Multigram Synthesis of BMS-929075, an Allosteric, Palm Site Inhibitor of HCV NS5B Replicase, Involving the Synthesis of a Highly Functionalized Benzofuran through a Telescoped Process

Article abstract of DOI:10.1021/acs.oprd.0c00198

An efficient scale-up synthesis of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (BMS-929075), an allosteric, palm site inhibitor of the HCV NS5B replicase, is described. The highlights of the process involve (a) the copper-mediated, one-pot synthesis of 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetic acid (21) from regiospecifically lithiated 1-bromo-2-fluoro-4-methoxybenzene (13) and ethyl 2-bromoacetate (18); and (b) the formation of the highly functionalized benzofuran core 26 through a chromatography-free, telescoped process that proceeds via acylation and a subsequent concomitant demethylation and Boc deprotection using BBr3, followed by an acid-catalyzed cyclization from Boc-protected 2-(3-bromo-2-fluoro-6-methoxyphenyl)-N-methylacetamide 23. This process was applied to the preparation of 110 g of high-quality BMS-929075 to enable preclinical toxicology studies.

Full text of DOI:10.1021/acs.oprd.0c00198

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Full Paper
Multigram Synthesis of BMS-929075, an Allosteric, Palm Site
Inhibitor of HCV NS5B Replicase, Involving the Synthesis of a
Highly Functionalized Benzofuran through a Telescoped Process
Daniel Smith, Subramaniam Krishnananthan, Nicholas A. Meanwell, Arvind Mathur, and Jianqing Li
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00198 • Publication Date (Web): 27 May 2020
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Multigram Synthesis of BMS-929075, an Allosteric, Palm Site Inhibitor of HCV NS5B Replicase,
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Involving the Synthesis of a Highly Functionalized Benzofuran through a Telescoped Process
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Daniel Smith,*† Subramaniam Krishnananthan,† Nicholas A. Meanwell,† Arvind Mathur† and Jianqing Li*‡
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†Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton,
NJ 08543-4000, United States
‡Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, 100 Binney St.,
Cambridge, MA 02142, United States
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For TOC
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F
F
NH
F
Br
Br
Br
N
Boc
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HN
O
N
F
30% overall yield; 99.2% AP
Pd = 10 ppm
H
N
N
F
chromatography-free
O
O
BMS-929075
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ABSTRACT: An efficient scale-up synthesis of 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-
2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (BMS-929075), an allosteric, palm site inhibitor of
the HCV NS5B replicase is described. The highlights of the process involve: a) the copper-mediated, one-pot
synthesis of 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetic acid (21) from regio-specifically lithiated 1-bromo-2-
fluoro-4-methoxybenzene (13) and ethyl 2-bromoacetate (18); b) formation of the highly functionalized
benzofuran core 26 through a chromatography-free, telescoped process that proceeds via acylation and a
subsequent concomitant demethylation and Boc deprotection using BBr3, followed by an acid-catalyzed
cyclization from Boc-protected 2-(3-bromo-2-fluoro-6-methoxyphenyl)-N-methylacetamide 23. This process was
applied to the preparation of 110 grams of high quality BMS-929075 to enable preclinical toxicology studies.
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KEYWORDS. HCV NS5B inhibitor, selective lithiation, benzofuran, one-pot, telescoped process
INTRODUCTION
BMS-929075 (Figure 1) is an allosteric, palm site inhibitor of the HCV NS5B replicase that was advanced into
phase 1 clinical trials to assess its potential as a therapy for the treatment of hepatitis C virus (HCV) infection.1
Preclinical studies with BMS-929075 revealed that it exhibited high inhibitory potency in cell-based assays and
demonstrated excellent oral bioavailability and pharmacokinetic properties. During the course of preclinical
development of BMS-929075, over 100 grams of high quality API were needed to support toxicology and
formulation studies.
HN
O
N
F
H
N
N
F
O
O
BMS-929075
Figure 1. Structure of BMS-929075
The medicinal chemistry approach to the preparation of BMS-929075 was straightforward and provided
sufficient material for preclinical profiling that allowed its identification as a candidate for development. As
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shown in Scheme 1, this route consisted of 10 steps originating from 4-fluorobenzoic acid (1) that involved 7
isolations and resulted in an overall yield of 2.5%. While a couple of low yielding steps were of some concern for
large-scale preparation, the major challenge posed by this synthesis was the non-regiospecific fluorination of
phenol intermediate 3. The reaction of 3 with SelectfluorTM provided a mixture of the desired 4-F intermediate
and the 6-F isomer in a ratio of approximately 3:1. After silica gel column chromatography to purify the crude
reaction material, the inseparable mixture of the 4-F and 6-F isomers was subjected to ester hydrolysis using
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o
NaOH at 90 C and pure 4 was isolated by preparative reversed-phase HPLC in 24% overall yield over the two
steps from 3. The tedious chromatographic purification and the low overall yield for these two steps rendered
the discovery route unsuitable for scale-up to deliver the amount of high quality material required for preclinical
development activities.
Scheme 1. Discovery Synthesis of BMS-929075
EtO
O
1. SelectfluorTM
MeCN, rt, 24 h
O
O
O
O
O
1. CDI, THF, rt to 30 o
C
HO
OEt
OH
F
2.
ZnCl2, EtOH, 95 o
C
O
O
2. NaOH (1N)
MeOH/THF (1:1)
90 °C, 6 h
O
F
F
2
3
1
KO
MgCl2, THF, rt to 30 o
3. HCl
OEt
78%
32%
see ref. 2
C
HO
HN
HN
O
F
O
F
O
F
PhN(OTf)2, Et3N
CH2Cl2, rt
MeNH2·HCl,
HOBT, EDC, i-Pr2NEt
HO
HO
TfO
F
F
F
O
DMF, rt,
O
O
6
4
5
24%
93%
98%
N
HO
O
B
HN
HN
O
NH2
2HCl
O
O
F
N
H
F
N
O
O
HO
N
7
9
N
F
F
O
O
(PPh3)4Pd, Cs2CO3
Dioxane/H2O (10:1), 95 °C,
TBTU, i-Pr2NEt
O
DMF, rt
8
BMS-929075
58%
79%
2.5% overall yield
In order to deliver the required amounts of BMS-929075 in a timely manner, the rapid development of
a scalable process was required, the results of which are presented in this article.
RESULTS AND DISCUSSION
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To avoid potential problems associated with the low yields and lack of regioselectivity in the fluorination of 3,
we began our new route design by searching for commercially-available fluorinated substrates, with 4-bromo-3-
fluorophenol (10) and 4-bromo-3-fluoroanisole (13) particularly attractive starting materials. As illustrated in
Scheme 2, two approaches to BMS-929075 were proposed based on literature precedent that began from 10
and 13 and proceeded through the regioselective construction of the benzofurans 16a and 16b. Based on the
results of the discovery synthesis (Scheme 1), the Suzuki coupling of triflate 6 with boronate ester 7 afforded
product 8 in only a moderate 58% yield. The bromo substrates 16a and 16b would potentially allow for the
milder reaction conditions associated with Suzuki coupling and provide higher yields. Following the original
synthesis, no significant issues were anticipated for the transformation of 16a or 16b to BMS-929075. For
approach A, the regioselective lithiation and acylation of 11 to 12 should be facilitated by both the fluorine and
alkoxy directing groups.3,4 Base-catalyzed cyclization of ortho-benzyloxybenzo ketones is a known process;5
therefore, the formation of the bromo benzofuran 16a from the corresponding methyl 2-(3-bromo-2-fluoro-6-
((4-fluorobenzyl)oxy)phenyl)-2-oxoacetate (12) was anticipated to be facile. For approach B, the conversion of
13 to the aryl acetate 14 could be achieved through the selective lithiation of 13, formation of the
diorganocopper reagent (Ar2CuLi) and then coupling with an α-halo acetate, such as ethyl bromoacetate.6 α-
Acylation of 14 with para-fluorobenzoyl chloride promoted by LiHMDS should afford β-keto ester 15.7 Finally,
demethylation with BBr3 and acid-catalyzed cyclization and dehydration would lead to the formation of the
benzofuran 16b.8
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Scheme 2. Initial Synthetic Approaches to BMS-929075 that Proceed through the Intermediacy of Bromo
Benzofurans 16a and 16b
F
F
O
O
O
F
Br
Br
Br
O
OH
O
F
RO
10
11
12
F
O
HN
F
F
O
N
F
Br
H
Approach A
N
F
N
F
O
O
F
O
O
O
O
F
F
16a
16b
: R = Me
: R = Et
Br
BMS-929075
Br
O
Br
O
O
O
O
14
15
13
Approach B
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The construction of the bromo benzofuran 16a (approach A in Scheme 3) was investigated first. The
alkylation of 10 with 1-(bromomethyl)-4-fluorobenzene (17) in the presence of K2CO3 in CH3CN at rt for 18 h
gave 1-bromo-2-fluoro-4-((4-fluorobenzyl)oxy)benzene (11) in 99% yield with 97% HPLC purity. The crude
material 11, isolated by an aqueous work-up, was used without further purification. Lithiation of 11 using LDA at
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o
-65 to -78 C for 1 h followed by reaction with dimethyl oxalate afforded 12. Following an aqueous work-up,
pure compound 12 was obtained in 81% yield after crystallization from a mixture of EtOAc and heptane (1 : 20).
No other regio-isomer was detected by LCMS. The cyclization reactions of 12 to 16a were then examined. The
cyclization of 12 to 16a employing the literature conditions5 proved to be problematic, with no detectable
amounts of product 16a or its corresponding acid produced when 12 was treated with LiTMP or P4-t-Bu or LDA
as the base.5c Complex mixtures were observed and approach A was therefore abandoned.
Scheme 3. Attempted Approaches A to Bromo Benzofuran 16a
LiTMP
or P4-t-Bu
or LDA
O
O
O
F
F
O
F
LDA
Dimethyl oxalate
F
O
Br
Br
K2CO3
Br
Br
Br
+
THF, -65 to -78 o
C
O
F
X
CH3CN, rt, 18 h
O
F
OH
O
F
F
10
17
11
99%
12
81%
16a
not formed
Although approach A was not a viable option, we were particularly encouraged by the reaction profile
associated with the regioselective lithiation and acylation of 11 to give 12. Consequently, attention was directed
toward the exploration of approach B (Scheme 4). On a 4 gram scale, deprotonation of 13 with LDA in THF at -78
oC followed by treatment with CuI (0.55 equiv) at -5 oC led to the Cu-Li intermediate as judged by the formation
of a green solution. The addition of bromoacetate 18 to this solution followed by warming of the reaction
o
mixture from -78 C to rt afforded 14 as a colorless oil in 42% isolated yield after an extractive work-up and
chromatographic purification. The addition of a solution of 14 (1 equiv) and 4-fluorobenzoyl chloride (19) (1.5
o
equiv) in THF to a 1M solution of LHMDS in THF at -78 C afforded 15 as an oil that was a mixture of the keto
and enol forms by 1H NMR analysis. The product 15 was isolated in 53% yield and used for the next step without
further purification. Treatment of the crude 15 with BBr3 (3 equiv) in CH2Cl2 under reflux gave the product 20 in
72% isolated yield after an extractive work-up and purification by column chromatography. As expected, the
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intermediate 20 was a mixture of the ketone and enol by LCMS and H NMR in CDCl3. Cyclization and
dehydration of 20 to benzofuran 16b was accomplished upon refluxing in a mixture of 12N HCl and dioxane to
afford 16b, which was isolated in 88% yield with 95% purity by a simple filtration after the reaction mixture was
cooled to room temperature.
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Scheme 4. Results of the Attempt to Exploit Approach B to Prepare Bromo Benzofuran 16b
F
F
1. LDA (1 eq.), THF, -78 oC, 1 h
2. CuI (0.55 eq.), -78 to -5 oC, 1 h
O
O
F
LHMDS, THF, -78 to 0 oC, 2 h
Br
O
Br
F
Br
O
-78 oC to rt
2 h
O
3.
O
14
42%
O
O
Br
O
13
O
O
Cl
18
15
53%
19
F
O
O
O
O
F
F
O
F
12N HCl, dioxane
reflux, 3.5 h
Br
BBr3 (3 eq.), CH2Cl2
Br
F
-10 oC to reflux, 15 mins
O
OH
16b
88%
20
72%
While the preliminary results from exploring approach B were successful, the tedious chromatographic
purification of compounds 14 and 20, which resulted in low recovery and yields, presented a major problem for
scale-up attempts. In order to surmount these scale-up issues, a modification of this route designed to avoid
purification by chromatography was developed, as illustrated in Scheme 5. Based on the clean profile associated
with the conversion of 13 to 14 and the oily nature of 14, it was envisioned that a one-pot conversion of ester
14 to acid 21 might eliminate the need for chromatographic purification of 14 by taking advantage of either an
acid/base extraction or crystallization. Indeed, after formation of ester 14, treatment of the reaction mixture
with a solution of 2.5N NaOH at 50-55 oC for 20 h led to the complete conversion of 14 to acid 21. After filtration
of the reaction mixture to remove the copper species, evaporation of the THF solvent, and extraction with
CH2Cl2 to remove organic impurities, the aqueous solution was titrated with conc. HCl to precipitate 21. Acid 21
was isolated by a simple filtration in 98% yield with 94% HPLC purity. This process was readily reproduced on
multiple 100 gram scale reactions to yield more than 0.5 kg quantities of acid 21. The subsequent procedures
for the conversion of acid 21 to 22 and Boc-protection of the amide 22 to give 23 were also robust. Amide 22
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was conveniently isolated by precipitation and filtration while the Boc-protected derivative 23 was purified by
crystallization, with each step allowing an upgrading of the purity of the material. The acylation of 23 with 4-
fluorobenzoyl chloride (19) was promoted by LHMDS and cleanly gave keto amide 24 as an oil. Amide 24 existed
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9
1
as a mixture of the keto and enol tautomers which was confirmed by LCMS and H NMR in CDCl3. Due to the
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difficulties associated with purifying 24, it was used directly as the crude material in the subsequent step.
Demethylation and Boc deprotection of crude 24 proceeded smoothly with BBr3 in CH2Cl2 at rt to give phenol 25
as a mixture of the ketone and its enol tautomer based on LCMS analysis of the reaction mixture. In order to
avoid complications with the purification of 25, which was a thick oil, a one-pot strategy to convert 25 to the
benzofuran 26 directly without isolation was examined. After the complete conversion of 24 to 25, as monitored
by LCMS, the reaction mixture was treated with EtOH and the CH2Cl2 was removed. The residual mixture was
treated with conc. HCl and heated at reflux for 3 hours to afford a suspension of 26 which was filtered off. The
bromo benzofuran 26 was further purified by trituration from EtOH and isolated in 60% yield with 99.3% HPLC
purity.
Scheme 5. Chromatography-free Preparation of Benzofuran 26
F
F
F
MeNH2, HATU
i-Pr2NEt, DMF
rt, 2 h
(Boc)2O
DMAP, i-Pr2NEt
rt, 24 h
1. LDA, THF, -78 oC, 1h
H
Br
OH
O
Br
N
Br
2. CuI (0.55 eq.), -5 oC, 1h
+
Br
O
O
O
3. 2.5 N NaOH, 50-55 oC, 20 h
4. HCl
O
O
O
18
13
21
22
83% yield, 98.3 %AP
98% yield, 94% AP
F
F
BBr3, CH2Cl2
0 oC to rt, 18 h
O
NH
O
F
Br
N
O
1. LHMDS, THF, -78 to 0 oC , 1 h
F
O
F
Br
O
O
2.
O
O
Br
N
O
-78 oC to rt, 3 h
23
94% yield, 98.6% AP
F
OH
O
O
Cl
O
25
24
97% (crude)
19
O
1. EtOH, 0 o
2. conc. HCl, reflux, 3 h
C
F
NH
Br
F
O
26
60% yield (one-pot from ), 99.3% AP
24
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With a robust large-scale preparative procedure developed for the bromo benzofuran 26 in hand, the
Suzuki coupling with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (7) was investigated
(Scheme 6). Using 1.2 equiv of 7 with tetrakis(triphenylphosphine)palladium(0) (2 mol%) as the catalyst and 4
equiv of K3PO4 as the base in a mixture of dioxane and H2O (5:1) as solvent, the reaction proceeded at 50 oC to
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afford a 47% conversion in 3 h. However, at 83 C, the reaction was complete in just two hours and afforded
product 8 in 85% isolated yield. It is important to note that after precipitation of the crude product from the
reaction mixture and filtration, hot trituration with EtOH followed by crystallization from EtOH was essential to
improve the purity (up to 99.3%) and to reduce the Pd content to 48 ppm.
The final step in the preparation of BMS-992075 required the installation of the amide moiety which
was accomplished by coupling acid 8 with the dihydrochloride salt of 1-(pyrimidin-2-yl)cyclopropanamine (9) in
a process promoted by HATU that proceeded cleanly both in DMF and NMP. However, precipitation of the
product from reaction mixture by the addition of water gave a much better filterable slurry from NMP as the
solvent compared to DMF. High quality API (99.2% HPLC, 10 ppm Pd content) was obtained by crystallization of
BMS-929075 from a mixture of EtOH and H2O.
Scheme 6. Conversion of Benzofuran 26 to BMS-929075
HO
O
B
O
O
7
1.2 eq
N
Pd(PPh3)4,(2 mol%)
K3PO4 (4 eq.)
dioxane/H2O (5:1)
O
NH2
2HCl
HN
O
F
NH
N
O
N
F
F
NH
H
Br
N
HO
9
N
F
83 oC, 2 h
F
F
HATU, NMP
i-Pr2NEt, rt, 3 h
O
O
O
O
O
8
26
BMS-929075
85% yield, 99.3% AP
80% yield, 99.2% AP
Thus, the overall process to convert 1-bromo-2-fluoro-4-methoxybenzene (13) to BMS-929075 required
just 7 individual reaction procedures and 2 extractive work-ups and completely avoided chromatographic
purification of any intermediate. Over 110 g of high quality BMS-929075 was rapidly delivered through this
route which proceeded in an overall yield of 30%.
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In conclusion, an efficient, large-scale preparation of the clinical compound BMS-929075 was developed. The
synthesis was enabled by the regioselective lithiation of 1-bromo-2-fluoro-4-methoxybenzene (13) and copper-
mediated alkylation. The formation of the benzofuran ring through an intramolecular cyclization of the keto
phenol intermediate 25 was highly effective and a chromatography-free, telescoped process was developed to
generate the highly functionalized key bromo benzofuran 26. This new process provided BMS-929075 with an
overall yield of 30% which compared with the 2.5% yield achieved with the discovery synthetic route.
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All reagents were obtained from commercial sources and used without purification. All reactions were
performed under a N2 atmosphere and all glassware was dried and purged with N2 before use. All reactions
were monitored using a Shimadzu LCMS system using the following method: Phenomenex C18 column 10 μm
4.6 x 50 mm. Solvent: A = 10% MeOH/90% H2O with 0.1% TFA; B = 90% MeOH/10% H2O with 0.1% TFA.
Gradient: 0-100% B over 4 min. Flow: 4 mL/min, wavelength: 220 nm. HPLC analyses were performed using a
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Shimadzu system (model SPD 10AV). All H NMR and 13C NMR spectra were recorded on a Bruker 300 MHz or
500 MHz spectrometer using DMSO-d6 or CDCl3 as the solvents.
Preparation of 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetic acid (21). 1-Bromo-2-fluoro-4-
methoxybenzene (13) (103 g, 500 mmol) and anhydrous THF (500 mL) were added to a 3 L, three necked round
bottom flask equipped with a mechanical stirrer. The solution was cooled to -78 oC with an IPA/dry ice bath and
bubbled with N2 for 10 minutes. A solution of lithium diisopropylamide (2M from Sigma-Aldrich Corporation,
1.05 equiv, 263 mL, 525 mmol) in THF was added dropwise over a period of 30 minutes while maintaining the
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temperature below -70 C. The reaction mixture was stirred at -78 C for 1 h and copper(I) iodide (52.4 g, 0.55
equiv, 275 mmol) was added. The reaction mixture was allowed to warm to -5 oC and stirred for 1 h to afford a
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dark green solution that was cooled to -78 C before adding ethyl 2-bromoacetate (18) (57.0 mL, 500 mmol)
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dropwise over 30 minutes while maintaining the internal temperature below -70 C. The reaction mixture was
allowed to warm to rt over a period of 20 h. A solution of 2.5N NaOH (1 L) was added at rt and the reaction
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mixture was heated to 50–55 C for 20 h. After cooling to rt, the reddish suspension was filtered through a
Celite pad and the pad was rinsed with a solution of 1N NaOH (100 mL). The filtrate was concentrated below 35
oC in vacuo to remove THF and the residual aqueous solution was washed with CH2Cl2 (2 x 500 mL). The basic
aqueous layer was transferred to a 3 L, four necked round bottom flask and acidified with conc. HCl (270 mL) to
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adjust the pH to 1 with ice bath cooling to maintain the internal temperature below 30 C. After the resulting
suspension was cooled to 15 oC, the ice bath was removed, the mixture was stirred for 30 minutes and filtered.
The filter cake was washed with H2O (500 mL) and dried under house vacuum suction for 18 h to give 2-(3-
bromo-2-fluoro-6-methoxyphenyl)acetic acid (21) (129.5 g, 492 mmol, 98% yield, 94% HPLC purity) as a slightly
yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.56 (t, J = 8.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.80 (s,
3H), 3.58 (br s, 2H); 13C NMR (75 MHz, DMSO–d6) δ 170.36, 157.08 (d, J = 7.50 Hz), 156.12 (d, J = 240.75 Hz),
130.76 (d, J = 2.25 Hz), 112.21 (d, J = 19.50 Hz), 107.90 (d, J = 3.75 Hz), 97.78 (d, J = 22.75 Hz), 55.67, 27.83 (d, J =
3.00 Hz). LRMS m/z: [M + Na]+ calcd for C9H8BrFO3, 284.95; found, 284.96.
Preparation of 2-(3-bromo-2-fluoro-6-methoxyphenyl)-N-methylacetamide (22). A solution of 2-(3-
bromo-2-fluoro-6-methoxyphenyl)acetic acid (21) (125 g, 475 mmol) in DMF (833 mL), O-(7-azabenzotriazol-1-
yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (217 g, 570 mmol) (added portionwise), N,N-di-
isopropylethylamine (166 mL, 950 mmol), and a solution of methylamine (2M, 475 mL, 950 mmol) in THF were
introduced into a 5 L, four necked round bottom flask with water bath cooling and overhead stirring to
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moderate the temperature which rose to 45 C. The reaction mixture was stirred at rt for 2 h before slowly
adding H2O (2 L) over 30 minutes. The resulting suspension was stirred at rt for 1 h, filtered and rinsed with H2O.
The filter cake was dried by vacuum suction for 18 h to afford 2-(3-bromo-2-fluoro-6-methoxyphenyl)-N-
methylacetamide (22) (108.5 g, 393 mmol, 83% yield, 98.3% HPLC purity) as a slightly yellow solid. 1H NMR (300
MHz, CDCl3) δ 7.44 (t, J = 8.4 Hz, 1H), 6.63 (dd, J = 9.0, 1.3 Hz, 1H), 5.49 (br s, 1H), 3.86 (s, 3H), 3.63 (d, J = 1.5 Hz,
2H), 2.78 (d, J = 4.8 Hz, 3H); 13C NMR (76 MHz, CDCl3) δ 169.76, 157.78 (d, J = 7.6 Hz), 157.58 (d, J = 247.76 Hz),
131.85 (d, J = 2.28 Hz), 113.01 (d, J = 19.76 Hz), 107.60 (d, J = 3.04 Hz), 100.22 (d, J = 22.04 Hz), 56.22, 30.98 (d, J
= 3.04 Hz), 26.43. LRMS m/z: [M + H]+ calcd for C10H11BrFNO2, 276.00; found, 276.01.
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Preparation of tert-butyl 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetyl(methyl)carbamate (23). A
suspension of 2-(3-bromo-2-fluoro-6-methoxyphenyl)-N-methylacetamide (22) (106 g, 384 mmol) in CH2Cl2 (2 L),
N,N-di-iso-propylethylamine (0.134 L, 768 mmol), 4-dimethylaminopyridine (46.9 g, 384 mmol) and di-tert-butyl
dicarbonate (168 g, 768 mmol) were introduced into a three necked, 5 L round bottom flask equipped with a
mechanical stirrer. The reaction mixture was stirred at rt for 24 h before being transferred to a 5 L separatory
funnel. The reaction flask was rinsed two times with CH2Cl2 (100 mL) and the washings was added to the
separatory funnel. The mixture was washed sequentially with 1N HCl (2 x 2 L), H2O (2 x 2 L) and brine (2 L), dried
over Na2SO4, filtered and concentrated in vacuo to give a yellow semi solid (~330 g) which was crystallized from
heptane (500 mL) (reflux to -10 oC). The crystals were filtered and the filter cake was washed with cold heptane
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(-20 C, 200 mL) to give tert-butyl 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetyl(methyl)carbamate (23) (137 g,
359 mmol, 94% yield, 98.6% HPLC purity) as a slightly yellow solid after drying by vacuum suction over 3 days. 1H
NMR (300 MHz, CDCl3) δ 7.36 (dd, J = 8.8, 8.1 Hz, 1H), 6.56 (dd, J = 9.0, 1.3 Hz, 1H), 4.19 (d, J = 1.5 Hz, 2H), 3.76
(s, 3H), 3.13 (s, 3H), 1.54 (s, 9H). 13C NMR (76 MHz, CDCl3) δ 172.31, 157.94, 157.60 (d, J = 245.48), 153.32,
131.28 (d, J = 2.28 Hz), 113.75 (d, J = 19.76 Hz), 107.25 (d, J = 3.04 Hz), 99.76 (d, J = 22.80 Hz), 83.13, 56.03,
33.05 (d, J = 3.80 Hz), 31.58, 28.00. LRMS m/z: [M + Na]+ calcd for C15H19BrFNO4, 398.04; found, 397.97.
Preparation
of
tert-butyl
(24).
2-(3-bromo-2-fluoro-6-methoxyphenyl)-3-(4-fluorophenyl)-3-
solution of tert-butyl 2-(3-bromo-2-fluoro-6-
oxopropanoyl(methyl)carbamate
A
methoxyphenyl)acetyl(methyl)carbamate (23) (56.4 g, 150 mmol) in anhydrous THF (600 mL) in a three necked,
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2 L round bottom flask was cooled to -78 C with an IPA/dry ice bath and mechanical stirring. A solution of
lithium bis(trimethylsilyl)amide (165 mL, 165 mmol) in THF was added over a period of 30 minutes while
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maintaining the temperature of the solution below -65 C. The reaction mixture was warmed to 0 C over a
period of 30 minutes, stirred for 1 h at 0 oC under cooling using a wet ice bath and then cooled to -78 oC with an
IPA/dry ice bath. 4-Fluorobenzoyl chloride (19) (26.16 g, 165 mmol) in anhydrous THF (75 mL) was added
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dropwise over a period of 30 minutes and the mixture was stirred at -78 C for 1 h before being allowed to
warm to rt over a period of 3 h. A saturated solution of NH4Cl (600 mL) was added protionwise over 20 minutes
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and the mixture was concentrated in vacuo to remove the majority of the THF. The residual mixture was
extracted with EtOAc (2 x 450 mL). The combined organic extracts were sequentially washed with 1N HCl (450
mL), a saturated solution of NaHCO3 (450 mL) and brine (450 mL), dried over Na2SO4, filtered and concentrated
in vacuo to give crude tert-butyl 2-(3-bromo-2-fluoro-6-methoxyphenyl)-3-(4-fluorophenyl)-3-
xopropanoyl(methyl)carbamate (24) (72.5 g, 145 mmol, 97% yield) as thick yellow oil which was used without
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further purification. H NMR (300 MHz, CDCl3) δ 7.897.72 (m, 2H), 7.38 (dd, J = 8.8, 7.7 Hz, 1H), 7.056.91 (m,
3H), 6.55 (dd, J = 8.8, 1.5 Hz, 1H), 3.74 (s, 3H), 3.22 (s, 3H), 1.39 (s, 9H).s LRMS m/z: [M – Boc + 1]+ calcd for
C17H15BrF2NO3, 398.01; found, 398.00.
Preparation of 5-bromo-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (26).
A
solution of tert-butyl 2-(3-bromo-2-fluoro-6-methoxyphenyl)-3-(4-fluorophenyl)-3-
oxopropanoyl(methyl)carbamate (24) (74.7 g, 150 mmol) in CH2Cl2 (300 mL) in a four necked, 2 L round bottom
flask equipped with a mechanic stirrer was cooled to 0 oC with a wet ice bath and a solution of 1M BBr3 (450 mL,
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450 mmol) in CH2Cl2 added dropwise over 50 minutes while maintaining the internal temperature below 10 C.
The reaction mixture was stirred while warming to rt over a period of 18 h at which point LCMS indicated the
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consumption of starting material and the formation of 25. The red solution was cooled to 0 C and 150 mL of
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absolute EtOH was added dropwise over 25 minutes while keeping the internal temperature below 15 C. A
solution of concentrated HCl (12N, 450 mL) was added to the reaction mixture in a fast stream via an addition
funnel. A Dean-Stark apparatus and condenser were attached to the reaction flask and the reaction mixture was
heated with a heating mantle to remove the CH2Cl2 azeotropically. After removal of the CH2Cl2, the Dean-Stark
apparatus was removed and then the reaction mixture was refluxed for an additional 3 h before being cooled to
rt. The light brown suspension was filtered and the filter cake was rinsed with H2O (3 x 100 mL) and dried by
vacuum suction for 40 minutes. The filter cake was suspended in 700 mL of EtOAc and the suspension was
refluxed for 30 minutes. The resulting hot tan suspension was cooled to rt. The suspension was filtered and the
filter cake was rinsed with EtOAc (100 mL), and then dried by vacuum suction for 18 h. 5-Bromo-4-fluoro-2-(4-
fluorophenyl)-N-methylbenzofuran-3-carboxamide (26) (33.1 g, 90.4 mmol, 60% yield, 99.3% HPLC purity) was
collected as a white solid. 1H NMR (300 MHz, DMSO–d6) δ 7.90 (br d, J = 4.4 Hz, 1H), 7.15-7.06 (m, 2H), 6.88-6.72
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(m, 2H), 6.66-6.54 (m, 2H), 2.02 (d, J = 4.8 Hz, 3H); 13C NMR (76 MHz, DMSO-d6) δ 162.18 (d, J = 250.04 Hz),
161.87, 152.69 (d, J = 9.12 Hz), 151.19, 151.13 (d, J = 252.32 Hz), 128.27, 128.15, 124.13 (d, J = 3.04 Hz), 116.82
(d, J = 18.24 Hz), 115.58 (d, J = 22.04 Hz), 110.47, 108.78 (d, J = 4.56 Hz), 101.10 (d, J = 57.76), 25.44. LRMS m/z:
[M + H]+ calcd for C16H10BrF2NO2, 365.99; found, 365.99.
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Preparation of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic
acid (8). 5-Bromo-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (26) (60 g, 164 mmol),
phosphoric acid, potassium salt (144 g, 664 mmol), dioxane (750 mL) and H2O (145 mL) were added to a three
necked, 1 L round bottom flask with mechanical stirring. The suspension was bubbled with N2 for 5 minutes and
then heated to 83 oC. 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (7) (52 g, 198 mmol)
portionwise and tetrakis(triphenylphosphine)palladium(0) (3.83 g, 3.31 mmol) were added in one portion. After
the reaction mixture was stirred at 83 oC for 2 h, the mixture was filtered hot through a thin layer Celite pad and
the pad was rinsed with a solution of 20% H2O in dioxane (2 x 150 mL). The filtrate was concentrated in vacuo to
remove the dioxane and the resulting yellow slurry was diluted with H2O (2 L) and acidified with conc. HCl (262
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mL) with ice bath cooling. The suspension was stirred at 5 C for 30 minutes, filtered and the filter cake was
washed with H2O (3 x 600 mL) before being dried by vacuum suction for 18 h. The dried filter cake was added to
EtOH (600 mL) and the mixture was heated at reflux for 1 h. The hot solution was filtered through a Celite pad
(to remove Pd content). The pad was rinsed with hot EtOH (2 x 90 mL) and the clear orange filtrate was
gradually cooled to rt to afford a thick yellow suspension which was filtered. The filter cake was washed with
cold EtOH (-20 oC, 2 x 75 mL) and dried under vacuum suction for 18 h to give 16.0 g of the product as the first
crop. The second and third crops of product were obtained from the mother liquor by repeating the above
crystallization procedure. The crops were combined to give 3-(4-fluoro-2-(4-fluorophenyl)-3-
(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (8) (59.0 g, 140.0 mmol, 85% yield) as an off white
solid. 1H NMR (300 MHz, DMSO–d6) δ 12.94 (br s, 1H), 8.738.65 (m, 1H), 7.977.88 (m, 3H), 7.78 (d, J = 1.5 Hz,
1H), 7.63 (d, J = 8.4 Hz, 1H), 7.517.31 (m, 4H), 2.79 (d, J = 4.4 Hz, 3H), 2.23 (s, 3H). LRMS m/z: [M + H]+ calcd for
C24H17F2NO4, 422.11; found, 422.17. Pd = 48 ppm.
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Preparation
of
4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-
yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (BMS-929075). 3-(4-Fluoro-2-(4-fluorophenyl)-3-
(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (8) (44 g, 104 mmol), 1-(pyrimidin-2-
yl)cyclopropanamine di-HCl salt (9) (23.91 g, 115 mmol), NMP (300 mL) and N,N-di-iso-propylethylamine (72.7
mL, 418 mmol) were added to a four necked, 2 L round bottom flask and the mixture stirred mechanically at rt
until it became a clear solution. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
(HATU) (47.6 g, 125 mmol) was added portionwise (no obvious exothermic reaction observed). The mixture was
stirred at rt for 3 h and then H2O (600 mL) was added over 10 minutes with stirring. The white suspension was
stirred at rt for 1 h and filtered. The filter cake was washed with H2O (3 x 100 mL) and dried under vacuum
suction for 20 h. The filter cake was dissolved in EtOH (750 mL) under gentle reflux and the solution was filtered
hot to remove a small amount of solid. H2O (360 mL) was added to the hot filtrate over a period of 15 minutes
(crystals formed at 62 oC). The suspension was gradually cooled to rt over a period of 2 h and then filtered. The
filter cake was washed with cold EtOH (-20 oC, 50 mL) and dried under vacuum suction for 24 h to give 4-fluoro-
2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-
carboxamide (BMS-929075) (45.2 g, 84 mmol, 80% yield, 99.2% HPLC purity) as a white solid. Mp 249.6 °C (by
DSC). 1H NMR (500 MHz, CD3OD)  8.65 (d, J = 5.04 Hz, 2H), 7.96 (dd, J = 9.14, 5.36 Hz, 2H), 7.91 (dd, J = 8.04,
2.05 Hz, 1H), 7.85 (d, J = 1.89 Hz, 1 H), 7.54 (d, J = 8.51 Hz, 1H), 7.46 (d, J = 7.88 Hz, 1H), 7.33 (dd, J = 8.35, 7.09
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Hz, 1H), 7.30 (t, J = 8.83 Hz, 2H), 7.23 (t, J = 4.89 Hz, 1H), 2.96 (s, 3H), 2.29 (s, 3H), 1.77 (m, 2H), 1.46 (m, 2H); 13
C
NMR (126 MHz, CD3OD)  171.48, 171.23, 167.11, 165.13 (d, J = 249.80 Hz), 158.38, 156.30 (d, J = 9.09 Hz),
154.14, 153.34 (d, J = 249.80 Hz), 142.48, 137.09, 133.40, 131.30, 130.92, 130.33, 130.26, 129.42 (d, J = 2.73 Hz),
128.42, 126.83 (d, J = 3.63 Hz), 124.47 (d, J = 15.44 Hz), 119.66, 118.01 (d, J = 20.90 Hz), 117.20 (d, J = 22.70 Hz),
112.11, 108.80 (d, J = 4.54 Hz), 38.24, 27.04, 20.57, 20.37; 19F NMR (500 MHz, CD3OD)  -123.11 (s, 1F), 112.73
(s, 1F). Anal. calcd for C31H24F2N4O3: C, 69.14; H, 4.49; N, 10.40. Found: C, 69.13; H, 4.56; N, 10.33. Pd = 10 ppm.
ASSOCIATED CONTENT
*Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
XX.XXX/acs.oprd.XXXXXX.
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1 H and 13C NMR spectra of compounds 21-23, 26 and BMS-929075. 1H NMR and LCMS of compound 24. 1H NMR
of compound 8 and 19F NMR of BMS-929075.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: Daniel.Smith@bms.com
*E-mail: Jianqing.Li@bms.com
ORCID
Daniel Smith: 0000-0003-0749-4763
Subramaniam Krishnananthan: 0000-0001-5864-3613
Nicholas A. Meanwell: 0000-0002-8857-1515
Arvind Mathur: 0000-0003-3146-8485
Jianqing Li: 0000-0002-8445-9796
Notes
The authors declare no competing financial interest.
REFERENCES
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P.; Bora, R. O.; Selvakumar, K.; Rigat, K.; Wang, Y-K.; Liu, M.; Lemm, J.; Mosure, K.; Sheriff, S.; Wan, C.;
Witmer, M.; Kish, K.; Hanumegowda, U.; Zhuo, X.; Shu, Y-Z.; Parker, D.; Haskell, R.; Ng, A.; Gao, Q.;
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Colston, E.; Raybon, J.; Grasela, D. M.; Santone, K.; Gao, M.; Meanwell, Ni. A.; Sinz, M.; Soars, M. G.;
Knipe, J. O.; Roberts, S. B.; Kadow, J. F. Discovery of a hepatitis C virus NS5B replicase palm site
allosteric inhibitor (BMS-929075) advanced to phase 1 clinical studies. J. Med. Chem. 2017, 60,
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(2) Burns, C. J.; Del Vecchio, A. M.; Bailey, T. R.; Kulkarni, B. A.; Faitg, T. H.; Sherk, S. R.; BlackLedge, C. W.;
Rys, D. J.; Lessen, T. A.; Swestock, J.; Deng, Y.; Nitz, T. J.; Reinhardt, J. A.; Feng, H.; Saha, A. K. Benzofuran
compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and
associated diseases. World Patent Application WO 2004/041201 A2, May 21, 2004.
(3) For alkoxy mediated ortho lithiation examples, see: (a) Mali, R. S.; Tilve, S. G. Useful synthesis of
coumestans. Synth. Commun. 1990, 20, 1781-1791; (b) Hewawasam, P.; Meanwell, N. A. A general
method for the synthesis of isatins: preparation of regiospecifically functionalized lsatins from anilines.
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