Process development on an efficient new convergent formal synthesis of MIV-150

Article abstract of DOI:10.1021/op0341871

Starting from a known linear route and a proposed convergent route, we have successfully developed a new hybrid convergent route to MIV-150 that takes advantage of the robust chemistry for the preparation of a fluoroketal and the stereospecific Negishi coupling of an iodocyclopropane moiety to a benzene ring. Stereoselective β- and cis-iodination chemistry was developed for the preparation of an enantiomerically pure iodocyclopropanecarboxylate. Following the Negishi coupling, proven chemistry from the linear route was incorporated, thus ensuring a similar high-purity profile for the final active pharmaceutical ingredient (API). In addition, we have prepared and evaluated a series of basic inorganic and organic MIV-150 salts that have drastically increased water solubility over the parent compound.

Full text of DOI:10.1021/op0341871

Organic Process Research & Development 2004, 8, 353−359
Process Development on an Efficient New Convergent Formal Synthesis of
MIV-150
Shaopei Cai, Martin Dimitroff, Tracey McKennon, Malcolm Reider, Lonnie Robarge, David Ryckman, Xiao Shang,* and
Joseph Therrien
Chemical DeVelopment Department, Chiron Corporation, 201 Elliott AVenue West, Suite 150,
Seattle, Washington 98119, U.S.A.
Abstract:
RTs, instead of forming covalent bonds.5 In contrast to
nucleoside analogues, NNRTIs are highly specific for HIV-1
isolates, do not bind to HIV-2 reverse transcriptase, and are
effective without toxic side effects at relatively high con-
centrations.6 Although combination therapy can slow the
emergence of drug-resistant strains of virus, a need exists
for the discovery and development of improved NNRTIs.
This contribution describes the chemical development of a
potent NNRTI, (1S,2S)-N-[cis-2-(6-fluoro-2-hydroxy-3-pro-
pionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea, which
is also known as MIV-150.7
Starting from a known linear route and a proposed convergent
route, we have successfully developed a new hybrid convergent
route to MIV-150 that takes advantage of the robust chemistry
for the preparation of a fluoroketal and the stereospecific
Negishi coupling of an iodocyclopropane moiety to a benzene
ring. Stereoselective â- and cis-iodination chemistry was de-
veloped for the preparation of an enantiomerically pure
iodocyclopropanecarboxylate. Following the Negishi coupling,
proven chemistry from the linear route was incorporated, thus
ensuring a similar high-purity profile for the final active
pharmaceutical ingredient (API). In addition, we have prepared
and evaluated a series of basic inorganic and organic MIV-150
salts that have drastically increased water solubility over the
parent compound.
Medicinal Chemistry/Linear Route
The medicinal chemistry route is outlined in Scheme 1.
This route was successfully scaled up, with some adjust-
ments, to deliver multiple kilograms of active pharmaceutical
ingredient (API) used in toxicology studies and early clinical
trials. This route produced material of high purity. However,
there were three major concerns. Our first and greatest
concern was the asymmetric cyclopropanation step. While
practical on smaller scales, scaling-up of this crucial trans-
formation suffers from low yield and poor diastereoselec-
tivity. Although the enantioselectivity of the reaction is
usually >98%, the yield is typically 45-55% and the cis:
trans ratio a disappointing 3:1. Other issues associated with
this step include reagent costs and lack of availability as well
as safety concerns. The chiral catalyst for the enantioselective
cyclopropanation is derived from (D)-tert-leucine, which is
an expensive unnatural amino acid with few worldwide
suppliers who typically quote very long lead times. In
addition, ethyl diazoacetate is potentially explosive, making
the sourcing and transportation of bulk quantities of this
reagent difficult. Our second concern was the low yield (18%
for two steps) for the n-BuLi-assisted formylation and
subsequent Wittig olefination reaction. The last concern was
with the linear nature of the route and the associated higher
risks for manufacturing. In addition, the linear route has a
long lead-time with a low overall yield of 1.0% (5.8% from
1 to 4, and 18% for the steps from 4 to MIV-150). In
anticipation of future deliveries of API, a safe, scalable,
efficient and cost-effective synthesis was needed.
Introduction
The identification of human immunodeficiency virus
type-1 (HIV-1) as the causative agent of acquired immuno-
deficiency syndrome (AIDS) has prompted an intense
research effort to find effective therapies for this devastating
disease.1 Current understanding of the events in HIV
proliferation proposes seven steps: viral entry, reverse
transcription, integration, gene expression, gene assembly,
budding, and maturation. HIV reverse transcriptase (RT) is
one of the essential enzymes for HIV replication and is
therefore one of the major targets in the search for effective
therapies.2 Substantial resources have been allocated for the
study of HIV and the development of antiretroviral agents,3
particularly reverse transcriptase inhibitors (RTIs).4 RTIs are
divided into two categories: nucleoside (NRTIs) and non-
nucleoside (NNRTIs) reverse transcriptase inhibitors. NRTIs
are phosphorylated by cellular enzymes to an active me-
tabolite, analogous to a natural nucleotide, and then incor-
porated into the growing viral DNA chain by HIV RT in a
competitive reaction. Once inserted into the chain, no further
nucleotides can be added, and therefore viral replication
ceases. NNRTIs are a diverse group of compounds that
inhibit HIV reverse transcription by allosteric binding to the
* Author for correspondence. Telephone: (206) 270 3311. Fax: (206) 272
8529. Email: xiao_shang@chiron.com.
(5) De Clercq, E. Med. Virol. 1996, 6, 97.
(1) Joint United Nations Programme on HIV/AIDS (UNAIDS) and World
Health Organization (WHO), December 2002, http://www.unaids.org.
(2) (a) Helm, K. Biol. Chem. 1996, 377, 765. (b) De Clercq, E. J. Med. Chem.
1995, 38, 2491. (c) Kiso, Y. Biopolymers 1996, 40, 235.
(3) Ashraf, B.; Wong, C.-H. Org. Biomol. Chem. 2003, 1, 5.
(4) De Clercq, E. Clin. Microbiol. ReV. 1995, 8, 200.
(6) Stern, A. M. Chemical and Structural Approaches to Rational Drug Design;
Weiner, D. B.; Williams, W. B., Eds. CRC Press: Boca Raton, 1995; pp
35-61.
(7) Ho¨gberg, M.; Sahlberg, C.; Engelhardt, P.; Nore´en, R.; Kangasmetsa¨, J.;
Johansson, N. G.; O¨ berg, B.; Vrang, L.; Zhang, H.; Sahlberg, B.-L.; Unge,
T.; Lo¨vgren, S.; Fridborg, K. Ba¨ckbro, K. J. Med. Chem. 1999, 42, 4150.
10.1021/op0341871 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/27/2004
Vol. 8, No. 3, 2004 / Organic Process Research & Development
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353

Scheme 1
Scheme 2
Scheme 3
Original Convergent Route
A retro-synthetic analysis of an earlier convergent route
is shown in Scheme 2.8 The key to this convergent strategy
would be a metal-mediated cross-coupling reaction between
a suitably substituted, enantiopure 7 and fluoroketal 2. After
a great deal of investigation, the medicinal chemistry group
at Chiron discovered that a palladium (II)-mediated Negishi
reaction could successfully couple fluoroketal 2 to iodo-
cyclopropyl phthalimide (ICP) 7 while maintaining the
stereochemical integrity of the cyclopropyl ring. One obvious
advantage of this route, besides being convergent, was the
ability to capitalize on the known chemistry developed for
the synthesis of fluoroketal 2 and to use the same reagent,
2-amino-5-cyanopyridine, 9, for the asymmetric urea forma-
tion step. The synthesis of 7 is a six-step sequence involving
the protection of cyclopropylamine with pivaloyl chloride,
iodination via a BuLi generated â-dianion, removal of the
pivaloyl group, reaction with phthalic anhydride, brucine
resolution, and final cyclization. Upon scaling up, however,
numerous issues were discovered with the preparation of ICP
7; the most serious was gel formation during the generation
of cyclopropyl pivalamide dianion. The intermediate resulting
from the removal of the pivaloyl group possesses a nucleo-
philic group and an electrophilic center in the same molecule
and is intrinsically unstable. Also, the late-stage resolution
(8) Details of this convergent chemistry will be published in a separate paper.
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Scheme 4
Scheme 5
calls for the use of brucine, a highly toxic chiral resolving
agent, and affords only a moderate yield. Therefore, this
convergent route was deemed to be unacceptable for large-
scale production.
Results and Discussion
Because of the problems with both the linear and the
earlier convergent route, we started to look for an alternative
synthesis for the production of additional MIV-150. First,
we examined and compared the previous two synthetic routes
to determine what information was of value. The convergent
route was attractive because it demonstrated that the Negishi
reaction could reliably and efficiently couple the aryl zinc
species derived from 2 to the functionalized iodocyclopropyl
ring with retention of configuration. The linear route had
demonstrated that it was robust and that the reactions
downstream from 5 provided material of high purity.
Conceivably, we could take advantage of both routes and
assemble the molecule through a similar Negishi coupling
of the same aryl zinc species with a functionalized and
protected cyclopropanecarboxylic acid moiety (Scheme 3).
A logical choice would be cis-2-iodocyclopropanecarbox-
ylate, as this would lead to a common late-stage intermediate
with the linear route. Preliminary studies indicated that the
coupling of 2 with racemic iodoester 10 proceeded well,
affording the desired ketoester 4 as a racemate without
epimerization at either the R- or the â-position of the
cyclopropane ring.
converted to its tertiary amide 12. Deprotonation with the
mild, chelating base, bis(diisopropylamido)magnesium
(Mg(NiPr2)2), presumably afforded the R-anion first, which
isomerized to afford the â-anion with a cis-configuration.
Iodination with I2 then gave the desired â-iodoamide.
BuMgNiPr2 proved to work more efficiently for this purpose,
affording higher yields for the desired â-iodination product.
The crude reaction mixture from this step, containing the
starting material 12 (ca. 6%), the desired product 13 (ca.
83%), and the R-iodination isomer of 12 (ca. 6%), was
hydrolyzed in hot 35% nitric acid to afford racemic 1410 in
97% purity.
Racemic acid 14 was resolved with a stable, less toxic,
and fairly inexpensive chiral amine, (S)-(-)-N-benzyl-R-
methylbenzylamine, in excellent optical purity and yield
(99+% ee and 39% yield for the desired enantiomer). In
addition, the chiral amine can be recovered after the
acidification of the diastereomeric salt with HCl and
subsequently reused for resolution.
It is more desirable to introduce chirality into the molecule
at an earlier stage; thus, the focus of the exploration of this
new route was shifted to the preparation of enantiomerically
pure iodoester 10. Ideally, the iodo group and chirality would
be introduced in a single step into cyclopropanecarboxylic
acid 11 or its derivatives. Towards this end, we have
attempted several iodination reactions of 11, its inorganic
salts, esters, and secondary amides, with or without a chiral
amine in the reaction mixture. The bases used for these
reactions included n-, s-, and t-BuLi, Bu2Mg, and Mg(NiPr2)2.
Preliminary studies of these reactions proved to be un-
successful.
The relatively less reactive acid, (+)-14, was esterified
in quantitative yield by refluxing in ethanol with p-toluene-
sulfonic acid as a catalyst, without loss of enantiomeric
purity.
With both the fluoroketal 2 and the enantiomerically pure
10 in hand, the stage was set for the critical Negishi coupling.
Under an inert atmosphere and anhydrous conditions using
freshly prepared ZnBr2 solution, this reaction went extremely
well, affording the desired coupling product 4 in excellent
yield. There was no detectable quantity of the trans-isomer
of 4 in the reaction mixture or isolated product, suggesting
that no epimerization at either the R- or â-position of the
cyclopropyl ring occurred. In the linear route and after the
subsequent acidic deketalization step, the trans ketone ester
was selectively hydrolyzed with NaOH and thus removed
from the cis ketone ester. Such a step was rendered
unnecessary in our new process.
Meanwhile, we devised an indirect route to the desired,
enantiomerically pure iodoester 10, by applying the â-
iodination chemistry discovered by Professor Eaton’s group
(Scheme 4).9 Cyclopropanecarboxylic acid 11 was first
(9) (a). Zhang, M.-X.; Eaton, P. E. Angew. Chem., Int. Ed. 2002, 41, 2169. (b)
Eaton, P. E.; Lee, C. H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016. (c)
Eaton, P. E.; Daniels, R. G.; Casucci, D.; Cunkle, G. T. J. Org. Chem.
1987, 52, 2100.
(10) Moss, R. A.; Wilk, B.; Krogh-Jespersen, K.; Westbrook, J. D. J. Am. Chem.
Soc. 1989, 111, 6729.
Vol. 8, No. 3, 2004 / Organic Process Research & Development
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355

Table 1. Aqueous solubilities of MIV-150 saltsa
salt form (CAS #)
solubility (mg/mL)
purity (area %)
melting range (°C)
appearance
benzathine (140-28-3)
tromethamine (77-86-1)
meglumine (6284-40-8)
diolamine (111-42-2)
olamine (141-43-5)
ammonium
sodium
potassium
neutral MIV-150
0.0019
0.0013
0.0017
0.0013
0.030
0.0010
0.033
99.0
99.8
100.0
99.9
97.0
99.9
99.6
99.5
100.0
-
sticky yellow paste
white powder
white powder
pale yellow/white powder
bright yellow powder
white powder
pale yellow powder
pale brown/white powder
white powder
169.2-169.7
162.6-166.2
154.6-159.2
122.3 (dec)
192.2-194.5
189.5 (dec)
164.3-168.1(dec)
192-194
0.019
0.000005
a NMR analyses conform to the structures of MIV150 and the bases.
Table 2. Solubilities of MIV-150 salts in buffered aqueous
solutions
The overall process of this hybrid route was successfully
completed by carrying intermediate 4 through to MIV-150
(Scheme 5), in a sequence similar to that in the linear route.
The reaction mixture from the Negishi coupling step,
consisting mainly of 4 and excess 2, was carried forward
through the subsequent acid and basic hydrolysis steps. The
neutral impurities (e.g., excess 2) were removed by extraction
before the HCl acidification step. For the urea formation and
coupling with 2-amino-5-cyanopyridine, the same acyl
azide11 and isocyanate chemistry was applied. Instead of
using expensive reagents, such as diphenyl phosphorazidate,
sample
pH
buffer
(0.05 M)
sodium salt potassium salt olamine salt
(mg/mL)
(mg/mL)
(mg/mL)
4.01 acetate
5.97 acetate
7.00 phosphate
7.98 phosphate
9.02 carbonate
10.01 carbonate
10.51 carbonate
0.00078
0.00090
0.00091
0.00086
0.00101
0.00135
0.00320
0.00084
0.00100
0.00089
0.00088
0.00098
0.00142
0.00297
0.00093
0.00120
0.00108
0.00103
0.00111
0.00154
0.00289
12
to make the acyl azide precursor, NaN3 was reacted with
the mixed anhydride of 5 and ClCO2Et.
9.89. These extremely low solubilities pose a great challenge
in drug bioavailability and formulation studies. To overcome
this limitation, the neutral molecule was converted into
various organic and inorganic basic salts via the phenolic
hydroxyl functional group by reacting MIV-150 with an
equimolar amount of an appropriate base.
Saturated solutions of the isolated salts were prepared by
equilibrating the salts in deionized water followed by
filtration. The solubilities were measured by comparing the
peak areas by reversed phase HPLC with those of gravi-
metrically prepared standards of neutral MIV-150 reference
material. The concentration of MIV-150 was calculated for
each salt solution. The results of these analyses are tabulated
in Table 1 along with the CAS numbers of the organic bases,
HPLC purities, melting ranges, and the appearance of the
isolated salts. As the data indicate, all of the basic salts have
greater aqueous solubility than neutral MIV-150. The
increase in solubility ranges from 208 times more soluble
for the ammonium salt to 6700 times more soluble for the
sodium salt.
To meet and/or surpass the requirements of high purity
for the API as set in our specifications, and at the same time
streamline the reaction sequence, we have installed a number
of check-points at which high purities of the intermediates
were required and successfully obtained through distillation,
recrystallization, or extraction, while the other steps were
telescoped without purification of the crude products. For
example, while compound 12 was vacuum distilled, ensuring
a highly pure starting material, the following iodination,
amide hydrolysis, and chiral resolution steps were telescoped
without purification. High chemical and optical purity of the
acid (+)-14 was achieved through crystallization and re-
crystallization at the optical resolution stage. Similarly, the
reaction mixture from the Negishi coupling step containing
excess 2 was carried through the subsequent acidic and basic
hydrolyses. Neutral impurities were completely removed
from the reaction mixture by extraction prior to acidification
of the lithium salt of 5. For the next four steps leading to 6,
no purification was performed on these reactive intermedi-
ates. After the BCl3 demethylation reaction, the crude product
was recrystallized in absolute ethanol to afford the final API.
Through this hybrid route, MIV-150 was obtained in good
purity and met all of our specification requirements, including
those for optical purity and heavy metal residues.
Furthermore, we have established the pH-solubility pro-
files in various buffered solutions for the sodium, potassium,
and olamine salts, and the results are tabulated in Table 2.
All three salts demonstrated the same trend of increased
solubility at elevated pHs.
Conclusions
Basic Salts
A significantly improved hybrid formal synthesis of MIV-
150 has been developed which incorporates key elements
from both the linear and the earlier convergent routes. We
were able to capitalize on the proven chemistry of the linear
route to prepare our fluoroketal coupling partner 2. More
importantly, the hybrid synthesis merged into the linear route
via common late-stage intermediates 4 and 5, thus allowing
The aqueous solubility of MIV-150 itself is no more than
5 ng/mL between pH 0.97 and 9.05 and is 12 ng/mL at pH
(11) Acyl azides are potentially explosive. Normally their solutions should not
be concentrated to dryness.
(12) For safety issues related to the use of sodium azide, refer to Urben, P. G.,
Ed. Bretherick’s Handbook of ReactiVe Chemical Hazards, 6th ed.;
Butterworth-Heinemann: Oxford, UK, 1999; Vol. 1, pp 1802-1804.
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the opportunity to use the same final steps and to avoid
generating a new/lower impurity profile for the final API.
In addition to having lower risks for the manufacturing
process, this new hybrid convergent route also affords higher
yields with less lead time. The overall yield for preparing
the iodoester (+)-10 was 32%, while the overall yield for
the fluoroketal 2 arm was 73%. From the convergent point
to the final API, the overall yield was 27%. This is a marked
improvement compared to the overall yield of only 1.0%
for the linear route. In addition, we have developed proce-
dures to prepare the basic salts with significantly higher
solubilities than that for the parent molecule, further facilitat-
ing studies in related areas.
addition, the reaction mixture was stirred at 25 °C and
monitored by GC for completeness. When the reaction was
complete, water (1 L) was added. The phases were separated,
and the opaque yellow organic layer was washed with 2 M
HCl (500 mL), 20% aqueous solution of NaHCO3, and NaCl
(25% aqueous solution, 600 mL). Solvent was removed under
reduced pressure and the product isolated by simple vacuum
distillation (bp: 97-100 °C, 20 mmHg) as a clear, colorless
liquid (706 g, 86%). HPLC purity: 100%. 1H NMR (CDCl3)
δ 3.49 (q, 2H, J ) 7), 3.39 (q, 2H, J ) 7), 1.69 (m, 1H),
1.25 (t, 3H, J ) 7), 1.11 (t, 3H, J ) 7), 0.97 (m, 2H), 0.74
(m, 2H). 13C NMR (CDCl3) δ 172.92, 42.46, 41.23, 15.15,
13.63, 11.52, 7.77. FT-IR (neat, cm-1): 3009, 2975, 2934,
1640, 1259, 1139. HRMS (m/z) for C8H16NO (M+ + 1):
calcd 142.1232, found 142.1192.
Experimental Section
General. Unless otherwise indicated, all anhydrous
solvents were commercially obtained and stored in Sure-
Seal bottles under nitrogen. All other reagents and solvents
were purchased and used without purification. Both (S)-
(-)-N-benzyl-R-methylbenzylamine and (S)-(-)-R-methyl-
benzylamine were purchased from Aldrich. NMR spectra
were measured on a Bruker 400 MHz instrument. Chemical
shifts (δ) are reported in parts per million (ppm) referenced
(()-(cis)-2-Iodocyclopropyl-N,N-diethylcarboxamide (()-
13. A 3-L, four-necked reactor equipped with an overhead
stirrer, thermometer, and pressure equalizing addition funnel
was charged with dibutylmagnesium (1.0 M in heptane, 372
mL, 372 mmol). Diisopropylamine (52.0 mL, 372 mmol)
was added via an addition funnel, keeping the internal
temperature below 40 °C. The reaction mixture was allowed
to stir without external heating for 45 min and then heated
to reflux for 5 min and allowed to cool to room temperature.
A solution of 12 (50.0 g, 355 mmol) in anhydrous THF (600
mL) was added via addition funnel. Heating was resumed
and the reaction mixture was refluxed for 1 h. To a separate
5-L reactor equipped with an overhead stirrer and thermom-
eter was added iodine (180.0 g, 709 mmol) and anhydrous
THF (900 mL). The mixture was stirred at room tempera-
ture13 until all iodine had dissolved, and then the solution
was cooled to -20 °C. Heating of the diethylamide anion
was discontinued and the solution cooled to 5 °C before being
added via cannula to the reactor containing I2/THF. The
reaction was slightly exothermic, and the rate of addition
was controlled so as to keep the internal temperature below
0 °C. After complete addition, the reaction mixture was
stirred at 0 °C for 15 min and then transferred to a separatory
funnel containing 150 mL of concentrated H2SO4. The THF
phase was concentrated under vacuum and the resulting
aqueous solution was extracted with DCM (2 × 500 mL).
The combined organic phases were washed with 12%
aqueous solution of Na2S2O3 (3 × 300 mL) and brine (1 ×
300 mL). The combined extracts were concentrated under
reduced pressure to give a dark oil (79.6 g of crude product,
66% w/w for the desired product, yield: 56%). For a sample
1
to TMS at 0.00 or CHCl3 at 7.27 for H, and TMS at 0.00
or CDCl3 at 77.23 for 13C. Coupling constants (J) are reported
in hertz. FT-IR spectra were obtained on a Perkin-Elmer
Paragon 1000 as KBr pellets or film with a scan range of
4500-500 cm-1. Mass spectra data were acquired on a JEOL
LCMate, double-focusing mass spectrometer, in either APCI
positive or negative mode. For high-resolution mass spectra,
the resolving power was set at 3000. Optical rotations were
determined on a Perkin-Elmer model 241 polarimeter.
Analytical HPLC was conducted on an Agilent 1100 using
a 250 mm × 4.6 mm octadecylsilane (ODS), 5 µm, 100 Å
column at a flow rate of 1.0 mL/min, and processed with
Chemstation software. Peaks were monitored at 254 or 215
nm. GC analyses were conducted on an Agilent 6890, with
either a DB-WAXETR column (30 m × 0.32 mm i.d., and
1 µm film thickness) or a HP-5 column (30 m × 0.32 mm
i.d., 0.25 µm film thickness). Peaks were monitored by a
flame ionization detector.
Cyclopropyl-N,N-diethylcarboxamide (12). A 2-L, three-
necked reactor equipped with an overhead stirrer, thermom-
eter, a pressure equalizing addition funnel, and a heating
mantle was charged with thionyl chloride (430 mL, 5.89 mol,
1.01 equiv). Cyclopropanecarboxylic acid (500.0 g, 5.80 mol)
was then added via the addition funnel to the stirred thionyl
chloride. The reaction was endothermic, and heat was applied
during the addition to maintain a temperature between 0 and
5 °C. After the addition was completed, stirring was
maintained at 20 °C, and the reaction progress was monitored
by GC. An additional 5-L, three-necked flask equipped with
an overhead stirrer, thermometer, a pressure-equalizing
addition funnel, and an ice bath was charged with diethyl-
amine (1.26 L, 12.1 mol, 2.08 equiv) and dichloromethane
(DCM) (2 L) and cooled to 0 °C. The acid chloride solution
was transferred to the addition funnel and added to the cooled
diethylamine solution at such a rate that the temperature
could be maintained between 25 and 30 °C. After the
1
purified by column chromatography, H NMR (CDCl3): δ
3.62 (m, 2H), 3.37 (dt, 1H, J1 ) 14.9, J2 ) 7.2), 3.24 (dt,
1H, J1 ) 13.6, J2 ) 7.1), 2.81 (dt, 1H, J1 ) 5.8, J2 ) 8.1),
1.94 (dt, 1H, J1 ) 6.3, J2 ) 8.4), 1.58 (q, 1H, J ) 6.0), 1.41
(dt, 1H, J1 ) 6.2, J2 ) 8.0), 1.26 (t, 3H, J ) 7.2), 1.17 (t,
3H, J ) 7.1). 13C NMR (CDCl3): δ 168.06, 42.10, 41.16,
19.44, 14.72, 14.65, 13.73, -13.27. FT-IR (neat, cm-1):
2974, 2933, 1640, 1262, 1236, 1140. HRMS (m/z) for
C8H15INO (M+ + 1): calcd 268.0199, found 268.0253.
(13) Heating a solution of iodine in THF may cause a free radical decomposition
of the solvent.
Vol. 8, No. 3, 2004 / Organic Process Research & Development
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357

(()-(cis)-2-Iodocyclopropanecarboxylic Acid (()-14. A
1-L, three-necked flask was equipped with an overhead
stirrer, thermometer, and a reflux condenser. Compound 13
(66.5 g, 0.249 mol) was charged to the flask. An aqueous
solution of HNO3 (170 mL of 63% HNO3 and 160 mL of
water) was added. The reaction mixture was stirred and
heated to reflux for 20 h, and a second portion of concen-
trated HNO3 (68 mL, 63%) was added. Reaction progress
was monitored by HPLC. Upon reaction completion, the
reaction mixture was cooled to room temperature and
extracted with ethyl acetate (3 × 200 mL). The combined
ethyl acetate extracts were washed with brine (2 × 300 mL),
dried over MgSO4, filtered, and concentrated to give a light
were charged 200 mg (0.94 mmol) of the resolved cis-2-
iodocyclopropanecarboxylic acid and 1 mL of DCM. Under
an N2 atmosphere, SOCl2 (0.14 mL, 1.86 mmol, 2.0 equiv)
was added. The reaction mixture was stirred at room
temperature for 45 min. (S)-(-)-R-Methylbenzylamine (0.48
mL, 3.76 mmol, 4.0 equiv) in 3 mL of DCM was added to
the acid chloride solution which was cooled in an ice bath.
The resulting reaction mixture was stirred at room temper-
ature for 1 h. Some precipitates formed which did not
interfere with the de determination. An aliquot (0.1 mL) of
the suspension was diluted with MeOH (ca. 1.5 mL). The
resulting clear solution was diluted 3× with MeOH and
analyzed by GC. The diastereomeric excess of the dia-
stereomeric amides represents the enantiomeric excess of 14.
Ethyl (1R,2R)-2-Iodocyclopropanecarboxylate (+)-10.
A 2-L, four-necked reactor equipped with an overhead stirrer,
thermometer, and reflux condenser was charged with the
resolved iodoacid (+)-14 (114.0 g, 538 mmol), p-toluene-
sulfonic acid, (5.10 g, 26.8 mmol, 0.05 equiv), and absolute
ethanol (1.14 L). The reaction mixture was stirred and heated
to reflux for 24 h. Reaction completion was monitored by
HPLC. The reaction mixture was allowed to cool to room
temperature and the solvent removed under reduced pressure.
The resulting liquid residue was taken up in EtOAc (1.6 L)
and water (60 mL), washed with saturated NaHCO3 (2 ×
170 mL) and brine (1 × 170 mL), dried over MgSO4, filtered,
and concentrated to give a colorless oil (120.0 g, 93% yield).
1
yellow solid (48.6 g, 92%). HPLC purity: 97%. H NMR
(CDCl3): δ 2.89 (m, 1H), 1.95 (m, 1H), 1.55 (m, 1H), 1.42
(m, 1H). 13C NMR (CDCl3): δ 176.29, 19.37, 17.66. FT-IR
(KBr, cm-1): 3040 (br), 1699, 1224. HRMS (m/z) for
C4H4IO2 (M- - 1): calcd 210.9256, found 210.9292.
(1R,2R)-2-Iodocyclopropanecarboxylic Acid (+)-14. To
a jacketed, 4-L cylindrical reaction vessel that was equipped
with a circulating heating/cooling bath, a water condenser,
a N2 inlet, an overhead stirrer, and an internal temperature
probe was charged a solution of the racemic acid 14 (311.1
g, 1.47 mol) in 2170 mL of 2-propanol and a solution of
(S)-(-)-N-benzyl-R-methylbenzylamine (311.1 g, 1.47 mol,
1.00 equiv) in 1240 mL of 2-propanol. A suspension of the
salt began to form within 5 min and was heated to 75 °C.
The suspension turned clear and was then cooled. The onset
of crystallization occurred at around 56 °C. The slurry was
held at 53 °C, stirred for 30 min, and cooled further to 20
°C. The crystalline solid was collected by vacuum filtration,
washed with 2-propanol (2 × 670 mL), and air-dried (260.0
g). The partially resolved salt was mixed with 1910 mL of
2-propanol, and the mixture was heated to 76 °C and cooled.
The crystalline salt was collected by vacuum filtration,
washed with 2-propanol (2 × 350 mL), and dried to give
the product (243.3 g, 39% yield). HPLC purity: 99.8%.
To a 4-L reactor were added the above salt (241.3 g, 0.57
mol), 1340 mL of 0.5 N NaOH (0.67 mol, 1.2 equiv) and
670 mL of DCM. The mixture was stirred for 5 min and
transferred to a 4-L separatory funnel. After draining off the
DCM layer, the aqueous layer was washed with DCM (2 ×
670 mL) and acidified with 2 M HCl (670 mL). The resolved
iodoacid was extracted with tert-butyl methyl ether (TBME,
3 × 670 mL). The combined TBME extracts were washed
with brine, dried over MgSO4, filtered, concentrated on a
rotavap and further concentrated at 0.5 Torr at room
temperature for 30 min. The product solidified as a white
solid (117.9 g, 98% yield). Mp ) 68.8-70.1 °C. HPLC
purity: 98.2%. Enantiomeric excess by GC: 99.1% (vide
Purity: 99.2% by GC and 98.2% by HPLC. Bp ) 38.5 °C/
1
260 mTorr. [R]24 ) +32.54 (c 0.10, MeOH). H NMR
D
(CDCl3): δ 4.23 (m, 2H), 2.81 (dt, 1H, J ) 6.5, 8.1), 1.87
(dt, 1H, J ) 6.4, 8.3), 1.52 (dt, 1H, J ) 6.2, 8.2), 1.41 (q,
1H, J ) 5.4), 1.31 (t, 3H, J ) 7.1). 13C NMR (CDCl3): δ
170.14, 61.47, 19.46, 16.55, 14.66, -14.36. FT-IR (neat,
cm-1): 3060, 2982, 2937, 1728, 1279, 1249, 1178. HRMS
(m/z) for C6H10IO2 (M+ + 1): calcd 240.9726, found
240.9696.
Ethyl (1S,2S)-2-[3-(2-Ethyl(1,3-dioxolan-2-yl))-6-fluoro-
2-methoxyphenyl]cyclopropanecarboxylate (4). A 3-L,
five-necked round-bottomed flask equipped with an overhead
mechanical stirrer, temperature probe, pressure equalizing
addition funnel, and a N2 inlet was charged with 1-(2-ethyl-
(1,3-dioxolan-2-yl))-4-fluoro-2-methoxybenzene 2 (131.2 g,
580 mmol) and THF (850 mL) at room temperature. The
stirred solution was then cooled to -78 °C. n-Butyllithium
(213.8 mL, 2.5 M in hexanes, 555.8 mmol) was added
dropwise via the addition funnel at a rate so that the internal
temperature did not rise above -70 °C. The solution
gradually became yellow and remained homogeneous. After
the addition of n-BuLi was complete, the mixture was stirred
at -70 °C for 3 h during which time white precipitates
formed on the inside wall of the flask. During the 3 h stir
period, a fresh 1.6 M solution of zinc bromide in THF was
prepared: a 1-L, three-necked flask under N2 with magnetic
stirring was charged with THF (350 mL) and cooled to 0
°C. Nitrogen was rapidly flushed through the system, and
zinc bromide (125.2 g, 555.9 mmol) was added in portions
to the stirred solution. The zinc bromide solution was allowed
to warm to room temperature and then transferred to an
infra). [R]24 ) +47.22 (c 0.10, MeOH). 1H NMR
D
(CDCl3): δ 2.91 (dt, 1H, J ) 6.7, 8.2), 1.92 (dt, 1H, J )
6.4, 8.3), 1.60 (dt, 1H, J ) 6.2, 8.2), 1.44 (q, 1H, J ) 5.4).
13C NMR (CDCl3): δ 176.71, 19.80, 17.71, -14.29. FT-IR
(KBr, cm-1): 3091 (br), 1707, 1223. HRMS (m/z) for
C4H4IO2 (M- - 1): calcd 210.9256, found 210.9261.
Determination of Enantiomeric Excess (ee) of the
Resolved Acid (+)-14. To a 10-mL round-bottomed flask
358
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addition funnel. Addition of the zinc bromide THF solution
to the aryllithium solution commenced after the 3 h stir
period expired, at a rate that maintained the internal
temperature below -65 °C. After the addition was complete,
the pale yellow homogeneous arylzinc solution was allowed
to warm to room temperature. A solution of ethyl (1S,2S)-
2-iodocyclopropylcarboxylate 10 (116.0 g, 483.3 mmol),
palladium acetate (1.09 g, 4.83 mmol), and tris(2,4-di-tert-
butylphenyl) phosphite (15.63 g, 24.2 mmol) in THF (225
mL) was prepared. The resultant clear, orange solution was
stirred for 10 min, transferred to an addition funnel and added
to the arylzinc solution. The resultant reaction mixture was
heated to reflux (∼64 °C). The reaction was deemed
complete when GC analysis indicated that less than 2%
iodide was present, typically within 24 h. The solvent was
removed under reduced pressure and replaced with ethyl
acetate (1.5 L). To this solution was added 2 M NaOH (1.0
L), which resulted in gel-like white precipitates. The slurry
was filtered through Celite, and the filter cake was rinsed
with EtOAc (200 mL) and water (200 mL). The organic layer
of the filtrate was separated and the aqueous phase extracted
with EtOAc (2 × 100 mL). The organic extracts were
combined, washed with 2 M NaOH (2 × 500 mL), water
(200 mL) and brine (100 mL), dried over Na2SO4, filtered
and concentrated under vacuum to give 168 g of 4 as an oil
that slowly crystallized (170 g, 85% yield, 84.8% purity by
HPLC (the residual being 2)). The following analytical data
are from a purified sample obtained through column chro-
) 8.0), 4.03-3.80 (m, 9 H), 2.21-2.04 (m, 4H), 1.60 (m,
1H), 1.53 (m, 1H), 1.08 (t, 3H, J ) 7.1), 0.79 (t, 3H, J )
7.4). 13C NMR (CDCl3): δ 171.68, 164.33, 161.87, 159.22,
130.25, 126.80, 119.0, 110.74, 109.86, 109.64, 64.72, 61.31,
60.09, 31.35, 20.08, 15.72, 14.01, 8.10. MS: 339.2 (M +
H+). FT-IR (KBr, cm-1): 2981, 2944, 2887, 1722, 1603,
1198, 1172, 1054. HRMS (m/z) for C18H24FO5 (M+ + 1):
calcd 339.1608, found 339.1600.
General Procedure for the Preparation of Basic Salts.
Neutral MIV-150 was dissolved in DCM at a concentration
of 1 g per 100 mL, and an equimolar amount of base was
added. In cases where base was not soluble in DCM, the
base was first dissolved in 1 mL of water which was then
added to the solution. The solutions were stirred for 30 min,
and the solution was concentrated at reduced pressure to
leave solid material, except in the case of the benzathine
salt which formed a yellow paste. The benzathine salt paste
was dried at high vacuum until a constant weight was
obtained.
Acknowledgment
We thank Dr. Mao-Xi Zhang for technical consultations
on the â-iodination reactions, Todd McPherron for synthesiz-
ing starting material 12, and Dr. Shuguang Zhu and Dr. Mark
Fromhold for technical advice.
Received for review December 8, 2003.
OP0341871
matography. Mp ) 71.0-72.0 °C. [R]24 ) +368 (c 2,
D
CH2Cl2). 1H NMR (CDCl3): δ 7.32 (m, 1H), 6.74 (t, 1H, J
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