Robust synthesis of methyl 5-chloro-4-fluoro-1 h -indole-2-carboxylate: A key intermediate in the preparation of an HIV NNRTI candidate

Article abstract of DOI:10.1021/op1001808

A synthetic preparation of methyl 5-chloro-4-fluoro-1H-indole-2- carboxylate, a key intermediate towards phosphoindole inhibitors of HIV non-nucleoside reverse transcriptase, is described. The five-step synthesis involved Boc protection of the commercially available 4-chloro-3-fluoroaniline and regioselective iodination at C-2. After facile Boc deprotection, cyclization of the resultant o-iodoaniline gave the corresponding 5-chloro-4-fluoro-indole- 2-carboxylic acid which was subsequently esterified to provide the target indole ester in 56% overall yield. Identification of 6-chloro-7-iodo-2(3H)- benzoxazolone as a significant side product in the iodination step led to the development of conditions which eliminated its formation in subsequent batches. Advantages of this alternative approach relative to existing methodologies include (1) potentially hazardous diazonium and azido species were not required, (2) regioisomeric products were not generated, and (3) chromatographic isolations were avoided, as all intermediates were easily crystallized. As a result, the key indole ester was produced rapidly at 100-fold increased scale compared to previous reports with a 10-fold improvement in overall yield.

Full text of DOI:10.1021/op1001808

Organic Process Research & Development 2010, 14, 1248–1253
Robust Synthesis of Methyl 5-Chloro-4-fluoro-1H-indole-2-carboxylate: A Key
Intermediate in the Preparation of an HIV NNRTI Candidate
Benjamin A. Mayes,* Narayan C. Chaudhuri, Christopher P. Hencken, Frederic Jeannot, G. Mark Latham, Steven Mathieu,
F. Patrick McGarry, Alistair J. Stewart, Jingyang Wang, and Adel Moussa
Idenix Pharmaceuticals Inc., 60 Hampshire Street, Cambridge, Massachusetts 02139, U.S.A.
Abstract:
A synthetic preparation of methyl 5-chloro-4-fluoro-1H-indole-2-
carboxylate, a key intermediate towards phosphoindole inhibitors
of HIV non-nucleoside reverse transcriptase, is described. The five-
step synthesis involved Boc protection of the commercially avail-
able 4-chloro-3-fluoroaniline and regioselective iodination at C-2.
After facile Boc deprotection, cyclization of the resultant o-
iodoaniline gave the corresponding 5-chloro-4-fluoro-indole-2-
carboxylic acid which was subsequently esterified to provide the
target indole ester in 56% overall yield. Identification of 6-chloro-
7-iodo-2(3H)-benzoxazolone as a significant side product in the
iodination step led to the development of conditions which
eliminated its formation in subsequent batches. Advantages of this
alternative approach relative to existing methodologies include (1)
potentially hazardous diazonium and azido species were not
required, (2) regioisomeric products were not generated, and (3)
chromatographic isolations were avoided, as all intermediates were
easily crystallized. As a result, the key indole ester was produced
rapidly at 100-fold increased scale compared to previous reports
with a 10-fold improvement in overall yield.
Figure 1
able and until very recently, neither were its 2-carboxylic acid
2 and 2-ethyl ester 3 analogues. Supplies of these materials,
however, are limited and expensive for large scale use.
Accordingly, in order to rapidly fulfill the requirements of the
HIV research program, investigations were conducted into the
synthesis of 1 on multigram scale. Multiple methodologies exist
for the synthesis of variously substituted indoles,5 however, there
are relatively few accounts of the efficient formation of 4,5-
dihaloindole-2-carboxylates. The literature on 5-chloro-4-fluoro
derivatives is limited to three distinct published examples, all
of which bear certain synthetically unappealing aspects.
The initial route, by Silvestri et al. in 2002, to the ethyl ester
3 utilized the Fischer indole cyclization in three steps from
3-fluoroaniline ($420/kg).6 The resultant 1:2 mixture of 5-chloro-
4-fluoro 3 and 5-chloro-6-fluoro 4 regioisomers was separated
by repeated chromatographic purification and provided 900 mg
of the desired isomer 3 in a mere 5% overall yield.
The second published route to 1, by Ohta et al., used the
Hemetsberger indole procedure from 1-(bromomethyl)-3-chloro-
2-fluorobenzene ($1660/kg) on 440 mg scale.7 Although this
three-step method did not generate regioisomers, it was
hampered by a low overall yield (4.3%), multiple chromato-
graphic purifications, and the use of the potentially hazardous
methyl 2-azidoacetate.8
Introduction
This report describes a robust synthetic preparation of methyl
5-chloro-4-fluoro-1H-indole-2-carboxylate, 1 (Figure 1).1 This
key functionalized scaffold was required during a campaign to
evaluate novel phosphoindoles as non-nucleoside reverse tran-
scriptase inhibitor (NNRTI) candidates for the treatment of HIV
infection.2 The 2-carboxy-5-chloro-4-fluoroindole moiety has
also been incorporated as an important feature of other NNRTIs,
in particular indolyl aryl sulfones,3 and of various heterocyclic
anticoagulants.4 The methyl ester 1 is not commercially avail-
* Author to whom correspondence should be addressed. E-mail:
mayes.ben@idenix.com.
(1) Part of this research is presented in the following patents: Storer, R.;
Alexandre, F.-R.; Dousson, C.; Moussa, A. M.; Bridges, E. WO/2008/
042240, 2008 (CAN 148:449766); Storer, R.; Alexandre, F.-R.;
Dousson, C.; Moussa, A. M.; Bridges, E.; Stewart, A.; Wang, J.;
Mayes, B. A. U.S. Pat. 2008/0213217, 2008.
In the most recent (2008) literature preparation of ethyl ester
3, Silvestri et al. utilized a Reissert indole synthesis starting
(2) Patents WO/2008/042240, 2008, Vide supra. U.S. 2008/0213217, 2008,
Vide supra.
(3) La Regina, G.; Coluccia, A.; Piscitelli, F.; Bergamini, A.; Sinistro,
A.; Cavazza, A.; Maga, G.; Samuele, A.; Zanoli, S.; Novellino, E.;
Artico, M.; Silvestri, R. J. Med. Chem. 2007, 50, 5034–5038. Piscitelli,
F.; Coluccia, A.; Brancale, A.; La Regina, G.; Sansone, A.; Giordano,
C.; Balzarini, J.; Maga, G.; Zanoli, S.; Samuele, A.; Cirilli, R.; La
Torre, F.; Lavecchia, A.; Novellino, E.; Silvestri, R. J. Med. Chem.
2009, 52, 1922–1934.
(5) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(6) Silvestri, R.; De Martino, G.; Sbardella, G. Org. Proced. Prep. Int.
2002, 34, 517–520.
(7) Ohta, T.; Komoriya, S.; Yoshino, T.; Uoto, K.; Nakamoto, Y.; Naito,
H.; Mochizuki, A.; Nagata, T.; Kanno, H.; Haginoya, N.; Yoshikawa,
N.; Nagamochi, M.; Kobayashi, S.; Ono, M. U.S. 2005/0020645, 2005
(CAN 142:176829).
(4) Ohta, T.; Komoriya, S.; Yoshino, T.; Uoto, K.; Nakamoto, Y.; Naito,
H.; Mochizuki, A.; Nagata, T.; Kanno, H.; Haginoya, N.; Yoshikawa,
N.; Nagamochi, M.; Kobayashi, S.; Ono, M. WO/2003/000680, 2003
(CAN 138:89801).
(8) Urben, P. G., Ed. Bretherick’s Handbook of ReactiVe Chemical
Hazards, 7th ed.; Academic Press: Oxford, 2007; Vol. 2, see p51.
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10.1021/op1001808  2010 American Chemical Society
Published on Web 08/16/2010

Scheme 1. Formation of indole ester 1
Table 1. Effect of scale, reagent quantities, and internal temperature on the formation of benzoxazolone 9 and yield of 7
entry
scale (g)
n-BuLi (equiv)
I2 (equiv)
internal temperature (°C)
ratioa 7:6
ratioa 7:9
isolated yield of 7
1
2
3
4
5
6
7
8
10
80
87
141
5
4.0
4.0
2.6
2.6
2.5
3.6d
3.0
3.1
3.4
3.4
3.4
3.4
3.3
3.4
3.4
3.5
-70 to -75
-64 to -78
-68 to -73
-68 to -72
-90 to -100
-80 to -95
-75 to -82
-75 to -80
11.6:1
5.8:1
2.54:1
4.62:1
4.22:1
6.10:1
n.d.c
75.8:1
>200:1
119:1
10 g, 66%
72 g, 60%
90.3 g, 68%
95.3 g, 44%b
n.d.
6.1 g, 81%
3.95 g, 87%
114 g, 94%
45.2:1
31.0:1
0.32:1
14.6:1
32.5:1
43.7:1
5
3
80
a In-process LCAP ratio at 272 nm. b Isolated 42.3 g of benzoxazolone 9 (25% yield). c Not determined. d 2.6 + 1.0 equiv.
from 3-fluoro-2-methylaniline ($1400/kg).9 This six-step pro-
cedure gave 3 on a 330 mg scale, and although the overall yield
(37%) was superior to the two previous methods, this route
presented drawbacks in that three of the intermediates were oils
requiring chromatographic isolation.
As a result of these limitations, an alternative approach to 1
was investigated to provide more rapid and convenient access
to this valuable synthetic intermediate.
iodo regioisomer, with iodine installation para to fluorine, as
reported for the analogous methyl carbamate using N-iodosuc-
cinimide.12 In a similar regioselective fashion, direct iodination
of aniline 5 using I2/CaCO3 was found to give 85% yield of
the undesired 4-chloro-5-fluoro-2-iodoaniline. Treatment of Boc
aniline 6 with ICl/AcOH resulted in only the deprotected aniline
5. Instead therefore, ortho-lithiation13 was performed at low
temperature using n-BuLi, followed by treatment with iodine
in THF to give the desired 2-iodo Boc aniline 7.14 Initially, 4
equiv of n-BuLi were used with 3.4 equiv of iodine which
resulted in modest yields (60-66%) on 10-80 g scale (Table
1, entries 1, 2). Due to the mechanistic requirement for only 2
equiv of n-BuLi, one to deprotonate the carbamate, the other
to lithiate, an attempt was made to reduce this excess to 2.6
equiv which resulted in 68% yield on 87 g scale (Table 1, entry
3). A significant side product was consistently observed in these
Results and Discussion
The target indole-2-carboxylate 1 was prepared in five steps
from commercially available 4-chloro-3-fluoroaniline 5 ($450/
kg) as shown in Scheme 1. After Boc protection of the aniline
5 and regioselective introduction of iodine at the 2-position,
the free aniline 8 was liberated prior to indole cyclization. Final
esterification of the indole acid 2 gave the desired indole ester
1 in 56% overall yield.
(9) Piscitelli, F.; La Regina, G.; Silvestri, R. Org. Proced. Prep. Int. 2008,
40, 204–208.
Existing literature preparations of Boc aniline 6 report
reactions on modest scale (2.5-10 g), extensive reaction times
(3-4 days), and a high number of unit operations or moderate
yields (71-79%).10 In this instance, however, Boc protection
of aniline 5 was achieved on a 250 g scale by refluxing the
starting material in heptane with di-tert-butyl-dicarbonate. After
4 h, a simple isolation protocol was performed which entailed
cooling the reaction to 45 °C and reducing the solvent volume
by 75% Via distillation to give a thick slurry. After further
cooling, crystals of Boc aniline 6 were collected by filtration
in 93% yield with 99% LCAP purity.11
(10) Bachmann, S.; Pflieger, P.; Rimmler, G.; Scalone, M., WO/2009/
007259, 2009 (CAN 150:121489). Sugita, K.; Otsuka, M.; Oki, H.;
Haginoya, N.; Ichikawa, M.; Ito, M., Jpn. Pat. 2008/291018, 2008
(CAN 149:576645). Terauchi, J.; Kuno, H.; Nara, H.; Oki, H.; Sato,
K., WO/2005/105760, 2005 (CAN 143:460174).
(11) Full characterization of Boc-aniline 6 is provided here for the first
time.
(12) Conte, A.; Kuehne, H.; Luebbers, T.; Mattei, P.; Maugeais, C.; Mueller,
W.; Pflieger, P. U.S. 2007/185182, 2007.
(13) March, J.; Smith, M. B., Eds. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms and Structure, 6th ed.; John Wiley and Sons,
Inc.: NJ, 2007.
(14) Subsequent to the publication of Idenix patents WO/2008/042240 and
U.S. 2008/0213217 Vide supra, a similar procedure using the methyl
carbamate analogue was reported to give the corresponding protected
2-iodoaniline, Vide supra WO/2009/007259, 2009.
Direct iodination of the Boc aniline 6 was anticipated to
produce almost exclusively the undesired 4-chloro-5-fluoro-2-
Vol. 14, No. 5, 2010 / Organic Process Research & Development
•
1249

Scheme 2. Formation of benzoxazolone 9 at internal temperature above -75 °C
three batches, which were all performed at an approximate
internal reaction temperature of -70 °C. On scaling further,
this impurity made the isolation of 7 increasingly more
problematic, and as a result, the yield on 141 g scale dropped
to 44% (Table 1, entry 4). A substantial amount (25% yield)
of this side product was isolated and positively identified as
the benzoxazolone 9. It was presumed that a slight elevation
of the internal temperature led to the elimination of LiF with
concomitant formation of the benzyne intermediate, which then
underwent Boc side-chain cyclization, trapping with I2 and
subsequent release of isobutene on quenching to give 9 (Scheme
2). It is noteworthy that related reports with Boc aniline15 and
Boc 3-fluoroaniline16 required the use of t-BuLi to effect similar
ortho-lithiations, rather than n-BuLi. It was determined on small
scale that the reaction temperature was the major factor
controlling the extent of iodination and the impurity profile.
With an internal temperature of -90 to -100 °C, the reaction
mixture was observed to partially freeze, and a mere 25%
conversion was obtained (Table 1, entry 5). On elevating the
temperature to -80 to -95 °C and using 2.6 equiv of n-BuLi,
in-process analysis indicated a significant amount of 6 remained
unreacted, possibly due to partial precipitation of the starting
material. A further 1 equiv of n-BuLi was added which resulted
in a 7:6 ratio of 14.6:1. Importantly, a much improved ratio of
7 to benzoxazolone 9 (75.8:1) was obtained, raising the yield
to 81% (Table 1, entry 6). An internal temperature range of
-75 to -82 °C was next used along with 3 equiv of n-BuLi,
to ensure good solubility and full conversion of Boc aniline 6
whilst attempting to maintain low levels of benzoxazolone 9.
The reaction mixture was observed to be completely solubilized
in this temperature range, giving an improved conversion and
an almost undetectable level of 9 (Table 1, entry 7). As a result,
2-iodo Boc aniline 7 was isolated in 87% yield. Encouraged
by this data, the reaction was scaled to 80 g whilst raising the
internal temperature slightly to -75 to -80 °C. The formation
of 7 was smoothly effected, giving an improved 7:6 ratio of
43.7:1 whilst maintaining a highly beneficial ratio of 7:9 (119:
1) (Table 1, entry 8).17 After addition of the aqueous quenching
solutions, the organic solvents were distilled off, efficiently
precipitating the crude product 7. Purification was then achieved
by crystallizing the crude solid from hot aqueous ethanol to
give 7 in 94% isolated yield and 99% LCAP purity.
Deprotection of the Boc group to provide the free aniline 8
was achieved in a facile manner using conc. HCl in ethanol at
50-55 °C. After a reaction time of 2 h, the mixture was
neutralized with aqueous NaOH and the ethanol was distilled
off, causing the free aniline to precipitate readily from the
colorless aqueous solution. Recrystallization of the crude aniline
with hot aqueous ethanol gave two crops of pure 2-iodoaniline
8, both with 99% LCAP purity in a combined yield of 93%.
With the ortho-iodoaniline 8 in hand, the method of Chen
et al. was used for indole cyclization, in which initial enamine
formation with pyruvate is followed by an intramolecular Heck
coupling to provide the indole 2-carboxylate.18 In preliminary
attempts to make the indole ester 1 directly from 8 using methyl
pyruvate, only traces of the desired indole ester were observed
along with multiple side products and unreacted 8. This reaction
was abandoned in favor of the two step procedure shown in
Scheme 1, in which initial indole acid formation was followed
by esterification. Thus, on a 75 g scale, iodoaniline 8 was
dissolved in DMF at 7.7 v/w concentration with 3.1 equiv of
DABCO base. After thoroughly degassing the solution with
argon, an exothermic addition of 3 equiv of pyruvic acid was
performed followed by 1 mol % palladium acetate. Three hours
at 100-105 °C was sufficient to effect complete conversion of
8 to the indole acid 2 at which point a swift and simple workup
protocol was employed: whilst keeping the internal temperature
at 5-10 °C, dilute HCl was added gradually, until reaching
pH 3.5, generating a slurry. The resulting precipitate was then
collected by filtration and washed with water to provide indole
acid 2 in 95% yield with 99% LCAP purity, as a tan solid.
This crude material was determined to be of sufficiently high
quality for use directly in the ultimate esterification step, thus
bypassing the subsequent ethanol/water precipitation procedure
which was carried out to provide an analytical sample of 2. As
a result, aqueous separations and chromatographic purifications
were successfully avoided.
(15) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798–
4801.
Esterification of indole acid 2 was performed using CDI as
the carboxylic acid activating agent in DMF at ambient
(16) Clark, R. D.; Caroon, J. M. J. Org. Chem. 1982, 47, 2804–2806.
(17) It is also postulated that the improvement in conversion from 6 to 7
on scaling from 3 to 80 g may be in part due to more efficient stirring
and decreased splashing of the reaction mixture on the walls of the
vessel on larger scale.
(18) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider,
P. J. J. Org. Chem. 1997, 62, 2676–2677.
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temperature. After 3 h, in-process HPLC analysis indicated
complete conversion to the acylimidazole. On addition of excess
anhydrous methanol, the subsequent esterification occurred
cleanly. The product ester was then precipitated from the
reaction mixture with water and filtered to give 1 as a tan solid.
Residual water and any insolubles remaining from the previous
palladium coupling were removed by dissolving the crude ester
in dichloromethane/ethyl acetate, drying over sodium sulfate
and filtering through Celite. Partial distillation of the resulting
filtrate yielded a slurry of crystals in ethyl acetate and these
long white needles were collected by filtration to give the desired
indole ester 1 in two crops (42 g) with 72% yield and >98%
LCAP purity. Pending logical modifications, this process is
expected to be viable on multikilogram scale, fulfilling the
objective of an alternative scalable approach to 1.
(2.0 L) and di-tert-butyl-dicarbonate (450.3 g, 2.064 mol) was
stirred under argon at room temperature for 15 min, allowing
dissolution of the majority of the solids, prior to heating to reflux
(90 °C) (caution: CO2 gas evolution). After 4 h the reaction
was cooled to 50-55 °C, and a total of 1.5 L of distillate was
removed by concentration at 45 °C under reduced pressure to
give a peach-colored solution with white crystals. The slurry
was cooled to room temperature whilst stirring for 1.5 h and
then stored at 4 °C for 15 h. The resulting crystals were filtered
under vacuum and washed with 4 °C n-heptane (400 mL). After
drying under vacuum at 35 °C for 7 h, very fine white crystals
of tert-butyl-4-chloro-3-fluorophenylcarbamate 6 (393.1 g, 93%
yield, >99% LCAP at 272 nm) were obtained. Mp: 103-104
°C. MS (ESI-) m/z: 244.21 [M - H]-, 170.24 [M - C4H11O]-.
1
IR (KBr disk, cm-1) νmax: 3314, 1691, 1600, 1525. H NMR
δH (400 MHz, CDCl3): 1.51 (9H, s, C(CH3)3), 6.57 (1H, br-s,
N-H), 6.94 (1H, ddd, J6,5 8.7 Hz, J 2.3 Hz, J 1.0 Hz, H-6),
7.25 (1H, t, J 8.4 Hz, H-5), 7.43 (1H, br-dd, J2,F 11.2 Hz, J2,6
1.7 Hz, H-2). 13C NMR δC (100 MHz, CDCl3): 28.26
(C(CH3)3), 81.31 (C(CH3)3), 106.99 (2JC,F 26.1 Hz, C-2), 114.22
(C-1), 114.40 (C-6), 130.40 (C-5), 138.49 (2JC,F 9.8 Hz, C-4),
152.26 (CdO), 158.19 (1JC,F 245.2 Hz, C-3). 19F NMR δF (376
MHz, CDCl3, decoupled): -113.62 (1F, s). Anal. Calcd for
C11H13ClFNO2: C, 53.78; H, 5.33; N, 5.70. Found: C, 53.62;
H, 5.13; N, 5.62. HPLC: tR 6.22 min.
Conclusion
A robust five step preparation of functionalized indole 1 was
demonstrated on multigram scale, starting from 4-chloro-3-
fluoroaniline. This synthesis involved Boc protection of the
starting aniline followed by iodination and facile Boc depro-
tection to give the ortho-iodoaniline 8. Subsequent enamine
formation and immediate palladium catalyzed cross-coupling
gave the indole 2-carboxylic acid, which was then esterified to
provide the indole ester 1. Initial attempts to scale up the
iodination step were hindered by the formation of a major side
product. Isolation and identification of the side product as the
6-chloro-7-iodo-2(3H)-benzoxazolone 9 led to the discovery that
elevated reaction temperature was the major culprit. Maintaining
the internal temperature between -75 and -80 °C reproducibly
eliminated its production in subsequent batches. This approach
was shown to have several advantages enabling the rapid
production of 1 relative to the three previously published
syntheses: in particular, 1) the starting material was compara-
tively inexpensive; 2) the use of highly energetic and potentially
hazardous diazonium and azido compounds was avoided; 3)
there were no regioisomeric products generated to lower the
overall yield and complicate isolations; 4) the need for multiple,
time-consuming and low efficiency chromatographic purifica-
tions was made redundant, as all four intermediates, along with
indole ester 1, were well-defined, easily crystallized solids; and
5) the overall yield was 56%, representing a 51% increase over
the Reissert synthesis and a greater than 10-fold improvement
over the original Fischer and Hemetsberger methods.
tert-Butyl-4-chloro-3-fluoro-2-iodophenylcarbamate (7).
A solution of tert-butyl-4-chloro-3-fluorophenylcarbamate 6
(80.2 g, 0.326 mol) and anhydrous tetrahydrofuran (640 mL)
was cooled using a dry ice/acetone plus liquid nitrogen bath,
ensuring an internal temperature of -80 °C < T < -75 °C at
all times during the reaction. n-Butyllithium (2.5 M in hexane,
405 mL, 1.011 mol) was added over 2 h ensuring the drops
were thoroughly dispersed but not splashed. After aging for 40
min, a solution of iodine (289.9 g, 1.142 mol) in anhydrous
tetrahydrofuran (430 mL + 100 mL rinse) was added over 3 h,
maintaining an internal temperature of -80 °C < T < -75 °C.
The reaction mixture was warmed slowly to -30 °C over 14 h
at which point nearly complete conversion of starting material
(<1.6% LCAP) to product was observed. A solution of NH4Cl
(41.6 g in 160 mL water) was added, followed by a solution of
NaHSO3 (184.8 g in 560 mL water) ensuring internal T < -10
°C. The quenching mixture was warmed to 10 °C whilst stirring
for 1.5 h, water (500 mL) was added and 1370 mL of THF
distillate was removed under reduced pressure at 40 °C. The
mixture was stirred vigorously at 4 °C for 15 h and filtered.
After washing with water (400 mL) a beige solid was obtained
with a colorless filtrate which contained no product by HPLC.
The solid was digested with hot (65 °C) ethanol (700 mL) for
1 h and filtered whilst hot to remove insoluble material (3.5 g)
which contained no product by HPLC. The clear, red filtrate
obtained was concentrated at 45 °C under vacuum to a volume
of 150 mL at which point solids began to precipitate. Water
(32 mL) was added to the stirred mixture which was then cooled
slowly to 4 °C over 1.5 h. After filtration under vacuum and
washing with 4 °C ethanol/water, 2:1 (250 mL) the solid was
dried under vacuum at 40 °C for 5 h to give tert-butyl-4-chloro-
3-fluoro-2-iodophenylcarbamate 7 as a pale yellow solid (114.1
g, 94% yield, >99% LCAP at 272 nm). Mp: 66.0-67.0 °C.
Experimental Section
General. Reagents and materials obtained from commercial
suppliers were used without additional purification. All reactions
were performed under an argon atmosphere. Reduced pressure
distillations were performed between 250 and 50 mbar. HPLC
spectra were obtained on an Agilent 1100 series instrument
equipped with a UV detector at 272 nm and an Agilent Zorbax
Eclipse XDB C8 reverse phase column (4.6 mm × 75 mm ×
3.5 µm) at 25 °C; flow rate 1.4 mL/min; mobile phase A:
acetonitrile, B: 0.01 M ammonium acetate aqueous buffer; run
time 10 min; gradient: 5% to 80% A over 5.5 min, hold at
80% A for 4.5 min.
tert-Butyl-4-chloro-3-fluorophenylcarbamate (6). A mix-
ture of 4-chloro-3-fluoroaniline (250.3 g, 1.719 mol) n-heptane
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MS (ESI-) m/z: 370.03 [M - H]-. IR (KBr disk, cm-1) νmax
:
a stream of argon for 10 min. Pyruvic acid (98%, 58.50 mL,
0.824 mol) was added to the brown solution over 10 min, and
the internal temperature rose to 36 °C. The solution was again
degassed with argon for 10 min, and palladium acetate (98%,
0.691 g, 0.0030 mol) was added in one portion. The mixture
was heated to 100-105 °C for 3 h and then cooled and stirred
at 20-25 °C for 15 h. After cooling to 0-5 °C, aqueous HCl
(1.15 N, 575 mL then 0.115 N, 280 mL) was added, keeping
the temperature below 10 °C, monitoring until pH 3.5 was
achieved. A tan solid precipitated from the solution, and the
slurry was stirred for an additional 0.5 h at 5 °C. The solids
were filtered under vacuum and washed with 10 °C water (3
× 200 mL). After drying at 40 °C under vacuum for 36 h,
5-chloro-4-fluoro-1H-indole-2-carboxylic acid 2 (55.9 g, 95%
yield) was obtained as a tan solid (>99% LCAP at 272 nm).
An analytical sample of 2 was obtained by dissolving a small
portion of the tan solid in 10 vol of EtOH and then adding an
equivalent volume of water. The precipitate was recovered by
filtration and dried under vacuum at 50 °C to give 2 as an off-
white solid (99.7% LCAP at 272 nm). Mp: 270-280 °C
contracted and darkened; 280.5-281.8 °C melted. MS (ESI-)
m/z: 212.20 [M - H]-, 168.22 [M - CO2H]-. IR (KBr disk,
cm-1) νmax: 3463, 2925, 2625, 1676. 1H NMR δH (400 MHz,
d6-DMSO): 7.13 (1H, dd, J3,NH 2.1 Hz, J3,F 0.5 Hz, H-3), 7.29
(1H, dd, J7,6 8.8 Hz, J7,F 0.5 Hz, H-7), 7.33 (1H, dd, J6,7 8.8
Hz, J6,F 6.5 Hz, H-6), 12.32 (1H, s, NH), 13.35 (1H, br-s,
CO2H). 13C NMR δC (100 MHz, d6-DMSO): 102.40 (C-3),
108.78 (2JC,F 15.4 Hz, C-5), 110.15 (4JC,F 3.9 Hz, C-7), 116.92
(2JC,F 21.0 Hz, C-9), 125.40 (C-6), 130.25 (C-2), 137.89 (3JC,F
9.9 Hz, C-8), 150.92 (1JC,F 248.4 Hz, C-4), 162.04 (CO2H).
19F NMR δF (376 MHz, d6-DMSO, decoupled): -123.16 (1F,
s). Anal. Calcd for C9H5ClFNO2: C, 50.61; H, 2.36; N, 6.56.
Found: C, 50.44; H, 2.29; N, 6.48. HPLC: tR 3.63 min.
Methyl 5-chloro-4-fluoro-1H-indole-2-carboxylate (1).
5-Chloro-4-fluoro-1H-indole-2-carboxylic acid 2 (55.9 g, 0.262
mol) was added to anhydrous DMF (695 mL) at 20-25 °C
under argon and stirred for 20 min to obtain a brown solution.
1,1′-Carbonyldiimidazole (CDI) (51.0 g, 0.314 mol) was added
in one portion, giving a brown suspension (caution: CO2 gas
evolution). The mixture was stirred for 1 h under argon at
20-25 °C at which point starting material was still observed
(0.5% LCAP at 272 nm). Additional CDI (0.43 g, 0.0026 mol)
and DMF (45 mL) were added, and the reaction was stirred
for a further 2 h after which time analysis by HPLC indicated
complete disappearance of acid 7. Anhydrous methanol (297
mL, 7.34 mol) was added to the stirred reaction mixture under
argon at 20-25 °C to give a cloudy brown suspension. After
3 h, the reaction mixture was cooled, keeping the internal
temperature 15-20 °C, and water (2000 mL) was added over
0.5 h, precipitating a tan solid. The solid was filtered under
vacuum and washed with 5 °C water (2 × 400 mL). After air
drying, the solid was taken up in DCM (800 mL) and EtOAc
(1600 mL) and dried using anhydrous sodium sulfate (400 g).
Filtration through Celite and elution with DCM (1000 mL)
yielded a clear, orange solution. The solution was concentrated
under vacuum at 30 °C, leaving a slurry of crystals in EtOAc
(160 mL). The stirred slurry was cooled to 0-5 °C for 15 min.
Filtration under vacuum, washing with 4 °C EtOAc/n-heptane,
3387, 2983, 1728, 1573. 1H NMR δH (400 MHz, CDCl3): 1.54
(9H, s, C(CH3)3), 6.90 (1H, br-s, N-H), 7.34 (1H, t, J 8.6 Hz,
H-5), 7.89 (1H, dd, J6,5 9.0 Hz, J6,F 1.5 Hz, H-6). 13C NMR δC
(100 MHz, CDCl3): 28.25 (C(CH3)3), 81.77 (C(CH3)3), 114.26
(2JC,F 20.5 Hz, C-2), 115.17, 115.20 (C-1, C-6), 130.57 (C-5),
139.34 (2JC,F 3.0 Hz, C-4), 152.26 (CdO), 156.92 (1JC,F 241.9
Hz, C-3). 19F NMR δF (376 MHz, CDCl3, decoupled): -88.72
(1F, s). Anal. Calcd for C11H12ClFINO2: C, 35.56; H, 3.26; N,
3.77. Found: C, 35.57; H, 3.01; N, 3.75. HPLC: tR 6.80 min.
4-Chloro-3-fluoro-2-iodoaniline (8). A mixture of tert-
butyl-4-chloro-3-fluoro-2-iodophenylcarbamate 7 (110.0 g, 0.296
mol) and ethanol (900 mL) was cooled to 5 °C. HCl (37%,
145.9 mL) was added dropwise over 10 min keeping the internal
temperature below 15 °C. The mixture was warmed to 50-55
°C for 2 h (caution: gas evolution) by which point the solids
had completely dissolved. The reaction was cooled to 5 °C and
aqueous NaOH (80.0 g L-1, 865 mL) was added gradually over
1 h keeping the internal temperature below 15 °C, monitoring
the pH until neutral. The mixture was stored at 4 °C for 15 h.
A total of 970 mL of distillate was removed by concentration
under reduced pressure at 35 °C to give a colorless solution
with precipitated solids. The slurry was cooled to 4 °C for 1 h
after which time the solids were filtered under vacuum and
washed with 4 °C ethanol/water, 1:4 (200 mL). After drying at
35 °C under vacuum for 72 h, crude aniline 8 (80 g, 99% yield,
95% LCAP at 272 nm) was obtained. The solids were dissolved
in ethanol (450 mL) at 60 °C and filtered whilst hot to remove
the fine insoluble material. The filtrate obtained was concen-
trated at 35 °C under vacuum to a volume of 175 mL. Water
(70 mL) was added to the mixture over 3-4 h at 20 °C to
induce formation of solids. The slurry was cooled to 4 °C and
stirred for a further 0.5 h. Filtration under vacuum, washing
with 4 °C ethanol/water, 3:2 (100 mL) and drying under vacuum
at 35 °C gave 4-chloro-3-fluoro-2-iodoaniline 8 as orange
needles (70.5 g, 88% yield, >99% LCAP at 272 nm). A second
crop of material was obtained from the mother liquor by cooling
to 3 °C, adding water (50 mL) and stirring for 1.5 h. Filtration,
washing with 4 °C ethanol/water, 1:2 and drying under vacuum
at 35 °C gave additional 8 as pale yellow needles (4.6 g, 5%,
>99% LCAP at 272 nm). Combined yield of aniline 8 ) 75.1 g,
93%. Mp: 80.5-81.0 °C. MS (ESI-) m/z: 270.03 [M - H]-.
1
IR (KBr disk, cm-1) νmax: 3455, 3353, 1608, 1471. H NMR
δH (400 MHz, d6-DMSO): 5.71 (2H, br-s, NH2), 6.57 (1H, dd,
J6,5 8.8 Hz, J6,F 1.5 Hz, H-6), 7.20 (1H, t, J 8.8 Hz, H-5). 13
C
NMR δC (100 MHz, d6-DMSO): 71.06 (2JC,F 27.7 Hz, C-2),
104.12 (2JC,F 21.0 Hz, C-4), 110.12 (4JC,F 2.6 Hz, C-6), 129.87
(3JC,F 1.1 Hz, C-5), 150.07 (3JC,F 4.6 Hz, C-1), 156.60 (1JC,F
236.3 Hz, C-3). 19F NMR δF (376 MHz, d6-DMSO, decoupled):
-93.41 (1F, s). Anal. Calcd for C6H4ClFIN: C, 26.55; H, 1.49;
N, 5.16. Found: C, 26.71; H, 1.27; N, 4.97. HPLC: tR 5.48 min.
5-Chloro-4-fluoro-1H-indole-2-carboxylic Acid (2). 4-Chlo-
ro-3-fluoro-2-iodoaniline 8 (74.5 g, 0.275 mol) was dissolved
in anhydrous DMF (575 mL) at 20-25 °C. 1,4-
Diazabicyclo[2.2.2]octane (DABCO) (98%, 97.4 g, 0.851 mol)
was added in one portion and the internal temperature dropped
to 15 °C. The mixture was stirred for 20 min to effect
dissolution, and the solution was then vigorously degassed with
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1:1 (2 × 100 mL) then 1:3 (100 mL) and drying under vacuum
at 35 °C gave methyl 5-chloro-4-fluoro-1H-indole-2-carboxylate
1 as long, white needles (37.3 g, 63% yield, >99% LCAP at
272 nm). A second crop of 1 was obtained from the mother
liquor (after removing 360 mL of distillate) as off-white needles
(5.3 g, 9% yield, >98% LCAP at 272 nm). Combined yield of
indole ester 1 ) 42.6 g, 72%. Mp: 216.5-218.0 °C. MS (ESI-)
m/z: 226.20 [M - H]-. IR (KBr disk, cm-1) νmax: 3307, 1699.
1H NMR δH (400 MHz, d6-DMSO): 3.90 (3H, s, CH3), 7.19
(1H, d, J 0.4 Hz, H-3), 7.30 (1H, dd, J7,6 8.8 Hz, J7,F 0.8 Hz,
H-7), 7.36 (1H, dd, J6,7 8.8 Hz, J6,F 6.8 Hz, H-6), 12.49 (1H, s,
NH). 13C NMR δC (100 MHz, d6-DMSO): 52.12 (CO2CH3),
102.88 (C-3), 109.00 (2JC,F 15.3 Hz, C-5), 110.25 (4JC,F 4.0 Hz,
C-7), 116.83 (2JC,F 21.0 Hz, C-9), 125.82 (C-6), 128.77 (C-2),
137.99 (3JC,F 9.9 Hz, C-8), 150.97 (1JC,F 248.8 Hz, C-4), 161.00
(CO2CH3). 19F NMR δF (376 MHz, d6-DMSO, decoupled):
-122.92 (1F, s). Anal. Calcd for C10H7ClFNO2: C, 52.77; H,
3.10; N, 6.15. Found: C, 52.41; H, 2.84; N, 6.14. HPLC: tR
5.51 min.
6-Chloro-7-iodo-2(3H)-benzoxazolone (9). A solution of
tert-butyl-4-chloro-3-fluorophenylcarbamate 6 (141.3 g, 0.575
mol) in anhydrous tetrahydrofuran (706 mL) was cooled using
a dry ice bath, keeping the internal temperature -68 °C < T <
-72 °C. n-Butyllithium (2.5 M in hexane, 593 mL, 1.483 mol)
was added over 4 h. A solution of iodine (493.2 g, 1.943 mol)
in anhydrous tetrahydrofuran (940 mL) was added, maintaining
an internal temperature of -68 °C < T < -72 °C. The reaction
mixture was warmed slowly to 20 °C over 14 h. The mixture
was cooled to -5 °C < T < -15 °C, and a solution of NH4Cl
(74.4 g in 275 mL water) was added gradually over 40 min,
followed by a solution of NaHSO3 (325 g in 1.60 L water)
over 30 min. The quenching mixture was warmed to 20 °C
whilst stirring for 1.5 h. After adding water (650 mL), 2.26 L
of THF distillate was removed under reduced pressure at 40
°C. The mixture was stirred vigorously at 20-25 °C for 1.5 h
and filtered. After washing with water (450 mL) a beige solid
was obtained. The crude solid (146 g) was digested with ethanol
(287 mL) at 65 °C for 1 h, hot filtered under vacuum, washed
with ethanol (115 mL) and dried under vacuum. 6-Chloro-7-
iodo-2(3H)-benzoxazolone 9 (42.34 g, 25%, >99% LCAP at
272 nm) was obtained as an off-white solid. Mp: 314-316 °C.
MS (ESI-) m/z: 293.99 [M - H]-, 588.88 [2M - H]-. IR (KBr
1
disk, cm-1) νmax: 3254, 3085, 1742, 1443. H NMR δH (400
MHz, d6-DMSO): 7.06 (1H, d, J4,5 8.3 Hz, H-4), 7.33 (1H, d,
J5,4 8.3 Hz, H-5), 12.03 (1H, br-s, NH). 13C NMR δC (100 MHz,
d6-DMSO): 79.37 (C-7), 110.36 (C-4), 124.09 (C-5), 128.35
(C-9), 129.94 (C-6), 146.24 (C-8), 153.20 (C-2). Anal. Calcd
for C7H3ClINO2: C, 28.46; H, 1.02; N, 4.74. Found: C, 28.58;
H, 0.97; N, 4.69. HPLC: tR 4.72 min. Concentration of the
filtrate at 45 °C under vacuum, precipitation with water, and
filtration and drying gave tert-butyl-4-chloro-3-fluoro-2-io-
dophenylcarbamate 7 (95.3 g, 44% yield) analysis of which
corresponded to the previously stated data.
Acknowledgment
Ricerca Biosciences are acknowledged for demonstrating
some of the early phase chemistry in their facility.
Received for review June 25, 2010.
OP1001808
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