Practical synthesis of 2-(2-isopropylaminothiazol-4-yl)-7-methoxy-1H- quinolin-4-one: Key intermediate for the synthesis of potent HCV NS3 protease inhibitor BILN 2061

Article abstract of DOI:10.1055/s-2006-942472

Herein we describe the development of an efficient, safe and practical process for the synthesis of 7-methoxy-2-(2-amino-4-thiazolyl)quinoline. Our new process allowed for a more convergent approach and eliminates the use of potentially dangerous reagents such as diazomethane used in the previous discovery approach. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942472

PAPER
2563
Practical Synthesis of 2-(2-Isopropylaminothiazol-4-yl)-7-methoxy-1H-
quinolin-4-one: Key Intermediate for the Synthesis of Potent HCV NS3
Protease Inhibitor BILN 2061
P
ractical
S
ynthes
o
is of 2-(2-Iso
g
propylamino
e
thiazol-4-y
l
l)-7-m
e
i
thoxy-
o
1
H
-quinolin-4-oneP. Frutos,*a Nizar Haddad,a Ioannis N. Houpis,a,1 Michael Johnson,a,2 Lana L. Smith-Keenan,a Victor Fuchs,a
Nathan K. Yee,a Vittorio Farina,a Anne-Marie Faucher,*b Christian Brochu,b Bruno Haché,b Jean-Simon Duceppe,b
Pierre Beaulieub
a
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./P.O. Box 368, Ridgefield,
CT 06877 0368, USA
Fax +1(203)8374681; E-mail: rfrutos@rdg.boehringer-ingelheim.com
Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard St., Laval, Québec, H7S 2G5, Canada
b
Received 7 March 2006
the multi-kilogram synthesis of the different subunits uti-
Abstract: Herein we describe the development of an efficient, safe
lized in the assembly of BILN 2061. For example, at the
onset of our work there was no synthesis of subunit 3, and
development of an efficient synthetic process for 3 would
and practical process for the synthesis of 7-methoxy-2-(2-amino-4-
thiazolyl)quinoline. Our new process allowed for a more conver-
gent approach and eliminates the use of potentially dangerous re-
agents such as diazomethane used in the previous discovery result in a more convergent approach to BILN 2061 rela-
approach.
tive to the original discovery route, which employed a
more linear route featuring an Arndt–Eistert reaction.4 In
Key words: BILN2061, protease inhibitor, hepatitis C virus,
Sugasawa, quinolone
addition, we sought to eliminate the use of potentially
dangerous reagents such as diazomethane used previously
for the preparation of the isopropylthiazolylamine group
in 1.4 Herein we describe our efforts towards the develop-
ment of a safe, efficient and practical process for the syn-
thesis of the BILN 2061 hydroxyquinoline/quinolone
synthon 3.5
The selection of HCV (Hepatitis C Virus) protease inhib-
itor BILN 2061 (1; Scheme 1)3 as a development candi-
date created the need to establish a suitable synthetic
process capable of meeting the drug substance require-
ments for clinical evaluation, toxicology assessment, for-
mulation and DMPK studies. Accordingly, the need also
arose to develop safe, efficient and practical processes for
Our retrosynthetic analysis of 3 is shown in Scheme 2. We
envisioned the intramolecular cyclization of 4, which we
planned to obtain by the coupling of intermediates 5 and
MeO
N
S
N
N
H
O
BILN 2061 (1)
O
H
N
N
OH
O
O
MeO
O
N
N
MeO
H
S
O
N
3
N
N
H
HO
CO2Me
O
Scalable
route
Discovery
route
OSO2R
O
+
O
H
H
N
N
N
N
OMe
OR
O
O
O
O
O
O
N
H
NH
2
O
O
Scheme 1 Retrosynthetic disconnections for BILN 2061
SYNTHESIS 2006, No. 15, pp 2563–2567
x
x.
x
x
.
2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-942472; Art ID: M01206SS
© Georg Thieme Verlag Stuttgart · New York

2564
R. P. Frutos et al.
PAPER
O
O
OH
N
S
O
3
+
NHiPr
MeO
NH
MeO
NH2
N
S
4
O
NHiPr
5
6
Scheme 2 Retrosynthesis analysis for quinolone 3
6. The key to the success of the above strategy was the in- Noticeable improvements in the yield of the reaction were
tramolecular cyclization of aryl amides such as 4, which indeed realized by simply switching the electrophile from
is a well-established method for the synthesis of function- acetyl chloride to acetonitrile. However, the yield of 5 was
alized quinolones.6
still moderate (35–40%) due to regioselectivity problems.
This lack of regioselectivity in the acylation of m-anisi-
dine 9 had also been observed by Sugasawa.12 In an effort
to further improve both the yield and selectivity of the re-
action, we screened a variety of reaction conditions for the
Sugasawa acylation of 9 (Table 1). The use of TiCl4 or
GaCl3, used successfully by other researchers as AlCl3 re-
placements,13 failed to improve the yield (entries 1 and 2).
Only traces of product were detected when the reaction
was carried out at ambient temperature (entry 3), but bet-
ter results were obtained at reflux in toluene–dichlo-
romethane (50–52 °C) for 15–20 hours (entry 4). Under
the above conditions, the selectivity improved to a 4.2:1
mixture of 5 and 10 and the HPLC yield of 5 to 45–55%.
A more favorable ratio of 5 to 10 could be obtained by re-
placing dichloromethane with p-xylene or toluene (entries
5 and 6), but the yield decreased in the absence of dichlo-
romethane. However, using only dichloromethane as the
solvent resulted in both a low yield and low selectivity
(entry 7). Eventually, in spite of the modest yield, we de-
cided to utilize this reaction in our scale-up process due to
its simplicity and the extremely low cost and wide avail-
ability of the raw materials.
Thiazole acid 6 was prepared by the condensation of 3-
bromopyruvic acid (7) and isopropyl thiourea (8) as
shown in Equation 1.7 The above condensation proceeded
efficiently to provide 6 as a crystalline solid without the
need for purification.
H
HO2C
O
N
S
dioxane
89–96%
NH
Br–
+
Br
HO
H2N
N
S
H
O
6⋅HBr
7
8
Equation 1
As opposed to the straightforward preparation of 6 de-
scribed above, the synthesis of 5 required optimization of
the reaction conditions. Initially, we studied the modified
Friedel–Crafts acylation procedure (AcCl, BCl3, AlCl3,
CH2Cl2) described by Brown and coworkers8 for the re-
gioselective acylation of m-anisidine (9). After numerous
attempts however, we were unable to obtain 5 in the 42%
yield reported by Brown.8 Instead, yields of 20–25% were
common, and isolation of the product (5) was further com-
plicated by the formation of persistent emulsions during
the work-up. We attributed the low yield mainly to the
lack of regioselectivity of the reaction that resulted in the
formation of undesired regioisomers.9 This lack of re-
gioselectivity, due to the typical tendency of conventional
electrophilic aromatic substitution to afford both ortho
and para isomers is, in principle, not a problem in the
original acylation procedure introduced by Sugasawa,
which uses a nitrile as the electrophile. This should result
in acylation ortho to the nitrogen via a cyclic transition
state in which boron coordinates to both the nitrogen at-
oms of the aniline and acetonitrile (Equation 2).10,11
We were able to isolate rather pure 5 without chromatog-
raphy. This was accomplished by a suitable work-up/iso-
lation procedure followed by crystallization. More
specifically, careful pH control during work-up was re-
quired to properly handle the large amounts of inorganic
salts present in the crude mixture, eliminate emulsions,
and also to remove undesired organic components. In this
manner, after the reaction mixture was quenched with iso-
propanol and water, the pH was slowly adjusted (pH 3)
with sodium hydroxide in order to leave the majority of
the impurities in the aqueous layer while the desired prod-
uct (5) remained in the organic layer. Further purification
was accomplished by crystallization of crude 5 from
methyl tert-butyl ether (MTBE)/heptanes to afford crys-
talline material in 40–50% isolated yield.
O
MeCN,
BCl3, AlCl3
MeO
NH2
+
MeO
NH2
MeO
NH2
toluene–CH2Cl2
0 °C to reflux
45–55%
O
5
10
9
Equation 2
Synthesis 2006, No. 15, 2563–2567 © Thieme Stuttgart · New York

PAPER
Practical Synthesis of 2-(2-Isopropylaminothiazol-4-yl)-7-methoxy-1H-quinolin-4-one
2565
Table 1 Synthesis of 5
O
MeCN,
BCl3, MCln
MeO
NH2
+
MeO
NH2
solvent
16–18 h
MeO
NH2
O
5
9
10
Entry
BCl3 solvent
CH2Cl2
Co-solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
MCl3
TiCl4
GaCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
Temp (°C)
5:10
3.3:1
6.7:1
N/A
Yield of 514
8%
1
2
3
4
5
6
7
52
52
24
52
57
80
43
CH2Cl2
4%
CH2Cl2
< 1%
48%
CH2Cl2
4.2:1
7.8:1
6.4:1
1.4:1
p-xylene
p-xylene
CH2Cl2
20%
36%
14%
H
Having established a procedure for the efficient synthesis
of 5, we turned our attention to the following steps for the
synthesis of 3. The coupling of 5 and 6 to give 4 was car-
ried out in a straightforward manner via the acyl chloride
of 6 generated upon treatment with oxalyl chloride
(Equation 3) followed by addition of 5 and triethylamine.
No purification was necessary and crude 4 was used for
the subsequent and final step.
N
S
N
MeO
11
N
H
O
Figure 1
To circumvent the above complications, alternative sol-
vents were tested in place of tetrahydrofuran–tert-butanol
and the best results were obtained with 1,2-dimethoxy-
ethane as the solvent (Equation 4). Accordingly, the reac-
tion was carried out by adding a solution of 4 in 1,2-
dimethoxyethane to a refluxing solution of potassium tert-
butoxide also in 1,2-dimethoxyethane, followed by
quenching with aqueous acid. Furthermore, the controlled
addition of aqueous acid resulted in precipitation of the
product, which was collected by filtration without the
need for work-up or further purification. Under the above
conditions, the isolated yield of 3 increased to 82%, and
formation of 11 was not observed even when the temper-
For the cyclization of 4 under basic conditions, the choice
of solvent was crucial for the overall efficiency of the re-
action. The intramolecular cyclization was initially car-
ried out by adding potassium tert-butoxide to a solution of
4 in tert-butanol, and heating to 75 °C. However, under
these conditions, we observed the formation of a side-
product, which was identified as 1115 (Figure 1), and
which formed in increased amounts at lower tempera-
tures.16 Although inverse addition of solid 4 to a hot solu-
tion of potassium tert-butoxide gave the product in high
yield, charging of solids in this way is undesirable in
scale-up operations for safety reasons.
O
–
O
Br
oxalyl
chloride
O
H
N
HO
+
MeO
NH
NH
CH2Cl2,
cat. DMF
Et3N (80%)
MeO
NH2
N
S
S
O
NH
5
6⋅HBr
4
Equation 3
O
O
t-BuOK
N
S
DME
93–96% assay
82% isolated
MeO
N
MeO
NH
H
NH
N
O
3
4
NH
S
Equation 4
Synthesis 2006, No. 15, 2563–2567 © Thieme Stuttgart · New York

2566
R. P. Frutos et al.
PAPER
aqueous solution was adjusted to 3 with 25% aq NaOH (125 mL).
The organic portion was collected and the aqueous layer was ex-
tracted with toluene (3 × 500 mL). The combined organic portions
were washed sequentially with 12.5% NaOH (600 mL) and H2O
(600 mL). Concentration under reduced pressure (rotary evaporator,
40 °C) afforded a brown solid. MTBE (322 mL) was added and the
mixture was heated to reflux (57–59 °C). Heptane (158 mL) was
then added over a period of 15 min. The mixture was heated to re-
flux (66–69 °C) for 1 h and then stirred at ambient temperature for
8–12 h. The resulting solid was collected by filtration at 10 °C and
washed with heptane (100 mL) to afford a light brown solid (55.4 g,
42%) after drying. NMR spectral data of the above product was con-
sistent with literature values.8
ature was purposely allowed to decrease to 50 °C in con-
trol experiments, confirming the decisive role of 1,2-
dimethoxyethane in directing the reaction to the exclusive
formation of 3.
In conclusion, we have developed a practical, safe, robust
and economic process for the synthesis of 3, which is a
key intermediate in the synthesis of the HCV protease in-
hibitor BILN 2061. Our process is highly convergent and
eliminates the use of potentially dangerous reagents such
as diazomethane used in the original discovery route. No
practical preparation for this compound (3) existed before
our work and considerable process research work, espe-
cially the optimization of the Sugasawa acylation of 9 and
the intramolecular cyclization of 4, was carried out. De-
velopment of the above process for the synthesis of 3 al-
lowed for the subsequent preparation of 1 in multi-
kilogram amounts for toxicology, formulation and clinical
studies.17
2-Isopropylaminothiazole-4-carboxylic Acid (2-Acetyl-5-meth-
oxyphenyl)amide (4)
Oxalyl chloride (6.97 mL, 79.9 mmol) was added dropwise to a
stirred solution of 6 (21.3 g, 79.9 mmol), DMF (0.2 mL) and CH2Cl2
(144 mL) at 5 °C over a period of 10 min. The mixture was then
stirred at 25 °C for 1 h. The resulting solution was cooled again to
5 °C and solid 5 (12.0 g, 72.6 mmol) was added in four portions over
a period of 1 h. The mixture was stirred for 30 min at 25 °C and Et3N
(40.5 mL, 291 mmol) was added at 10 °C over a period of 20 min.
The mixture was stirred at 25 °C for 1.5 h and quenched with sat. aq
NaHCO3. The organic portion was collected, washed with H2O (2 ×
100 mL), dried (Na2SO4) and concentrated under reduced pressure
to afford 4 (24.3 g; 100% crude yield) as a yellow solid. An analyt-
ical sample was purified by crystallization from CH2Cl2–hexanes to
afford a pale-yellow solid.
Unless otherwise specified, all reactions were carried out in oven-
dried glassware under an atmosphere of nitrogen. NMR spectra
were recorded on a Bruker DPX-400 NMR spectrometer. Chemical
shifts are reported in ppm relative to tetramethylsilane; coupling
constants (J) are reported in hertz, and refer to apparent peak multi-
plicities, and may not necessarily be true coupling constants. The
commercially available starting materials were used as received
without further purification and all solvents were dried by standard
methods prior to use. All melting points are recorded using a Fish-
er–Johns melting point apparatus and are uncorrected.
1H NMR (400 MHz, CDCl3): d = 1.34 (d, J = 6.4 Hz, 6 H), 2.63 (s,
3 H), 3.77 (m, 1 H), 3.91 (s, 3 H), 5.26 (br d, J = 7.7 Hz, 1 H), 8.65
(d, J = 2.6 Hz, 1 H), 6.64 (dd, J = 2.6, 9.0 Hz, 1 H), 7.42 (s, 1 H),
7.84 (d, J = 9.0 Hz, 1 H), 13.13 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.6, 28.1, 47.9, 55.4, 104.1,
2-Isopropylaminothiazole-4-carboxylic Acid Hydrobromide (6)
Pyruvic acid (5.00 g, 56.8 mmol) was charged into a 250 mL flask
equipped with mechanical stirrer, condenser and N2 inlet, and bro-
mine (9.07 g, 56.8 mmol) was added dropwise, allowing each drop
to decolorize between additions. The temperature of the reaction
was allowed to rise spontaneously to 40–50 °C. After completion of
the addition, the mixture was stirred for an additional 5 min and then
diluted with dioxane (125 mL). Isopropyl thiourea (6.70 g, 56.8
mmoL) was added all at once and the slurry was refluxed for 1 h.
After cooling, the precipitate was filtered and washed with Et2O,
then dried in vacuo to afford the product (11.3 g, 75%) as a white
solid; mp 191–192 °C.
109.7, 112.5, 116.0, 133.4, 143.2, 146.7, 161.0, 164.3, 167.8, 200.2.
Anal. Calcd for C16H19N3O3S: C, 57.64; H, 5.74; N, 12.60. Found:
C, 57.54; H, 5.58; N, 12.49.
2-(2-Isopropylaminothiazol-4-yl)-7-methoxy-4a,8a-dihydro-
1H-quinolin-4-one (3)
Solid t-BuOK (26.93 g, 240.0 mmol) was charged into a dry three-
neck flask followed by anhyd DME (260 mL) and the resulting mix-
ture was heated to reflux (87–89 °C). A solution of amide 4 (20 g,
60.0 mmol) and DME (120 mL) was then slowly added to the above
refluxing solution over a period of approximately 1 h. Upon com-
plete addition of 7, the mixture was held at reflux for an additional
15–20 min and then allowed to cool to 22–25 °C. HCl (1 N, 221 mL)
was added slowly over a period of 1 h, keeping the internal temper-
ature at 22–25 °C until the solution was neutral (pH 7). The result-
ing slurry was stirred at 22–25 °C for 3 h and then H2O (300 mL)
was added slowly over a period of 1 h. The slurry was stirred at am-
bient temperature for 4–12 h and the resulting solid was collected
by filtration to afford the product (18.0 g, 82% yield) as a tan solid;
mp 245–247 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.18 (d, J = 6.4 Hz, 6 H), 3.97
(m, 1 H), 7.60 (s, 1 H), 9.20 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 21.8, 48.1, 117.2, 133.5,
159.2, 167.1.
Anal. Calcd for C7H11BrN2O2S: C, 31.47; H, 4.15; N, 10.49. Found:
C, 31.47; H, 4.02; N, 10.38.
1-(2-Amino-4-methoxyphenyl)ethanone (5)
BCl3 (801 mL of a 1 M solution in CH2Cl2, 800.6 mmol) was added
dropwise to a solution of anisidine (5; 90.0 mL, 800.6 mmol) and
toluene (506 mL) over a period of 2 h, keeping the internal temper-
ature at 0–5 °C. MeCN (50.2 mL, 961 mol) was then added at 0–5
°C over a period of 20 min and the mixture was stirred for 40 min.
Solid AlCl3 (117 g, 881 mmol) was charged in one portion at 0–5
°C, the mixture was stirred for 5–10 min and heated to reflux (50–
51 °C). The mixture was kept at reflux for 12–16 h, cooled to 0 °C
and quenched by adding i-PrOH (370 mL) over a period of 30 min.
H2O (1.06 L) was then added over a period of 50 min, keeping the
temperature at 10 °C. The mixture was then stirred at reflux for 3 h
(50 °C) and allowed to reach ambient temperature. The pH of the
1H NMR (400 MHz, DMSO-d6): d = 1.22 (d, J = 6.5 Hz, 6 H), 3.87
(s, 3 H), 3.98 (m, 1 H), 6.52 (d, J = 1.6 Hz, 1 H), 6.89 (dd, J = 2.3,
8.9 Hz, 1 H), 7.28 (d, J = 2.3 Hz, 1 H), 7.50 (s, 1 H), 7.76 (d, J = 7.6
Hz, 1 H), 7.95 (d, J = 8.9 Hz, 1 H), 11.04 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 22.3, 46.2, 55.4, 99.6, 105.6,
106.7, 113.1, 119.5, 126.4, 141.8, 143.5, 144.0, 161.9, 167.6, 176.7.
HRMS (APCI): m/z calcd for C16H18N3O2S: 316.1114; found:
316.1112.
Anal. Calcd for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32. Found:
C, 60.89; H, 5.34; N, 13.26.
Synthesis 2006, No. 15, 2563–2567 © Thieme Stuttgart · New York

PAPER
Practical Synthesis of 2-(2-Isopropylaminothiazol-4-yl)-7-methoxy-1H-quinolin-4-one
2567
(7) For additional examples of thiazoles prepared from 3-
Acknowledgment
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R.; Echavarren, A.; Chandrakumar, N. S.; Koeksal, Y.
Tetrahedron Lett. 1984, 25, 2127. (b) Bailey, N.; Dean, A.
W.; Judd, D. B.; Middlemiss, D.; Storer, R.; Watson, S. P.
Bioorg. Med. Chem. Lett. 1996, 6, 1409.
The authors wish to acknowledge Dr. Paul-James Jones for valuable
discussions while characterizing compounds by NMR.
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(1) Present Address: Johnson and Johnson Pharmaceutical
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Pierre, C.; Vevert, J.-P. Bioorg. Med. Chem. Lett. 2000, 10,
1487. (i) Beney, C.; Hadjeri, M.; Mariotte, A.-M.;
Boumendjel, A. Tetrahedron Lett. 2000, 41, 7037.
(j) Niedzinski, E. J.; Lashley, M. R.; Nantz, M. H.
Heterocycles 2001, 55, 623.
(13) Houpis, I. N.; Molina, A.; Douglas, A. W.; Xavier, L.;
Lynch, J.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
1994, 35, 6811.
(14) The yield was determined by a quantitative HPLC assay.
(15) 2-Isopropylamino-7-methoxy-4-methylene-4,9-dihydro-3-
thia-1,9-diazabenz[f]azulen-10-one (11): 1H NMR (400
MHz, DMSO-d6): d = 1.14 (d, J = 6.4 H, 6 H), 3.72 (s, 3 H),
3.70–3.85 (m, 1 H), 5.30 (s, 1 H), 5.34 (s, 1 H), 6.70–6.75
(m, 2 H), 6.75 (d, J = 2.4 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H),
7.74 (d, J = 7.5 Hz, 1 H), 10.0 (s, 1 H). 13C NMR (100 MHz,
DMSO-d6): d = 22.7, 46.3, 55.7, 106.4, 110.6, 116.8, 123.1,
130.1, 131.5, 137.0, 139.6, 160.2, 161.4, 163.9.
(16) Up to 50% of 11 was formed when the reaction was carried
out at 50 °C. Electrophilic reaction of 2-aminothiazoles at C-
5 is well precedented. In this case, it may be promoted by
ionization of the C-2 isopropylamino group, although
usually strong bases like sodium amide have been employed
to obtain deprotonation at such amino groups. See:
Heterocyclic Compounds; Weissberger, A.; Taylor, E. C.,
Eds.; Wiley: New York, 1979.
(17) A manuscript describing the complete assembly of BILN
2061 using 3 is in preparation and will be published in due
course.
Synthesis 2006, No. 15, 2563–2567 © Thieme Stuttgart · New York