Development of a safe and scalable route towards a tau PET tracer precursor

Article abstract of DOI:10.1016/j.bmc.2017.10.007

A scalable 5-step synthesis of the diazacarbazole derivative 1 used as tau PET tracer precursor is reported. Key features of this synthesis include a Buchwald-Hartwig amination, a Pd catalyzed C–H activation and a Suzuki-Miyaura cross-coupling.

Full text of DOI:10.1016/j.bmc.2017.10.007

Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Development of a safe and scalable route towards a tau PET tracer
precursor
⇑
Bjoern Bartels, Philipp Cueni, Dieter Muri, Matthias Koerner
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A scalable 5-step synthesis of the diazacarbazole derivative 1 used as tau PET tracer precursor is reported.
Key features of this synthesis include a Buchwald-Hartwig amination, a Pd catalyzed CAH activation and a
Suzuki-Miyaura cross-coupling.
Received 10 July 2017
Revised 6 October 2017
Accepted 11 October 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Buchwald-Hartwig amination
CAH activation
Diazacarbazole
Direct arylation
PET tracer
Suzuki-Miyaura cross-coupling
Stille coupling
Tau
1
. Introduction
tracers based on brain uptake, radiometabolites, signal to back-
1
8
ground ratio, and distribution. [ F]RO6958948 exhibited the
desired profile and was selected to enter part 2 of this trial which
was focusing on test-retest variabilites and radiation dosimetry cal-
Beta amyloid (Ab) plaques and tau aggregates are key
histopathological characteristics of Alzheimer’s disease (AD). In
the past years huge efforts have been dedicated to develop thera-
pies and to investigate suitable biomarkers for in vivo imaging of
Ab plaques. Several therapies are in late stage clinical development
and several positron emission tomography (PET) tracers to visualize
Ab plaques in vivo have been discovered.1 On the other hand, there
is emerging evidence that tau aggregates in the form of neurofibril-
lary tangles (NFT) or neuropil threads (NT) seem to be indicators of
clinical symptoms of Alzheimer’s disease.3 Recently, a number of
PET tracers targeting tau aggregates have been identified.
internal program was initiated with the goal to investigate tau
PET tracers with favorable selectivity versus Ab plaques, high sensi-
tivity and good PK properties. This work resulted in 3 tracers, [ C]
1
8
culations. Overall, [ F]RO6958948 showed favorable properties to
visualize tau aggregates in human brains and might be a valuable
biomarker for the development of therapies targeting NFTs and
NTs in Alzheimer’s disease (Fig. 1).
,2
For the first preclinical in vitro and in vivo studies Medicinal
Chemistry developed a four-step synthesis sequence to the nitro-
1
8
precursor 1 of the tau PET tracer [ F]RO6958948. This route
included several chromatographic purifications and was suitable
for mg-scale syntheses. To cope with an increasing demand of pre-
cursor which is required to supply clinical studies, an improved
process was highly desirable. In this paper we wish to report the
evaluation of different routes and the elaboration of a safe and
scalable synthesis route towards precursor 1 (Fig. 2).
4
–8
An
9
11
1
1
18
RO6924963, [ C]RO6931643, and [ F]RO6958948 which were
selected for a phase 1 clinical trial in healthy volunteers and AD
patients. Part 1 of this trial was dedicated to the selection of the best
2
. Results and discussion
Abbreviations: calcd, calculated; h, hour(s); IPC, in-process control; min,
minutes; NFT, neurofibrillary tangle; NSB, non-specific binding; NT, neutropil
thread; r.t., ambient (room) temperature.
2
.1. Medicinal Chemistry approach to 1
⇑
Corresponding author.
E-mail address: matthias.koerner@roche.com (M. Koerner).
The route for the preparation of 1 that was designed and exe-
cuted by the Medicinal Chemistry team is outlined in Scheme 1.
https://doi.org/10.1016/j.bmc.2017.10.007
968-0896/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
B. Bartels et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
N
Thus, our initial attempts focused on a) the evaluation of alter-
native access routes to intermediate 3 and b) finding alternative
conditions and reagents for the final coupling step to 1.
11C
O
N
N
11
18F
C
N
N
N
N
N
H
N
N
NH2
H
[11
C]RO6931643
[18F]RO6958948
[11
C]RO6924963
Our first approach started from either 2-chloro-6-methoxypyr-
idin-3-amine or 2-chloro-6-methoxypyridine (Scheme 2). Diazoti-
zation of 2-chloro-6-methoxypyridin-3-amine with sodium nitrite
and subsequent Sandmeyer reaction using CuCl/HCl gave the
Fig. 1. Tau PET tracers tested in phase 1.
1
2
dichloropyridine intermediate 5 after facile purification yet in
slightly lower isolated yield than the chlorination of 2-chloro-6-
methoxypyridine using N-chlorosuccinimide in acetonitrile. Even
though 2-chloro-6-methoxypyridine was converted completely
under the employed conditions, silica gel chromatography was
indispensable to isolate the desired regioisomer from the obtained
4:1 mixture of 2,3- and 2,5-bis-chlorinated products. Buchwald-
Hartwig amination with 4-aminopyridine using a Pd-BINAP cata-
lyst system in refluxing toluene afforded bipyridylamine 6 in good
yield (78%). The critical intramolecular ring closure towards
diazacarbazole 7 was approached via Pd-catalyzed CAH activation
N
N
1
8
N
F
N
NO
2
N
N
H
N
N
H
[18
1
F]RO6958948
Fig. 2. Tracer precursor 1 used for the radiosynthesis of [18F]RO6958948.
Central to this approach is the construction of the tricyclic
diazacarbazole core via ring closure under relatively mild basic
conditions. Starting from tert-butyl 3-iodopyridin-4-ylcarbamate
and 2,6-dichloropyridin-3-ylboronic acid, bipyridyl intermediate
and direct arylation using tert-butylphosphonium tetrafluorobo-
13,14
rate and palladium acetate.
High temperature and dioxane as
2
was formed using classical Suzuki-Miyaura type cross-coupling
solvent were necessary to achieve a good conversion. Replacement
of the methoxy group by chlorine was accomplished using stan-
dard chemistry. Cleavage of the methoxy group by aqueous HBr
gave pyridone 8 which was subsequently converted to chloride 3
conditions. Purification can be accomplished by either normal
phase silica gel chromatography or crystallization in order to
obtain the product in good quality. Intramolecular cyclization of
to form 1,6-diazacarbazole 3 was attempted by modifying the
procedure of Achab et al. using equimolar amounts of 18-
crown-6 and K CO in DMF. The crown ether is facilitating the acti-
vation of the base via complexation and, thus, promoting the
intramolecular nucleophilic substitution. However, these condi-
tions also resulted in complete loss of the Boc protective group.
Direct conversion of 3 to 1 under Suzuki-Miyaura conditions using
the respective 2-nitropyridine-5-boronic acid pinacol ester and Pd
II)Cl
2
3
using POCl in sulfolane.
1
0
Starting from crucial intermediate 3, the final conversion to 1
was examined in more detail. As outlined above, the protection
of the ANH group was necessary for applying Suzuki-Miyaura
cross-coupling conditions with 2-nitropyridine-5-boronic acid
pinacol ester. Another draw-back of this strategy was the mixture
of protected and unprotected 1 obtained under these conditions.
Performing this reaction in opposite direction was impossible as
the transformation of 3 into its boronate ester by using tetram-
ethyl-dioxoborolane dimer failed. Use of the corresponding potas-
sium trifluoroborate instead of the boronate ester also failed.
Negishi-type chemistry also seemed to be attractive. However,
the transformation of 5-bromo-2-nitropyridine into its Zn-bromide
did not work either in our hands.
2
3
à
(
2
(dppf) as catalyst failed . Re-protection of the pyrrole nitrogen
to 4 was found to be advantageous and final Suzuki-Miyaura coupling
gave the desired product 1 as mixture of 1 and Boc-protected 1 as
side product. Separation of both products via preparative HPLC gave
1
in good purity yet low yield.11
An alternative access to 3 via the corresponding N-acetyl pro-
tected bipyridyl intermediate and subsequent intramolecular
cyclization proved to be feasible but did not offer any advantages
compared to the route outlined above.
Eventually, Stille cross-coupling conditions turned out to be the
method of choice for the desired transformation. The necessary
trimethylstannane reagent 9 could be prepared in moderate yield
Even though the original Medicinal Chemistry route (Scheme 1)
represents a very short, four-step access to 1 and proved successful
for the preparation of low mg-quantities, a number of points
needed to be addressed in order to get a more robust and repro-
ducible route for the preparation of multi-gram quantities of 1.
The involved starting materials are rather expensive and the proto-
cols towards 1 are far from being robust which results in variable
yields for each step. Chromatographic purifications were essential
in 3 out of 4 steps. Finally, due to the loss of the Boc group during
the intramolecular ring closure to 3 an additional protection step
was necessary in order to get the final coupling reaction to
proceed.
5,15
from 5-bromo-2-nitropyridine.
The subsequent coupling reac-
tion with 3 in dioxane at 120 °C (closed reactor) resulted in up to
2% conversion to 1. Preliminary purification using silica gel chro-
7
matography gave the crude product in 60% yield. Due to the low
solubility of 1, the final crystallization had to be done from hot
DMSO which afforded 1 in good quality but poor yield (11% for this
step).
Compared to the Medicinal Chemistry synthesis route, the
number of steps increased yet the overall yield decreased. In addi-
tion, the presumably toxic tin reagent 9 used for the final coupling
step needed to be prepared separately. On the other hand, the
robustness of the route improved significantly. The final purifica-
tion remained a challenge due to the low solubility of 1 in basically
all common organic solvents.
Further evaluations of various steps resulted in a re-design of
the route towards 1 while maintaining the overall synthesis strat-
egy (Scheme 3). Bipyridylamine 10 was obtained via Buchwald-
Hartwig amination from commercial 2-chloro-6-methoxypyridine
and 4-amino-3-chloropyridine using a Pd/xanthphos catalyst sys-
tem. Extraction and precipitation from methanol/water furnished
2
.2. Process chemistry approaches to 1
After selecting the development candidate, route optimization
was initiated with the aim to find a scalable synthesis route to 1
which allows this compound to be produced on a multi-gram scale.
Availability of starting materials, process safety, facile purifica-
tions, improved yields and overall cost of goods are other
important aspects that were taken into account during route
optimization.
1
0 as white solid that was used directly in the next step. The direct
arylation of 10 via Pd-catalyzed CAH activation using tert-
butylphosphonium tetrafluoroborate, palladium acetate and potas-
sium carbonate in dimethylacetamide at 135 °C remained the
method of choice for the intramolecular cyclization to 7. Silica
à
A catalyst screening was not performed.
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B. Bartels et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
3
Cl
Cl
N
N
a
N
N
N
b
I
+ (HO)2
B
Cl
Cl
Cl
c
N
N
R
1
NHBoc
NHBoc
2
3: R1 = H
: R1 = Boc
4
O
N
d
B
4
+
O
NO
2
N
NO
2
N
N
H
N
1
0
0
Scheme 1. Medicinal Chemistry synthesis route to 9H-dipyrido[2,3-b;3 ,4 -d]pyrrole 1. Reagents and conditions: a) Pd(OAc)
2
, PPh
3 3 2 3
, Et N, DMF, 100 °C, 3 h, 63%; b) K CO ,
1
8-crown-6, DMF, 100 °C, 3 h, 63%; c) NaH, DMF, 0 °C to rt, then Boc
2
O, DMF, 0 °C to rt, 18 h, 73%; d) [PdCl
2
(dppf)]ꢀCH
2
2
Cl , K
2
CO , DMF, 90 °C, 18 h, 13%.
3
H N
2
*
HCl
a
b
N
NH2
Cl
N
Cl
N
N
O
Cl
Cl
N
d
O
N
N
c
N
H
N
O
N
H
7
N
O
5
6
Cl
O
Sn
N
N
N
g
NO
2
N
e
f
9
O
Cl
N
H
N
NO2
N
H
N
H
N
H
N
8
3
1
2 2
Scheme 2. First Process Research synthesis route to tracer precursor 1. Reagents and conditions: a) NaNO , CuCl, HCl/H O, 0 °C, then rt, 16 h, 60%; b) NCS, MeCN, 82 °C, 22 h,
t
t
7
0%; c) 4-aminopyridine, Pd(OAc)
2
, BINAP, K
2
CO
3
, toluene, 110 °C, 20 h, 78%; d) Pd(OAc)
2
, ( Bu
3
PH)BF
4
2
, NaO Bu, 1,4-dioxane, 135 °C, 19 h, 81%; e) HBr, H O, 80 °C, 16 h, 82%; f)
POCl
3
, sulfolane, 100 °C, 22 h, 46%; g) Pd(PPh
)
3 4
, 17 h, 1,4-dioxane, 120 °C, 4 h, 11%.
Cl
N
NH2
N
N
Cl
N
b
c
O
O
N
N
H
Cl
N
O
a
N
H
N
O
O
N
H
N
H
10
7
8 *HBr
B
O
N
NO
2
N
N
d
OTf
10
N
N
NO2
N
H
e
N
H
N
1
1
1 *AcOH
f
1
t
Scheme 3. Final route to tracer precursor 1. Reagents and conditions: a) Pd(xantphos)Cl
8 h, 80%; c) HBr, AcOH, 80 °C, 18 h, 80%; d) C N(SO CF , DIPEA, DMF, 20–25 °C, 2.5 h, then KHCO
then AcOH, reflux, 27%; f) Et N, methanol, 60–65 °C, 1 h, 96%.
2
, Cs
2
CO
3
, 1,4-dioxane, 102 °C, 72 h, 71%; b) Pd(OAc)
2
, ( Bu
3
PH)BF
4 2 3
, K CO , DMA, 135 °C,
1
H
6 5
2
3
)
2
3
, H
2
O, 50 °C, 18 h, 97%; e) Pd(xantphos)Cl
2
, 1,4-dioxane, KF, 90 °C, 3.5 h,
3
gel filtration and crystallization from tert-butyl methyl ether/n-
heptane was necessary for the purification of this intermediate.
Cleavage of the methoxy group using HBr in acetic acid at elevated
temperature afforded pyridone 8 as its HBr salt, a white solid pre-
cipitating from acetic acid/ethyl acetate. Instead of converting
pyridone 8 into chloride 3, the hydroxy group was activated as tri-
flate 11 employing bis(trifluoromethylsulfonyl)aniline under mild
conditions. This final intermediate was isolated from DMF/water
as light yellow solid. This activation and the use of potassium flu-
oride as base facilitated the final Suzuki-Miyaura cross-coupling
reaction with 2-nitropyridine-5-boronic acid pinacol ester and Pd
converted into its acetate salt after several crystallization-dissolu-
tion-filtration cycles and isolated in moderate yield. Finally,
treatment with triethylamine in methanol provided the free base
of the desired tracer precursor 1 almost quantitatively as yellow
crystalline solid.
3. Conclusions
In summary, a safe and scalable synthesis route for the tau PET
tracer precursor 1 devoid of any chromatographic purifications
was developed. Key features of the route are three Pd-catalyzed
reactions: Buchwald-Hartwig amination to bipyridylamine 10,
intramolecular ring closure to 7 via Pd-catalyzed CAH activation
and finally Suzuki-Miyaura cross-coupling starting from triflate
(
2
xanthphos)Cl as catalyst. Triflate 11 converted almost quantita-
tively to the desired tracer precursor 1. What remained a challenge
was the final purification of the product due to its intrinsic low
solubility in organic solvents. The crude product was at first
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4
B. Bartels et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
1
1. The robustness of the process could be demonstrated on multi-
was added and the crude product suspension was extracted twice
with ethyl acetate. The combined organic layers were washed with
gram scale and 1 could be prepared in five linear steps (11.4% over-
all yield) and high purity.
water (3ꢁ), dried over anhydrous Na
2 4
SO and the solvent was
evaporated. Trituration of the crude product with dichloromethane
afforded 1.92 g of the desired product. The dichloromethane phase
4
. Experimental section
was evaporated and purified by flash chromatography (SiO
acetate to n-heptane gradient) to yield in total 3.39 g (ꢃ90% purity,
3% yield) of 2 as light yellow solid. This material was used as such
2
; ethyl
4.1. General methods
6
1
in the following step. H NMR (300 MHz, DMSO d
7
1
6
) d 1.42 (s, 9H),
.66 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 8.1 Hz,
H), 8.28 (s, 1H), 8.48 (d, J = 5.8 Hz, 1H), 9.08 (s, 1H); LC-HRMS
Unless otherwise noted, all reagents and chemicals were
obtained from commercial suppliers and used without further
purification. Non-aqueous reactions were carried out under an
inert atmosphere of argon or nitrogen. Reactions and purifications
were monitored using the following IPC methods: TLC (TLC plates
F254, Merck), HPLC (Agilent 1260 Infinity with quaternary pump,
ALS autosampler and DAD detector and InfinityLab Poroshell 120
+
+
(m/z): [M+H] calcd for
C
15
2 3 2
H15Cl N O +H : 340.0621, found:
3
40.0624.
0
0
2-Chloro-9H-dipyrido[2,3-b;3 ,4 -d]pyrrole (3). Method A (from 2).
A
suspension of tert-butyl N-[3-(2,6-dichloro-3-pyridyl)-4-
mol), K CO (215 mg, 1.55
mmol) and 18-crown-6 (226 mg, 854 mol) in DMF (15.8 mL)
pyridyl]carbamate 2 (264 mg, 776
l
2
3
EC-C18 2.7
l
m, 4.6 ꢁ 50 mm column using A = acetonitrile, B =
l
water/acetonitril 95:5% v/v, C = 1‰ tetrabutylammonium hydro-
was stirred at 100 °C under argon for 3 h. water was added and
the product was extracted twice with ethyl acetate. The combined
organic layers were washed twice with water and brine, dried over
anhydrous Na SO and the solvent was evaporated. Trituration of
2 4
the crude product with a small amount of MeOH and drying
afforded 3 (105 mg, 63%) as light yellow solid. Method B (from 8):
A suspension of 2-oxo-2,9-dihydro-1H-pyrrolo[2,3-b:4,5-c ]dipyri-
dine 8 (1.0 g, 5.4 mmol) was suspended in sulfolane (20 mL). Phos-
phorus oxychloride (5.0 mL, 53.6 mmol) was added and the
mixture was stirred at 100 °C for 22 h. After cooling down to r.t.
the reaction mixture was diluted with water (80 mL) and neutral-
gen sulfate in acetonitrile/water 80:20% v/v at 25 °C at a flow of
1
mL/min with the following gradient: 0 min, 90% B; 1 min 90%
B, 7 min, 10% B, 12 min 10% B, 13 min, 90% B and constantly 5%
C), GC (Agilent 6850 with FID detector, integrated autosampler,
Agilent HP-1 30 m x 0.32 mm x 0.25 lm column and the following
gradient: 0 min, 60 °C; 2 min, 60 °C, 10 °C/min to 150 °C, 40 °C/min
to 300 °C; 2 min, 300 °C) and LCꢂMS (Waters Acquity UPLC with
binary pump, 2777C sample manager, column manager, PDA
detector and SQD1 mass detector; Agilent Zorbax EclipsePlus C18
column) analysis. Flash column chromatography was carried out
either using cartridges packed with silica gel (Isolute columns,
Telos flash columns) on an ISCO machine or using glass columns
packed with silica gel 60 (32–60 mesh, 60 Å). Preparative HPLC
purification was carried out with a system consisting of Varian
SD1 pumps, Gilson 215 Liquid Handler, Dionex UVD340U detector
and SEDEX 75 ELS detector using a YMC Triart C18 100 x 30mm col-
umn and a MeOH/water (0.1% formic acid) eluent system with 40
mL/min flow rate. The purity of isolated products was determined
by HPLC (using the above described IPC method) or UPLC (Waters
0
2 3
ized with Na CO until pH 5–7 was reached. The reaction mixture
was further diluted with water (50 mL) and extracted with ethyl
acetate/THF (1:1) twice. The combined organic layers were dried
2 4
over anhydrous Na SO , filtered and evaporated to dryness. The
residue was suspended in isopropanol/water (1:3, 100 mL). The
slowly forming light-yellow precipitate was filtered off, washed
with water and dried in vacuo to obtain 510 mg (46%) of 3. 1
H
NMR (300 MHz, DMSO d
6
) d 7.41 (d, J = 8.1 Hz, 1H), 7.51 (d, J =
5
.5 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.68 (d, J = 8.1 Hz, 1H), 9.39
Acquity UPLC, Acquity BEH C18 1.7
l
m, 2.1 x 50 mm column at 35
+
(
6
s, 1H), 12.47 (br s, 1H); LC-HRMS (m/z): [M+H] calcd for C10H -
°C using A = 0.1% v/v formic acid in water and B = 0.1% v/v formic
+
3
ClN +H : 204.0323, found: 204.0333.
acid in acetonitrile and a flow rate of 0.7 mL/min with the follow-
ing gradient: 0 min, 5% B; 0.1 min 5% B; 5.0 min, 60% B; 5.9 min
0
0
2
-Chloro-dipyrido[2,3-b;3 ,4 -d]pyrrole-9-carboxylic acid tert-
butyl ester (4). A suspension of NaH (60%, 26.5 mg, 607 mol) in
dry DMF (1.5 mL) was cooled under argon to 0 °C and a solution
of 2-chloro-9H-dipyrido[2,3-b;3 ,4 -d]pyrrole
l
l
6
0% B; 5.91 min, 5% B; 8.0 min, 5% B) . High-resolution LC-MS spec-
tra were recorded with an Agilent LC system consisting of an Agi-
lent 1290 high-pressure system, a CTC PAL autosampler, and an
Agilent 6520 QTOF. The separation was achieved on a Zorbax Eclip-
sePlus C18 1.7 lm, 2.1 x 50 mm column at 55 °C (A = 0.01% v/v for-
mic acid in water; B = 0.01% v/v formic acid in acetonitrile) at a
flow of 1 mL/min with the following gradient: 0 min, 5% B; 0.3
min, 5% B; 4.5 min, 99% B; 5 min, 99% B. H NMR spectra were mea-
sured on a Bruker 300 MHz instrument, a Bruker 600 MHz instru-
ment, or a Bruker Avance 400 MHz instrument. 13C NMR spectra
were measured at 151 MHz on a Bruker 600 MHz instrument in
a 5 mm TCI cryoprobe at 298 K. A TMS internal standard was used
0
0
3
(103 mg, 506
mol) in dry DMF (3.0 mL) was added. Stirring was continued at
°C for 10 min, then at rt for 30 min. After cooling down to 0 °C
L, 1.05
0
and addition of di-tert-butyl dicarbonate (132 mg, 141
l
mmol) in dry DMF (0.75 mL), stirring was continued at r.t. over-
night. Water was added and the reaction mixture was extracted
twice with ethyl acetate. The combined organic layers were
washed twice with water and brine, dried over anhydrous Na SO ,
2 4
filtered and evaporated. 4 was obtained after purification by silica
1
gel chromatography (dichloromethane:MeOH gradient) and drying
in vacuo as off-white solid (113 mg, 73%). H NMR (300 MHz,
1
for experiments done in CDCl
signal was used as the reference with 2.50 ppm.
3 6
. The deuterated DMSO d solvent
6
DMSO d ) d 1.70 (s, 9H), 7.64 (d, J = 8.1 Hz, 1H), 8.11 (dd, J = 0.9,
5
.8 Hz, 1H), 8.69 (d, J = 5.7 Hz, 1H), 8.76 (d, J = 8.1 Hz, 1H), 9.48
+
(
O
3
d, J = 0.8 Hz, 1H); LC-HRMS (m/z): [M+H] calcd for C15H14ClN -
+
4.2. Synthesis procedures
2
+H : 304.0854, found: 304.0851.
,3-Dichloro-6-methoxypyridine (5). A solution of 3-amino-2-
2
tert-Butyl N-[3-(2,6-dichloro-3-pyridyl)-4-pyridyl]carbamate (2).
chloro-6-methoxypyridine hydrochloride (6.2 g, 31.6 mmol) in
A pre-heated flask under argon was charged with tert-butyl 3-
iodopyridin-4-ylcarbamate (4.56 g, 14.2 mmol), 2,6-dichloropy-
ridin-3-ylboronic acid (5.46 g, 28.4 mmol), palladium (II) acetate
concentrated hydrochloric acid (100 mL) was cooled down to ꢂ5
2
°C. At this temperature a solution of NaNO (10.9 g, 158 mmol) in
water (50 mL) was added within 30 min. After stirring for 15
min, CuCl (31.3 g, 316 mmol) was added slowly within 30 min.
Stirring was continued at r.t. for 16 h and ammonia (25% aqueous
solution, 150 mL) was slowly added at 10 °C. The reaction mixture
was extracted with tert-butyl methyl ether (3 ꢁ 50 mL) and the
(
320 mg, 1.42 mmol) and triphenylphosphine (371 mg, 1.41
mmol). Triethylamine (4.32 g, 5.94 mL, 42.7 mmol) in DMF (137
mL) was added and the reaction mixture was stirred at 100 °C
for 3 h. The solvent was evaporated almost completely. Water
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B. Bartels et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
5
organic phases were dried and evaporated. The crude product was
dissolved in n-heptane (50 mL), charged on silica gel (25 g) and
eluted with n-heptane (250 mL) under reduced pressure. The fil-
trate was evaporated and the solid was dried in vacuo to obtain 5
13.28 (s, 1H), 14.80 (br s, 1H); LC-HRMS (m/z): [M+H]+ calcd for
+
C H
10 7
N
3
O+H (free base): 186.0669, found: 186.0672.
Trimethyl-(6-nitro-3-pyridyl)stannane (9). 5-Bromo-2-nitropy-
ridine (4 g, 19.7 mmol) was dissolved in 1,4-dioxane (48.0 mL)
and tetrakis(triphenylphosphine)palladium(0) (800 mg, 692 mmol)
was added, followed by hexamethylditin (9.48 g, 6.00 mL, 28.9
mmol). The mixture was stirred until conversion was complete
for 1.5 h at 100 °C. The mixture was concentrated and dried in
vacuo (5 mbar) at 55 °C. The residue was dissolved in ethyl acetate
(80 mL) and n-heptane (320 mL) and silica gel (20 g) was added.
The resulting slurry was stirred for 10 min at r.t., filtered over a
plug of silica gel (20 g, pretreated with n-heptane) and washed
with ethyl acetate/n-heptane 1:4 (v/v, 100 mL). The filtrate was
concentrated in vacuo (5 mbar) at 55 °C. The brown residue was
triturated with n-heptane (10 mL), filtered and the precipitate
was washed with n-heptane and dried in vacuo (5 mbar) at 55 °C
as white solid (3.4 g, 60%). 1H NMR (400 MHz, DMSO d
) d 3.93
s, 3H), 6.65 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H); LC-MS (m/
6
(
+
+
z): [M+H] for C
-Chloro-6-methoxy-N-(4-pyridyl)pyridin-2-amine (6). Under
argon atmosphere, palladium acetate (110 mg, 0.49 mmol) and
6 5 2
H Cl NO+H : 178.0.
3
0
0
2
,2 -bis(diphenylphosphino)-1,1 -binaphthyl (BINAP; 310 mg, 0.5
mmol) were suspended in toluene (8 mL) and stirred at 100 °C
for 15 min. The reaction mixture was allowed to cool down to r.t.
and 2,3-dichloro-6-methoxypyridine
-aminopyridine (1.25 g, 13.3 mmol), K
5
CO
(1.8 g, 10.1 mmol),
(5 g, 36.2 mmol) and
4
2
3
toluene (28 mL) were added consecutively and the reaction mix-
ture was stirred at 110 °C for 20 h. After cooling down to ambient
temperature the reaction mixture was filtrated and the residue
was rinsed with toluene (20 mL). The clear filtrate was evaporated
to a small volume (10 mL) and purified by silica gel chromatogra-
phy using an ethyl acetate/n-heptane gradient (80:20 to 100:0 (v/
v)). Evaporation of the product fractions and drying in vacuo
1
to yield 3.01 g (53%) of 9 as brown crystals. H NMR (400 MHz,
CDCl
3
) d 0.43 (s, 9H), 8.14 (dd, J = 1.6 Hz, 7.8 Hz, 1H), 8.18 (dd, J
+
= 0.8 Hz, 7.8 Hz, 1H), 8.63–8.70 (m, 1H); LC-MS (m/z): [M+H] for
+
C H
8 12
N
O
2 2
Sn+H : 289.0.
N-(3-Chloropyridin-4-yl)-6-methoxypyridin-2-amine (10). A 4.5 L
glas reactor was purged with argon and charged with 1,4-dioxane
(1.8 L). 2-Chloro-6-methoxypyridine (80.0 g, 557 mmol), 3-
1
afforded 6 as white solid (1.95 g, 78%). H NMR (400 MHz,
DMSO d
6
) d 3.97 (s, 3H), 6.32 (d, J = 8.6 Hz, 1 H), 7.08 (br s, 1H),
7
.51 (d, J = 8.6 Hz, 1H), 7.58–7.63 (m, 2H), 8.42–8.49 (m, 2H); LC-
2 3
chloropyridin-4-amine (88 g, 685 mmol), Cs CO (252 g, 775
+
+
MS (m/z): [M+H] for C11
H
10ClN
3
O+H : 236.1.
mmol) and acetic acid (3.2 mL, 56 mmol) were consecutively
added. The suspension was stirred at r.t. for 20 min. Dichloro[9,9-
dimethyl-4,5-bis(diphenyl-phosphino)xanthene]palladium(II) (22.1
g, 29.2 mmol) in 1,4-dioxane (210 mL) was added and the reaction
mixture was stirred at 100 °C for 4 h. After cooling down to r.t.
toluene (2.0 L) was added. The suspension was filtered off and
the solid was washed with toluene (300 mL). The filtrate was evap-
orated under reduced pressure and the obtained yellow solid was
dissolved in methanol (1.2 L) at r.t.. Water (800 mL) was slowly
added within 75 min and the slurry was stirred at r.t. for 15 min
and subsequently at 0–5 °C overnight. The crystalline product
was filtered off, washed with a methanol/water mixture (1:2,
0
2
-Methoxy-9H-pyrrolo[2,3-b:4,5-c ]dipyridine (7). A 4.5 L glas
reactor was purged with argon and charged with palladium (II)
acetate (5.15 g, 23 mmol), tri-tert-butylphosphonium tetrafluorob-
orate (7.73 g, 26.6 mmol) and dimethylacetamide (200 mL). This
mixture was stirred at r.t. for 15 min. N-(3-chloropyridin-4-yl)-6-
methoxypyridin-2-amine 10 (100.0 g, 424 mmol), K
70 mmol) and dimethylacetamide (800 mL) were added and the
reaction mixture was heated under vigorous stirring to 135 °C for
6 h. The dark mixture was cooled down to r.t., diluted with ethyl
2 3
CO (120 g,
8
1
acetate/ethanol 9:1 (1 L), filtrated and rinsed with little ethyl acet-
ate. The filtrate was evaporated under reduced pressure and the
residue was dried in vacuo and re-dissolved in 1,4-dioxane (1.5 L)
and ethyl acetate/methanol 8:2 (1.5 L) at 75 °C. The green suspen-
sion was cooled down to r.t., charged to conditioned silica gel (300
g) and eluted under slightly reduced pressure with 1,4-dioxane/
ethyl acetate/methanol (50:45:5, 1.2 L). The clear filtrate was evap-
orated under reduced pressure and the residue was dissolved in
tert-butyl methyl ether (300 mL). n-Heptane (300 mL) was slowly
added within 45 min and the obtained suspension was stirred at
r.t. for 75 min. The solid was filtered off, washed with n-heptane
600 mL) and subsequently dried in vacuo to obtain 10 as white
1
solid (111 g, 71%; GC: 97.9% a/a). H NMR (400 MHz, DMSO d
6
) d
3.85 (s, 3H), 6.41 (dd, J = 0.7, 8.1 Hz, 1H), 6.91 (dd, J = 0.7, 7.8 Hz,
1H), 7.64 (t, J = 7.9 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 5.6
1
3
6
Hz, 1H), 8.45 (s, 1H), 8.76 (br s, 1H); C NMR (151 MHz, DMSO d )
d 53.8, 102.7, 105.4, 113.6, 119.0, 141.2, 144.5, 148.6, 149.4, 152.7,
+
+
162.7; LC-HRMS (m/z): [M+H] calcd for
11 3
C H10ClN O+H :
236.0592, found: 236.0608.
0
9H-Pyrrolo[2,3-b:4,5-c ]dipyridin-2-yl trifluoromethanesulfonate
and dried in vacuo to obtain 7 as greenish solid (72.3 g, 80%; GC:
(11). A 4.5 L glas reactor was purged with argon and charged with
1
0
0
9
=
8
4.1% a/a). H NMR (600 MHz, DMSO d
6
) d 3.95 (s, 3H), 6.74 (d, J
DMF (800 mL). 1,9-Dihydro-dipyrido[2,3-b;3 ,4 -d]pyrrol-2-one
hydrobromide 8 (80.0 g, 231 mmol) and N,N-diisopropylethy-
lamine (175 mL, 1.0 mol) were consecutively added. The mixture
was cooled to 5 °C and treated with N,N-bis(trifluoromethylsul-
fonyl)aniline (125 g, 350 mmol) and DMF (100 mL). After warming
up to r.t. the reaction mixture was stirred for 1 h and another por-
tion of N,N-bis(trifluoromethylsulfonyl)aniline (42 g, 118 mmol)
and DMF (100 mL) was added. Stirring was continued at r.t. for
8.5 Hz, 1H), 7.41 (dd, J = 1.0, 5.6 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H),
.48 (d, J = 8.5 Hz, 1H), 9.23 (d, J = 0.9 Hz, 1H), 12.21 (br s, 1H);
1
3
C NMR (151 MHz, DMSO d
32.2, 141.8, 142.1, 143.7, 150.3, 163.2; LC-HRMS (m/z): [M+H]
6
) d 53.4, 103.6, 106.5, 106.6, 118.0,
+
1
+
calcd for C11
9 3
H N O+H : 200.0826, found: 200.0840.
0
0
1
,9-Dihydro-dipyrido[2,3-b;3 ,4 -d]pyrrol-2-one hydrobromide (8).
A 4.5 L glas reactor was purged with argon and charged with 2-
0
methoxy-9H-pyrrolo[2,3-b:4,5-c ]dipyridine (7) (72 g, 361 mmol).
another 3.5 h. The orange suspension was treated with KHCO
3
Acetic acid (575 mL) was added and the mixture was treated with
HBr (33 wt% in AcOH, 290 mL, 1.66 mol). The milky suspension was
stirred at 80 °C for 16 h. The reaction mixture was cooled down to
r.t. and ethyl acetate (1.3 L) was added within 20 min. Stirring was
continued for 15 min and the solid was filtered off. The residue was
washed with ethyl acetate (300 mL) and n-heptane (200 mL) and
dried in vacuo to obtain 8 as HBr salt (white solid; 100.3 g, 80%).
(120 g, 1.2 mol) and water (400 mL) and stirred at 50 °C for 18 h.
Water (1.0 L) was added slowly and the mixture was cooled to
0–5 °C and stirred at that temperature for 90 min. The precipitate
was filtered off, washed with water (500 mL) and n-heptane
(200 mL) and dried in vacuo to obtain 11 as light-yellow solid
1
(73.3 g, 97%; HPLC (220 nm): 96.9% a/a). H NMR (400 MHz,
6
DMSO d ) d 7.46 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 1.1, 5.6 Hz, 1H),
1
This material was used as such in the following step. H NMR
8.57 (d, J = 5.6 Hz, 1H), 8.95 (d, J = 8.3 Hz, 1H), 9.47 (d, J = 1.0 Hz,
1
3
(
400 MHz, DMSO d
6
) d 6.78 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 6.4 Hz,
1H), 12.83 (br s, 1H); C NMR (151 MHz, DMSO d
6
) d 107.0,
1
H), 8.62 (d, J = 6.4 Hz, 1H), 8.63 (d, J = 8.3 Hz, 1H), 9.62 (s, 1H),
107.2, 114.6, 116.7, 118.2 (q, JCF = 320 Hz), 134.4, 143.8, 144.0,
Please cite this article in press as: Bartels B., et al. Bioorg. Med. Chem. (2017), https://doi.org/10.1016/j.bmc.2017.10.007

6
B. Bartels et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
+
1
O
45.6, 149.5, 153.0; LC-HRMS (m/z): [M+H] calcd for C11
H
6
F
3
N
3
-
acetic acid/ethyl acetate 1:1 (200 mL), ethyl acetate (500 mL) and
n-pentane (500 mL) and dried in vacuo to obtain a yellow-brown-
ish crude product (HPLC (260 nm): 99.6% a/a, contains inorganic
impurities). The crude acetate (27 g) was suspended in acetic acid
(540 mL) and water (27 mL) and heated to reflux. The hot and tur-
bid solution was hot filtrated and the brown residue was washed
with acetic acid. The filtrate was warmed up until getting clear,
cooled to r.t., stirred for 18 h and filtrated. The crystalline residue
was washed with acetic acid/ethyl acetate 1:1, ethyl acetate and
n-pentane and dried in vacuo to obtain 19.6 g of a dark yellow
crude product (HPLC (260 nm): 99.5% a/a) which was suspended
in acetic acid (390 mL) and water (20 mL) and heated to reflux.
The clear solution was cooled to 80–90 °C and charged with char-
coal (5 g). After heating to reflux, the suspension was filtrated and
the residue was washed with acetic acid. The clear filtrate was
partly evaporated and ethyl acetate was added to the resulting
slurry. After cooling to r.t. the slurry was filtered off and the crys-
tals were washed with ethyl acetate and n-pentane and dried in
vacuo to obtain 1 as acetate salt (yellow crystalline powder; 17.2
g, 27%; HPLC (260 nm): 99.8% a/a). b) A 500 mL flask was purged
with argon and charged with 2-(6-nitropyridin-3-yl)-9H-pyrrolo
+
3
S+H : 318.0162, found: 318.0166.
-(6-Nitro-pyridin-3-yl)-9H-dipyrido[2,3-b;3 ,4 -d]pyrrole
Method A (from 4): 2-Chloro-dipyrido[2,3-b;3 ,4 -d]pyrrole-9-car-
boxylic acid tert-butyl ester 4 (285 mg, 938
ridine-5-boronic acid pinacol ester (469 mg, 1.88 mmol), [1,1 -bis
diphenylphosphino)ferrocene]dichloropalladium(II)
methane complex (34.5 mg, 42.2 mol) and K CO
mmol) were combined under argon in a reaction flask. DMF (24
mL) was added and the flask was sealed. The reaction mixture
was stirred at 90 °C for 18 h. Filtration through CeliteÒ and subse-
quently through a small pad of silica gel (neutral, 60 Å, mesh 32–
0
0
2
(1).
0
0
lmol), 2-nitropy-
0
(
dichloro-
l
2
3
(389 mg, 2.81
6
3) was followed by rinsing with DMF and evaporation to dryness.
The brown solid was dissolved in DMF (20 mL) and DMSO was
added until a clear solution resulted. After filtration, the solvents
were evaporated to almost dryness. Purification by preparative
HPLC (YMC Triart C18 100 ꢁ 30 mm–5
Et N/MeCN gradient) provided 1 as yellow solid (37 mg, 13%).
Method B (from 3): 2-Chloro-9H-dipyrido[2,3-b;3 ,4 -d]pyrrole (3)
500 mg, 2.46 mmol) was dissolved in 1,4-dioxane (25.0 mL) and
-nitro-5-(trimethylstannyl)pyridine 9 (1.00 g, 3.49 mmol) and
lm; water with 0.1%
3
0
0
(
2
0
tetrakis(triphenylphosphine)palladium(0) (1.00 g, 865 mmol) were
consecutively added under an argon atmosphere in a pressure vial.
The vial was capped and the mixture was stirred at 120 °C for 4 h.
After that time, the conversion was ca. 65% by HPLC. After cooling
to r.t., the mixture was diluted with ethyl acetate (50 mL) and silica
gel (10 g) was added. The resulting slurry was concentrated in
vacuo and dried at 55 °C and 20 mbar. The residue was directly
subjected to a column chromatography using silica gel (50 g) and
an ethyl acetate/methanol (100:0 to 92:8 v/v) gradient. The pro-
duct containing fractions were combined and concentrated in
vacuo to obtain the crude product as a yellow solid (460 mg). The
crude products of 4 identical experiments were pooled and dis-
solved in ethyl acetate/methanol 9:1 (v/v, 800 mL) at 60 °C. Silica
gel (20 g) was added and the resulting mixture was concentrated
to a volume of ca. 200 mL. 1,4-Dioxane (100 mL) was added and
the slurry was concentrated and dried in vacuo at 55 °C and 5 mbar.
The resulting yellow powder was directly purified by column chro-
matography using silica gel (100 g) and eluting with a gradient of
ethyl acetate/methanol (98:2–92:8 v/v, 1.5 L) and 1,4-dioxane
[2,3-b:4,5-c ]dipyridine acetate (15.50 g, 44.1 mmol). Methanol
(310 mL) and triethylamine (9.5 mL, 68.2 mmol) were added and
the reaction mixture was heated to 60–65 °C for 1 h. After cooling
to r.t. stirring was continued for another 2 h. The suspension was
filtrated and the yellow solid was washed with little methanol,
dried, treated with water (60 mL) and ultrasonicated until a homo-
geneous suspension was obtained. All volatiles were removed and
the product was obtained after drying in vacuo (5 mbar) at 60 °C as
1
yellow solid (12.5 g, 96%; UPLC (263 nm): 99.2% a/a). H NMR (400
MHz, DMSO d ) d 7.52 (dd, J = 1.1, 5.6 Hz, 1H), 8.20 (d, J = 8.3 Hz,
6
1H), 8.49 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.84 (d, J =
8.1 Hz, 1H), 8.95 (dd, J = 2.1, 8.6 Hz, 1H), 9.43–9.47 (m, 2H),
1
3
12.53 (s, 1H); C NMR (151 MHz, DMSO d
6
) d 106.8, 114.4,
114.8, 117.2, 118.6, 130.6, 138.2, 139.9, 144.0, 144.1, 145.8,
+
9
147.1, 149.1, 152.1, 156.2; LC-HRMS (m/z): [M+H] calcd for C15H -
+
N
5
O
2
+H : 292.0829, found: 292.0827.
Author contributions
(
500 mL). The product fractions were combined and concentrated
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
in vacuo to yield 1.04 g of purified product. This material was dis-
solved in DMSO (18 mL) at 150 °C and after cooling to r.t. the solu-
tion was stirred for 4 h. The resulting suspension was filtered, the
crystals were washed with ethyl acetate (5 mL) and dried in vacuo
Notes
(
5 mbar) at 55 °C to afford 360 mg of a yellow crystalline powder.
The powder was suspended in water (22 mL) at 80 °C and stirred
for 15 min at that temperature, followed by 1 h at r.t.. The suspen-
sion was filtered, the crystals were washed with water and dried in
vacuo (5 mbar) at 60 °C to afford 1 as a yellow crystalline powder
The authors declare no competing financial interest.
Acknowledgments
(
310 mg, 11% yield). Method C (from 11): a) A 4.5 L glas reactor
We sincerely thank Cyrill Loetscher and Roland Humm for
excellent synthetic support. We acknowledge the analytical sup-
port given by Caroline Wyss-Gramberg, Philippe Cron, and Markus
Buerkler (NMR) as well as Sophie Brogly and Oliver Scheidegger
was purged with argon and consecutively charged with 9H-pyr-
rolo[2,3-b:4,5-c ]dipyridin-2-yl
0
trifluoromethanesulfonate
11
(
57.2 g, 180 mmol), 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)pyridine (86.2 g, 345 mmol), potassium fluoride
114 g, 1.96 mol), 1,4-dioxane (1.40 L) and water (570 mL) and
was stirred at r.t. for 15 min. Then dichloro[9,9-dimethyl-4,5-bis
diphenylphosphino)-xanthene]palladium(II) (22.8 g, 30.2 mmol) in
(
MS). We also thank Luca Gobbi and Henner Knust for helpful
(
discussions.
(
1
9
,4-dioxane (280 mL) was added and the mixture was stirred at
0 °C for 4.5 h. After cooling to r.t., the reaction mixture was trea-
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