Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor

Article abstract of DOI:10.1021/acs.joc.8b02690

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.

Full text of DOI:10.1021/acs.joc.8b02690

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Article
Discovery and Development of Metal#Catalyzed Coupling Reactions
in the Synthesis of Dasabuvir, an HCV#Polymerase Inhibitor
David M. Barnes, Shashank Shekhar, Travis B. Dunn, Jufang H Barkalow, Vincent S. Chan, Thaddeus
S. Franczyk, Anthony R. Haight, John E Hengeveld, Lawrence Kolaczkowski, Brian J. Kotecki, Guangxin
Liang, James Christopher Marek, Maureen A. McLaughlin, Donna K Montavon, and James J. Napier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02690 • Publication Date (Web): 10 Jan 2019
Downloaded from http://pubs.acs.org on January 11, 2019
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Discovery and Development of Metal-Catalyzed Coupling Reactions in
the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor
David M. Barnes,* Shashank Shekhar,* Travis B. Dunn,* Jufang H. Barkalow, Vincent S. Chan,
Thaddeus S. Franczyk, Anthony R. Haight, John E. Hengeveld, Lawrence Kolaczkowski, Brian J.
Kotecki, Guangxin Liang, James C. Marek, Maureen A. McLaughlin, Donna K. Montavon, James J.
Napier
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†Process Chemistry, AbbVie Inc., North Chicago, Illinois, USA
*Corresponding author email: david.barnes@abbvie.com, shashank.shekhar@abbvie.com and travis.dunn@abbvie.com
OMe
Me
O
Me
Me
O
MeO
P
Me
O
N
O
O
N
i-Pr
i-Pr
O
N
O
NH
NH
NH
50
NH
N
NH
O
N
H
O
O
16
CN
O
O
i-Pr
Pd2(dba)3, K3PO4
O
+
+
S
I
CuI, K3PO4
DMSO
H2
N
Me
Me
Me
Me
Me
Me
Me
I
Me
Me
Me OMe
Me OMe
I
OSO2C4F9
Me OMe
NHSO2Me
Me
O
8
Me
1
dasabuvir (
)
9
33
ABSTRACT: Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three component direct
acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling
reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16
as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflates was developed,
promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made
possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden
of the process.
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INTRODUCTION
.
Hepatitis C virus (HCV) infection is a global epidemic, with an estimated global prevalence of
1.6%1 to 2.8%2 corresponding to about 115,000,000 infected people worldwide, including
approximately 3,000,000 in the United States.3 Although HCV infection can remain
asymptomatic for years, it is responsible for about 500,000 deaths per year as it is a causative
agent of conditions such as cirrhosis and hepatocellular carcinoma.3
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60
Prior to 2011, the standard therapy for HCV was treatment with interferon and ribavirin.4 This
regimen had severe side effects, while affording poor response rates. In 2011, FDA approved the
first direct-acting antiviral (DAA) medicines, telaprevir and boceprevir. When added to the
interferon/ribavirin regimen, these DAAs significantly improved cure rates; however, the side
effects associated with interferon remained a significant issue for these new therapies, as did new
side effects related to the DAAs themselves.4
Dasabuvir (1, Figure 1) is a non-nucleoside HCV polymerase inhibitor developed as part of an
interferon-free DAA combination therapy (Viekira Pak®) which includes the NS5A inhibitor
ombitasvir (2) and the NS3/4A protease inhibitor paritaprevir (3). This combination affords a
high-sustained viral response 12 weeks after dosing (SVR12) and is generally safe and better
tolerated than interferon-based regimens.5
O
N
Me
Me
Me
N
Me
N
Me
Me
Me
NH
N
O
MeO2CHN
NHCO2Me
O
O
O
O
H
N
O
H
H
O
N
S
O
N
N
N
H
O
Me
N
N
N
Me
O
N
H
O
O
Me OMe
Me
NHSO2Me
dasabuvir (1)
ombitasvir (2)
paritaprevir (3)
Figure 1. Dasabuvir (1), ombitasvir (2) and paritaprevir (3)
Our initial retrosynthetic analysis identified a highly convergent synthesis of dasabuvir through
the coupling of a uracil-substituted halogenated arene core, represented by A, with an
appropriate naphthyl nucleophile B (Scheme 1). Therefore, our first-generation approach
targeted efficient syntheses of the requisite N1-aryl uracil derivative A and methanesulfonamide-
substituted naphthyl coupling partner B. During process development, we discovered that N-
naphthyl methanesulfonamide derivatives B represented a significant mutagenic impurity
liability. Therefore, we developed
a
second-generation synthesis in which the
methanesulfonamide moiety was introduced at the end of the synthesis. This required
development of a metal-catalyzed sulfonamide coupling, as well as a new ligand family to
facilitate the sulfonamide coupling.6
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First-generation synthesis
O
O
6
NH
NH
7
8
N
O
N
O
M
9
Me
Me
Me
Me
X
10
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51
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59
60
NHSO2Me
Me OMe
Me OMe
NHSO2Me
B
A
dasabuvir, 1
Second-generation synthesis
O
O
O
N
NH
NH
NH
N
O
N
O
O
O
O
S
H2N
Me
Me
Me
Me
Me
Me
Me
M
X
Me OMe
Me OMe
Me OMe
NHSO2Me
OR
OR
A
D
C
dasabuvir, 1
Scheme 1. Retrosynthesis of dasabuvir (1) via aryl uracil A
RESULTS AND DISCUSSION
.
Previous work had demonstrated that the condensation of aniline 4 with acyl isocyanate 5
afforded bromide 6 (Scheme 2).7 Coupling of bromide 6 to boronate ester 7, using palladium(II)
(1,1’-bis(di-tert-butylphosphino)ferrocene) dichloride (Pd(dtbpf)Cl2), afforded dasabuvir in
acceptable yield. However, this approach suffered from the thermal sensitivity of the acyl
isocyanate reagent 5 which was purified by distillation; when this distillation was scaled up,
extensive decomposition was observed. We therefore investigated alternate approaches to
halogenated N1-aryl uracil derivatives such as 6.8
t-Bu2
P
PdCl2
O
O
Fe
Me
O
Pt-Bu2
Me
Me
Me
NH
O
NH
NH2
5
O
B
K3PO4
N
O
MeO
NCO
N
O
+
Me
Me
THF/water
74% yield
Br
NHSO2Me
Me
Me
Me
Me
Me OMe
7
Br
Me OMe
dasabuvir (
4
Me OMe
NHSO2Me
1
)
6
Scheme 2. Synthesis of dasabuvir (1) via bromide 6
A conceptually elegant and direct approach to the desired N1-aryl uracil derivatives is the
metal-catalyzed coupling of uracil to a 2,4-dihaloanisole derivative (eq 1). Inherent to this
approach is the combined challenge of ensuring the desired chemoselectivity on both the uracil
(N1 vs N3) and the dihaloarene (C4 vs C2) coupling partners. Initial experiments with a
dibromoarene substrate and copper catalysts (vide infra) provided some coupling product 6, but
low conversion and multiple side products were observed, presumably due to the high
temperatures, which detracted from the use of the bromo electrophile (data not shown). Given
the expected higher reactivity of aryl iodides in copper-catalyzed reactions, we explored
coupling of uracil with diiodoanisole 8 to prepare iodide 9.
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O
I
I
4
NH
HN
I
O
O
O
5
6
7
8
N
O
O
N
O
I
NH
Me
Me
Me
Me
(1)
+
+
+
+
N
NH
N
Me
Me
I
N
H
O
Me OMe
Me MeO
Me
Me
Me
Me
O
O
N
H
Me OMe
I
Me OMe
Me OMe
9
8
9
10
11
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10
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59
60
N1/C4 Isomer
N3/C4 Isomer
N1/C2 Isomer
N3/C2 Isomer
Literature precedent for the selective coupling at the C4-iodide of 8 was not clear. Sonogashira
coupling of the related acetylated substrate afforded a mixture of mono- and bis-alkyne products
(eq 2).9 While this result indicated that the C4-iodide was more reactive, it did suggest that
reaction at C2 could be a complicating issue.
C2TIPS
C2TIPS
I
Pd(OAc)2
CuI, PPh3, Et3N
21% starting
material
Me
Me
Me
Me
(2)
TIPS
+
+
+
Me
Me
I
C2TIPS
I
Me OAc
62%
Me OAc
17%
Me OAc
The literature precedents for chemoselective coupling of uracil were also unclear (Figure 2).
Zhou and coworkers described the copper-catalyzed arylation of uracil with diaryliodonium salts
which resulted in a moderate yield of the desired N1-arylated uracil (Figure 2a).10 On the other
hand, Maruyama and coworkers found that the Gabriel reaction of uracil with iodobenzene led to
the diaryl product (Figure 2b).11 While our studies were underway, Rad, Behrouz and coworkers
described the N1-arylation of uracil using copper nanoparticle-doped silica cuprous sulfate.12
Yields up to 60% of 1-phenyluracil were observed in the reaction of uracil with iodobenzene
(Figure 2c).
OMe
O
O
CuI, NaOAc
DMF, 40 °C
BF4
NH
NH
(a)
+
I
N
H
O
N
O
p-MeOPh
53% yield
MeO
O
O
Cu2O
I
I
Ph
NH
N
(b)
+
Me3pyr, 170 °C
N
H
O
N
O
Ph
37% yield
O
Cu nanoparticle-
doped silica
cuprous sulfate
O
NH
(c)
NH
+
N
O
DBU, DMF, reflux
N
H
O
Ph
60% yield
Figure 2. Copper-catalyzed arylations of uracil
Preparation of Iodo-Substituted 1-Aryluracil 9
.
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The preparation of diiodoanisole 8 from 2-tert-butylphenol proved to be straightforward
(Scheme 3). Treatment of 2-tert-butylphenol with NaI and bleach13,14 proved an efficient method
for installing the iodides in diiodophenol 13. Methylation (NaOH, MeI, acetone) then completed
the synthesis of diiodoanisole 8. The major impurity in 8 was the 2-chlorinated derivative 8-Cl,
which was observed at up to 6%. Impurity 8-Cl was carried forward into the next step.
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I
I
I
I
NaI
NaOCl
NaOH, MeI
Me
Me
+
Me
Me
+
Me
Me
Me
Me
Me
Me
Cl
I
I
Cl
acetone
Me OH MeOH, water
88% yield
Me OH
Me OH
Me OMe
Me OMe
92% yield
13
13-Cl
8
8-Cl
(~6%)
(~6%)
Scheme 3. Preparation of diiodoanisole 8
As planned, the coupling of uracil with 8 proceeded to give the desired product 9 (Table 1).
Due to the low solubility of uracil, the reaction proceeded only in polar solvents, with the
optimal solvent being DMSO. The major byproduct was the N3 isomer 10; neither of the C2
isomers 11 or 12 (eq 1) was identified as a significant byproduct. A small ligand screen revealed
that 8-hydroxyquinoline15 and N-methylproline afforded moderate conversion, but with rather
low selectivity. On the other hand, 2-(2-pyridyl)-benzimidazole (14) afforded better selectivity
(up to 15:1) and somewhat higher reactivity. This screen also indicated that potassium phosphate
was generally superior to potassium carbonate as a base.
Table 1. Ligand Screen in Coupling of Diiodoanisole 8 with Uracil
O
NH
HN
I
N
O
O
N
O
I
O
Ligand, CuI
NH
+
+
Me
Me
Me
Me
Me
Me
I
I
Base, DMSO
N
H
O
Me OMe
Me OMe
Me OMe
8
9
10
N1 Isomer
N3 Isomer
Entry
Ligand
Base % Conversion at % Conversion Ratio
18 h/50 °Ca after additional N1/N3b
24 h/80 °Ca
1
2
3
4
5
6
N-Methyl Proline
8-Hydroxyquinoline
2-(2-Pyridyl)-benzimidazole (14) K2CO3
K2CO3
21
33
40
23
23
35
53
46
63
44
46
69
5.7
4.6
K2CO3
13.2
5.6
N-Methyl Proline
K3PO4
K3PO4
8-Hydroxyquinoline
7.4
2-(2-Pyridyl)-benzimidazole (14) K3PO4
14.9
All experiments were conducted with CuI (10 mol%), Ligand (20 mol%), base (2.1 equiv), uracil (1.2
equiv) in DMSO (16 mL/g 8). (a) Conversion determined by HPLC as (area% of 9)/(area% 8 + area%
9). (b) Ratio at 24 h time point.
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With demonstrable impact of ligand on selectivity, we decided to modify the structure of 2-(2-
pyridyl)-benzimidazole 14 (Figure 3). Specifically, we envisioned that opening the
benzimidazole ring of 14 would afford an N-arylpicolinamide structure, which maintained the
1,4-relationship of the pyridine nitrogen with an acidic proton, as in ligand 14. Making the
assumption that the acidity of the amide would be important, electron-withdrawing substituents
on the aniline were examined to lower the pKa of the N-H bond. N-Arylpicolinamide ligands 4-
cyanophenyl (15) and 2-cyanophenyl (16) derivatives were prepared and evaluated in the uracil
coupling.
10
11
12
13
14
15
16
17
18
19
20
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22
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50
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60
O
NH
N-Arylpicolinamide
N
O
ring-open
de-coupling
R
R
N
NH2
N
H
N
HO
N
14
O
O
NH
16
N
NC
NH
15
N
CN
Figure 3. N-Arylpicolinamide ligand design
To our delight the 4-cyanophenylpicolinamide 15 provided an excellent N1:N3 selectivity of
>25:1 when potassium phosphate was employed as the base (Table 2, entry 3). Anthranilonitrile-
derived 2-cyano derivative 16 was even better with selectivity of >60:1, with even higher
reactivity.7 Interestingly, no evidence of uracil coupling at C2 was observed. Typically, the use
of potassium phosphate as the base led to higher reactivity and selectivity. Also, the ratio of
ligand to metal had little impact on either reactivity or selectivity.
Table 2. Ligand and Base Study in Coupling of Diiodoanisole 8 with Uracil
O
NH
HN
I
N
O
O
N
O
I
O
Ligand, CuI
NH
+
+
Me
Me
Me
Me
Me
Me
I
I
Base, DMSO
60 °C
N
H
O
Me OMe
Me OMe
Me OMe
8
9
10
N1 Isomer
N3 Isomer
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N1/N3
Conversiona Selectivity
Entry
Ligand L/M ratio
Base
6
7
8
9
51
41
67
57
72
69
86
80
19.0
17.1
27.5
29.0
65.6
66.9
69.1
73.4
1
2
3
4
5
6
7
8
15
15
15
15
16
16
16
16
2:1
1.2:1
2:1
K2CO3
K2CO3
K3PO4
K3PO4
K2CO3
K2CO3
K3PO4
K3PO4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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31
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50
51
52
53
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57
58
59
60
1.2:1
2:1
1.2:1
2:1
1.2:1
All reactions were conducted with CuI (10 mol%), uracil (1.2
equiv), base (2.1 equiv) in DMSO (16 mL/g 8) at 60 °C. (a)
Conversion determined by HPLC as (area% of 9)/(area% 8 +
area% 9).
The synthesis of the 2-cyanopicolinamide 16 was accomplished in two ways (Figure 4).
Reaction of anthranilonitrile with picolinoyl chloride hydrochloride formed 16 directly in 83%
yield. The acid chloride was moisture sensitive so alternatively treatment of picolinic acid with
toluenesulfonyl chloride afforded the mixed anhydride 17 in situ which was reacted directly with
anthranilonitrile to afford 16 in comparable yield (85%).16
O
O
Et3N, DCM
83% yield
NH
N
NH2
+
Cl
N
HCl
CN
CN
16
NH2
O
O
O
TsCl, Et3N
DCM
CN
85% yield
NH
N
HO
N
ArO2SO
N
CN
17
16
Figure 4. Syntheses of picolinamide ligand 16
In preparation for executing the process on multi-kilogram scale, we examined the effect of the
physical properties of the potassium phosphate on reactivity (Table 3). Powdered potassium
phosphate afforded higher reactivity than granular material. Because of the hygroscopicity of the
powdered base, we were concerned about the potential impact of water on the reaction rate and
selectivity. However, when a reaction was conducted in the presence of 70 mol% water with
respect to 8, little effect on the outcome of the reaction was observed.
Table 3. Base and Water Effects on the Uracil Coupling
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3 h
22 h
Conversiona
Ratio
N1/N3
Ratio
Condition
Conversiona
N1/N3
7
8
9
b
Powdered K3PO4
53
38
60
49:1
89
82
91
58:1
55:1
61:1
c
Granular K3PO4
Powdered K3PO4 with 70 mol% H2O
47:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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49
50
51
52
53
54
55
56
57
58
59
60
55:1
All reactions were conducted with CuI (10 mol%), 16 (12 mol%), K3PO4 (2.1 equiv) in DMSO (10 mL/g 8) at 60 °C.
(a) Conversion determined by HPLC as (area% of 9)/(area% 8 + area% 9). (b) K3PO4 was milled to less than 120
micron. (c) Chunks up to mm.
The reaction was sensitive to the presence of oxygen. Typically, the atmosphere above the
reaction was maintained below 20 ppm O2 to ensure reproducible results. Establishing and
maintaining an anaerobic atmosphere was accomplished through nitrogen sparging of the large-
scale batch reactors. The optimized conditions provided 80–90% conversion before stalling after
about 17 hours at 60 °C.The optimized reaction conditions, therefore, employed powdered
potassium phosphate as the base, 10 mol% of copper(I) iodide and 12 mol% of ligand 16
(Scheme 4). An aqueous Cu(OAc)2 wash was incorporated in the workup to extract the ligand,
which was not purged in the crystallization. The product (9) was isolated by crystallization from
i-PrOAc/heptanes. The side product diaryluracil 18 (~15% formed in the reaction) and the small
amount of undesired N3 isomer 10 could be rejected in the crystallization. Recrystallization of 9
from 2-propanol further improved the purity profile. The major impurity in isolated 9 was
chlorinated derivative 9-Cl (the daughter impurity of 8-Cl), which was rejected in the next two
steps.
O
NH
I
N
O
16
CuI, , K3PO4
O
recrystallization from
2-propanol
DMSO, 60 o
C
NH
+
Me
Me
Me
Me
I
aq workup and
crystallization from
i-PrOAc/heptanes
I
N
H
O
Me OMe
Me OMe
8
9
Major impurities
I
OMe
O
O
N
N
Me
Me
NH
Me
N
O
O
I
Me
Me
Me
Cl
Me
Me OMe
Me OMe
9-Cl
18
Scheme 4. Four-step synthesis of 9
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Conducting the process on multi-kilogram scale provided 63–64% yield of 9 over the four-step
sequence, starting from 2-tert-butylphenol (Table 4).
6
7
8
Table 4. Representative Examples of Large-Scale Preparation of 9
O
3)
O
N
O
N
9
NH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH
NH
N
O
H
I
O
O
16
CuI, , K3PO4
DMSO, 60 o
1) NaI, NaOCl
MeOH, water
C
Me
Me
Me
Me
Me
Me
Me
Me
aq workup and
crystallization from
i-PrOAc/heptanes
I
I
Cl
2) NaOH, MeI
acetone
Me OMe
Me OMe
Me OMe
Me OH
8
4) recrystallization
from 2-propanol
9
9-Cl
Purityb
(area%)
Amount of 9-
Clb (area%)
Potencyc,d
(w/w%)
Entry Scale (kg)a
Yield 9 kg
1
2
3
4
85.0
85.0
85.0
85.0
141.7 (63%)
99.3
97.8
98.9
99.3
0.47
1.91
0.39
0.36
99.5
99.7
98.2
99.2
142.0 (63%)
143.8 (64%)
142.8 (63%)
(a) Charge of 2-tert-butylphenol. (b) Determined by HPLC. (c) Potency value determined by HPLC analysis
against a standard. (d) Potency value includes 9-Cl.
The First-Generation Synthesis
.
For our first-generation synthesis of dasabuvir, we anticipated that a late-stage coupling of 9 to
a fully elaborated naphthyl boronate ester 7 would provide the most convergent synthesis
(Scheme 5). Our initial target, therefore, was bromonaphthylsulfonamide 19, the immediate
precursor of 7.17
O
O
NH
NH
Me
Me
Me
Me
N
O
I
N
O
O
B
Br
O
Me
Me
Me
Me
NHSO2Me
NHSO2Me
Me OMe
Me OMe
NHSO2Me
19
7
9
1
dasabuvir ( )
Scheme 5. First-generation retrosynthesis of dasabuvir (1)
Our initial route employed the Bucherer reaction to convert readily available 6-bromo-2-
naphthol 20 to 6-bromo-2-naphthyl amine 21 (Scheme 6). While this chemistry led to the
shortest route conceivable for 19, the highly corrosive nature of the reaction rendered it
untenable for long-term use.18 As a result, a second route to 19 employing Semmler–Wolff
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chemistry was developed.19 Although significantly longer, this reaction sequence was not
corrosive to the reactor components.
Bucherer Reaction
7
8
9
Br
Br
Br
NH4OH, (NH4)2SO3
80% yield
MsCl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
90% yield
OH
NH3Cl
NHMs
20
21
19
Semmler-Wolff Chemistry
1) oxalyl chloride
2) AlCl3, ethylene
NH2OH
Br
Br
Br
Br
Br
OH
OH
N
O
O
75-85% yield
(3 steps)
CH2Cl2
22
23
24
19
Br
AcOH, HCl
MsCl, pyridine
OH
2-methyl THF
94-95% yield
NH3Cl
NHSO2Me
N
73-79% yield
21
24
Scheme 6. Routes to bromonaphthylsulfonamide 19
The Borylation Reaction
.
Miyaura borylation of 19 employed typical conditions (Figure 5).20 We found that the amount
of reduced product, naphthyl methanesulfonamide 25, was a function of the catalyst load. When
1% of Pd(dppf)Cl2 was employed, 3% of the reduced product 25 was formed. However, at 0.25
mol% of the catalyst, 34% reduction was observed. Control experiments demonstrated that the
reduced product was not the product of proteodeborylation of the boronate ester 7.21 Typically,
1% of the catalyst was employed as a compromise between catalyst cost and reaction yield.
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
B
B
B
Me
Me
Me
Me
O
O
Br
O
+
Pd(dppf)Cl2 (x mol%)
KOAc, THF
NHMs
NHMs
NHMs
19
7
25
reduced product
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Figure 5. Effect of catalyst load on the reduction product 25 in the borylation reaction
Even with the catalyst loading held constant at 1 mol%, batch-to-batch variability in the
amount of 25 was observed. This variability was ultimately correlated with residual copper (at
the ppm level) remaining in 19. The copper was present as carry over from an aqueous copper(II)
acetate wash employed in early deliveries to remove naphthol sulfonamide 27 that was formed as
an impurity during the mesylation reaction. Impurity 27 was derived from mesylation of
naphthol amine 26 which was a side product observed in the Semmler–Wolff aromatization step
(Scheme 7).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cu(OAc)2
wash
Br
Br
Br
Br
AcOH, HCl
MsCl, pyridine
2-methyl THF
NH3Cl
OH
NHMs
NHMs
N
19
24
19
21
27
Removal of
Br
Br
NH2
NHMs
27
OH
OH
26
26
Impurity formed during
Semmler-Wolff aromatization
Daughther impurity of
formed during mesylation
Scheme 7. Naphthol sulfonamide 27 arising from side product in the Semmler–Wolff
The relationship between the reduced product 25 and copper levels in 19 was linear when 1
mol% of the palladium catalyst was employed (Figure 6). This is especially interesting as 150
ppm of copper represents only about 0.1 mol% of copper, or 1/10 the level of palladium. In later
deliveries, the copper(II) acetate wash was omitted, and so this complicating pathway was
avoided.
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
B
B
B
Me
Me
Me
Me
O
O
Br
O
+
Pd(dppf)Cl2 (1 mol%)
KOAc, THF
NHMs
NHMs
NHMs
19
7
25
reduced product
Figure 6. Effect of copper level on the amount of reduced product 25 in the borylation reaction
When the process was conducted on multi-kilogram scale, the yield of the borylation step
ranged from 70–90% (Table 5).
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Table 5. Representative Examples of the Borylation Reaction
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
O
B
B
B
Me
Me
Me
Me
Br
7
O
8
9
Pd(dppf)Cl2 (1 mol%)
KOAc, THF
NHMs
NHMs
19
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Potency
Entry
1
Scale (kg)a
24.9
Yield 7 (kg)
(w/w%)b
Purity (area%)c
99.5
23.9 kg (81%)
99.1
99.9
99.9
99.7
2
3
4
13.5
48
10.9 kg (70%)
49.9 kg (90%)
48.3 kg (88%)
99.1
99.9
99.8
47.4
(a) Charge of 19. (b) Potency value determined by HPLC analysis against a standard. (c)
Determined by HPLC.
The Suzuki Coupling
.
With the aryl iodide 9 and the boronate ester 7 in hand, we were able to investigate the Suzuki
coupling. As noted earlier, aryl bromide 6 had undergone coupling with 7 employing
Pd(dtbpf)Cl2 as catalyst (Scheme 8). However, aryl iodide 9 did not give 1 in acceptable yield
under similar conditions. A ligand screen was performed, from which the Epstein–Buckler
phosphaadamantane ligand 2822-24 was observed to provide extremely good reactivity.
O
N
O
N
t-Bu2
NH
NH
Me
O
P
Me
Me
Me
PdCl2
O
O
O
B
Fe
Pt-Bu2
+
Me
Me
Me
Me
K3PO4, THF/water
Br
NHMs
Me OMe
Me OMe
NHMs
6
1
7
74% yield
Me
O
O
O
O
NH
NH
Me
O
Me
Me
Me
28
Me
Me
P Ph
O
N
O
N
O
O
B
Me
Pd2dba3
+
Me
Me
Me
Me
I
NHMs
K3PO4, THF/water
Me OMe
Me OMe
NHMs
9
1
7
91% yield
Scheme 8. Suzuki couplings of bromoarene 6 and iodoarene 9
Development of a Palladium-Catalyzed Coupling of Methanesulfonamide with Aryl
Nonaflate in the Second-Generation Synthesis
.
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7
8
9
While the first-generation synthesis of dasabuvir was efficient and served for the preparation of
clinical materials, it suffered from two major deficiencies. First, the synthesis of the boronate
ester 7 was rather long (6 steps) and linear. A greater concern was the use of the boronate ester at
a late stage of the synthesis; the boronate ester 7, its precursor 19, related byproducts 25 and 29
were all mutagenic, as determined by Ames test (Figure 7).While analytical techniques had been
developed to demonstrate that the clinical materials were acceptable for use, the generation of
these impurities at the end of the synthesis, and the need to control them at very low levels (20
g/day, or 40 ppm for a 500 mg/day dose)25, indicated that this could be a risk for the
commercial synthesis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
HO
B
O
B
Me
Me
Br
HO
O
NHMs
NHMs
NHMs
NHMs
19
(Precursor to Boronate
7
25
29
(Byproduct of the Suzuki step)
7
)
(Byproduct of both Borylation
and Suzuki steps)
Figure 7. Mutagenic impurities in the 1st generation route
An analysis of alternate disconnections indicated that the installation of the methane
sulfonamide moiety in the final step would avoid a number of mutagenic impurities, especially
those associated with boronate ester 7 (Scheme 9). We envisioned a palladium-catalyzed cross-
coupling of an aryl sulfonate E with methanesulfonamide might be feasible. Although little
precedent for this transformation existed in the literature,26 we thought the benefits in terms of
mutagenic impurity control warranted investigation of this coupling.27 Further disconnection of
biaryl E led back to aryl iodide 9 and naphthyl fragment F. This approach allowed us to leverage
our existing synthesis of 9 and knowledge about the Suzuki coupling of 9.
O
O
O
NH
NH
NH
N
O
N
O
N
O
O
O
Me
Me
Me
Me
(RO)2B
Me
Me
S
I
H2N
OSO2R
Me
Me OMe
Me OMe
Me OMe
NHSO2Me
OH
9
F
E
1
dasabuvir (
)
Scheme 9. Second-generation synthetic disconnection that avoids mutagenic impurities
Demonstration of Palladium-Catalyzed Sulfonamide Coupling
.
Initial screening of ligand, solvent and base indicated that tert-butyl-XPhos (30) in conjunction
with tert-amyl alcohol (2-methyl-2-butanol) and potassium phosphate enabled the desired
coupling reactions. A series of aryl sulfonate esters was evaluated using the reaction conditions
shown below (Figure 8). The tosylate 31 was insufficiently reactive. While the triflate 32 had
good reactivity it also proved to be sensitive to hydrolysis. As a result, about 10% of the
naphthol byproduct (35, Table 6) was observed in the reaction. The rejection of the naphthol
byproduct by crystallization was rather difficult; therefore the triflate was not a suitable coupling
partner for this application as the final step of the dasabuvir synthesis.
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6
P(t-Bu)2
7
8
9
O
N
i-Pr
i-Pr
O
N
NH
NH
30
O
i-Pr
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
t-Bu-XPhos (4 mol%)
O
O
Pd2dba3 (1 mol%),
S
Me
Me
Me
Me
+
H2N
OSO2R
(R = p-tolyl), insufficiently reactive
CH3
O
O
K3PO4, t-amyl alcohol
Me OMe
Me OMe
S
N
Me
90 °C, 18 h
H
1
31
32
33
1
1
(R = CF3), ~ 90% along with ~10% hydrolysis
(R= C4F9), > 95%
Figure 8. Coupling of sulfonate esters with methanesulfonamide
Aryl nonaflates are known to behave similarly to aryl triflates in Pd-catalyzed couplings but
are more resistant to hydrolysis than aryl triflates.28 Indeed, the reaction of aryl nonaflate 33 with
methanesulfonamide proceeded to over 95% yield, with less than 1% of the hydrolysis
byproduct. Preparation of 33 was accomplished in high yield in two steps from iodoarene 9 as
described below.
Preparation of Aryl Nonaflate 33
.
The Suzuki coupling with hydroxynaphthylboronic acid 34 performed well with the previously
employed ligand 28 (Table 6). Although the combination of Pd2dba3 and ligand 28 rapidly
catalyzed this Suzuki reaction, a fairly high loading of palladium was required to completely
consume 9. At the nominal charge of 1 mol% Pd2dba3 (2 mol% Pd), the reaction reached
complete conversion in under 1.5 hours, but all attempts to reduce the palladium loading to
below 1.7 mol% were met with incomplete conversion of 9 (e.g. 1.5 mol% Pd stalled with 3.2%
9 remaining). Complete consumption of 9 was essential because iodoarene 9 was found to be a
potent catalyst poison of the sulfonamidation reaction (vide infra). On scale, the Suzuki coupling
performed well and delivered > 90% yield of naphthol 35 in high purity (Table 6).
Table 6. Representative Examples of Suzuki Coupling to Prepare Naphthol 35
O
O
N
Pd2dba3 (1 mol%)
Me
NH
NH
O
O
N
O
O
Me
Me
Ph
28
O
P
(HO)2B
Me
(4.5 mol%)
Me
Me
+
Me
Me
I
K3PO4, THF/water
60-65 °C
OH
Me OMe
Me OMe
OH
34
9
35
Potency
(w/w%)b
Entry Scale (kg)a Yield 35 kg
Purity (area%)c
99.7
1
2
88.0
88.0
85.1 (93%)
83.9 (92%)
98.2
98.2
99.6
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88.0
88.0
85.8 (94%)
86.2 (94%)
99.8
98.1
99.4
99.4
7
(a) Charge of 9. (b) Potency value determined by HPLC analysis
8
against a standard. (c) Determined by HPLC.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the course of these studies an unusual rearrangement byproduct 38 was identified, which
formed at 0.7 to 1.45 area% during the reaction (Figure 9). This byproduct is believed to be the
result of C-H insertion of the aryl-palladium species 36 into the methyl ether, which is forced
into proximity of the palladium atom because of the bulk of the adjacent tert-butyl group.
Whether the C-C bond is formed by transmetallation of 37 with 34 and reductive elimination or
by some other unknown mechanism is not certain.
O
O
O
O
NH
NH
NH
NH
N
O
N
O
N
O
N
O
(HO)2B
34
PdLn
Rearrangement
OH
I
Me
Me
OH
Me
Me
Me
Me
Me
Me
I
Pd
H
L
Me
O
Me
O
Me
O
Me
O
CH3
CH3
CH2
L Pd
9
36
37
38
I
Figure 9. Rearrangement byproduct observed in Suzuki coupling
Preparation of the nonaflate 33 from naphthol 35 was best accomplished in a mixed
DMF/MeCN solvent system (Table 7). Naphthol 35 is poorly soluble in many common organic
solvents, but has reasonable solubility in DMF and other polar aprotic solvents.
Perfluorobutanesulfonyl fluoride was chosen as the nonaflating reagent because it is inexpensive
and tolerates a wide range of solvents, including the polar aprotic solvents DMF and
acetonitrile.28,29 Though reactions of 35 in DMF were rapid, some decomposition of the
unpurified reaction mixture was observed upon holding. Acetonitrile is an excellent solvent for
nonaflation of other phenols,27 but the limited solubility of naphthol 35 and product 33 in pure
acetonitrile caused complications. Ultimately a mixture of the two solvents provided the right
balance of solubility and reactivity. Potassium carbonate was a suitable base for the reaction,
provided it was of small enough particle size; commercially available 325-mesh K2CO3 was
adequate, while granular material resulted in incomplete conversion. With a reliable and scalable
synthesis in hand, multiple batches of 33 were prepared in reproducible yield and purity (Table
7).
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Table 7. Representative Examples of Preparation of Aryl Nonaflate 33
O
O
NH
NH
7
8
9
N
O
N
O
F
F F
F
F
F
K2CO3 (2 equiv)
S
F
Me
Me
Me
Me
+
O
O F
F
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeCN/DMF (3:2)
Me OMe
Me OMe
30 C
OH
OSO2C4F9
1.2 equiv
35
33
Potency
Total impurities
(w/w%)c
Entry Scale (kg)a
Yield 33 kg
(w/w%)b
1
2
3
4
82.4
82.4
82.4
82.4
123.4 (89%)
99.9
99.9
0.06
0.07
0.08
0.08
122.9 (89%)
121.8 (88%)
120.0 (87%)
99.8
100.3
(a) Charge of 35. (b) Potency value determined by HPLC analysis against a standard. (c)
Determined by HPLC.
Intermediate 33 was a key control point for several potential impurities in dasabuvir which had
been determined to be of mutagenic concern (Scheme 10). Naphthol species 34, 40, and 42 were
identified as impurities in isolated naphthol 35 which would result in potentially mutagenic
impurities 29, 25, and 44 in dasabuvir. Fortunately, the daughter impurities 39, 41, and 43 were
well rejected in the isolation of nonaflate 33, serving as a robust control point for this family of
impurities. Impurities 39, 41, and 43 were routinely rejected to below 100 ppm in 33, which was
sufficient to ensure that the daughter impurities would be present below 40 ppm in dasabuvir.
35
33
1
Impurities in napthol
Impurities in nonaflate
Mutagenic impurities in dasabuvir
OH
OH
OH
B
B
B
HO
HO
HO
NHMs
OSO2C4F9
OH
OH
29
34
39
41
NHMs
OSO2C4F9
25
40
MsHN
C4F9O2SO
HO
NHMs
OSO2C4F9
OH
44
42
43
29 25
44
39 41
,
43
, and
The presence of potential mutagenic impurities
33
,
, and
in dasabuvir was avoided by rejecting
to less than 100 ppm during the isolation of
Scheme 10. Upstream control of potentially mutagenic impurities in dasabuvir
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Optimization of the Palladium-Catalyzed Sulfonamidation
.
The Pd-catalyzed sulfonamidation reaction was further optimized with the goal of identifying a
more active catalyst than the combination of Pd2(dba)3 and tert-Bu-XPhos. A screen of ligands
identified tert-Bu-BrettPhos (45) as the optimal ligand;30 >99.5% conversion of aryl nonaflate 33
was observed within 6 hours with 1 mol% palladium and 1.1 mol% ligand (Figure 10).
Importantly, less than 0.5% of the hydrolysis impurity 35 was observed.31 Pre-mixing of
Pd2(dba)3, tert-Bu-BrettPhos, and K3PO4 in a solvent at elevated temperatures (catalyst pre-
activation) prior to the addition of 33 and methanesulfonamide was necessary to ensure
reproducible results.32,27,33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The initial screen of reaction conditions identified tert-amyl alcohol as the optimal solvent.
However, the product of those reactions crystallized as an anhydrate form, which formed a thick
slurry that was very difficult to stir and filter. The resistance of a 6-inch cake of the product in
anhydrate form was quite high (1.6 × 1011 ft/lb) and it took over 5 hours to filter. This anhydrate
form of the product crystallized from most solvents that are commonly employed for palladium-
catalyzed reactions. Although ethyl acetate is not a common solvent for Pd-catalyzed cross-
coupling reactions, when the reaction was run in ethyl acetate the product precipitated as larger
crystals of an ethyl acetate solvate that stirred readily and filtered well. A 6-inch cake of the ethyl
acetate solvate filtered in less than 0.5 hours (resistance of 1.6 × 109 ft/lb).
O
O
NH
NH
N
O
N
O
Pd2(dba)3 (0.50 mol%),
tert-Bu-BrettPhos (1.1 mol%)
O
O
Me
Me
Me
Me
+
S
H2N
Me
K3PO4 (1.5 equiv)
Ethyl acetate, 90 °C
Me OMe
33
Me OMe
dasabuvir ( )
OSO2C4F9
NHSO2Me
1.2 equiv
OMe
1
MeO
i-Pr
P(t-Bu)2
i-Pr
i-Pr
45
tert-Bu-BrettPhos (
)
Figure 10. Palladium-catalyzed sulfonamidation in ethyl acetate
Although ethyl acetate was a superior solvent for the Pd-catalyzed sulfonamidation reaction
from the standpoint of the product physical properties, we noted run-to-run variability of
conversion which was ultimately traced back to the batch of tert-Bu-BrettPhos employed (Table
8). Reactions in ethyl acetate proceeded to >99% conversion under standard conditions with one
batch of ligand (entry 1). However, less than 5% conversion was observed when a different batch
of ligand was used (entry 2). ICP analysis of the two batches of ligand revealed that while Batch
1 contained less than 5 ppm copper with respect to the tert-Bu-BrettPhos, 8600 ppm copper was
present in Batch 2. A portion of Batch 2 was purified by washing an ethyl acetate solution of the
ligand with aqueous ammonia until the aqueous layer was clear, followed by concentration and
recrystallization from methanol.34 The purified tert-Bu-BrettPhos contained less than 5 ppm
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copper and performed well in the reaction (entry 3), supporting the hypothesis that the copper
was responsible for inhibiting the reaction.35-38
6
7
Table 8. Dependence of Reaction Conversion in EtOAc on Copper Level in tert-Bu-BrettPhos
8
9
Ligand
source
Copper
(ppm)
Prod
(%)
Entry
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Batch 1
Batch 2
Batch 3a
<5
8600
< 5
>95
<5
2
3
>95
All reactions were performed with 1 g of 33 inside an inert atmosphere glove box in EtOAc (12 mL/g 33) for 16–18 h.
(a) Batch 2 was dissolved in EtOAc, washed with aqueous ammonia, then recrystallized from MeOH prior to use.
The mechanism for inhibition of the sulfonamidation reaction due to the presence of sub-
stoichiometric amounts of copper (with respect to Pd) is not apparent to us.37,39 One observation
of relevance was that palladium black precipitated out during the catalyst pre-activation step with
Pd2(dba)3, K3PO4, and tert-Bu-BrettPhos Batch 2 (containing 8600 ppm of copper) in ethyl
acetate (Table 9, entry 1).40 Interestingly, no palladium black was formed, and the catalysis was
not inhibited, when the reaction was conducted with Batch 2 in tert-AmOH or 2-MeTHF (Table
9, entries 2 and 3). The reason why the reaction was not inhibited by copper when using tert-
AmOH or 2-MeTHF as the solvent is not known.
The observation that 2-MeTHF mitigated the impact of high copper content in tert-Bu-
BrettPhos suggested that a mixed solvent system might be beneficial. When a 1:1 (v/v) mixture
of 2-MeTHF and ethyl acetate was used for catalyst pre-activation with tert-Bu-BrettPhos Batch
2, the reaction proceeded to 72% conversion (entry 4). A much higher yield (88%) was observed
when the catalyst pre-activation was performed in neat 2-MeTHF and ethyl acetate was
employed as the reaction solvent (entry 5). Importantly, the coupled product was obtained as the
easily filtered ethyl acetate solvate from a 3:1 mixture of ethyl acetate/2-MeTHF.
Table 9. Effect of Solvent on Reactions Conducted with a High-Copper Batch of t-Bu-BrettPhos
Step 1, Catalyst Pre-Activation
Step 2, Coupling Reaction
O
O
OMe
NH
NH
MeO
i-Pr
P(t-Bu)2
N
O
N
O
i-Pr
Catalyst
Solution
Pd2dba3 (0.50 mol%)
K3PO4 (1.5 equiv)
Catalyst Solution
Solvent 2,
O
O
Me
Me
+
Me
Me
S
H2N
Me
90 °C
i-Pr
Me OMe
Me OMe
dasabuvir (
Solvent 1,
80 °C, 30 min
OSO2C4F9
NHSO2Me
Ligand (1.2 mol%)
1.2 equiv.
33
1
)
Batch 2
(Cu = 8600 ppm)
Vol solvent 1 Solvent 2 Vol solvent 2
Solvent 1
Entry
1
(activation)
(mL/g 33)
(reaction)
EtOAc
(mL/g 33) Time (h) 1 (%)a 33 (%)a,b
EtOAc
4
8
8
18
18
<1
>95
1.5
2
t-AmOH
4
t-AmOH
>95
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Vol solvent 1 Solvent 2 Vol solvent 2
Solvent 1
(activation)
Entry
3
(mL/g 33)
(reaction)
2-MeTHF
(mL/g 33) Time (h) 1 (%)a 33 (%)a,b
2-MeTHF
4
8
8
18
14
>95
72
<0.5
23
4
4
EtOAc
EtOAc/2-MeTHF
(1:1 v/v)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
2-MeTHF
3
EtOAc
9
14
88
8
All reaction were conducted with Pd2(dba)3 (0.5 mol%), tert-Bu-BrettPhos (1.2 mol%, Batch 2), K3PO4 (1.5 equiv), 33 (1
equiv), and methanesulfonamide (1.2 equiv) at 90 °C. (a) HPLC area% at 210 nm. (b) HPLC area% of unreacted 33.
Further studies with Pd2(dba)3 (0.50 mol%) and various batches of tert-Bu-BrettPhos (1.2
mol%), containing 40–8600 ppm Cu, demonstrated that the sulfonamidation in EtOAc was
robust as long as less than 1000 ppm copper was present in the ligand. In addition, the catalyst
pre-activation was performed in 2-MeTHF (3 mL/g nonaflate 33) followed by dilution of the
reaction with EtOAc (9 mL/g nonaflate 33) to ensure robustness of the reaction.
Invention and Use of Ligand 50 in the Sulfonamidation Reaction.
.
Given the sensitivity of the sulfonamidation reaction to residual copper in tert-Bu-BrettPhos
and the variability of copper levels in commercial batches of tert-Bu-BrettPhos, the use of biaryl
phosphines that do not require copper for synthesis was explored. A biaryl phosphacycle
containing the same biaryl backbone as in tert-Bu-BrettPhos was prepared according to the
method shown in Scheme 11.41-45 Lithium-halogen exchange of biaryl iodide 46 followed by the
reaction of the resulting Li-biaryl species with diethyl chlorophosphate generated biaryl
phosphonate 47, which was reduced to the biaryl primary phosphine 48 in the presence of
LiAlH4 and TMSCl.46 Conjugate addition of the primary phosphine to phorone formed the
phosphacycle 49. The carbonyl in 49 was then converted to a ketal to form ligand 50.47
OMe
OMe
OMe
O
LiAlH4 (3 equiv)
TMSCl (3 equiv)
OEt
MeO
PH2
O
P
MeO
I
MeO
P
n-BuLi (1.2 equiv)
THF, -78 C
Cl
OEt
OEt
i-Pr
+
i-Pr
i-Pr
i-Pr
i-Pr
THF, 0 C
i-Pr
OEt
1.2 equiv
i-Pr
i-Pr
46
i-Pr
47
48
(57%)
(98%)
O
OMe
OMe
O
O
HO
(10 equiv)
OH
MeO
P
(4 equiv)
MeO
P
O
i-Pr
i-Pr
i-Pr
i-Pr
p-toluenesulfonic acid (10 mol%)
160 C, 22 h
toluene, reflux, 16 h
i-Pr
i-Pr
50
(90%)
49
(66%)
Scheme 11. Synthesis of VincePhos (50)
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Seemingly minor changes in the structure of the phosphine ligand are well known to have
profound impact on reactivity.48-54 Thus, the utility of 50 in the sulfonamidation reaction was not
obvious to us. Gratifyingly, dasabuvir (1) was formed in >95% yield when the sulfonamidation
reaction was conducted with 50 as ligand. More importantly, the performance of the
sulfonamidation reaction was consistent when various batches of 50 were evaluated in this
transformation.55
10
11
12
13
14
15
16
17
18
19
20
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22
23
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25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Optimization of Reaction Parameters to Develop a Robust Sulfonamidation Reaction
.
The Pd-catalyzed sulfonamidation reaction is the last bond-forming step for the synthesis of
dasabuvir. It was therefore imperative to understand the influence of reaction parameters such as
temperature, concentration, equivalents of reagents, effect of moisture, particle size of base, and
effect of oxygen on both yield and purity profile to ensure a robust scale up procedure. The level
of moisture, particle size of the base, and the amount of oxygen present in the reactor had the
most profound impact on the reaction.
Not surprisingly, the higher the level of moisture present in the reaction mixture the higher the
amount of the hydrolyzed impurity (35) observed. Potassium phosphate was identified as the
largest source of moisture. Potassium phosphate with less than 2% w/w water was used in the
process to ensure formation of less than 0.5% 35 in the reaction.
The sulfonamidation reaction is heterogeneous because potassium phosphate is insoluble in the
reaction solvent mixture (2-MeTHF/EtOAc). We anticipated that the proper suspension of
potassium phosphate in solvent would be critical to ensure reproducible reaction on scale.56,57
The particle size of K3PO4 and the speed of agitation can impact the extent of suspension of
potassium phosphate in 2-MeTHF/EtOAc. Thus, studies were conducted to understand the effect
on conversion of the particle size of potassium phosphate and the speed of agitation. In a set of
experiments (Table 10), the agitation speed of 450 rpm was maintained during the catalyst pre-
activation while the agitation during the reaction was varied between 125–475 rpm.
Greater than 99% consumption of the starting material was observed when potassium
phosphate containing particles on the order of several millimeters in size was used and the
contents were mixed at 475 rpm (entry 1). Lowering the agitation speed to 300 and 125 rpm
allowed the reaction to proceed to only 58 and 45% conversion, respectively (entries 2 and 3). It
was clear that the reaction was sensitive to the speed of agitation if potassium phosphate with
large particle size was used in the process. Therefore, additional studies were performed using
potassium phosphate milled to 60–352 µm in size. Agitation at 300 rpm with the particle size of
352 µm improved the conversion to 73% (entry 4). Quantitative consumption of nonaflate was
observed when the particle size was further lowered to 120–60 while agitating at 300 rpm
(entries 5, 6, and 8). Quantitative consumption of nonaflate was also observed when the agitation
speed was reduced to 125 rpm while using potassium phosphate of D90 100 µm (entry 7). The
data shown in Table 10 suggest that there is a strong correlation between the particle size of
potassium phosphate and the necessary agitation speed. Thus, to minimize the dependence of the
reaction on the agitation speed in large reactors, milled potassium phosphate with D90 less than
120 μm was used.
Table 10. Correlation Between the Particle Size of K3PO4 and the Reaction Agitation Speed
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O
N
O
N
NH
NH
O
O
Pd2(dba)3 (0.50 mol%),
50
(1.1 mol%)
O
O
Me
Me
Me
Me
+
S
H2N
Me
K3PO4 (1.5 equiv)
Ethyl acetate/2-MeTHF, 90 °C
Me OMe
33
Me OMe
OSO2C4F9
NHSO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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33
34
35
36
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1.2 equiv
Entry
1
K3PO4 D90 (µm)
rpm
475
Conv (%)a
> 99
Chunks up to mm
Chunks up to mm
Chunks up to mm
352
2
3
4
5
300
125
300
300
58
45
73
120
>99
6
7
8
100
100
60
300
125
300
>99
> 99
>99
All experiments were performed with 33 (1 equiv), methanesulfonamide (1.2 equiv), K3PO4 (1.1 equiv), Pd2(dba)3 (0.005
equiv) and 50 (0.012 equiv) in a mixture of 2-MeTHF (4 mL/g 33l)/EtOAc (8 mL/g 33) at 90 °C. (a) (100 –area)% of the
unreacted nonaflate at 210 nm.
The reaction was inhibited by the presence of oxygen in the reactor. The level of O2 in the
reactor was controlled to less than 50 ppm to ensure reproducible reactions. Interestingly, the
reaction was much more sensitive to O2 during the early stages of the reaction than in the latter
stages. For examples, no consumption of nonaflate was observed when all the reagents were
charged in air and the reaction was heated to 90 °C for an extended period. Either Pd or
phosphine or both get oxidized and fail to catalyze the reaction. In contrast, no impact on the
reaction progress was observed when the reactor was opened to air after 30–40% conversion.
The resting-state of the catalyst is believed to be a Pd(II) species because reductive elimination is
likely the rate-limiting step.27 It is likely that most of the active Pd species are in oxidation-state
II after a few turnovers and cannot be further oxidized by air; thus, the reaction continues to
progress despite exposure to air.
During our optimization studies, we found that iodoarene 9 is a potent catalyst poison in the
sulfonamidation reaction. Under otherwise nominal reaction conditions (1.0 mol% Pd and 1.2
mol% 50), a reaction spiked with 0.17 mol% of 9 (with respect to nonaflate 33) stalled at 53%
conversion. The sulfonamidation proceeded to >99% conversion in the presence of 0.087 mol%
of 9, however. Buchwald and coworkers58 have demonstrated that Pd-catalyzed C-N couplings of
aryl iodides are inhibited by the iodide byproduct in polar solvents. Presumably, iodoarene 9
undergoes oxidative addition with active catalyst and the iodide anion byproduct inhibits the
sulfonamidation reaction by sequestering the Pd in an inactive state.
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The process was scaled up to multi-kilogram scale using both tert-Bu-BrettPhos (45) and
VincePhos (50). The performance of the reaction was comparable with the two ligands, yielding
90% of dasabuvir in >99.5% purity (Table 11).
7
8
Table 11. Scale up of Pd-Catalyzed Sulfonamidation Reaction
9
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH
NH
N
O
N
O
Pd2dba3 (0.5 mol%),
Ligand (1.2 mol%)
Me
Me
O O
S
Me
Me
+
Me OMe
H2N
Me
Me OMe
OSO2C4F9
K3PO4, 2-MeTHF/EtOAc
90 °C
NHSO2Me
33
1
dasabuvir ( )
Entry Scale (kg)a Ligand Yield 1 (kg) Purity (area%)b
1
2
3
4
100
99.5
100
100
45
45
50
50
63.2 (89.4%)
63.7 (90.8%)
63.1 (89.4%)
62.3 (88.2%)
99.7
99.8
99.8
99.8
(a) Charge of 33. (b) Determined by HPLC.
CONCLUSION
.
In the course of the development of the synthesis of dasabuvir, two novel coupling reactions
were developed. A copper-catalyzed coupling of uracil to diiodoarene 8, employing picolinamide
ligand 16, afforded the 1-aryl uracil derivative 9 in very good yield, with excellent
regiochemistry on both the uracil and diiodoarene coupling partners. The first-generation
synthesis of dasabuvir then employed the Epstein–Buckler phosphaadamantane ligand 28 in the
Suzuki coupling to deliver dasabuvir. Because of the introduction of mutagenic intermediates in
the final step, a second-generation route was developed in which the methanesulfonamide moiety
was introduced to a fully elaborated intermediate. Commercially available tert-Bu-BrettPhos
afforded good reactivity in the coupling of methanesulfonamide with nonaflate 33 to generate
dasabuvir. Additionally, novel phosphacycle ligand 50 was found to provide comparable yield
and purity in the sulfonamidation reaction. Finally, the sensitivity of the sulfonamidation reaction
to extremely low levels of copper was mitigated by employing ligand 50, which does not use
copper in the synthesis.
Experimental Section
.
General methods. All copper- and palladium-catalyzed reactions were performed in a nitrogen
glove box or using Schlenk techniques under N2/Ar atmosphere. Unless noted specifically,
reagents, Pd2(dba)3, CuI, phosphine ligands, bases, and solvents were purchased from
commercial sources and were used without further purification. Unless otherwise noted, reaction
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mixtures were heated to the indicated temperature using conventional heating sources (e.g. oil
bath, heating mantle, heating block, jacketed reactor). 1H NMR and 13C{1H} NMR spectra were
recorded on a 400, 500, 600 or 700 MHz spectrometer, with shifts reported in parts per million
downfield from tetramethylsilane and referenced to residual proton (1H) or deuterated solvent
(13C). HPLC analyses were performed using spectroscopic grades of acetonitrile and water with
either 0.1 % H3PO4 or 0.1% HClO4 as eluents. HRMS analyses were performed on a time-of-
flight mass spectrometer equipped with an ESI source. Elemental analysis was performed using
optimum combustion analysis on an elemental analyzer. Melting points were determined by
either conventional visual analysis or by differential scanning calorimetry, as denoted by DSC.
10
11
12
13
14
15
16
17
18
19
20
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22
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27
28
29
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31
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33
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,4-Diiodo-6-tert-butylphenol (13):59 2-tert-Butylphenol (99.95 g, 665.4 mmol) was dissolved
in 1250 mL of methanol. Sodium hydroxide pellets (30.96 g, 799.0 mmol, 1.20 equiv) were
added. The mixture was stirred at room temperature until the pellets had dissolved and the
resulting green solution was cooled with an ice/salt bath. Sodium iodide (299.34 g, 1997 mmol, 3
equiv) was added in four approximately equal portions. Each sodium iodide addition was
followed by the slow dropwise addition of sodium hypochlorite solution (8.3% by weight, 1313
g, 1465 mmol, 2.2 equiv) in four approximately equal portions. During the hypochlorite
additions the reaction temperature was kept at NMT 0 °C. A solution of 100 g of sodium
thiosulfate in 500 mL of water was added over a 20 minute period. The reaction mixture was
acidified to pH 3 using concentrated HCl (approximately 200 mL). The slurry was filtered and
the wet cake was washed with 2 liters of water. The solid was deliquored by passing a stream of
air through the cake overnight. The solid weighed 289.33 g and the potency by HPLC was 88%,
yielding 254.61 g potency-adjusted yield (95%). Most of the remaining mass balance was water,
1
and the product was not further purified. H NMR (400 MHz, CDCl3)  7.79 (d, J = 2.06 Hz,
13
1H), 7.46 (d, J = 2.06 Hz, 1H), 1.35 (s, 9H). C{1H} NMR (176 MHz, CDCl3)  152.3, 142.6,
138.9, 136.3, 89.9, 83.1, 35.8, 29.4.
1-(tert-Butyl)-3,5-diiodo-2-methoxybenzene (8):6 2,4-Diiodo-6-tert-butylphenol, 13 (93 wt%,
21.6 g, 20.1 g assay, 50 mmol) was dissolved in 140 mL acetone, and MeI (4.2 mL, 67.5 mmol,
1.35 equiv) was added followed by 50% aq. NaOH (5.0 g, 62.5 mmol, 1.25 equiv). After stirring
overnight, less than 1% phenol remained, and the reaction was concentrated to 50–60 mL.
Heptane (80 mL) was added, and the solution was washed with 50 mL water. The aqueous layer
was back extracted with 20 mL heptane. The combined heptane layers were washed with 2 × 50
mL 10% aq. NaCl to yield 91.1 g of a heptane solution of 8 (assay 19.1 g by HPLC, 92% yield).
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 3.87 (s, 3H),
1.36 (s, 9H).
1-(3-(tert-Butyl)-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (9): Uracil (33.3 g,
297 mmol, 1.2 equiv), K3PO4 (106 g, 500 mmol, 2.1 equiv), CuI (4.6 g, 24 mmol, 0.1 equiv), and
ligand 16 (6.4 g, 29 mmol, 0.12 equiv) were charged to a flask and inerted with argon. The
diiodoanisole 8 (103 g) was concentrated and distilled with MeCN, dissolved in 1 L DMSO,
sparged with argon then added to the above reactor. The reactor was heated to 60 °C for 16 h.
After cooling, the reaction mixture was diluted with 2 L EtOAc and washed with 2.6 L water.
The aqueous layer was back extracted with 3 × 1 L EtOAc. The combined organic layers were
washed with 2 × 1 L of 0.25 M Cu(OAc)2, 2 × 830 mL 15% NH4Cl and 800 mL brine. The
organic layer was concentrated and chased with 1 L heptane, then treated with refluxing 85:15
(v/v) heptane:i-PrOAc for 4 h. After cooling, the product was collected by filtration and washed
with an additional 330 mL of 85:15 (v/v) mixture of heptane:i-PrOAc . The product was dried
under vacuum to yield 66.9 g (68% yield) of 9 as a white solid. 1H NMR (400 MHz, DMSO-d6)
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δ 11.40 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 5.63
13
(d, J = 7.9 Hz, 1H), 3.85 (s, 3H), 1.35 (s, 9H). C{1H} NMR (101 MHz, DMSO-d6) δ 163.7,
158.7, 150.5, 145.5, 144.2, 136.4, 135.2, 126.5, 101.5, 92.4, 61.8, 35.3, 30.6. mp 198–200 °C.
Anal. Calcd for C13H9N3O: C, 45.02; H, 4.28; N, 7.00. Found C, 44.69; H, 3.84; N, 6.77.
7
8
9
Purification of 1-(3-(tert-Butyl)-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione
(9):6
A vial was charged with 1-(3-(tert-butyl)-5-iodo-4-methoxyphenyl)pyrimidine-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,4(1H,3H)-dione 9, (2.20 g) and 11 mL of 2-propanol (5.0 mL/g 9). The mixture warmed to 80–
83 °C with magnetic stirring for 1 h, then cooled to 20–25 °C. The product was isolated by
filtration and the filter cake was washed with 1.2 mL of 2-propanol. The wet cake was dried in a
vacuum oven at 45 °C overnight. The desired product 9 was isolated as a solid (1.92 g, 87%
yield).
N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide
(7):6 N-(6-Bromonaphthalen-2-yl)methanesulfonamide (19) (9.0 g, 30 mmol),
bis(pinacolato)diboron (9.9 g, 39 mmol. 1.3 equiv), (1,1’-bis(diphenylphosphino)ferrocene)
dichloropalladium(II) dichloromethane complex (1.22 g, 1.5 mmol, 0.05 equiv), potassium
acetate (7.36 g, 75 mmol, 2.5 equiv) and 90 mL of degassed THF were charged to a reactor and
heated to reflux for 7 h. After cooling to ambient temperature, the reaction was diluted with 405
mL of EtOAc and treated with 450 mg of Darco G-60. After stirring for 12 h, the solution was
filtered through filter aid and the carbon was rinsed with 150 mL of EtOAc. The resulting
solution was concentrated to about 25 mL, and 495 mL of heptanes was added slowly. The
product was collected by filtration and rinsed with 90 mL of heptanes.
The resulting wet cake was treated with 41 g of filter aid in 200 mL of THF overnight, then
filtered and again treated with 23.7 g of Darco G-60 carbon for 2 h. After filtration, the product
was crystallized by concentrating to about 25 mL, then adding 450 mL of heptanes. The title
compound was collected by filtration and dried to yield 7.0 g (67%) of the product solid. An
additional 1.16 g (11%) could be recovered by concentration of the mother liquors and
crystallization from heptane. 1H NMR (600 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.25 (s, 1H), 7.99
(d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 8.3, 1.2 Hz, 1H), 7.66 (d, J = 2.2 Hz,
13
1H), 7.39 (dd, J = 8.8, 2.2 Hz, 1H), 3.09 (s, 3H), 1.32 (s, 12H). C{1H} NMR (151 MHz,
DMSO-d6) δ 137.4 (C), 135.7 (CH), 135.2 (C), 130.8 (CH), 130.0 (CH), 129.2 (C), 126.5 (CH),
124.6 (C), 120.1 (CH), 114.4 (CH), 83.7 (C), 39.5 (CH3), 24.7 (CH3). mp 214–216 °C (DSC).
Anal. Calcd for C17H22BNO4S: C, 58.80; H, 6.39; N, 4.03; S, 9.23. Found C, 58.66; H, 6.33; N,
4.00; S, 9.25.
1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-
dione (35):6 This reaction is air-sensitive and the reaction was conducted under nitrogen
atmosphere. A round-bottom flask was purged with nitrogen gas and charged with Pd2(dba)3
(0.69 g, 0.75 mmol, 0.020 equiv Pd), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-
phosphatricyclo[3.3.1.13,7]decane 28 (1.01 g, 3.46 mmol, 0.0460 equiv) and a magnetic stir bar.
The flask was sealed with a septum and the atmosphere above the solids was purged with
nitrogen gas. One hundred eighty (180) mL of nitrogen-sparged THF was added to the flask and
the mixture was stirred under a nitrogen atmosphere for 36 minutes.
A 1000-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and
the atmosphere was purged with nitrogen gas. The reactor was charged with 1-(3-(tert-butyl)-5-
iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione 9, (30.05 g, 75.1 mmol, 1.00 equiv), 6-
hydroxynaphthalen-2-ylboronic acid 34 (15.2 g, 81.0 mmol, 1.08 equiv) and potassium
phosphate tribasic (30.3 g, 143 mmol, 1.90 equiv). The reactor was charged with 305 mL of
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THF, 155 mL of water, and the mixture was stirred to dissolve the solids. The biphasic mixture
was sparged with nitrogen gas. The catalyst solution of Pd2(dba)3 and 28 was transferred to the
main reactor by positive nitrogen pressure through a cannula. The resulting biphasic mixture was
stirred and warmed to an internal temperature between 60 and 65 °C under nitrogen. Reaction
progress was monitored by HPLC for consumption of 9, and the reaction was complete after 1 h,
15 min at 60 °C. The reaction mixture was cooled to an internal temperature between 50 and 55
°C before quench.
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The workup of the reaction was conducted under anaerobic conditions at an internal
temperature between 50 and 55 °C. Sodium chloride (45.4 g) and cysteine (3.0 g) were dissolved
in 240 mL of water, and the resulting solution was sparged with nitrogen for 0.7 h. This solution
was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting
biphasic mixture was stirred vigorously for 0.7 h. The mechanical agitation was halted, the two
solutions were allowed to separate, and the aqueous solution was discarded. Sodium chloride
(45.4 g) and cysteine (3.0 g) were dissolved in 235 mL of water, and the resulting solution was
sparged with nitrogen for 0.8 h. This solution was transferred to the reaction mixture by cannula
with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 0.8 h.
The mechanical agitation was halted, the two solutions were allowed to separate, and the
aqueous solution was discarded. The reaction mixture was diluted with 270 mL of a THF/water
solution (92:8 w/w%) to dissolve precipitated product.
The organic solution was filtered through filter paper while warm. The reactor and filter were
rinsed with 60 mL of THF and 150 mL of EtOAc was added to the organic solution. The solution
was concentrated in vacuo on a rotary evaporator to an approximate volume of 180 mL and 330
mL of EtOAc was added. The mixture was concentrated in vacuo on a rotary evaporator to an
approximate volume of 120 mL and mixed at 30 °C for approximately 2 h. The product was
isolated by filtration and the filter cake was washed twice with 60 mL portions of EtOAc. The
wet cake was dried in a vacuum oven at 50 °C overnight. The desired product 35 was isolated as
an off-white solid (27.3 g, 87% yield).1H NMR (600 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.83 (s,
1H), 7.96–7.91 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 8.5 Hz,
1H), 7.59 (dd, J = 8.5, 1.8 Hz, 1H), 7.33 (d, J = 2.7 Hz, 1H), 7.28 (d, J = 2.7 Hz, 1H), 7.18–7.15
(m, 1H), 7.12 (dd, J = 8.8, 2.4 Hz, 1H), 5.64 (d, J = 7.9 Hz, 1H), 3.24 (s, 3H), 1.42 (s, 9H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 163.8, 156.6, 155.8, 150.6, 145.9, 143.4, 135.2, 134.0,
133.8, 132.5, 129.7, 128.0, 127.8, 127.0, 126.9, 126.3, 124.4, 119.0, 108.5, 101.4, 60.2, 35.0,
30.5. mp 300–301 °C (DSC). Anal. Calcd for C25H24N2O4: C, 72.10; H, 5.81; N, 6.73. Found C,
71.78; H, 6.04; N, 6.71.
6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-
methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (33):6
A
250-mL, jacketed reactor equipped with an overhead stirrer was charged with 1-(3-tert-butyl-5-
(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione 35 (10.0 g, 24.0
mmol, 1.00 equiv) and powdered potassium carbonate (325 mesh, 6.60 g, 47.8 mmol, 2.0 equiv).
N,N-Dimethylformamide (40 mL, 4 mL/g 35) and acetonitrile (61 mL, 6 mL/g 35) were charged
to the reactor and the slurry was stirred. The internal temperature was adjusted to 30 °C.
Perfluorobutanesulfonyl fluoride (8.65 g, 28.6 mmol, 1.19 equiv) was charged to the well-stirred
mixture over 1.25 h. A trace (<0.1 area%) of 35 was detected by HPLC analysis of an aliquot
after 0.5 h of reaction time. The acetonitrile/dimethylformamide solution was filtered over a
coarse fritted funnel to separate the inorganic solids, and the flask and filter were rinsed with 15
mL of 3:2 (v/v) acetonitrile/dimethylformamide.
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With stirring, 7.5 mL of water was added to the organic solution over 15 min, and the mixture
was allowed to stir for 0.5 h to allow solids to crystallize. An additional 42.5 mL of water was
added to the slurry over 1 h, and the mixture was allowed to stir for 1 h. The wet cake was
isolated by filtration with recirculation of the liquors to recover all the solids. The wet cake was
washed with a pre-mixed solution of 8 mL of N,N-dimethylformamide, 12 mL of acetonitrile and
10 mL of water.
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The wet cake was dissolved in 82 mL of EtOAc. The resultant organic solution was washed
twice with 42 g portions of a 4.8 wt% aqueous sodium chloride solution. The organic solution
was filtered into a reactor and the filter rinsed with 30 mL of EtOAc. The bulk of the solvent was
removed by distillation at approximately 95 torr with heating to 40 °C until the total volume was
approximately 30 mL. The slurry was heated to 53 °C and 13 mL of EtOAc was added to
completely dissolve the precipitated solids. Heptanes (154 mL) were added to the warm (53 °C)
slurry over 0.9 h. The mixture was cooled to room temperature with stirring and the desired
product was isolated by filtration. The wet cake was washed with 25 mL of heptanes. The wet
cake was dried in a vacuum oven at 45 °C with a gentle nitrogen sweep. The title compound was
1
isolated as a white solid (13.36 g, 80% yield). H NMR (600 MHz, DMSO-d6) δ 11.43 (s, 1H),
8.23–8.09 (m, 4H), 7.84 (dd, J = 8.5, 1.8 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.57 (dd, J = 9.0, 2.6
Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 5.67 (d, J = 7.9 Hz, 1H), 3.20 (s, 3H),
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1.40 (s, 9H). C{1H} NMR (151 MHz, DMSO-d6) δ 163.8, 156.8, 150.7, 147.2, 145.8, 143.7,
137.4, 134.4, 134.2, 132.4, 132.2, 131.3, 128.6, 128.5, 128.1, 127.3, 125.2, 119.9, 119.2, 101.6,
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60.5, 35.1, 30.4. (The carbon signals for the nonaflate are extensively split by C-19F coupling
and are not reported.) mp 213–215 °C (DSC). Anal. Calcd for C29H23F9N2O6S: C, 49.86; H,
3.32; N, 4.01; F, 24.48; S, 4.59. Found C, 49.77; H, 3.35; N, 3.95; F, 24.01; S, 5.05.
N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-
methoxyphenyl)naphthalene-2-yl)methanesulfonamide, dasabuvir (1):6 Pd2(dba)3 (0.164 g,
0.179 mmol, 0.005 equiv), 50 (0.238 g, 0.429 mmol, 0.012 equiv) and tripotassium phosphate
(8.36 g, 39.4 mmol, 1.2 equiv) were charged to a 1-L stainless-steel Parr reactor equipped with
an overhead agitator and a thermocouple. The reactor was closed and was subjected to 5 cycles
of vacuum/purge with nitrogen then purged with nitrogen until less than 30 ppm O2 was detected
in the reactor headspace.60 2-Methyltetrahydrofuran (100 mL) was charged to a separate 250-mL
round-bottom flask, capped with a rubber septum and was sparged with nitrogen until less than
30 ppm O2 was detected in the reactor headspace. The sparged solvent was transferred to the 1-L
Parr reactor using a stainless-steel cannula under a positive atmosphere of nitrogen. The reactor
was sealed; the contents were heated to 80 °C, stirred for 30 min, then cooled down to 60 °C.
6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (33) (25.0 g, 35.8 mmol, 1 equiv),
methanesulfonamide (4.09 g, 43 mmol, 1.2 equiv) and EtOAc (200 mL) were charged to a
separate 500-mL round-bottom flask, capped with a rubber septum and sparged with nitrogen
until less than 30 ppm O2 was detected in the reactor headspace, then heated to 60 °C with
stirring.61 The resulting solution was transferred to the 1-L Parr reactor using a stainless-steel
cannula under a positive pressure atmosphere of nitrogen. The Parr reactor was sealed, the
contents were heated to 90 °C and stirred for 14 h.
The reaction mixture was cooled down to 65 °C. A 5% w/w aqueous solution of N-acetyl-L-
cysteine (50 mL) was charged to the reactor and the contents were mixed for approximately 15
min.62 The coupled product (1) was collected by filtration, washed successively with water (50
mL) and EtOAc (3 × 50 mL). The solid was dried under the house high vacuum for 2 h.
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The crude product isolated above was charged to a suitable reactor. Dimethylformamide (125
mL), N-acetyl-L-cysteine (0.50 g), and glacial acetic acid (0.75 g) were charged to the reactor.
The reactor temperature was raised to 60 °C and the contents were mixed for 1 h. The warm
solution was filtered through a 0.2 micron filter and rinsed with DMF (25 mL). The filtrate was
cooled to 25 °C. Methanol (300 mL) was charged over 10 h then mixed for an additional hour.
The desired product (1) was collected by filtration, washed with methanol (3 × 50 mL) and dried
in a vacuum oven at 60–80 °C to afford 1 (16.02 g, 32.5 mmol, 90.7%) as a white solid. 1H NMR
(400 MHz, DMSO-d6) δ 11.42 (d, J = 2.0 Hz, 1H), 10.05 (s, 1H), 8.04 (br, 1H), 7.96 (t, J = 9.6
Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 8.6, 2.5, 1H), 7.58 (dd,
J = 8.6, 2.0, 1H), 7.38 (d, J = 2.8 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 5.66 (dd, J = 8.0 Hz, 2.0,
1H), 3.26 (s, 3H), 3.09 (s, 3H), 1.43 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 163.8,
156.7, 150.6, 145.9, 143.5, 136.5, 134.8, 134.7, 134.1, 132.7, 130.1, 129.5, 128.1, 127.6, 127.5,
127.0, 124.8, 120.7, 114.9, 101.4, 60.4, 39.4, 35.1, 30.5. mp 219–223 °C (DSC). Anal. Calcd for
C26H27N3O5S: C, 63.27; H, 5.51; N, 8.51. Found C, 63.05; H, 5.55; N, 8.43.
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N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-
methoxyphenyl)naphthalene-2-yl)methanesulfonamide, dasabuvir (1) by Suzuki coupling
of Aryl Iodide 9: A solution of 100 mL of water and 300 mL of THF was sparged with nitrogen
and then transferred with cannula under nitrogen pressure to a flask containing 1-(3-(tert-butyl)-
5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (9) (20.0 g, 50.0 mmol), boronate ester
(7), (20.8 g, 60.0 mmol, 1.20 equiv) and potassium phosphate tribasic (21.9 g, 103.0 mmol, 2.06
equiv) which had been purged with nitrogen. The resulting solution was again sparged with
nitrogen.
THF (100 mL) was sparged with nitrogen and then transferred by cannula under nitrogen
pressure to a flask containing Pd2(dba)3 (0.463 g, 0.510 mmol, 0.01 equiv) and ligand 28 (0.736
g, 2.52 mmol, 0.05 equivalents) which had been purged with nitrogen. The resulting solution was
again sparged with nitrogen.
The initial THF/water solution was transferred by cannula under nitrogen pressure to the flask
containing the catalyst and ligand in THF. The reaction was warmed to 50 °C and stirred
overnight under positive nitrogen pressure.
The reaction was cooled to room temperature and washed, in three portions, with a solution of
5.84 g of L-cysteine and 81.4 g of sodium chloride in 550 mL of water which had been sparged
with nitrogen. The THF solution was filtered through a celite pad. The pad was rinsed with 100
mL of THF, which was combined with the original THF solution. The THF solution was
concentrated on a rotary evaporator to 136 g. To the white slurry was added 405 mL of EtOAc
with good agitation. The slurry was filtered after stirring overnight. The wet cake was washed
with 2 × 50 mL of EtOAc. The solid, an EtOAc solvate, was dried in the vacuum oven at 50 °C.
The solid and 8.7 g of mercaptopropyl-derivatized silica gel was stirred in 500 mL of THF then
filtered through a celite pad. The filtrate was concentrated on the rotary evaporator to give 13.08
g of white solid. The solid that had been filtered off on the celite pad was extracted with 500 mL
of THF at 60 °C to recover additional product. The THF solution was concentrated to 66 g and
treated with 206 mL of EtOAc. The solid which precipitated was filtered and dried, yielding 9.13
g of product. This solid was combined with the original solid and slurried in 100 mL of 200
proof 3A ethanol. It was filtered and dried in the vacuum oven at 50 °C to give 20.74 g (84%) of
dasabuvir.
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Synthesis of dasabuvir (1) by Suzuki coupling of bromide 6
A flask was charged with bromide 6 (7.0 g, 20 mmol), boronate ester 7 (10.3 g, 29.7 mmol, 1.5
equiv), PdCl2(dtbpf) (0.64 g, 0.98 mmol, 0.05 equiv), and K3PO4 (8.4 g, 40 mmol, 2.0 equiv).
The reactor was sealed and inerted then a sparged solution of 4:1 THF:water (140 mL) was
added. The reaction was heated to 50 °C and stirred for 16 h.
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The layers were separated and the organic layer was washed with 50 mL of 25% NaCl
solution. The resulting solution was concentrated and 150 mL of ethanol was added and distilled
to afford a very thick slurry. The solids were collected by filtration and washed with 8 mL of
ethanol. The wet cake was dissolved in 200 mL of THF and treated overnight at ambient
temperature with carbon (Acticarbone ENO-PC, 1.5 g) and mercaptopropyl-derivatized silica gel
(1.0 g) then filtered. The resulting solution was concentrated to ~50 mL, then 250 mL of ethanol
was added in portions and distilled. The product was collected by filtration, washed with 20 mL
of ethanol, and dried at 60 °C in vacuo to afford 7.2 g (74%) of dasabuvir (1) as a white solid.
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N-(4-Cyanophenyl)picolinamide (15):63 To a suspension of picolinoyl chloride hydrochloride
(5.9 g, 33 mmol, 1.2 equiv) in 65 mL dichloromethane at less than 5 °C was added 4-
aminobenzonitrile (3.25 g, 27.5 mmol) in 16 mL dichloromethane and triethylamine (10.4 mL,
74.0 mmol, 2.7 equiv), keeping the temperature less than 20 °C. The reaction mixture was stirred
overnight at ambient temperature. The reaction was quenched with addition of 50 mL water and
the layers were separated. The aqueous layer was extracted with 50 mL dichloromethane. The
combined organic layers were washed twice with 50 mL of 0.3 molal pH 7 buffer (0.15 molal
KH2PO4/0.15 molal K2HPO4) and then 50 mL of 10% NaCl. After drying over MgSO4, the
product solution was concentrated to a thick slurry, chased with isopropyl acetate, then triturated
with 40 mL of boiling isopropyl acetate to afford 4.96 g (81% yield) of the title product as a
white solid. 1H NMR (400 MHz, CDCl3)  10.25 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.28 (d, J =
4.8 Hz, 1H), 7.95–7.92 (m, 1H), 7.91 (d, J = 5.2 Hz, 2H), 7.66 (d, J = 5.2 Hz, 2H), 7.54–7.52 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3)  162.5, 149.1, 148.2, 141.8, 138.0, 133.5, 127.2, 122.8,
119.7, 119.0, 107.3. mp 168–170 °C, Lit. 162.8–164.2 °C.63 Anal. Calcd for C13H9N3O: C,
69.95; H, 4.06; N, 18.82. Found C, 69.83; H, 3.78; N 18.88.
N-(2-Cyanophenyl)picolinamide (16):64 To a suspension of picolinoyl chloride hydrochloride
(25.9 g, 146 mmol, 1.2 equiv) in 172 mL dichloromethane was added 2-aminobenzonitrile (14.3
g, 121 mmol) and triethylamine (42.3 mL, 303 mmol, 2.5 equiv), keeping the temperature < 20
°C. The bath was removed and the reaction was stirred 2 h at ambient temperature. The reaction
was quenched with 150 mL water and the layers were separated. The organic layer was washed
with 100 mL each of water, 0.2 molal pH 7 buffer (0.1 molal KH2PO4/0.1 molal K2HPO4) and
10% NaCl. After drying over MgSO4, the product solution was concentrated to a thick slurry,
and chased with MeOH, then crystallized from ~270 mL hot MeOH to afford 22.3 g (83% yield)
of the title product as a white solid. 1H NMR (400 MHz, CDCl3)  10.82 (s, 1H), 8.71–8.68 (m,
2H), 8.29 (d, J = 6.4 Hz, 1H), 7.95–7.91 (m, 1H), 7.67–7.63 (m, 2H), 7.55–7.51 (m, 1H), 7.21
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(appt, J = 7.6 Hz, 1H). C{1H} NMR (101 MHz, CDCl3)  162.7, 149.0, 148.6, 140.7, 137.9,
134.3, 132.7, 127.2, 124.2, 122.6, 120.8, 116.5, 102.4. mp 140–142 °C, Lit. 126–128 °C.64 Anal.
Calcd for C13H9N3O: C, 69.95; H, 4.06; N, 18.82. Found C, 69.86; H, 3.82; 19.00.
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Alternate preparation of N-(2-Cyanophenyl)picolinamide (16): Picolinic acid (100 g, 812
mmol, 1.20 equiv) was charged to a reactor. Dichloromethane (680 mL) and triethylamine (190
mL, 1.36 mol, 2.02 equiv) were added and the mixture was stirred to give a clear, colorless
solution. The solution was cooled in an ice bath. With the reaction solution at 1 °C, tosyl
chloride (156 g, 0.817 mol, 1.22 equiv) was added and the reaction temperature climbed to 15 °C
as solid triethylamine hydrochloride separated from solution. After approximately 15 minutes
anthranilonitrile (79.7 g, 0.675 mol, 1.0 equiv) was added to the reaction mixture. The reaction
mixture was heated to 40 °C and mixed at 40 °C for 19 h. The reaction was cooled to 20 °C and
washed with 500 mL of 0.2 N HCl, 500 mL of water, and 300 mL of water. The combined
aqueous washes were back-extracted with 300 mL of dichloromethane. The combined
dichloromethane solutions were concentrated to a solid on the rotary evaporator. The solid was
slurried in 750 mL of methanol at 50 °C, then cooled to 20 °C. The slurry was filtered and the
wet cake washed with 250 mL of methanol. Drying in a vacuum dryer at 50 °C yielded 126.6 g
(85%) of the product as a white solid.
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Four-step synthesis of 7,7,9,9-Tetramethyl-8-(2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-
2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (VincePhos, 50):
Diethyl 2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2-ylphosphonate (478):47
A 250-mL
round-bottom flask equipped with a magnetic stir bar was charged with 2-iodo-2',4',6'-
triisopropyl-3,6-dimethoxybiphenyl65 (46, 6.0 g, 13 mmol, 1.0 equiv), sealed with a septum, then
purged with nitrogen. Anhydrous, degassed THF (43 mL) was added to the flask and the
resulting solution was cooled to –78 °C. n-Butyllithium (2.5 M in hexanes, 6.18 mL, 15.4 mmol,
1.2 equiv) was added dropwise to the cold mixture over 6 min. After the addition, the reaction
mixture was allowed to stir at –78 °C for 90 min. Chlorodiethylphosphate (2.2 mL, 15 mmol, 1.2
equiv) was added to the reaction mixture over 3 min. The reaction was allowed to proceed at –78
°C for an additional 30 min, after which time the flask was removed from the cooling bath and
warmed to room temperature. After 3 h, the reaction mixture was diluted with aqueous saturated
sodium bicarbonate (50 mL). The resultant mixture was transferred to a separatory funnel, the
layers were separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The
combined organic layer was washed with an aqueous saturated solution of sodium chloride (100
mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was
purified by silica gel column chromatography on an Isco CombiFlash Companion (120-g
column; gradient: 1.5 column volumes (CV) CH2Cl2, ramp up to 88:12 CH2Cl2:acetone over 8
CV, hold for 7.5 CV) to give 3.51 g of a white solid (92 area% by HPLC, 57% isolated yield). 1H
NMR (400 MHz, CDCl3) δ 7.02–6.89 (m, 4H), 3.98–3.85 (m, 2H), 3.91 (s, 3H), 3.60 (s, 3H),
3.51 (ddq, J = 10.1, 9.2, 7.1 Hz, 2H), 2.93 (hept, J = 6.9 Hz, 1H), 2.49 (hept, J = 6.8 Hz, 2H),
1.28 (d, J = 6.9 Hz, 6H), 1.17 (d, J = 6.8 Hz, 6H), 1.02 (t, J = 7.0 Hz, 6H), 0.97 (d, J = 6.8 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.6, 151.6, 151.4, 146.8, 145.8, 133.9, 133.8, 132.0,
120.6, 120.0, 118.7, 113.92, 113.89, 110.7, 110.6, 61.3, 61.2, 56.7, 55.7, 34.5, 31.2, 24.9, 24.5,
23.9, 16.74, 16.68. (C spectrum is complicated because of 13C-31P coupling). 31P{1H} NMR (200
MHz, CDCl3) δ 13.1 ppm.
(2',4',6'-Triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (48):47 A 100-mL round-bottom
flask was purged with nitrogen. Anhydrous, degassed THF (14 mL) was added to the flask and
cooled to 0 °C. Lithium aluminum hydride (LAH) (2.0 M in THF, 10.9 mL, 21.8 mmol, 3.0
equiv) was added to the cooled THF. Chlorotrimethylsilane (2.8 mL, 22 mmol, 3.0 equiv) was
added dropwise to the LAH solution over 4 min. This solution was allowed to stir at 0 °C for 25
min. A solution of diethyl 2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2-ylphosphonate 47 (3.47
29
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