Copper-catalyzed C-N coupling in the synthesis of integrase inhibitors of immunodeficiency viruses

Article abstract of DOI:10.1021/op400228z

This contribution describes the total synthesis of a complex macrocyclic integrase inhibitor, a key enzyme involved in the infection process of various immunodeficiency viruses. The key transformation of the synthetic strategy was the selective C-N coupling of a sulfonamide to a heteroaryl bromide in the presence of potentially competing amide and carbamate functionalities. The transformation was accomplished with CuI catalysis using bypiridine as the ligand in the presence of base and enabled a convergent approach to the target molecule.

Full text of DOI:10.1021/op400228z

Article
pubs.acs.org/OPRD
Copper-Catalyzed C−N Coupling in the Synthesis of Integrase
Inhibitors of Immunodeficiency Viruses
Jinguan Lin,† Ioannis N. Houpis,*,‡ Renmao Liu,† Youchu Wang,† and Jianqian Zhang†
†Janssen Pharmaceutica, API Development Small Molecules, 30 Turnhoutseweg, 2340 Beerse, Belgium
‡STA, a subsidiary of WuxiApptec, Department of Process Chemistry, 9 Yuegong Street, Jingshan District, Shanghai, P.R. China
S
* Supporting Information
ABSTRACT: This contribution describes the total synthesis of a complex macrocyclic integrase inhibitor, a key enzyme
involved in the infection process of various immunodeficiency viruses. The key transformation of the synthetic strategy was the
selective C−N coupling of a sulfonamide to a heteroaryl bromide in the presence of potentially competing amide and carbamate
functionalities. The transformation was accomplished with CuI catalysis using bypiridine as the ligand in the presence of base and
enabled a convergent approach to the target molecule.
via a C−N bond formation reaction. Alternatively, an intra-
molecular C−N coupling step could serve as the macro-
cyclization operation in the final step (see eq 5). A less
ambitious approach, which could perhaps serve for initial gram-
quantity deliveries, entailed a stepwise disconnection sequence
to give the key intermediates 4 and 5. The latter could be con-
structed via a similar C−N bond formation but between the
simpler fragment 6 and 2.
Predicting the most successful approach is difficult, and we
decided therefore to examine each one of the possibilities
discussed above. As the synthesis of the various building blocks
would be common to each of the approaches, such investiga-
tions could be done rapidly. We also felt, initially, that it would
be prudent to develop orthogonal protecting schemes of all the
various functional groups, although that eventually proved
unnecessary.
INTRODUCTION
■
The C−heteroatom bond-forming reaction has become the staple
of medicinal and process chemists and is used frequently in the
construction of complex APIs.1 The C−N bond formation
in particular has had a rich history starting from the Ullmann
condensation reaction and its Goldberg modification, and
evolving into the modern palladium-catalyzed process.2 The
original reaction, although revolutionary technology at the time,
suffered from high temperatures and did not enjoy the utility it
deserved for many years until a variety of bidentate ligand
complexes allowed the reaction to take place under mild
conditions and low catalyst loads.3
In this article we present our synthetic efforts towards the
large-scale preparation of HIV integrase inhibitor 1, which de-
pends on a selective metal-catalyzed arylation of a sulfonamide
nitrogen with a highly functionalized heteroaryl halide (Figure 1).
The general synthetic scheme for the synthesis of 2 is shown
in Scheme 2. Specifically, the chloropyridine derivative 7 was
reacted with ethyl glycinate in the presence of triethylamine
acetic acid (1:1 ratio) and molecular sieves in a reductive
amination to form the substituted glycine ethyl ester 9. The
latter was treated without isolation with tosyl chloride and Et3N
to give the sulfonamide, 10, which could be isolated in 80%
yield or used directly in the next step after aqueous workup and
solvent switch to ethanol. In the telescoped process, care must
be taken to eliminate all sulfur-containing species by thorough
extractions and/or pretreatment of the solution with activated
charcoal to ensure reproducibility of the subsequent palladium-
catalyzed carbonylation reaction. The latter proceeded
smoothly, albeit under forcing conditions of temperature and
pressure, to afford 11 in 86% yield.4
Figure 1. Structure of target molecule.
This project started as a discovery chemistry support program,
requiring modest amounts of material, but as the biological
results evolved, we thought it prudent to invest in enabling
technology for an eventual multikilogram GMP production.
Formation of the aza-isoquinoline derivative 12 proceeded
by treatment of 11 with NaOEt in ethanol in a sequence
RESULTS AND DISCUSSION
■
Our retrosynthetic analysis of the target molecule is shown in
Scheme 1. The most efficient disconnection (A) that would
meet our requirement of “scaleable enabling technology” would
afford fragments 2 and 3 following a macrolactamization dis-
connection (to give 33). These synthons could be combined
Special Issue: Transition Metal-Mediated Carbon-Heteroatom Cou-
pling Reactions
Received: August 20, 2013
Published: October 15, 2013
© 2013 American Chemical Society
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Scheme 1. Retrosynthetic possibilities
a
Scheme 2. Synthesis of key intermediate 2
a
Reagents and conditions: (a) Et3N (1.0 equiv), DCM (0.74 M), AcOH, then NaBH(OAc)3 (1.4 equiv), 25 °C, 18 h, 84%. (b) TsCl (1.2 equiv),
Et3N (2 equiv), DCM (0.5 M), 15 °C, 16 h, 80% . (c) CO (75 psi), Pd(OAc)2 (1.36 mol %), dppp (1.47 mol %), Et3N (0.78 mL/g), EtOH
(0.36 M), 100 °C, 16 h, 86%. (d) NaOEt (4 equiv), EtOH (0.25 M), 20 °C, 12 h, 72%. (e) NBS (1.0 equiv), DCM (0.46 M), 0 °C, 2 h, 88%.
involving initial Claisen condensation followed by elimination
of sulfinic acid to give 12 in 72% yield after recrystallization
from ethanol. Finally, electrophilic bromination was readily
accomplished to afford 2 in good overall yield on multikilo
scale. Although 2 was the starting material that was used for
scale up, other substrates (e.g., 2a−c) were also prepared using
this sequence so that they could be tested in the key C−N
coupling reaction. For example 2b was prepared by using
glycine methyl ester as the starting material and the cor-
responding product (2a, eq 1) was methylated using NaH and
dimethyl sulfate.
The various derivatives of the sulfonamide chain were pro-
duced by the synthetic sequence shown in Scheme 3, and
although the process was not optimized, it enabled us to
produce and deliver the requisite amount of l for this early stage
of development. Thus, 13 was dissolved in thionyl chloride and
treated with DMF (7% by volume) to give 14 which was con-
verted to 15 with MeNH2 hydrochloride salt under Schotten−
Baumann conditions. Conversion to the nitrile 18 required
initial protection of the sulfonamide nitrogen with a Boc group,
in order to avoid the competing cyclization reaction. Sub-
sequent treatment of 16 with KCN in the presence of 18-
crown-6 in acetonitrile followed by hydrolysis of the Boc group
gave 18 in 70% overall yield. Reduction of the nitrile could be
accomplished in 80% yield by hydrogenation over Raney Ni in
the presence of NH4OH used in order to prevent secondary
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a
Scheme 3. Synthesis of fragment 6
a
Reagents and conditions: (a) SOCl2 (4 M), DMF (7%), 90 °C, 2d; (b) MeNH2−HCl (1.7 equiv), DCM (0.63 M), K2CO3 (3 equiv), 10 °C, 15 h,
83%; (c) Boc2 (1.8 equiv), DMAP (1.26 equiv), DCM (1 M), 10 °C, 15 h; (d) KCN 2 equiv), 18-c-6 (1 w/w %), ACN (0.58 M), 80 °C, 15 h, 70%;
(e) 4 N HCl (1.8 equiv) in EtOAc−DCM (0.72 M), 15 °C, 83%; (f) Raney Ni (50 w/w %), MeOH−NH4OH (1:3, 0.44 M), 60 psi H2, 50 °C, 5 h, 80%.
a
Scheme 4. Synthesis of fragment 4
a
Reagents and conditions: (a) MeOH0.74 M), H2SO4 (1.2 equiv), 65 °C, 16 h; (b) NBS (1.0 equiv), (PhCO)2O2 (10 mol %), MeCN (0.75 M),
70 °C; (c) HN(Boc)2 (1.0 equiv), 2-butanone (0.5 M), Cs2CO3 (0.64 equiv), 70 °C, 16 h; (d) 4 N HCl (10 equiv), EtOAc (1 M), 20 °C, 16 h; (e)
(BOC)2O (1.2 equiv), Et3N (1.0 equiv), THF (1 M), 0 °C, 16 h; (f) NaOH (aq, 4 equiv) 25 °C, 16 h, 26% over 6 steps.
reaction between the product and the imine intermediate
generated in the first step of the reduction. This would result in
the formation of the corresponding, undesired secondary amine
byproduct.
Initial attempts at coupling of the above side chain with
derivatives of 2 took place with the protected analogues 6a
and 6c which were prepared by reaction of 13 with MeNH2
followed by protection with pivaloyl chloride and reaction of 6b
with phthalic anhydride, respectively.
The remaining fragment 4 was synthesized according to
the sequence depicted in Scheme 4. Thus, the commercially
available fluorotoluic acid 20 was converted to the hydrochloric
acid salt 24 by the following sequence of telescoped opera-
tions: conversion to the methyl ester 21 followed by benzylic
bromination and displacement with bis-Boc amine to the
intermediate 23. The use of NH3 synthons such as KHMDS
resulted in significant benzyne formation, while azide was not
considered due to safety concerns. Global Boc deprotec-
tion afforded the HCl salt 24 which served as a convenient
purification point before mono-Boc reprotection and hydrolysis
of the ester to give 4 in 26% overall yield.
With all the requisite building blocks in hand, we focused on
the key C−N coupling reaction. The initial efforts involved the
coupling of 6a, as the substrate with the least competing func-
tionality, with derivatives of 2 in the presence of stochiometric
or catalytic amounts of copper.5 Preliminary coupling attempts
with palladium catalysts will be discussed later. The results of
the Cu study are shown in Table 1. The fully protected 2c was
examined first with super-stoichiometric amounts of Cu2O and
bipyridine L1 (Table 1, entries 1−4).6 The reaction took place
even in the absence of base, to give 26c in modest yield (54%).7
Addition of base initially appeared to have a detrimental effect
on the reaction although it was quickly discovered that the
main byproduct (20−25%) was just the hydrolysis product
26b. Unfortunately, when the acid derivative 2b was used as
the starting material, the yield of 26b was radically diminished
with the reaction proceeding to a maximum 50% conversion
(Table 1, entry 5). Similarly 2d gave no reaction under the
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Table 1. Coupling attempts of derivatives of 2 and 6
a
entry
substrate A
substrate B
catalyst (mol %)
ligand (mol %)
solvent
base
temp (°C)
conv (%) (yield of 26[%])
1
2
3
4
5
6
7
8
2c
2c
2c
2c
2b
2c
2c
2c
6a
6a
6a
6a
6a
6a
6a
6a
Cu2O (300)
Cu2O (300)
Cu2O (300)
Cu2O (300)
Cu2O (300)
Cu2O (50)
Cu2O (10)
CuI (15)
L1 (300)
L1 (300)
L1 (300)
L1 (300)
L1 (300)
L1 (150)
L1 (15)
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
−
Et3N
120
120
120
120
120
80
100 (54)
b
100 (45)
b
DBU
100 (40)
b
Cs2CO3
c
100 (42)
5−50
c
KHCO3
KHCO3
K2CO3
100 (66)
d
80
30 (22)
L2 (30)
85
100 (68)
a
All screenings were performed on 1-g scale. The starting materials, the ligand, and base (∼1−3 equiv) were added in a Schlenck-type flask and
dissolved in the solvent (∼0.3 M). The mixture was degassed thoroughly, and then the appropriate Cusalt was added and the mixture heated to the
b
c
reaction temperature within 10−15 min. ∼20% of 20b could also be detected by HPLC. Bases such as DBU, K3PO4, LiHMDS, and no base were
d
tried with similar results: 5−50% conversion and/or complex reaction mixtures. Ratio of 20c:20b= 6.6:1.
Figure 2. Ligands.
Scheme 5. Coupling of 2 with phthalimide-protected 5
reaction conditions, presumably due to the complete lack of
solubility of that substrate in basic media. After examining each
parameter in detail, the hydrolysis issue was partially resolved
by the combination of reducing the catalyst load, reaction
temperature, and base strength. Thus, reducing the amount of
Cu2O to 50 mol % and using KHCO3 as the base afforded 26c
in ∼66% yield along with ∼10% of 26b (Table 1, entry 6).
Further reduction in the amount of Cu2O, variation of the
Cu:L1 ratio, and the equivalents of base were not beneficial
(Table 1, entry 7). Finally, examination of other copper sources
and ligands, frequently used in these C−N coupling reactions
(L2−L5, Figure 2), revealed that trans-N,N-dimethylcyclohex-
ane-1,2-diamine (L2) and CuI gave the best results for these
particular substrates (∼78% yield for 26c + 26b, Table 1, entry 8).
Despite this positive outcome, the coupling of 2c (or 2,
Scheme 5) with 6a was not pursued further. Attempts to
elaborate 26c or 26b to the N-bearing derivatives of 5 was
tedious as displacement of the alkyl chain oxygen with nitrogen
nucleophiles required multiple steps, gave bis-alkylation
products, or required hazardous reagents (e.g., NaN3).8
It is worth noting that Pd catalysis was not particularly
successful for our substrates (eq 2). Substrates 2a−2d were
examined under a variety of conditions: ligands (X-phos, dppf,
DPEphos, (c-Hex)3PHBF4), bases (tBuOK, K2CO3, t-AmylONa)
and solvents (toluene, THF, dioxane) with limited success.9,10
In the next stage of our investigation, the N-protected sub-
strate 6c was examined initially with the protected substrate 2e
and finally with the unprotected compound 2 (Scheme 5 and
Table 2).
Many of the lessons learned from the coupling attempts with
substrate 2a were useful for these substrates as well. Thus, high
temperature and catalyst loads were not helpful to the reaction
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own challenges, in particular its removal in 5b. The latter
required conditions that also hydrolyzed the ethyl ester, thus,
requiring elaborate protection/deprotection schemes to be able
to form the amide bond with 4 to produce 5.
The inspiration for the final solution that allowed us to
reduce the number of steps and achieve a convergent synthesis
arose as we were examining the monoprotected derivative 6d.
Although the yields of this transformation were not sub-
stantially better than the previously examined substrates, we
noticed that none of the alternative coupling product (27d)
was produced (eq 3).
(Table 2, entries 1 and 2), while a high L1:Cu ratio (Table 2,
entry 3) resulted in low conversion. The best L1:Cu ratio was
1:1, and L1 was the best ligand examined, while the ethyl ester
in 2e was, as expected, much less susceptible to hydrolysis than
the methyl ester. As before, lower catalyst loads gave the best
results (Table 2, entry 10), while DMF and K2CO3 were the
best solvent and base combination. When the unprotected
substrate 2 was examined, we were delighted to find that the
reaction worked well (Table 2, entry 4) to afford the desired
product in ∼60% yield. This was a significant accomplishment
as it obviated the need for protection of the hydroxyl group,
which required the use of genotoxic alkylating agents, and
deprotection (with HBr) which produced MeBr. The latter has
to be scrubbed meticulously due its high toxicity and environ-
mental impact.
The use of the unprotected hydroxyl compound 2 does cause
the formation of the dimeric impurity 29, but its formation was
minimized by using 10−15% excess of 6c. Additional issues
with this substrate combination were the formation of by-
product 28 and hydrolysis of the ethyl ester as well as mono-
hydrolysis of phthalimide protecting groups if the water content
of the mixture was not carefully controlled. Nonetheless,
despite the advantages of having the nitrogen already in the side
chain, using the phthalimide protecting group presented its
As a consequence we decided to attempt the fully convergent
and protection-free (or at least limited protection) approach
that we had originally envisioned (Scheme 1, disconnection A).
Thus, compound 3 was reacted with the aromatic halides 2,
2c, and 2e (eq 4), and the results are shown in Table 3.
Remarkably, the reaction works efficiently to produce the de-
sired compound in excellent in situ yields and good isolated
yield (∼68%). What is most interesting is the selectivity of
sulfonamide nitrogen in the presence of an amide and carba-
mate N−H groups. Both amide and sulfonamide coupling reac-
tions with aromatic halides have been studied in the literature,
and several Pd−ligand systems have been developed10 to effect
smooth C−N coupling. However the Cu-catalyzed reaction has
Table 2. Coupling attempts of 2 with 6
a
entry
substrate A
substrate B
catalyst (mol %)
ligand (mol %)
solvent
base
temp (°C)
conv (%) (yield of 5a, 5b[%])
1
2e
2e
2e
2e
2e
2e
2e
2e
2e
2
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
Cu2O (300)
CuI (300)
Cu2O (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (15)
L1 (300)
L1 (300)
L1 (300)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L2 (30)
NMP
NMP
NMP
DMF
NMP
DMA
THF
−
K2CO3
120
120
120
70
80 (48)
90 (59)
65 (35)
100 (71)
46 (32)
37 (25)
55 (43)
0 (ND)
21 (15)
89 (60)
50 (ND)
2
3
−
4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
5
70
6
70
7
70
8
EtOH
CH3CN
DMF
DMF
70
9
70
10
11
70
2e
85
a
All screenings were performed on 1-g scale. The starting materials, the ligand, and base (∼1−3 equiv) were added in a Schlenck-type flask and
dissolved in the solvent (∼0.3 M). The mixture was degassed thoroughly, and then the appropriate Cu salt was added and the mixture heated to the
reaction temperature within 10−15 min.
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The macrocyclization final step involved significant develop-
ment work, which will not be described here. A stopgap
solution was identified to ensure timely delivery of the API
involving cyclization using T3P as the activating agent. The
sparingly soluble product was isolated by slurrying in water and
DMF at high temperature to afford the final compound in
pharmaceutically acceptable purity for toxicological studies.
Finally, we expended some effort in an attempt to construct
the molecule as shown in eq 5. Thus, intermediate 31 was
not been studied extensively. For example, the coupling of
aromatic bromides and iodides required microwave irradiation
to afford good yield of coupling products under Cu catalysis,
but in the absence of ligand.11 Thus, at this juncture, the exact
nature of this selectivity (pKa of the N−H bond vs the nucleo-
philicity of the resulting deprotonated species) is not clear and
will be examined further at a later date.
In a bit more detail, the best combination (Table 3, entry 2)
was CuI (30%) with bipyridine (30%) as the ligand in DMF
and K2CO3, while unexpectedly, 2 appeared to be the best
substrate for this transformation. Minimal optimization studies
indicated that the cleanest reaction mixtures were obtained by
using one equiv of CuI and bipyridine ligand in addition to 4
equiv of base (Table 3, entry 4). As the development time was
limited, we decided to use these reaction conditions to ensure
robustness for the scale-up in the pilot plant.
So the final construction of the API was performed as shown
in Scheme 6. The amine 6b was coupled directly with the
benzoic acid derivative 4 under standard conditions to give the
coupling partner 3 in good yield. The latter was reacted with
the heteroaromatic bromide 2 using CuI and bipyridine as the
ligand to afford 5, after work up with EDTA to remove copper
salts, as a single isomer. Although a thorough material balance
investigation has not been carried out to-date, in the reaction
mixture we identified ∼10% of unreacted starting material 2
while a significant 15% of the product was lost in the unoptimized
work up and crystallization. The byproduct of debromination
of 2 was not detected by LC/MS analysis. The Cu-content at
this intermediate was determined to be ∼15 ppm and was
undetectable at the final drug substance. Hydrolysis of the ethyl
ester and Boc deprotection afforded the final intermediate 33.
constructed from 3 after Boc deprotection and coupling with
2c. Attempts to effect the macrocyclization via a C−N coupling
under our standard conditions did give ∼15% of the desired 1,
but large amounts of dimeric and oligomeric by products were
also detected by LC/MS.
In conclusion, we were able to prepare the desired API by a
convergent synthesis that featured a site-selective Cu-catalyzed
C−N coupling of a sulfonamide NH bond with a heteroaryl
halide in the presence of potentially reactive NH−carboxamide
and NH−carbamate bonds.
EXPERIMENTAL SECTION
■
Experimental details are supplied for all the compounds
mentioned in the schemes and discussion above. For the sake
of brevity only select structural information is supplied for the
most critical intermediates relevant to the topic of the article.
All solvents and reagents used for these investigations and
preparative work were obtained from our production facilities
and were used as such. All purity numbers were obtained by
HPLC analysis with appropriately validated methods and against
a qualified standard.
Preparation of Ethyl 2-(((2-chloropyridin-3-yl)-
methyl)amino)acetate (9). To a 30 L reactor, 8 (1.5 kg,
14.83 mol) were suspended in DCM (20 L) at 15−20 °C. Et3N
(1.5 kg, 14.83 mol) and AcOH were added to adjust the pH of
reaction mixture to 6−7. The aldehyde 7 (2.1 kg, 14.83 mol) was
added to the mixture which was stirred for 1−2 h at 15−20 °C
followed by NaBH(OAC)3 (6.16 kg, 20.8 mol) which was
added in portions in order to keep the temperature between
Table 3. Convergent coupling attempts between 2 and 3
a
entry
substrate A
substrate B
catalyst (mol %)
ligand (mol %)
solvent
K2CO3 equiv
temp (°C)
conv (%) (yield of 5 [%])
1
2
3
4
5
6
2
2
3
3
CuI (30)
CuI (30)
L1 (30)
L1 (30)
L1 (100)
L1 (100)
L1 (20)
L1 (20)
DMF
DMF
DMF
NMP
DMF
DMF
0
3
4
4
4
4
75
75
75
75
75
75
10 (ND)
90 (68)
2
3
Cu2O (100)
CuI (100)
CuI (20)
84 (47)
2
3
85 (68)
2c
2e
6c
6c
<10 (ND)
80 (50)
CuI (20)
a
The reactions were carried out 15−20-g scale with overhead stirring. The starting materials, L1, and milled K2CO3 (4 equiv) were added in a
jacketed reactor under N2 and dissolved in DMF (or NMP) (∼0.3 M). The mixture was degassed thoroughly, and then the appropriate CuI was
added under a N2 blanket. The mixture was heated to the reaction temperature within 20−30 min.
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a
Scheme 6. Final assembly to the API 1
a
Reagents and conditions: (a) EDCI (1.15 equiv), HOBt (1.15 equiv), DMF (0.74 M), 0−10 °C, 3h, 75%; (b) CuI (0.3 to 1 equiv), bipyridine
(0.3 to 1 equiv), K2CO3 (4 equiv), DMF (0.3 M), 70−80 °C, 16 h, 68%; (c) KOH (3.2 equiv), MeOH−H2O−THF (0.1 M), 60 °C, 5 h, 80%; (d)
HCl (4N, 2 equiv)), EtOAc−DCM (0.4 M), 10−20 °C, 3 h, 91%; (e) T3P (3 equiv), EtOAc−DMF (0.03 M), DIPEA (3 equiv), 5 °C, 16 h, 45%.
15 and 20 °C. The resulting mixture was stirred for about 16 h
at 15−20 °C, then sat. NaHCO3 aq solution (5 L) was added
and the layers were separated. The organic layer was washed
with water (21 L × 2) and sat. NaCl aq. solution (21 L × 2).
The resulting mixture was concentrated to remove the solvent
under reduced pressure 9 (2.8 kg, 84% yield).
Preparation of Ethyl 2-(N-((2-chloropyridin-3-yl)methyl)-
4-methylphenylsulfonamido)acetate (10). In a 50-L reactor
9 (2.8 kg, 12.5 mol) was dissolved in DCM (25 L) at 15−20 °C
under N2. TsCl (2.8 kg, 15.0 mol) and TEA (2.5 kg, 25.0 mol)
were added to the mixture which was stirred at 15−20 °C for
16 h. After completion of the reaction, water (25 L) was added,
and the layers were separated. The organic layer was washed
sequentially with H2O (28 L), 10% KHSO4 solution (28 L),
and sat. NaCl aq solution (28 L × 2). The resulting mixture was
concentrated to remove the solvent under reduced pressure and
afford 10 (3.8 kg, 80% yield).
Preparation of Ethyl Ethyl 3-((N-(2-ethoxy-2-oxoethyl)-
4-methylphenylsulfonamido)methyl)picolinate (11). In a
50-L reactor, 10 (3.8 kg, 12.5 mol) was dissolved in EtOH
(35 L) at 15−20 °C followed by thorough degassing. Pd(OAc)2
(380 g, 0.17 mol), TEA (3000 mL), and Ph2P(CH2)3PPh2
(760 g, 0.184 mol) were added to the mixture. The latter was
heated to 90−100 °C and stirred at this temperature for 16 h
under CO atmosphere (75 psi). After the completion of the
reaction, active carbon (380 g) was added to the reaction mixture
which stirred at 70 °C for an additional 2 h. The reaction mixture
was filtered hot at 50−70 °C, and the filtrate was concentrated
to ∼10 kg, and the solid was collected by filtration and dried
under reduced pressure to give 11 (3.6 kg, 86.3% yield).
Preparation of Ethyl 8-Hydroxy-1,6-naphthyridine-7-
carboxylate (12). In a 30-L reactor, 11 (3.6 kg, 8.6 mol) was
dissolved in EtOH (35 L) and cooled to 0−10 °C. Freshly
prepared NaOEt (2.34 kg, 34.4 mol) was added by portions to
the reaction at 0−10 °C, and upon completion of the addition,
the reaction mixture was stirred at 20−25 °C for 3 h. After the
completion of the reaction, solid carbon dioxide (or bubble
CO2 gas) was added by portions to the mixture in order to
adjust the pH to 7−8. The reaction mixture was concentrated
to ∼7 kg; water (35 L) and EtOAc (35 L) were added, and the
layers were separated. The aqueous layer was adjusted pH to
4−6, and the mixture was extracted with DCM (36 L × 2). The
organic layers were combined and solvent switched to EtOH
(10.8 L) from which the product crystallized and was collected
by filtration. The crystals was dried under reduced pressure to
give 12 (1.35 kg, 72% yield) with 98.3% purity.
Preparation of Ethyl 5-Bromo-8-hydroxy-1,6-naphthyr-
idine-7-carboxylate (2). In a 30-L reactor was dissolved 12
(1.3 kg, 5.94 mol) in DCM (13 L) under N2. The reaction
mixture was cooled to 0−10 °C, and N-bromosuccinamide
(1.05 kg, 5.94 mol) was added in portions in order to keep the
temperature between 0 and 5 °C. The reaction mixture was
stirred at this temperature for 2 h and, upon completion, was
quenched with saturated NaHCO3/NaHSO3 (1:1) aq (13 L),
and the layers were separated. The aqueous layer was extracted
with DCM (13 L), and the combined organic layers were
solvent switched to EtOH (3.9 L). The resulting crystals were
collected by filtration and dried under reduced pressure to give
1
2 (1.55 kg, 88% yield) with 99% purity. H NMR (400 MHz,
DMSO-d6) δppm 1.34−1.38 (m, 3 H), 4.39 − 4.45 (dd, J = 14
Hz, J = 7.2 Hz, 2 H), 7.96 − 7.80 (dd, J = 8.4 Hz, J = 4 Hz,
1 H), 8.55 − 8.58 (dd, J = 8.8 Hz, J = 1.6 Hz, 1 H), 9.23 − 9.25
(dd, J = 4.4 Hz, J = 1.6 Hz, 1 H), 11.57 (s, 1 H); 13C NMR
(100 MHz, DMSO-d6) δ 14.61, 62.10, 126.47, 126.98, 127.21,
130.94, 136.98, 143.76, 154.02, 154.98, 166.83; HRMS calcd
for C11H10BrN2O3 (M + H)+: 296.9869, found 296.9866.
211
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Preparation of 4-Chlorobutane-1-sulfonyl chloride
(14). In a 2-L three-necked flask was dissolved 13 (510 g,
3.745 mol)in SOCl2 (900 mL) and treated with DMF (65 mL).
The reaction mixture was stirred at 70−90 °C under N2 for
2 days, cooled to 20−30 °C, and concentrated to minimum
volume under reduced pressure. The residual SOCl2 was
removed by repeated distillations with toluene (1 L × 3).
The residual (600 g, 70% yield) dark oil of 14 was obtained and
used without further purification in the next step.
Preparation of 4-Chloro-N-methylbutane-1-sulfonamide
(15). In a 10-L three-necked flask were mixed crude 14 (600 g,
3.14 mol), MeNH2HCl (370 g, 5.48 mol), and DCM (5 L)
mixed under N2 and the resulting slurry was cooled to 0−5 °C
and treated with sat. K2CO3 solution (800 g) at 0−10 °C. The
reaction mixture was stirred at 10−15 °C for 15 h, the pH was
adjusted to 5−6 with sat. citric acid aq (1.5 L), and the layers
were separated. The organic layer was washed with brine (1.5 L)
and water (1.5 L), and then concentrated to dryness to give 15
as dark oil.
Preparation of tert-Butyl (4-chlorobutyl)sulfonyl(methyl)-
carbamate (16). In a 5-L flask were dissolved crude 15 (700 g,
3.77 mol), and DMAP (450 g, 4.42 mol) in DCM (3 L). The
reaction mixture was stirred at 0−5 °C under N2 for 1 h, fol-
lowed by addition of (Boc)2O (1500 g, 6.87 mol) at 0−10 °C
under N2. The reaction temperature was adjusted to 10−15 °C,
and the mixture was stirred at this temperature for 15 h. After
the completion of the reaction, the organic layer was washed
with sat. citric acid aq. (∼1.5 L), brine (1.5 L), and water (1.5 L).
The resulting mixture was concentrated to dryness to give 16
(1 kg, 60% yield) as a dark oil.
Preparation of tert-Butyl (4-cyanobutyl)sulfonyl-
(methyl)carbamate (17). To a 10-L flask were added crude
16 (1 kg, 3.50 mol), KCN (450 g, 6.93 mol), 18-Crown-6
(90 g), and CH3CN (6 L). The reaction mixture was stirred at
80−90 °C under N2 for 15 h. After the completion of the
reaction, the reaction mixture was cooled to 10−15 °C. The solid
was filtered off, and the cake was washed with DCM (1000 mL).
The filtrate was concentrated to dryness. The residue was
purified though a flash column (1500 g of silica gel, eluted by
DCM). The fractions were combined and washed with water,
followed by concentration to dryness to give 17 as a dark oil.
Preparation of 4-Cyano-N-methylbutane-1-sulfonamide
(18). Crude 17 (900 g, 3.26 mol) was dissolved in DCM (3 L),
and the reaction mixture was cooled to 0−5 °C. HCl
(4 N(gas)) in EtOAc solution (1.5 L) was added to the
mixture slowly at 0−5 °C under N2, and the reaction mixture
was stirred at 15−25 °C for 5 h. After the completion of the
reaction, the mixture was concentrated to dryness. The residue
was purified by passage over a pad of silica gel (1500g of silica
gel, eluted by DCM:EA = 3:1) to give 18 (500 g, 83% yield) as
solid.
(d, J = 4.52 Hz, 1 H), 8.09 (br s, 1 H); 13C NMR (100 MHz,
DMSO-d6) δ 23.07, 24.86, 26.88, 29.07, 38.78, 49.34; HRMS
calcd for C6H17N2O2S (M + H)+: 181.1005, found 181.1008.
Preparation of Methyl-5-fluoro-2-methylbenzoate
(21). In a 10-L vessel was dissolved 20 (500 g, 2.97 mol) in
MeOH (4 L), and conc. H2SO4 (200 mL) was added to the
solution. The mixture was heated to 65−70 °C and stirred at
this temperature for 16 h. After the completion of the reaction,
it was solvent-switched to EtOAc (2 L), and the solution was
washed with 7% aq. NaHCO3 (5 L) to pH 5−6. The organic
layer was solvent-switched to CH3CN and 21 with 96.8%
HPLC purity was used in the next step without isolation.
Preparation of Methyl-2-(bromomethyl)-5-fluoroben-
zoate (22). The solution of 21 (∼498.3 g, 2.9 mol) in CH3CN
(4 L) was treated with NBS (543 g, 2.9 mol) and benzoyl
peroxide (71.4 g, 0.29 mol) at ambient temperature. The reac-
tion mixture was heated to 65−70 °C and stirred at this tem-
perature for 16 h. After completion of the reaction, the reaction
mixture was solvent switched to DCM (1.5 L), and any un-
disolved solids were filtered. The filtrate containing 22 was
solvent switched to 2-butanone (∼7 L) and used for the next
reaction.
Preparation of Methyl-2-(aminomethyl)-5-fluoroben-
zoate Hydrochloride (24). The solution of 22 (∼900.0 g,
3.64 mol) in 2-butanone (7 L) was treated with NH(Boc)2
(790.5 g, 3.64 mol) and Cs2CO3 (1187 g, 0.64 mol) at ambient
temperature. The mixture was heated to 70−80 °C and stirred
at this temperature for 16 h. After the completion of the reac-
tion, the reaction mixture was cooled to 20−25 °C, and any
undissolved solids were filtered. The filtrate was solvent
switched to EtOAc (3 L) to dissolve the product (23). The
resulting solution was cooled to 0−5 °C, and 4 N HCl in
EtOAc (800 mL) was added dropwise in order to maintain the
temperature between 0 and 5 °C. Then the reaction mixture
was warmed to 20−25 °C and stirred for 16 h. The resulting
slurry was filtered and dried under reduced pressure to give 24
with 99.0% purity.
Preparation of 2-(((tert-Butoxycarbonyl)amino)methyl)-
5-fluorobenzoic Acid (4). The salt 24 (590 g, 2.68 mol) was
suspended in THF (3 L), and the reaction mixture was cooled
to 0−5 °C. Boc2O (702 g, 3.22 mol) and TEA (270.0 g,
2.68 mol) were added at 0−5 °C, and the mixture was warmed
to 20−25 °C and stirred at this temperature for 2 h. After the
completion of the reaction, NaOH (428.0 g, 10.7 mol) was
added to the mixture and stirred at 20−25 °C for 24 h. After
the completion of the reaction, citric acid was added to adjust
the pH to 3−4. The reaction mixture was filtered, and the wet
cake was dried under reduced pressure to give 4 (227 g, 26%
yield over 6 steps). 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s,
9 H), 4.31−4.57 (m, 2 H), 7.27 (s, 1 H), 7.37−7.47 (m, 2 H),
7.55−7.63 (m, 1 H); 13C NMR (100 MHz, DMSO-d6) δ 28.64,
41.91, 78.42, 116.98, 117.20, 119.10, 119.31, 129.96, 130.04,
131.58, 131.65, 137.80, 137.83, 156.21, 159.62, 162.04, 167.68,
167.71; HRMS calcd for C13H16FNNaO4 (M + Na)+:
292.0956, found 292.0977.
Preparation of tert-Butyl-4-fluoro-2-(((5-(N-methyl-
sulfamoyl)pentyl)carbamoyl)benzylcarbamate (3). In a
1-L flask 6b (84.3 g, 467.9 mmol), 4 (120 g, 445.6 mmol), and
HOBt (66 g, 514.7 mmol) were dissolved in DMF (600 mL).
The reaction mixture was cooled to 0−10 °C, and EDCI (94 g,
514.7 mmol) was added in portions. The reaction mixture was
stirred at 0−10 °C for 3 h and then diluted with DCM (1500
mL) and washed in sequence with 5% aq HCl (400 mL × 2),
Preparation of 5-Amino-N-methylpentane-1-sulfonamide
Hydrochloride (6b·HCl). A 1-L flask containing 18 (40 g,
0.23 mol), Raney Ni (20 g), NH4OH (120 mL), and MeOH
(400 mL) was stirred at 40−50 °C under H2 at 50−60 psi for
15 h. After completion of the reaction, the reaction mixture
was filtered via a pad of Celite, and the cake was washed with
MeOH (200 mL). The filtrate was solvent switched to EtOAc,
and the solution was treated with 4 N HCl in EtOAc solution.
The solid was filtered and dried under reduced pressure to give
6b·HCl salt (40 g, 80% yield). 1H NMR (400 MHz, DMSO-d6)
δ 1.35−1.51 (m, 2 H), 1.52−1.73 (m, 5 H), 2.55 (d, J = 4.89 Hz,
4 H), 2.75 (d, J = 4.64 Hz, 2 H), 2.93−3.08 (m, 2 H), 6.95
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5% aq NaHCO3 (400 mL × 2), brine (400 mL × 2), and water
(400 mL × 2). The organic layer was washed and crystallized
from MTBE (270 mL) to afford 3 (145 g, 75% yield) as off-
white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 11 H),
1.55 (br s, 2 H), 1.62−1.73 (m, 2 H), 2.54−2.61 (m, 3 H),
2.93−3.07 (m, 2 H), 3.24 (q, J = 6.57 Hz, 2 H), 4.16−4.26 (m,
2 H), 6.86 (d, J = 5.02 Hz, 1 H), 7.20 (d, J = 8.78 Hz, 2 H),
7.24−7.31 (m, 1 H), 7.31−7.38 (m, 1 H), 8.39−8.50 (m, 1 H);
13C NMR (100 MHz, DMSO-d6) δ 23.36, 25.47, 28.66, 28.9,
29.03, 39.15, 41.21, 49.66, 78.46, 114.43, 114.65, 116.55, 116.75,
129.81, 129.89, 134.38, 137.87, 137.94, 156.16, 159.64, 162.06,
167.58, 167.60; HRMS calcd for C19H31FN3O5S (M + H)+:
432.1963, found 432.1969.
stirred at 10−20 °C for 3 h. After the completion of the reac-
tion, the resulting slurry was filtered to give 33 (822 g, 90%
yield) in 91.0% purity.
Preparation of 6H-5,22-Iminopyrido[3,2-k][8,2,9,16]-
benzothiatriazacyclononadecine-14,21-dione, 16-Fluoro-
8,9,10,11,12,13,19,20-octahydro-23-hydroxy-6-methyl-
7,7-dioxide (1). A solution of 33 (822 g, 1.48 mol) in DMF
(4 L) was added to EtOAc (40 L) with efficient stirring to
ensure good mixing of the resulting slurry. The mixture was
cooled to 0−5 °C, and DIPEA (576 g, 4.44 mol) and 50% T3P
in EtOAc (2840 g, 4.44 mol) were added dropwise successively
to the solution at 0−5 °C. The reaction mixture was warmed
to 5−15 °C and stirred for 16 h. After the completion of the
reaction was added water (41 L × 2), the layers were separated,
the organic layer was solvent switched to water (5 L), and the
resulting slurry was stirred at 80 °C for 5 h. Then the mix-
ture was cooled to 25−30 °C and filtered. The filter cake was
washed with water to afford 275 g of solid. The solid was
suspended in DMF (550 mL) and stirred at 80 °C for 5 h. The
reaction mixture was cooled to 5−10 °C and filtered. The solid
was dried under reduced pressure at 50 °C for 24 h to give 1
Preparation of ethyl 5-(5-(2-(((tert-Butoxycarbonyl)-
amino)methyl)-5-fluorobenzamido)-N-methylpentylsul-
fonamido)-8-hydroxy-1,6-naphthyridine-7-carboxylate
(5). In a 20-L reactor 3 (1330 g, 3.08 mol) was dissolved
in DMF (10 L). The solution was treated with 2 (1370 g,
4.62 mol), bipyridine (481.6 g, 3.08 mol), and K2CO3 (1700 g,
12.3 mol) under N2. The reaction mixture was degassed by
purging with N2 three times. CuI (588.0 g, 3.10 mmol) was
added to the reaction mixture under a nitrogen blanket, and the
reaction was heated to 70−80 °C. After the completion of the
reaction, the reaction mixture was concentrated in vacuo to
remove the maximum amount of DMF, and then THF (13 L)
and water (13.3 L) were added followed by 2 N HCl aq (6.0 L)
to change the pH to 3−4. After separating the layers, the
organic layer was washed twice with 5% aq EDTA disodium
(13.3 L) and finally water (13.3 L). The organic layer was
solvent switched to MTNE and the product 5 (1430 g, 68%
1
(220 g, 32.5% yield) with 98.7% purity. H NMR (400 MHz,
DMSO-d6) δ 1.27−1.44 (m, 2 H), 1.58 (br s, 2 H), 1.81−1.88
(m, 2 H), 3.25−3.34 (m, 2 H), 3.38 (s, 5 H), 4.64−4.80 (m, 2
H), 7.26−7.36 (m, 1 H), 7.40 (d, J = 8.41 Hz, 1 H), 7.63 (t, J =
6.71 Hz, 1 H), 7.78 (d, J = 4.14 Hz, 1 H), 7.93−7.96 (m, 1 H),
8.44−8.55 (m, 1 H), 8.65 (br s, 1 H), 9.05 (br s,1 H), 9.68−
9.85 (m, 1 H); 13C NMR (100 MHz, DMSO-d6) δ 21.72,
21.85, 24.43, 27.84, 31.23, 36.25, 37.98, 38.73, 41.42, 49.90,
115.45, 115.68, 116.98, 117.19, 124.43, 125.16, 125.60, 133.53,
134.66, 135.04, 137.76, 153.74, 160.26, 162. 79, 167.82, 168.44,
172.64; HRMS calcd for C23H25FN5O5S (M + H)+: 502.1555,
found 502.1541.
1
yield) isolated from MTBE:EA (6.6 L, 5:1) . H NMR (400
MHz, DMSO-d6) δ 1.27−1.40 (m, 13 H), 1.45−1.63 (m, 4 H),
1.79−1.90 (m, 2 H), 3.25 (d, J = 6.02 Hz, 3 H), 3.32 (s, 4 H),
3.55−3.64 (m, 2H), 4.21 (d, J = 6.02 Hz, 2 H), 4.42 (d, J = 7.03
Hz, 2 H), 7.15−7.24 (m, 2 H), 7.24−7.31 (m, 1 H), 7.34 (br s,
1 H), 7.88−7.99 (m, 1 H), 8.44−8.50 (m, 1 H), 8.60 (d, J =
1.38 Hz, 1 H), 9.19−9.28 (m, 1 H); 13C NMR (100 MHz,
DMSO-d6) δ 14.56, 22.65, 25.76, 27.29, 28.64, 28.81, 38.49,
39.14, 41.23, 49.18, 50.05, 61.91, 78.44, 114.42, 114.65, 116.57,
116.78, 124.76, 124.97, 126.18, 129.88, 134.42, 134.88, 137.88,
143.89, 143.93, 153.48, 154.64, 156.15, 159.63, 162.05, 167.23,
167.59; HRMS calcd for C30H39FN5O8S (M + H)+: 648.2498,
found 648.2476.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectra of all key intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*yhoupis@its.jnj.com
Preparation of 5-(5-(2-(((tert-Butoxycarbonyl)amino)-
methyl)-5-fluorobenzamido)-N-methylpentylsulfonamido)-
8-hydroxy-1,6-naphthyridine-7-carboxylic acid (5e). In a
20 L reactor, 5 (930 g, 1.44 mol) was dissolved in THF (4.5L),
MeOH (4.5L) and water (4.5 L). KOH (415 g, 7.4 mol) was
added, and the reaction mixture was heated to 60−70 °C and
stirred at this temperature for 5 h. After the completion of the
reaction, the reaction mixture was cooled to 20−25 °C. The
majority of the solvent was removed in vacuo, water (500 mL)
was added and the pH adjusted to 3−4 using 2 N HCl. The
aqueous solution was extracted with EtOAc (5 L × 2). The
combined organic layers containing 5e (990 g, 80% yield) with
95.5% purity were solvent switched to DCM and used without
isolation in the next reaction.
Preparation of 5-(5-(2-((aminomethyl)-5-fluorobenz-
amido)-N-methyl)pentyl)sulfonamido-8-hydroxy-1,6-
naphthyridine-7-carboxylic Acid Hydrochloride (33). In a
10-L reactor 5e (990 g, 1.60 mol) in DCM (3 L) was cooled
to 0−5 °C. Four normal HCl in EtOAc (800 mL) was added
dropwise to the solution at 0−5 °C. The reaction mixture was
Notes
The authors declare no competing financial interest.
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■
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(3) For comprehensive and informative reviews in these topics, see:
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(6) Control experiments in the absence of Cu and ligand showed that
there was no reaction even after prolonged heating.
(7) The reported yields of probe reactions are HPLC yields based on
highly purified standard and validated analytical methods. For
preparatory runs the yields reported are of isolated compound unless
the sequence was telescoped.
(8) Deprotection of the pivaloyl group followed by activation with
TsCl and reaction with amines gave low yields of 5 (X = NHR) and/
or bis-alkylation products. Only NaN3 succeeded in producing 5 (X =
N3); however, the use of azide was undesirable due to its well-known
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(11) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385.
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