FULL PAPER

DOI: 10.1002/ajoc.201200014

Practical Large-Scale Synthesis of the Hepatitis C Virus Protease Inhibitor

BI 201335

Carl A. Busacca,*[a] Xudong Wei,*[a] Nizar Haddad,[a] Suresh Kapadia,[a]

Jon. C. Lorenz,[a] Anjan K. Saha,[a] Richard J. Varsolona,[a] Thilo Berkenbusch,[b]
Scot C. Campbell,[a] Vittorio Farina,[a] XuWu Feng,[a] Nina C. Gonnella,[a]
Nelu Grinberg,[a] Paul-James Jones,[a] Heewon Lee,[a] Zhibin Li,[a] Oliver Niemeier,[b]
Wendelin Samstag,[b] Max Sarvestani,[a] Juergen Schroeder,[b] John Smoliga,[a]
Earl M. Spinelli,[a] Jana Vitous,[a] and Chris H. Senanayake[a]

Abstract: A concise synthetic route
for large-scale manufacture of the
hepatitis C virus (HCV) protease in-
hibitor BI 201335 has been developed.
A convergent synthetic design was
achieved by using three advanced in-
termediates: a densely functionalized
thiazole-quinoline, a hydroxyproline-
containing dipeptide acid, and an opti-
cally pure vinylcyclopropane. Only
three subsequent synthetic steps were
then required for the final assembly practical process is suitable for large
of this complex target. The first step is scale production of BI 201335, re-
a critical C O bond formation to join quires no protecting groups or chro-
the heterocycle and the peptidic por- matography, and every isolated inter-
tion of the molecule, which was done mediate is a crystalline solid.
by using a newly-designed heterocy-
clic sulfone. The second step uses an
inexpensive peptide coupling of the
Keywords: antiviral agents · BI
aminocyclopropane and ester saponi-
201335 · HCV protease · nucleo-
fication, then recrystallization com-
philic substitution
pletes the route. This economical and

Introduction drug candidate was ultimately discontinued. This finding

Hepatitis C virus (HCV) infection is believed to affect
about 3 % of the worlds population, and potential thera-
pies that involve attacking various components of the viral
machinery is a very active research area. One of the most
promising targets has been HCV NS3 protease, an enzyme
which is essential to viral replication.[1] The first small-mol-
ecule inhibitor of this target was developed by Boehringer–
Ingelheim with proof-of-principle in humans achieved with
the macrocycle BILN 2061.[2] However, development of this
[a] C. A. Busacca, X. Wei, N. Haddad, S. Kapadia, J. C. Lorenz,
A. K. Saha, R. J. Varsolona, S. C. Campbell, V. Farina, X. Feng,
N. C. Gonnella, N. Grinberg, P.-J. Jones, H. Lee, Z. Li,
M. Sarvestani, J. Smoliga, E. M. Spinelli, J. Vitous, C. H. Senanayake
Chemical Development and Analytical Development
Boehringer-Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Rd. Ridgefield, CT 06877 (USA)
Fax: (+ 1) 203-791-6130
E-mail: carl.busacca@boehringer-ingelheim.com
xudong.wei@boehringer-ingelheim.com
[b] T. Berkenbusch, O. Niemeier, W. Samstag, J. Schroeder
Process Development Chemicals
Boehringer-Ingelheim Pharma GmbH
Binger Strasse, 173, 55216 Ingelheim (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ajoc.201200014.
then led to the identification of the nonmacrocyclic inhibi-
tor of HCV NS3 protease BI 201335,[3] a molecule which
possesses the key features of in vivo potency, safety, and
bioavailability needed for a HCV therapy. This inhibitor is
now in late-stage human clinical trials.[4] A coherent effort
by a team of chemists was required to develop a route that
is suitable for large scale production and commercializa-
tion.
BI 201335 is an architecturally complex molecule with
a molecular weight of nearly 900 amu and five stereogenic
centers. We required an economical and practical synthesis
of this important target, free of protecting groups, cryogenic
conditions, and chromatography. The retrosynthetic route
to BI 201335 that was ultimately developed is shown in
Scheme 1. The assembly was performed with the three ad-
vanced intermediates shown: dipeptide acid 1, aminoester
cyclopropane[5] 2, and thiazole-quinoline 3. Unlike the
double SN2 approach used in the discovery synthesis,[4] the
strategy for developing an efficient large-scale synthesis
was to join 1, derived from trans-hydroxyproline, and 3 by
a more straightforward SNAr reaction. The selection of the
optimum leaving group (LG) in 3 had not been finalized at
this early stage. The SNAr reaction would then be followed
by a coupling with the more expensive building block 2,
thereby avoiding tedious transformations and greatly reduc-
ing the waste generated.

80  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 80 – 89

Scheme 1. BI 201335 retrosynthesis. LG = leaving group.
Results and Discussion
The synthesis commences with the development of a practi-
cal and economical route to 1, and a protecting-group-free
process with isolation of crystalline intermediates was also
highly preferred. The chloroformate 4, derived from cyclo-
pentanol, was prepared by using triphosgene in tetrahydro-
furan (THF) with pyridine as a base (Scheme 2). Stability
Scheme 2. Synthesis of dipeptide acid 1.
studies with 4 showed little decomposition at approximately
10 8C in the presence of hydroxide bases, and the coupling
with tert-leucine was thus achieved in a Schotten–Bau-
mann-type reaction without measurable racemization.[6]
The capped tert-leucine 5 was obtained as a crystalline solid
in 87 % overall yield from cyclopentanol.
Although many different types of peptide-coupling proto-
cols could be applied to 5, coupling with the hydroxyproline
ester was conveniently carried out with the inexpensive ac-
tivator tosyl chloride[7] and N-methylmorpholine (NMM) as
base. The intermediate ester 6 was not isolated, rather
aqueous lithium hydroxide was charged at the conclusion of
Asian J. Org. Chem. 2012, 1, 80 – 89  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
the coupling to effect the
saponification. The target
dipeptide acid 1 was then
crystallized directly after ad-
justing the pH value in 91 %
overall yield for the one-pot
sequence, which achieves all
of the process goals detailed
above.
The synthesis of “north-
ern” heterocyclic fragment 3
is shown in Scheme 3 a.
Lithiation of pivalimide 7
and subsequent bromination
with dibromotetrachloro-
ethane gave the brominated
intermediate, which was
then hydrolyzed in situ with
6 n HCl to furnish the HCl salt 8 directly in 91 % overall
yield. A variety of brominating reagents could be used in
the synthesis of 8, provided that the anion solution was
added to the electrophile and the temperature was main-
tained at under 5 8C, though yields were not high. Table 1
shows the results with different brominating reagents. 1,2-
Dibromoethane gave a promising 51 % yield of 8, although
toxicity concerns with this reagent led to the search for
a better electrophile.
One of the most effective brominating reagents was bro-
moperfluorooctane, which does not appear to have been
previously applied to this type of transformation. Initial re-
search quantities of 8 were prepared in 81 % yield by using
this reagent, although its commercial availability at larger
scales later proved to be problematic. A search for a readily
available and economical reagent for this reaction was un-
dertaken. It was found that 1,2-dibromotetrachloroethane
was superior to all brominating reagents tested in this trans-
formation, and it was selected based upon its improved
yield, better atom economy, and ready availability on multi-
kilogram scale as a high melting point crystalline solid. One
caveat for the use of this electrophile was competing chlori-
nation, which required careful temperature control to
reduce the chlorinated impurity 9 (Scheme 4) in bromide 8
to less than 0.5 %.
Considerable optimization was required for the subse-
quent Sugasawa[8] acylation step to install the methyl
ketone. The conditions that were ultimately developed for
this Sugasawa acylation involve a combination of BCl3 and
AlCl3 (Scheme 3 a), and include several key parameters.
Direct use of the HCl salt 7 was successful, so that a salt
break to give the free base became unnecessary. Unwanted
cleavage of the methyl ether by the Lewis acids occurred
initially to give 13, yet the cleavage could be effectively
minimized by charging MeCN prior to addition of the
second Lewis acid (AlCl3), and by using only 0.5 equiva-
lents. The use of only five equivalents of MeCN, rather
than an excess, helped to reduce the amount of the amidine
impurity 14 that was formed from MeCN. Several different
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 Carl A. Busacca, Xudong Wei et al.
FULL PAPER
The order of addition of
the reagents was crucial,
with sequential charges of
aniline HCl salt 8, BCl3,
MeCN, and then AlCl3
giving optimum results.
Under these carefully opti-
mized conditions, Sugasawa
product 9 was formed in
80 % isolated yield. Aniline
9 was then acylated with the
acid chloride derived from
thiazole acid 10, itself pre-
pared in two steps from
thiourea by a Hantzsch[9]
synthesis, as shown in
Scheme 3 b. The initial acy-
lation was most efficiently
performed without added
base of any kind. The inter-
mediate 11 was not isolated,
but was cyclized in situ to
quinolone 12 by using
tBuOK at 100 8C, then
chlorinated with POCl3 to
chloroquinoline 3 a (LG =
Scheme 3. a) Synthesis of the “northern” heterocycle. b) Synthesis of acid 10.
Cl) in 81 % yield.
The key consideration in
the assembly of BI 201335
Table 1. Screen of brominating reagents for the conversion of 7 into 8. was how to carry out the C O bond forming reaction be-
Brominating reagent Yield of 8 [%] tween the “southern” peptide and the “northern” heterocy-
C3H5Br trace cle. A double SN2 approach[4] had been successfully used
NBS 21 for related compounds, yet a direct SNAr reaction was
Br2 25 chosen at this juncture, as it is a more straightforward and
BnBr 44 less wasteful strategy. The SNAr reaction in turn required
BrC2H4Br 51
BrC8F17 81
the synthesis of a thiazole-quinoline bearing a leaving
BrACHTUNGRE(CCl2)2Br 91 group at the 4-position. Several leaving groups were exam-
NBS = N-bromosuccinimide; Bn = benzyl.
ined, and chloride was chosen for the first SNAr studies.
The initial research thus focused on 3 a, which could be pre-
pared from 12 by using POCl3.
The use of any peptide esters as nucleophiles in this reac-
tion led to very complex reaction mixtures, and reasonable
conversions were obtained only with the free carboxylic
acids. This may reflect partial racemization at the hydroxy-
Scheme 4. Bromide 8 and chloride impurity 9.
proline ester a position under the strongly basic conditions
of the reaction.[10] Another major SNAr side product was
Table 2. Optimization of the solvent for the Sugasawa reaction.
the quinolinyl methyl ether 16 (Scheme 5) formed by reac-
Solvent Yield of 8 [%]
tion of 3 a with methoxide generated from the decomposi-
PhMe 89 tion of the hydroxyproline methyl ester. Further optimiza-
PhCl 78
1,2-DCE 94
tion of the SNAr reaction between 3 a and 1 revealed that
PhF 93 the reaction could be performed at 18–22 8C with 4.5 equiv-
DCE = dichloroethane alents of tBuOK in dimethylsulfoxide (DMSO), and re-
quired about five hours to reach completion. In a process
solvents could be used (Table 2), yet fluorobenzene proved safety evaluation, however, this strong base/DMSO system
to be the optimal solvent, as a reaction temperature of proved to be hazardous. The decomposition onset tempera-
about 75 8C was needed for full conversion and the use of ture was found to be 120 8C for the reaction mixture, which
solvents with lower boiling points thus became problematic. was presumably as a result of the deprotonation of DMSO

82 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 80 – 89
Synthesis of HCV Protease Inhibitor
Scheme 5. trans-Carbamoylation and ether impurities.
and further decomposition, possibly generating the methyl-
ene carbene. Potassium dimethyloctanoxide (KDMO) has
far greater stability in N,N-dimethylacetamide (DMAc) and
N,N-dimethylformamide (DMF) than in DMSO, yet when
a less-polar solvent such as THF was used, the SNAr reac-
tion was sluggish and more complicated mixtures were ob-
tained. Additional base (ca. 4.8–5.0 equivalents total) was
then needed to drive the reaction to completion, yet 5–
10 % of the quinolone impurity 12 was always formed, and
this species was very difficult to remove by crystallization.
In the initial scale-up work, this sparingly soluble impurity
had to be removed by filtration.
An additional problem associated with this process was
the formation of trans-carbamoylation species 17, the tert-
butyl carbamate analogue of 20 (Scheme 5), in which the
cyclopentyl group was replaced by the tert-butyl group from
tBuOK. This species was present at levels of approximately
5 %. The use of KDMO largely eliminated the trans-carba-
moylation problem, as the corresponding DMO-carbamate
18 was much more soluble and could be easily removed
during the crystallization of 20. Applying 4.25 equivalents
of KDMO in DMSO at room temperature gave the desired
SNAr product 20 in 87 % isolated yield. Presumably all
acidic protons on each coupling partner must be deproton-
ated for efficient SNAr reactions.
Initial multikilogram quantities of BI 201335 were pre-
pared by using this sequence, yet a more acceptable solvent
than DMSO was desirable, as were an increase in the fun-
damental reaction rate of the SNAr reaction and a more
economical base.
Sulfones are known to be competent leaving groups for
nucleophilic substitution.[11] Crystalline sulfone 3 b was pre-
pared from 12 by a one-pot tosylation (to give 19) and sub-
sequent sulfinate addition in 87 % yield, as shown in
Scheme 6. This transformation has the advantage of avoid-
Asian J. Org. Chem. 2012, 1, 80 – 89  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 6. Synthesis of sulfone 3 b.
ing the use of excess POCl3 as chlorinating reagent, which
can present safety issues. Competition experiments between
sulfone 3 b and chloride 3 a were carried out. The sulfone
gave a cleaner reaction and was also significantly more re-
active than 3 a. Addition of acetic acid to the SNAr reaction
mixture was beneficial. The unusual role of HOAc here
may be as a proton donor to the sulfonate leaving group
oxygen or the quinoline nitrogen, thereby accelerating the
reaction rate. HOAc is an extremely weak acid in dipolar
aprotic solvents relative to its acidity in water.[12] Complete
protonation of the sulfinate nucleophile is not likely to
occur in the solvent system used for the SNAr reaction.
The more economical base tBuOK could then again be
used because of the greater reactivity of the sulfone in
a THF/DMF mixture. These optimized conditions com-
bined with the superior sulfone coupling partner furnished
SNAr adduct 20 in 86 % isolated yield at room temperature
by using 3.8 equivalents of base, as shown in Scheme 7. The
intermediate was then crystallized from nPrOH after sol-
vent switching prior to the final isolation.
The initial peptide coupling of acid 20 with the vinylcy-
clopropane aminoester 2 was carried out with 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC) and N-hydroxy-
benzotriazole (HOBT), to give final intermediate 21 in
high yield. HOBT is relatively expensive and is also classi-
fied as shock-sensitive, which creates likely supply-chain
and transportation issues. We examined several HOBT sub-
stitutes,[13] yet detectable amounts of the diastereomer de-
rived from racemization of the proline stereocenter were
obtained. Isobutylchloroformate (IBCF) was identified as
an inexpensive activating reagent for this transformation[14]
that could provide optically pure 20 provided that careful
control of the reaction temperature was maintained. Slow
addition of NMM to 20 at 10 8C then slow addition of
IBCF and holding the reaction at 10 8C generated the acti-
vated intermediate. Peptide coupling was then achieved by
adding 2 to the intermediate described then adding of
a second quantity of NMM while maintaining the reaction
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 Carl A. Busacca, Xudong Wei et al.
FULL PAPER
Acyl thiourea 15

Thiourea (15 kg, 197 mol, 1 equiv)

Scheme 7. Synthesis of BI 201335.
temperature below 8 8C, and finally warming the reaction
to 10 8C. Ester 21 was then crystallized from denatured eth-
anol and isolated. Under these optimized conditions, final
intermediate 21 was obtained in 88 % isolated yield with no
detectable racemization. Synthesis of the active pharma-
ceutical ingredient was then achieved by simple ester sapo-
nification and crystallization, again from denatured ethanol,
in 85 % yield. Verification of the absolute configuration of
all stereocenters was achieved through single crystal x-ray
structure analysis.
Conclusions
In summary, a multikilogram route to the new HCV drug
BI 201335 has been developed. It is a robust and conver-
gent synthesis without the need for protecting groups or
chromatography. Each raw material used is inexpensive, all
peptide couplings are achieved without racemization, and
every intermediate is produced as a single enantiomer or
diastereomer. Each isolated intermediate is a stable crystal-
line solid, and all process safety concerns were addressed
by choosing inherently safer alternatives for scale-up. The
chemistry described here has now been successfully per-
formed on large scale in chemical production to support
the final clinical development phases of BI 201335.
Experimental Section
Unless otherwise specified, all reactions were performed in equipment
pre-purged with N2 before charging the reagents.
and toluene (150 L) were charged
to a 500 L glass-lined reactor. Iso-
butyryl chloride (21 kg, 197 mol,
1 equiv) was then added by a dia-
phragm pump over 2 h. The resul-
tant mixture was then gradually
heated to reflux, and significant
foaming of the batch was ob-
served. The batch was maintained
at reflux for 48 h, cooled to 60 8C,
then saturated NaHCO3 (45 kg)
was added. The mixture was then
cooled to 0 8C, left to stand for
12 h, and filtered. The filter cake
was washed with H2O (2  30 L),
then toluene (2  30 L), and the
filter cake was dried at 40 8C
under vacuum for 72 h to give
20.1 kg (70 %) of acyl thiourea 15
as a white solid; m.p. 110–111 8C.
1
H NMR (500 MHz, [D6]DMSO,
30 8C): d = 9.66 (br s, 1 H, N-H),
9.27 (br s, 1 H, N-H), 2.67 (septet,
J = 7 Hz, 1 H, C-H), 1.02 ppm (d,
J = 7 Hz, 6 H, Me). 13C NMR
(125 MHz, [D6]DMSO, 30 8C): d =
181.9 (s), 178.6 (s), 34.3 (d),
18.8 ppm (q). IR: ~ n = 651, 722,
881, 936, 1018, 1094, 1112, 1141, 1188, 1285, 1390, 1411, 1456, 1525,
1601, 1701, 3168, 3310 cm 1. HRMS: m/z: calcd for C5H11N2OS:
147.0587 [M + H] + ; found: 147.0580; error = 4.497 ppm. Elemental anal-
ysis calcd (%) for C5H10N2OS: C 41.07; H 6.89; N 19.16; found: C 40.90;
H 7.11; N 18.99.
Thiazole acid 10
Acyl thiourea 15 (17.5 kg, 120 mol, 1 equiv) and dioxane (180 kg) were
charged to a 500 L reactor. Bromopyruvic acid (20 kg, 120 mol, 1 equiv)
was then charged portionwise, which caused an exotherm to 40 8C. The
resultant slurry was heated to 100 8C and left to stand at that tempera-
ture for 3 h. The batch was concentrated to a final volume of 50 L under
vacuum, and then H2O (150 L) was charged. The resulting mixture was
agitated at 23 8C for 12 h, cooled to 0 8C, and then filtered. The resultant
filter cake was then washed with H2O (3  125 L), until the filtrate
reached pH 3.0. The filter cake was dried in a vacuum oven for 72 h to
give 19.0 kg (74 %) of thiazole acid 10 as a white solid; m.p. 246–248 8C.
1
H NMR (500 MHz, [D6]DMSO): d = 7.95 (s, 1 H, Ar-H), 2.71 (septet,
J = 7 Hz, 1 H, C-H), 1.10 ppm (d, J = 7 Hz, 6 H, Me). 13C NMR
(125 MHz, [D6]DMSO, 30 8C): d = 175.7 (s), 162.4 (s), 157.9 (s), 141.9 (s),
n = 655, 717, 733, 850, 868, 938, 981,
122.1 (d), 33.9 (d), 19.0 ppm (q). IR: ~
1095, 1105, 1149, 1190, 1222, 1292, 1350, 1416, 1461, 1552, 1699, 2508,
2969, 3134 cm 1. HRMS: m/z: calcd for C8H11N2O3S: 215.0485 [M + H] + ;
found: 215.0476; error = 4.141 ppm. Elemental analysis calcd (%) for
C8H10BrN2O3S·0.25 H2O: C 43.93; H 4.84; N 12.81; found: C 43.68; H
4.45; N 12.57.
Bromoanisidine HCl 8
Part 1: Piv-m-anisidine 7 (2.5 kg, 12.1 mol, 1 equiv) and THF (17 L)
were charged to a 50 L reactor and the solution cooled to 25 8C.
nBuLi/hexane (2.5 m, 12 L, 30 mol, 2.5 equiv) was then slowly charged
(< 10 8C). This mixture was agitated at ~ 15 8C for 3 h. In a separate
reactor dibromotetrachloroethane (5.9 kg, 18.2 mol, 1.5 equiv) and THF
(4 L) were charged, and the mixture was cooled to 30 8C. The cold dia-
nion solution from the first reactor was then slowly added to the electro-
phile solution over approximately 3 h and the internal temperature was
maintained at approximately 20 8C. After 1 h, the reaction was
quenched by the slow addition of HCl (1 n, 5 L), and the phases were

84 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 80 – 89
Synthesis of HCV Protease Inhibitor
separated. The organic phase was washed with H2O (1  10 L) and con-
centrated to a minimal stirrable volume at 30 8C/10 mmHg. This material
was then used directly for the subsequent hydrolysis. 1H NMR
(500 MHz, CDCl3, 30 8C): d = 8.15 (br s, 1 H, N-H), 8.08 (d, J = 8.5 Hz,
1 H, Ar-H), 7.28 (m, 1 H, Ar-H), 6.68 (d, J = 8 Hz, 1 H, Ar-H), 3.91 (s,
3 H, OMe), 1.68 ppm (s, 9 H, tBu). 13C NMR (125 MHz, CDCl3): d =
176.7 (s), 155.9 (s), 137.1 (s), 128.2 (d), 113.7 (d), 103.2 (d), 103.2 (s),
56.4 (q), 40.3 (s), 27.5 ppm (q). IR: 650, 772, 946, 1030, 1077, 1158, 1179,
1227, 1259, 1292, 1366, 1410, 1470, 1522, 1596, 1690, 2962 cm 1. HRMS:
m/z: calcd for C12H17BrNO2 : 286.0437 [M + H] + ; found: 286.0433;
error = 1.46 ppm. Elemental analysis calcd (%) for C12H16BrNO2 : C
50.37; H 5.64; N 4.89; found: C 50.03; H 5.21; N 4.68.
Bromoanisidine HCl 8
Part 2: The crude solution of the bromoanisyl amide described above
was diluted with ethanol (16 L), and HCl (12 n, 12 L) was slowly added.
The resulting mixture was heated to reflux for 24 h, then allowed to cool
slowly to 23 8C, which caused a precipitate of the product to form. The
slurry was cooled to 0 8C, left to stand for 2 h, and filtered. The filter
cake was then washed with n-heptane/methyl tert-butyl ether (MTBE,
1:1, 4 L), and then dried under vacuum at 35 8C until H2O < 1.0 % (as
monitored by Karl Fischer (KF) coulometry) was obtained, to give
2.55 kg (89 %) of bromoanisidine HCl 8 as a light brown solid;
m.p. 85 8C (dec). 1H NMR (500 MHz, [D6]DMSO, 30 8C): d = 8.15 (br s,
3 H, NH2 + HCl), 7.21 (dd, J = 8, 8 Hz, 1 H, Ar-H), 6.86 (d, J = 8 Hz, 1 H,
Ar-H), 6.69 (d, J = 8 Hz, 1 H, Ar-H), 3.82 ppm (s, 3 H, OMe). 13C NMR
(125 MHz, [D6]DMSO, 30 8C): d = 156.4 (s), 139.8 (s), 128.7 (d), 112.3
(d), 105.7 (d), 101.5 (s), 56.3 ppm (q). IR: ~n = 621, 648, 705, 750, 770,
883, 913, 962, 1036, 1063, 1102, 1115, 1163, 1257, 1289, 1443, 1467, 1508,
1551, 1580, 1610, 1936, 2598, 2798 cm 1. HRMS: m/z: calcd for
C7H9BrNO: 201.9862 [M + H] + ; found: 201.9857; error = 2.48 ppm. Ele-
mental analysis calcd (%) for C7H9BrClNO: C 35.25; H 3.80; N 5.87;
found: C 35.10; H 3.56; N 5.83.
Anilinoketone 9
BCl3 in a solution of fluorobenzene (1.886 kg, 4.182 mol, 1.33 equiv) was
added to a stirring suspension of bromoanisidine HCl 8 (0.750 kg,
3.145 mol, 1 equiv) in fluorobenzene (1.50 L) at 0–5 8C over 15 min and
the internal temperature was maintained below 5 8C. The reaction mix-
ture was allowed to slowly warm up to 22 8C over 0.5 h, and stirred at
ambient temp (20–22 8C) for 1 h. MeCN (0.723 kg, 17.61 mol, 5.6 equiv)
was then slowly added to the reaction mixture over 20 min and the inter-
nal temperature was maintained at 25 8C or below by using a cold water
bath (18–20 8C). The mixture was stirred at 20–22 8C for 1 h. Fluoroben-
zene (1.68 L) was added to the reaction mixture, a water bath (18–20 8C)
was placed under the flask, and AlCl3 (0.236 kg, 1.77 mol, 0.56 equiv)
was added in one portion (internal temperature rose from 22 to 32 8C).
The reaction mixture was then stirred at approximately 22 8C for 1 h,
then stirred at 75–77 8C (reflux) for 3.5 h. The resulting mixture was
then cooled to approximately 10 8C (ice-water bath) and quenched by
slow addition of H2O (3.75 L) over 20 min and the internal temperature
was maintained at 25 8C or below. The reaction was then stirred at 50 8C
for 2 h. The reaction mixture was cooled to 22 8C and stirred for 10 h.
Celite (0.325 kg) was charged to the reactor, stirred for 15 min., and fil-
tered. The flask and filter cake were washed with additional fluoroben-
zene (2.25 L), the layers were separated, and the aqueous layer was ex-
tracted with fluorobenzene (1.0 L). The combined organic extracts were
washed with H2O (3.0 L). The organic extract was concentrated to
1.75 L by distillation, and isoproyl alcohol (IPA, 3.0 L) was added. The
mixture was again concentrated to 2.40 L. At this stage analysis of the
supernatant by NMR spectroscopy (or GC) showed the complete ab-
sence of fluorobenzene. H2O (3.0 L) was added over 15 min (ratio of
H2O/IPA ca. 3:2), then the mixture stirred for 2 h and filtered. The flask
and filter cake were washed with H2O/IPA (3:2, 1.50 L), and dried at
22 8C under a flow of N2 at 80 mmHg to give 0.615 kg (80.0 %) of prod-
uct 9 as an off-white solid; m.p. 95–96 8C. HPLC purity: 99.9 %; H2O =
0.16 % (KF); 1H NMR (400 MHz, CDCl3, 30 8C): d = 7.72 (d, J = 8 Hz,
1 H, Ar-H), 7.10 (br s, 2 H, NH2), 6.28 (d, J = 8 Hz, 1 H, Ar-H), 3.94 (s,
3 H, OMe), 2.56 ppm (s, 3 H, Me). 13C NMR (100 MHz, CDCl3, 30 8C):
Asian J. Org. Chem. 2012, 1, 80 – 89  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
d = 198.6 (s), 160.0 (s), 149.0 (s), 132.9 (d), 113.9 (s), 99.4 (d), 98.4 (s),
56.3 (q), 27.6 ppm (q). IR: 615, 641, 784, 931, 972, 1022, 1046, 1131,
1187, 1256, 1308, 1361, 1422, 1463, 1484, 1522, 1564, 1604, 1631, 1640,
1631, 1640, 3285, 3426 cm 1. HRMS: m/z: calcd for C9H11BrNO2 :
243.9968 [M + H] + ; found: 243.9968; error = 0.138 ppm. Elemental anal-
ysis calcd (%) for C9H10BrNO2 : C 44.29; H 4.13; N 5.74; found: C 44.36;
H 3.79; N 5.48.
Quinolone 12
A 1 L jacketed reactor fitted with a mechanical stirrer, thermocouple,
N2 inlet, and addition funnel was charged with thiazole carboxylic acid
10 (25.0 g, 117 mmol, 1 equiv). The solid was then dissolved in 180 mL
of N-methylpyrrolidone (NMP). Thionyl chloride (8.94 mL, 122 mmol,
1.05 equiv) was added dropwise by syringe and the internal temperature
was maintained below 25 8C. After 30 min, a sample was removed and
quenched into diethylamine to confirm conversion to the acid chloride.
A solution of anilinoketone 9 in 70 mL NMP was then added all at
once, and the charge port was rinsed with 5 mL of NMP. The reaction
was stirred at 25 8C, and after 10 h a sample was taken for HPLC analy-
sis to confirm formation of the intermediate amide. Additional NMP
was then charged to the reactor (58 mL) followed by slow addition of
tBuOK (13.1 g, 117 mmol, 1 equiv). The internal temperature was main-
tained below 30 8C. The reaction was then heated to 80 8C, and the re-
maining tBuOK (65.5 g, 584 mmol, 5 equiv) was added slowly over
about 30 min through a solid addition funnel. The internal temperature
was maintained below 100 8C. The reaction darkened to almost black.
After the addition was complete, the reaction was heated to 100 8C.
After 1 h, HPLC analysis indicated complete conversion of 10 into 12.
The reaction was cooled to 60 8C, then HCl (6 m, 124 g, 628 mmol,
5.4 equiv) was charged through the addition funnel. The internal temper-
ature was maintained below 70 8C, which caused a solid to precipitate
out of solution. The reaction mixture was held at 65 8C for 30 min as
a thick slurry developed. A small sample was taken from the reaction,
diluted with H2O, filtered, and the pH value was measured to be
pH 1.5–2.0. A peristaltic pump was used to charge 350 g of H2O over ap-
proximately 60 min, and the reaction was then cooled to 40 8C over ap-
proximately 30 min, then held at this temperature for 1 h. The solid was
collected by vacuum filtration by using a Bchner funnel. The filter cake
was washed with NMP/H2O (1:1 w/w, 80 g), H2O (120 g), and finally
EtOAc (80 g). The filter cake was dried on the funnel until the light
gray solid could be transferred to a dish and dried in a vacuum oven at
45 8C/70 mmHg. After drying to a constant weight, 41.9 g (81.5 % over
two steps corrected for both water content and purity) of 12 was ob-
tained. HPLC purity: 98.8 %; H2O = 3.05 % (KF); m.p. 283–284 8C.
1
H NMR (400 MHz, [D6]DMSO, 30 8C): d = 12.42 (s, 1 H, N-H), 8.21 (s,
1 H, Ar-H), 8.13 (d, J = 9 Hz, 1 H, Ar-H), 7.31 (d, J = 9 Hz, 1 H, Ar-H),
6.91 (br s, 1 H, N-H), 4.02 (s, 3 H, OMe), 2.84 (septet, J = 7 Hz, 1 H, C-
H), 1.16 ppm (s, 6 H, Me). 13C NMR (125 MHz, [D6]DMSO, 30 8C): d =
175.9 (s), 158.8 (s), 158.4 (s), 125.6 (d), 118.9 (s), 115.4 (d), 110.3 (d),
n = 677, 708, 798, 826, 876,
103.3 (d), 57.0 (q), 33.7 (d), 19.0 ppm (q). IR: ~
951, 1006, 1066, 1105, 1159, 1182, 1195, 1236, 1268, 1288, 1367, 1401,
1433, 1456, 1479, 1528, 1548, 1568, 1602, 1632, 1682, 2970, 3073,
3291 cm 1. HRMS: m/z: calcd for C17H17BrN3O3S: 422.0169 [M + H] + ;
found: 422.016158; error = 1.779 ppm. Elemental analysis calcd (%) for
C17H16BrN3O3S·H2O: C 46.37; H 4.12; N 9.54; found: C 46.01; H 3.70; N
9.42.
Chloroquinoline 3 a
CAUTION! This compound is Ames positive. Handle with proper per-
sonal protective equipment. A 20 gallon reactor was charged with quino-
lone 12 (2.70 kg, 6.4 mol, 1.0 equiv), 1,4-dioxane (19.2 L), then POCl3
(2.94 kg, 19.2 mol, 3 equiv). The resulting mixture was heated to 85 8C
over 1 h and kept at this temperature for 2 h. HPLC analysis showed
that the reaction was complete (99.4 % conversion). The reaction mix-
ture was cooled to room temperature. In a separate 50 gallon reactor,
NaHCO3 (8.72 kg) was dissolved in H2O (90.8 L), and about 20 L of the
solution was taken out for use in a rinse afterwards. The reaction mix-
ture from the 20 gallon reactor was slowly transferred to the aqueous
NaHCO3 solution at such a rate that the foaming of CO2 was under con-
www.AsianJOC.org 85
 Carl A. Busacca, Xudong Wei et al.
FULL PAPER
trol and the temperature remained below 20 8C. Reactor 1 was rinsed Sulfone 3 b
with 1,4-dioxane (5 L) and sodium bicarbonate solution (20 L), and the
Tosylate 19 was prepared as described above but was not distilled or iso-
rinse was transferred to reactor 2. The reaction mixture was stirred at
lated. Instead, after the reaction mixture was left to stand at 32  2 8C
approximately 20 8C for 1 h, and the slurry was filtered with a Nutsche
for 0.5 h then cooled to 22 8C over 0.5 h, sodium benzenesulfinate
filter. The filter cake was washed with H2O (35 L, pH 7) and n-heptane
(15 L). The wet product was dried under vacuum (80 mm) at 40 8C for (0.777 kg, 4.73 mol, 2.0 equiv) was charged in one portion at 22 8C to the
reaction mixture, and subsequently acetic acid (1.50 L) was also added.
2 days (H2O = ca. 0.1 % (KF)). In total, 2.44 kg (90 %) of 3 a was ob-
The reaction mixture was then heated to 56  1 8C and stirred for ap-
tained as a pink solid, which was directly used in the next step. An
HPLC assay showed the product to be 98.5 % pure. A crystalline sample proximately 3 h. HPLC analysis showed that 0.1 % of unreacted 19 re-
was obtained by suspending the material in DMAc at 50 8C and agitating mained. The reaction mixture was then cooled to 22 8C over 0.5 h and
left to stand at this temperature for 0.5 h. The reaction mixture was then
for 1 h. The hot slurry was filtered, the filter cake was washed with H2O,
quenched by addition of H2O (1.75 L) over 30 min and stirred for 0.5 h
then dried on the frit to give 3 a as the DMAc monosolvate; m.p. >
250 8C. 1H NMR (500 MHz, [D6]DMSO, 30 8C): d = 12.33 (s, 1 H, N-H), at 22 8C. Test filtration showed that the mother liquor losses at this time
were normal, at 5.7 mg mL 1. The product was then filtered and the
8.21 (d, J = 9.3 Hz, 1 H, Ar-H), 8.15 (s, 1 H, Ar-H), 8.10 (s, 1 H, Ar-H),
filter cake was washed with MeCN/H2O (3:1 v/v, 2.84 L), then with H2O
7.70 (d, J = 9.3 Hz, 1 H, Ar-H), 4.08 (s, 3 H, OMe), 2.95 (s, 3 H, DMAc
solvate), 2.82 (m, 1 H, C-H), 2.79 (s, 3 H, DMAc solvate), 1.96 (s, 3 H, (3.0 L). The crude sulfone was then dried under vacuum at 50 8C/
DMAc solvate), 1.16 ppm (d, J = 6.8 Hz, 6 H, iPr). 13C NMR (125 MHz, 80 mmHg for 12 h until H2O = 7.8 % (KF). The moist filter cake
(1.22 kg) was charged back to the reactor and DMF (5.92 L) was added.
[D6]DMSO, 30 8C): d = 175.7 (s), 158.7 (s), 158.0 (s), 153.0 (s), 147.7 (s),
The mixture was then heated to 70 8C, which caused all solids to dissolve
146.2 (s), 142.3 (s), 124.4 (d), 120.6 (s), 117.1 (d), 115.4 (d), 114.8 (d),
109.3 (s), 57.1 (q), 37.4 (q), 34.5 (q), 33.8 (d), 21.4 (q), 19.1 ppm (q). IR: and a dark brown solution was obtained. The resultant mixture was
n = 656, 671, 710, 718, 740, 753, 764, 806, 825, 871, 907, 948, 981, 1007,
~ cooled to 50 8C and left to stand for 1 h, which caused some solid to
crystallize out. H2O (2.0 L) was then added over 15–20 min and the in-
1057, 1091, 1141, 1161, 1182, 1200, 1218, 1257, 1301, 1360, 1398, 1426,
1445, 1463, 1489, 1519, 1537, 1585, 1606, 1661, 2979, 3175 cm 1. HRMS: ternal temperature was maintained at 50–55 8C. The reaction mixture
m/z: calcd for C17H16BrClN3O2S: 439.9830 [M + H] + ; found: 439.9823; was then cooled to 22 8C over 0.5 h and left to stand at this temperature
error = 1.509 ppm. Elemental analysis calcd (%) for C17H15BrClN3O2S: for 1 h. Aqueous NaOH (1 m, 0.625 L) was then charged until a pH 12.5
was reached. The mixture was then stirred for 1 h at 22 8C. The resultant
C 46.33; H 3.43; N 9.53; found: C 46.08; H 3.38; N 9.23.
slurry was filtered and the filter cake washed with DMF/H2O (2:1 v/v,
Tosylate 19 5.33 L) until the pH value of the filtrate was 7–8. Sulfone 3 b was then
dried for 12 h at 70 8C/80 mmHg with an N2 bleed to constant weight, to
Quinolone 12 (1.25 kg, H2O = 4.25 % (KF), 2.37 mol) was charged to
give 1.10 kg (78.5 %) of 3 b as the mono-DMF solvate. HPLC purity:
a 20 L three-neck flask fitted with a thermocouple, a condenser, and me-
99.0 %; wt % purity: 91.7 %; H2O = 0.25 % (KF); m.p. > 250 8C. 1H NMR
chanical stirrer. n-Propanol (12.5 L, H2O = 0.054 % (KF)) was then
(500 MHz, [D6]DMSO, 30 8C): d = 8.89 (s, 1 H, N-H), 8.48 (d, J = 9.2 Hz,
charged to the reactor and stirred at moderate speed. The suspension
1 H, Ar-H), 8.09 (s, 1 H, Ar-H), 8.06 (d, J = 7.2 Hz, 2 H, Ar-H), 7.95 (s,
was agitated at 95 8C for 2 h, then cooled to 22 8C linearly over 2 h and
1 H, DMF), 7.73 (t, J = 6.6 Hz, 1 H, Ar-H), 7.66 (m, 3 H, Ar-H), 4.02 (s,
filtered. (filtrate H2O = 0.61 % (KF)). The solid was washed with n-prop-
3 H, OMe), 2.89 (s, 3 H, DMF), 2.80 (quintet, J = 6.8 Hz, 1 H, C-H), 2.73
anol (3.0 L) and dried under vacuum (80 mmHg) at 80 8C for 17 h (with
(s, 3 H, DMF), 1.17 ppm (d, J = 6.6 Hz, 6 H, iPr). 1H NMR (500 MHz,
N2 bleed) to give 1.124 kg (90 %) of anhydrous quinolone 12 (H2O =
CDCl3): d = 9.82 (s, 1 H, N-H), 8.87 (s, 1 H, Ar-H), 8.57 (d, J = 9.4 Hz,
0.76 % (KF)). Residual n-propanol was determined to be 0.03 mol % by
1 H, Ar-H), 8.15 (s, 1 H, Ar-H), 8.11 (s, 1 H, Ar-H), 7.97 (d, J = 8.2 Hz,
GC. The anhydrous quinolone 12 (1.00 kg, 2.367 mol, H2O = 0.76 %
2 H, Ar-H), 7.56 (m, 1 H, Ar-H), 7.48 (m, 2 H, Ar-H), 7.32 (d, J = 9.4 Hz,
(KF), 1 equiv) was charged to a 20 L three neck flask fitted with a ther-
1 H, Ar-H), 4.04 (s, 3 H, OMe), 2.99 (s, 3 H, DMF), 2.92 (s, 3 H, DMF),
mocouple, a condenser, and mechanical stirrer. MeCN was then charged
2.81 (quintet, J = 6.8 Hz, 1 H, C-H), 1.35 ppm (d, J = 6.9 Hz, 6 H, iPr).
(7.48 L, H2O = 0.05 %(KF)) then N,N-dimethylacetamide (1.11 L, H2O = 13
C NMR (125 MHz, [D6]DMSO, 30 8C): d = 175.8 (s), 162.3 (d, DMF),
0.05 %(KF)) and the mixture was stirred at medium speed. N-methylpyr-
159.0 (s), 157.7 (s), 152.8 (s), 147.6 (s), 146.6 (s), 145.2 (s), 139.6 (s),
rolidine (0.32 L, 0.262 kg, 3.08 mol, 1.3 equiv) was added in one portion
134.5 (d), 130.0 (d), 127.4 (d), 124.1 (d), 117.8 (d), 116.29 (d), 116.23 (d),
at 22 8C and left to stand for approximately 10 min. p-Toluenesulfonyl
115.2 (d), 110.0 (s), 57.0 (q), 35.7 (q, DMF), 33.9 (d), 30.7 (q, DMF),
chloride (0.519 kg, 2.72 mol, 1.15 equiv) was then charged at 25 8C over
19.0 ppm (q). 13C NMR (125 MHz, CDCl3): d = 175.3 (s), 162.8 (d,
15–20 min, which caused an exotherm to 29–30 8C. The reaction mixture
DMF), 158.2 (s), 157.7 (s), 153.1 (s), 148.5 (s), 147.5 (s), 145.8 (s), 140.5
was then left to stand at 32  2 8C for 0.5 h, then cooled to 22 8C over
(s), 133.9 (d), 129.5 (d), 127.7 (d), 124.3 (d), 118.5 (d), 117.3 (d), 115.6
0.5 h. The batch was then distilled at 40 8C/20 mm to remove most of the
(d), 115.0 (d), 111.5 (s), 57.0 (q), 36.6 (q, DMF), 35.5 (d), 31.5 (q, DMF),
MeCN. The batch was then diluted with H2O (7 L), the resultant slurry
19.2 ppm (q). IR: 618, 662, 672, 687, 710, 728, 744, 754, 763, 774, 806,
filtered, and the filter cake washed with additional H2O. Solid 19 was
823, 856, 871, 901, 947, 980, 995, 1008, 1057, 1082, 1094, 1140, 1154,
then dried in a tray drier (60 8C) to constant weight of 1.26 kg (92 %);
1186, 1199, 1259, 1297, 1321, 1355, 1384, 1398, 1423, 1446, 1461, 1491,
m.p. 216–217 8C. 1H NMR (400 MHz, [D6]DMSO, 30 8C): d = 12.38 (s,
1516, 1556, 1579, 1604, 1651, 1687, 2974 cm 1. HRMS: m/z: calcd for
1 H, N-H), 8.06 (d, J = 4.9 Hz, 2 H, Ar-H), 7.90 (d, J = 8.3 Hz, 2 H, Ar-H),
C23H21BrN3O4S2 : 546.0151 [M + H] + ; found: 546.0150; error = 0.252 ppm.
7.80 (d, J = 9.2 Hz, 1 H, Ar-H), 7.51 (d, J = 9.3 Hz, 1 H, Ar-H), 7.46 (d,
Elemental analysis calcd (%) for C26H27BrN4O5S2 : C 50.40; H 4.39; N
J = 8.2 Hz, 2 H, Ar-H), 4.02 (s, 3 H, OMe), 2.83 (quint, J = 6.8 Hz, 1 H, C-
9.04; found: C 50.46; H 4.26; N 8.93.
H), 2.39 (s, 3 H, Ar-Me), 1.16 ppm (d, J = 6.9 Hz, 6 H, iPr). 13C NMR
(125 MHz, [D6]DMSO, 30 8C): d = 174.9 (s), 162.7 (d, DMF), 157.9 (s),
157.8 (s), 154.4 (s), 153.9 (s), 149.0 (s), 147.9 (s), 146.1 (s), 132.0 (s), Capped tert-leucine 5
130.0 (d), 128.4 (d), 121.8 (d), 117.3 (s), 115.0 (d), 113.7 (d), 110.4 (s), Cyclopentanol (3.45 g, 40 mmol) was slowly added over approximately
108.8 (d), 57.0 (q), 36.5 (q), 35.6 (d), 31.5 (q), 21.7 (q), 19.2 ppm (q). IR: 5 min to a solution of triphosgene (4.45 g, 15 mmol) in THF (40 mL) at
n = 663, 677, 708, 725, 741, 769, 809, 832, 874, 944, 993, 1008, 1034, 1070,
~ 0–5 8C, and the resultant mixture was stirred for 5 min to dissolve the
1101, 1122, 1178, 1269, 1382, 1408, 1462, 1498, 1519, 1547, 1600, 1661, solids. Pyridine (3.16 g, 40 mmol) was then added to the reaction mix-
1695, 2970 cm 1. HRMS: m/z: calcd for C17H17BrN3O3S: 422.0169 ture over 25 min and the internal temperature was maintained below
[M OTs + H] + ; found: 422.0168; error = 0.121 ppm. Elemental analysis 5 8C. The cold bath was then removed and the reaction mixture was
calcd (%) for C24H22BrN3O5S2·0.35 H2O: C 49.46; H 3.93; N 7.21. stirred at 23 8C for 3 h. The reaction mixture was then filtered and the
Found: C 49.11; H 4.15; N 7.49. filter cake was washed with THF (7 mL). The filtrate containing the
chloroformate was assayed by HPLC and used as such in the next step.
1
H NMR (400 MHz, CDCl3): d = 1.40–1.90 (m, 8 H), 5.25–5.35 ppm (m,
1 H).

86 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Asian J. Org. Chem. 2012, 1, 80 – 89
Synthesis of HCV Protease Inhibitor
NaOH (2 n, 38 mL) was added to a stirring suspension of tert-leucine
(3.00 g, 22.80 mmol) in THF (15 mL, ACS grade) at ~ 10 8C over 5 min
and the internal temperature was maintained below 15 8C. The mixture
was stirred at approximately 15 8C for 15 min, and a solution of the
chloroformate described above (5.75 g, 38.8 mmol) in THF (15 mL) was
then added to the stirring reaction mixture over 15–20 min at 10–15 8C.
The cold bath was then removed and the reaction mixture was stirred at
23 8C for 3 h. MTBE (25 mL) was added, the mixture was stirred vigo-
rously for 10 min, then the layers were separated. The aqueous layer
was acidified with concentrated HCl to approximately pH 2 and the
product was extracted with ethyl acetate (2  25 mL). The combined or-
ganic layers were concentrated, n-heptane was added to the residue, and
it was again concentrated. The slurry thus obtained was filtered, washed
with n-heptane, and dried to give 4.55 g (82 %) of 5 as a white solid;
m.p. 155–156 8C. 1H NMR (400 MHz, CDCl3): d = 11.2 (br s, 1 H, O-H),
5.20 (m, 1 H, C-H-O), 5.10 (br s, 1 H, N-H), 4.20 (d, J = 10 Hz, 1 H, C-H-
N), 1.84–1.57 (m, 8 H, C-H2), 1.03 ppm (s, 9 H, tBu). 1H NMR (500 MHz,
[D6]DMSO, 30 8C): d = 12.5 (br s, 1 H, O-H), 7.06 (d, J = 9.0 Hz, 1 H, N-
H), 4.94 (m, 1 H, C-H-O), 3.79 (d, J = 8.8 Hz, 1 H, C-H-N), 1.80 (m, 2 H,
C-H2), 1.69–1.48 (m, 6 H, C-H2), 0.94 ppm (s, 9 H, tBu). 13C NMR
(125 MHz, [D6]DMSO, 30 8C): d = 172.8 (s), 156.3 (s), 76.3 (d), 62.6 (d),
n = 581, 654, 696,
33.2 (s), 32.31 (t), 32.28 (t), 26.7 (q), 23.3 ppm (t). IR: ~
965, 1018, 1063, 1172, 1213, 1261, 1329, 1369, 1416, 1477, 1529, 1663,
1727, 2963, 3336 cm 1. HRMS: m/z: calcd for C12H22NO4 : 244.1543 [M +
H] + ; found: 244.1541; error = 0.962 ppm. Elemental analysis calcd (%)
for C12H21NO4 : C 59.24; H 8.70; N 5.76; found: C 58.71; H 8.61; N 5.68.
Dipeptide acid 1
A 100 gallon glass reactor was charged with acid 5 (15.0 kg, 61.65 mol,
1 equiv) and MeCN (30.0 L). The mixture was agitated at 150 RPM for
15 min, and then cooled to 0 8C. NMM (31.4 kg, 308.3 mol, 5.0 equiv)
was then added over 20 min to give a colorless solution. The internal
temperature was then reduced to 2 8C and a solution of tosyl chloride
(12.15 kg, 63.75 mol, 1.03 equiv) in MeCN (30.0 L) was added over
80 min. The internal temperature was maintained below 5 8C. The result-
ing mixture was left to stand for 1 h from the end of the addition at 0 8C,
then cooled to 2 8C. A slurry of 4-hydroxyproline methylester HCl
(12.25 kg, 67.50 mol, 1.1 equiv) in MeCN (30.0 L) was then added over
25 min. The temperature was maintained below 10 8C during the addi-
tion. The mixture was held for 1.5 h at 0–15 8C, and HPLC analysis
showed that less than 0.22 % of 5 remained (checked as the benzylamide
derivative). LiOH (3.2 m, 90.0 L, 12.10 kg in 85.5 L H2O; 288.0 mol,
4.67 equiv) was then added to this mixture of ester 6 over 40 min, and
the internal temperature was maintained at 15 8C or below. The mixture
was then warmed to 23 8C and left to stand for 1 h, at which time HPLC
analysis showed complete consumption of the intermediate ester. The
MeCN wasremoved by distillation under reduced pressure (30–45 8C/
30 mm), then HCl (6 n, 25.5 L, 28.4 kg, 153.0 mol) was added over
25 min and the internal temperature was maintained below 35 8C. The
final pH value was 7–8 (pH 7.98 was measured). Residual MeCN was
then removed by distillation (45 8C/30 mm) to below 1 % w/w. The mix-
ture was heated to 60 8C and HCl (6 n, 28.75 kg, 154 mol) was slowly
added to reach pH 3.6, then the batch was seeded with 75 g dipeptide
acid 1 seeds in 1 L H2O as a slurry. The agitation was continued at 60 8C
for 30 min to establish a seed bed. An additional charge of HCl (6 n,
11.05 kg) was then added over 1 h to reach pH 0.99 at 60 8C (pH 1.3 at
23 8C). After standing for 1 h at 60 8C, the mixture was cooled to 23 8C
over 1 h, and then left to stand at that temperature for a further 1 h.
The slurry was then filtered (50 min), and the filter cake was washed
with HCl (0.1 n, 2  25.0 L), then finally washed with H2O (25.0 L). The
solid was dried at 50 8C/30 mm with an N2 bleed for 36 h to give 20.65 kg
(91 % over two steps) of dipeptide acid 1 as a white crystalline solid.
HPLC purity: 99.91 %; wt % purity: 101.14 %; H2O = 0.093 % (KF);
thermogravimetric analysis loss = 0.854 %. m.p. 117–124 8C; aD = 58.6
(c 2.17, MeOH). A crystalline sample for further characterization was
obtained by recrystallization from hot MTBE, which provided the 0.33
MTBE solvate crystalline form: m.p. 184–185 8C. 1H NMR (400 MHz,
CDCl3, major rotamer reported, 30 8C): d = 5.51 (d, J = 9.2 Hz, 1 H, N-
H), 5.02 (br s, 1 H, O-H), 4.70 (t, J = 8.8 Hz,1 H, CHO), 4.52 (s, 1 H,
Asian J. Org. Chem. 2012, 1, 80 – 89  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
OH), 4.31 (d, J = 9.2 Hz, 1 H, CHN), 4.01 (d, J = 11.2 Hz, 1 H, CHN),
3.68 (dd, J = 3.6, 11.6 Hz, 1 H, CHO), 3.06 (s, 1 H, 0.33 MTBE), 2.08 (m,
1 H, C-H2), 1.87–1.48 (m, 9 H, C-H2), 1.09 (s, 3 H, 0.33 MTBE), 0.92 ppm
(s, 9 H, tBu). 13C NMR (100 MHz, CDCl3, both rotamers, 30 8C): d =
173.5 (s), 172.5 (s), 157.1 (s), 78.5 (d), 69.8 (d), 59.1 (d), 58.2 (d), 56.8
(t), 49.6 (MTBE), 36.7 (t), 35.5 (s), 32.8 (t), 32.7 (t), 26.3 (d), 23.7 ppm
(t). IR: ~n = 681, 704, 870, 961, 989, 1015, 1051, 1069, 1085, 1181, 1213,
1276, 1309, 1361, 1433, 1501, 1630, 1716, 2950, 3442 cm 1. HRMS: m/z:
calcd for C17H29N2O6 : 357.2020 [M + H] + ; found: 357.2010; error =
0.038 ppm. Elemental analysis calcd (%) for C17H28N2O6 : C 57.29; H
7.92; N 7.86; found: C 56.89; H 8.36; N 7.76.
SNAr product 20
A 200 L reactor was charged with DMF (89 L), then sulfone 3 b·DMF
(15.09 kg, 24.21 mol, 0.98 equiv), and dipeptide acid 1 (8.95 kg,
24.69 mol, 1.0 equiv). The mixture was cooled to 4 8C, then tBuOK/
THF (0.97 m, 84.63 kg, 74.01 mol, 3.8 equiv) was added over 1 h and the
internal temperature was maintained at 1– 4 8C. The batch was left to
stand for 10 min at this temperature, then warmed to 19 8C over 1 h. The
mixture was then left to stand for a further 3 h at 19 8C, at which time
HPLC analysis indicated that 0.6 % of 3 b remained. The batch was then
cooled to 0 8C and quenched by the addition of HOAc (7.45 kg, 124 mol,
5 equiv) over approximately 30 min. The internal temperature was main-
tained at 0–10 8C. The reactor was then configured for distillation and
90 L of THF distillate was obtained at 35–40 8C/300 mmHg over 90 min.
GC analysis of an aliquot showed a THF/DMF ratio of 1:13 (target
< 1:10 w/w). The batch was cooled to 21 8C and 2-MeTHF (148 L) and
HCl (0.6 n, 120 L) were added. The pH value of the aqueous layer was
pH 4.65. The phases were separated, and the aqueous phase was discard-
ed. H2O (148 L) was then charged to the organic phase, and agitation
was continued for 10 min. After agitation was stopped, the aqueous
phase was discarded. The organic phase was then clarified by filtration
through a Seitz filter containing 0.5 kg Celite, and the reactor was
washed with an additional small charge of 2-MeTHF. The filtered organ-
ic solution was then charged back to the reactor and distillation per-
formed at 45–55 8C/200 mmHg. 97 L of distillate was collected. nPrOH
was then charged (74 L) and distillation at 50–65 8C/200 mmHg per-
formed. 24 L of distillate was collected. An additional charge of nPrOH
(25.55 kg) was then made, to give an approximately 20 % w/w solution
of SNAr product 20. The batch was heated to 75 8C, to give a clear solu-
tion. The mixture was then cooled to 22 8C over 2 h, then left to stand at
22 8C for 1.5 h. The resultant slurry was filtered and the filter cake
washed with nPrOH (36 L). The wet filter cake was dried at 70 8C/
100 mmHg with an N2 bleed for 5 h to give 16.0 kg (86 %) of 20; HPLC
purity: 99.4 %. Residual solvent analysis showed 0.03 % H2O and 0.06 %
nPrOH; m.p. > 250 8C. 1H NMR (500 MHz, [D6]DMSO, 30 8C): d = 12.33
(s, 1 H, O-H), 8.16 (d, J = 9.1 Hz, 1 H, Ar-H), 8.05 (br s, 1 H, N-H), 7.46
(s, 1 H, Ar-H), 7.36 (d, J = 9.2 Hz, 1 H, Ar-H), 6.98 (d, J = 9.2 Hz, 1 H,
Ar-H), 5.41 (br s, 1 H, C-H-O), 4.51–4.42 (m, 1 H, C-H-O), 4.10 (d, J =
8.6 Hz, 1 H, N-H), 4.02 (m, 1 H, C-H-N), 4.01 (s, 3 H, OMe), 3.91 (dd,
J = 2.6, 12 Hz, 1 H, C-H-N), 3.35 (br s, 2 H, C-H-N), 2.84 (sep, J = 6.8 Hz,
1 H, C-H-iPr), 2.71 (dd, J = 7.5, 14 Hz, 1 H, C-H2), 2.33 (m, 1 H, C-H2),
1.68–1.35 (m, 7 H, C-H2), 1.24 (br m, 1 H, C-H2), 1.16 (d, J = 6.8 Hz, 6 H,
iPr), 1.00–0.93 ppm (br s, 9 H, tBu). 13C NMR (125 MHz, [D6]DMSO,
30 8C): d = 175.7 (s), 172.7 (s), 170.5 (s), 160.2 (s), 158.4 (s), 157.3 (s),
156.3 (s), 154.1 (s), 149.3 (s), 146.7 (s), 122.6 (d), 116.4 (s), 113.8 (d),
112.5 (d), 108.7 (s), 97.9 (d), 76.7 (d), 76.3 (d), 59.1 (d), 57.4 (d), 56.7
(q), 52.9 (t), 34.1 (t), 34.2 (s), 34.1 (t), 33.7 (d), 32.2 (t), 31.9 (t), 26.2 (q),
23.14 (t), 23.06 (t), 19.13 (q), 19.06 ppm (q). IR: ~ n = 648, 772, 824, 840,
965, 1060, 1095, 1124, 1148, 1168, 1188, 1217, 1263, 1291, 1355, 1387,
1425, 1437, 1502, 1556, 1592, 1609, 1658, 1708, 2954 cm 1. HRMS: m/z:
calcd for C34H43BrN5O8S: 760.2010 [M + H] + ; found: 760.1995; error =
2.004 ppm. Elemental analysis calcd (%) for C34H42BrN5O8S: C 53.68; H
5.57; N 9.21; found: C 53.84; H 5.57; N 9.16.
Ester 21
A clean, dry 200 L glass lined steel reactor, capable of maintaining a re-
action at 15 8C, was dried under heat and vacuum. The reactor was
charged with acid 20 (15.7 kg, 20.6 mol, 1.0 equiv) and THF (110 L,
www.AsianJOC.org 87
 Carl A. Busacca, Xudong Wei et al.
FULL PAPER
H2O = 45 ppm (KF)). The mixture was agitated until a solution was BI 201335
formed, then the jacket was adjusted so that the internal temperature
A dry 400 L reactor was charged with ester 21 (16.32 kg, 15.76 kg cor-
was approximately 15 8C. N-methylmorpholine (2.31 kg, 22.9 mol,
rected for volatiles and purity, 17.83 mol, 1 equiv), purged with N2, then
1.1 eq) was then slowly added at a rate that maintained the internal tem-
THF (100 L) was charged. The mixture was agitated for 5 min to give
perature at 10 8C. By using a pre-calibrated metering valve, isobutyl
chloroformate (3.13 kg, 22.9 mol, 1.1 eq) was slowly added at a rate that a clear solution, which was then cooled to 2 8C. A solution of
LiOH·H2O (2.24 kg, 53.38 mol, 3.0 equiv) in H2O (32 L) was added to
maintained the internal temperature at 10 8C. On this scale the addi-
the cold mixture over 30 min and the internal temperature was main-
tion took 50 min. Note: controlling the temperature is critical for the
tained below 0 8C. The batch was then warmed to 21 8C over 1 h, then
success of this reaction. If the internal temperature goes above 10 8C
during the addition the yield will drop and additional impurities will be held at 21 8C for 8 h, at which time HPLC analysis of an aliquot showed
that less than 1 % of 21 remained. Isopropyl acetate (IPAc, 89 L) and
formed. The internal temperature was adjusted to 10 8C and held for
a solution of NaCl (28.1 kg) in H2O (79 L) were then charged. The re-
90 min. Aminocyclopropane salt 2 (7.12 kg, 22.9 mol, 1.1 eq) was then
sulting mixture was cooled to 5 8C, and 21.6 kg (ca. 80 % of the total) of
added through a solid-charging funnel and the internal temperature was
aqueous HCl (conc. HCl (5.06 kg) in H2O (22 L)) was added over
maintained at 8 8C. A second charge of N-methylmorpholine (2.29 kg,
30 min. The internal temperature was maintained below 6 8C. The
22.7 mol, 1.1 eq) was then added at a rate that maintained the internal
pH value was pH 7.0. Three additional small charges of the aqueous
temperature at 8 8C. The reaction was held at 10 8C for 2 h, then
HCl solution (1–2 kg) were then added and the pH value was checked
warmed to 10 8C, and held at that temperature until conversion was at
after each addition, until all of the HCl solution (27.1 kg) had been
least 95 % by HPLC analysis (this batch required 12 h). The reaction
added, and the final pH value was pH 4.3. The agitation was then
mixture was then warmed to 20 8C. 10 % aqueous NaCl (61 L) and 2-
stopped, and the aqueous phase was separated into a drum. The organic
MeTHF (63 L) were then charged, agitated for 10 min, and the layers al-
phase was drained into a separate drum. The aqueous phase was
lowed to separate. The aqueous layer was discarded. The organic layer
charged back to the reactor, then IPAc (89 L) was charged, and the mix-
was then distilled under reduced pressure to a minimum stirrable
ture agitated for 5 min. The agitation was stopped and the phases sepa-
volume (ca. 15 % of the original volume). Ethanol (126 L, denatured
rated. The aqueous phase was then discarded, and the first organic ex-
with 0.5 % toluene, SDA2B-3) was then added and the mixture again
tract was charged back to the reactor. H2O (79 L) was then charged, and
distilled to a minimum stirrable volume (ca. 15 % of the original
the mixture agitated for 5 min. The agitation was stopped once more
volume). An additional charge of SDA2B-3 ethanol (50 kg) was added
and the phases separated. The aqueous phase was again discarded. The
to make the solution 20 wt % in ester 21 based on an HPLC assay, and
organic solution was clarified by filtration through a Seitz filter contain-
then the solution was heated to 50 8C. H2O (36 L) was added over about
40 min and the internal temperature was maintained at 50 8C, to make ing 0.5 kg of Celite, and the reactor was washed out with additional
charge of IPAc (5 kg). This solution was stored for two days while
the final solution 29 wt % in H2O. Note: if the H2O is added too fast,
a second, identical hydrolysis reaction (17.4 kg) was carried out. The
there is the possibility of spontaneous crystallization. The reaction mix-
clarified organic solution from the second batch was combined with that
ture was held at 50 8C for 20 min. The resultant mixture was then seeded
with type A seed crystals of ester 21 (1 wt %, 157 g) as a slurry in etha- of the first batch and the IPAc was removed by distillation at a jacket
temperature of 61 8C and a pressure of 280 torr. After 6 h, a total of
nol/H2O (1:1). The reaction mixture was then cooled at 15 8C per hour
415 L of distillate was collected. The H2O content of the product was
to 25 8C and held at 25 8C for 1 h. The slurry was then filtered by using
0.25 % (KF). Distillation was stopped and the batch was heated to 70 8C,
14“ and an 18” Sparkler filters with polypropylene filter cloths. The
system was washed with SDA2B-3 ethanol/H2O (1/1, 56 kg) and blown then ethanol (12.9 kg) was charged. At 70 8C, a slurry of BI 201335 etha-
nol solvate seed crystals (332 g) in ethanol (4.0 L) was charged by N2
dry with N2. The solid product was dried to constant weight in a vacuum
pressure. The batch temperature was lowered to 65 8C and held at that
oven at 40 8C/100 mmHg with a N2 sweep to give 15.43 kg (85 %) of
temperature for 1 h. A visible seed bed developed. The batch tempera-
ester 21 (corrected for volatiles) as a light yellow solid; HPLC purity:
98.7 %; m.p. 182–184 8C. 1H NMR (400 MHz, [D6]DMSO, major rotamer ture was then lowered to 20 8C over 5 h, and held at 20 8C for 7 h. The
slurry was then centrifuged, and the filter cake washed with two volumes
reported, 30 8C): d = 12.32 (s, 1 H, N-H), 8.69 (s, 1 H, Ar-H), 8.14 (d, J =
of ethanol (31 L and 35 L). The filter cake was then dried at 80 8C/
9.2 Hz, 1 H, Ar-H), 8.03 (s, 1 H, Ar-H), 7.45 (s, 1 H), 7.33 (d, J = 9.4 Hz,
100 mmHg with an N2 bleed for 10 h. TGA showed 0.65 % weight loss.
1 H, Ar-H), 6.97 (d, J = 8.6 Hz, 1 H, N-H), 5.65 (m, 1 H, CH = CH2), 5.40
(br s, 1 H, CHOAr), 5.20 (dd, J = 1.5, 17 Hz, 1 H, CH=CH2), 5.06 (dd, J = The dry weight of the first crop of BI 201335 was 27.3 kg (85 %) HPLC
purity: 99.5 %; m.p. 235 8C. Detailed 1H, 13C, and 15N NMR assignments
1.6, 10.2 Hz, 1 H, CH=C-H2), 4.51 (m, 1 H, CHOACHTUNGRE(C=O)), 4.39 (t, J =
are given in the Supporting Information. IR: ~ n = 657, 772, 796, 810, 837,
8.4 Hz, 1 H, CHNACHTUNGRE(C=O)), 4.31 (d, J = 11.6 Hz, 1 H, NCHtBu), (4.08 (m,
865, 880, 900, 907, 934, 961, 997, 1012, 1039, 1059, 1094, 1154, 1170,
1 H, CH2N), 3.99 (s, 3 H, OMe), 3.90 (m, 1 H, CH2N), 3.56 (s, 3 H,
CO2Me), 2.81 (m, 1 H, NH), 2.51 (m, 1 H, CH2CHOAr), 2.25 (m, 1 H, 1203, 1217, 1264, 1283, 1317, 1354, 1417, 1448, 1479, 1503, 1544, 1587,
1610, 1699, 1720, 2874, 2962, 3229 cm 1. Elemental analysis calcd (%)
CH2-CHOAr), 2.07 (m, 1 H, CH (cyclopropane)), 1.70–1.32 (m, 7 H,
for C40H49BrN6O9S·0.5 H2O: C 54.67; H 5.73; N 9.56; found: C 54.74; H
CH2-CH2), 1.30 (m, 3 H, CH2 (cyclopropane) + CH2-CH2), 1.15 (d, J =
5.85; N 9.54.
8.1 Hz, 6 H, iPr), 0.95 ppm (s, 9 H, tBu). 13C NMR (100 MHz,
[D6]DMSO, all rotamers, 30 8C): d = 175.7 (s), 171.7 (s), 170.4 (s), 170.3 Crystal structure: CCDC 875522 contains the supplementary crystallo-
(s), 160.3 (s), 160.2 (s), 158.5 (s), 158.4 (s), 157.5 (s), 157.3 (s), 156.4 (s), graphic data for this paper. These data can be obtained free of charge
155.5 (s), 154.2 (s), 154.1 (s), 149.3 (s), 149.1 (s), 146.8 (s), 146.7 (s), from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
134.7 (d), 134.2 (d), 128.0 (s), 125.5 (s), 122.5 (d), 122.0 (d), 117.4 (t), c.uk/data_request/cif.
117.1 (t), 116.4 (s), 115.8 (s), 114.0 (d), 113.9 (d), 113.0 (d), 112.5 (d),
108.82 (s), 108.78 (s), 98.0 (d), 97.9 (d), 76.8 (d), 76.33 (d), 76.28 (d),
74.9 (d), 59.4 (d), 58.5 (d), 58.1 (d), 56.9 (q), 56.7 (q), 53.2 (t), 52.1 (q),
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Received: April 11, 2012
Published online: July 24, 2012
www.AsianJOC.org 89