 6.96 (d, 2 H, J ) 9.5 Hz), 7.05
(d, 2 H, J ) 9.0 Hz), 7.07 (d, 2 H, J ) 9.5 Hz), 7.40 (d, 2 H,
J ) 9.0 Hz), 11.26 (br s, 1H), 12.34 (br s, 1 H). 13C NMR
(500 MHz, DMSO-d6) δ 20.42, 21.87, 26.53, 30.81, 53.75,
65.82, 66.90, 116.11, 118.94, 120.78, 126.34, 129.68, 149.63,
154.22, 156.81, 173.48. IR 3436, 2950, 2599, 1729, 1503, 1484,
Supporting Information Available
This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review August 31, 2009.
OP900231J
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