Development of a Scalable Route for a Key Thiadiazole Building Block via Sequential Sandmeyer Bromination and Room-Temperature Suzuki-Miyaura Coupling

Article abstract of DOI:10.1021/acs.oprd.9b00495

To avoid the use and handling of Lawesson's reagent or other thiation agents in the in-house kilolab, a new scalable route to ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (1) was developed. The key to success was the use of a commercially available amino-thiadiazole building block, which was converted into the desired product via a sequence of Sandmeyer bromination and Suzuki-Miyaura coupling. The different parameters of the Pd-catalyzed coupling have been studied in detail and allowed the reaction to be performed under mild conditions at room temperature and with low catalyst loading. The inconsistencies of the initial scale-up runs with regard to the sluggish conversion of the Suzuki-Miyaura coupling due to Cu contamination were addressed, and the findings were directly implemented in the subsequent batches, which finally led to an improved overall understanding and robustness of the process.

Full text of DOI:10.1021/acs.oprd.9b00495

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Full Paper
Development of a Scalable Route for a Key Thiadiazole
Building Block via Sequential Sandmeyer Bromination
and Room-Temperature Suzuki-Miyaura Coupling
Gabriel Schaefer, Tony Fleischer, Muhamed Ahmetovic, and Stefan Abele
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00495 • Publication Date (Web): 28 Jan 2020
Downloaded from pubs.acs.org on January 29, 2020
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Development of a Scalable Route for a Key
Thiadiazole Building Block via Sequential
Sandmeyer Bromination and Room-Temperature
Suzuki−Miyaura Coupling
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Gabriel Schäfer,* Tony Fleischer, Muhamed Ahmetovic, and Stefan Abele
Chemistry Process R&D, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-
4123 Allschwil, Switzerland.
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Table of Contents graphic
Sandmeyer
reaction
Suzuki-Miyaura
coupling
with CuBr & tBu-ONO
with Pd/Xantphos
F
2
O
O
F
O
S
S
H N
2
Br
S
OEt
OEt
OEt
N N
N N
N N
F
F
B(OH)2
commercially available
on kg scale
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ABSTRACT. To avoid the use and handling of Lawesson’s reagent or other thiation
agents in the in-house kilolab, a new scalable route to ethyl 5-(2,4-difluorophenyl)-1,3,4-
thiadiazole-2-carboxylate (1) was developed. The key to success was the use of a
commercially available amino-thiadiazole building block, which was converted into the
desired product via a sequence of Sandmeyer bromination and Suzuki-Miyaura coupling.
The different parameters of the Pd-catalyzed coupling have been studied in detail and
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allowed the reaction to be performed under mild conditions at room temperature and with
low catalyst loading. The inconsistencies of the initial scale-up runs with regards to the
sluggish conversion of the Suzuki-Miyaura coupling due to Cu contaminations were
addressed, and the learnings directly implemented in the subsequent batches, which
finally led to an improved overall understanding and robustness of the process.
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KEYWORDS: thiadiazole, heterocycles, Suzuki-Miyaura coupling, Sandmeyer reaction,
Xantphos.
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INTRODUCTION. For a recent project at Idorsia Pharmaceuticals, a robust and
scalable route to ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (1) needed
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to be developed (Figure 1).1
F
F
O
S
OEt
N N
1,3,4-thiadiazole building block
(
1)
Figure 1: Structure of desired building block 1.
In our medicinal chemistry laboratories, 1 was synthesized via acylation of commercially
available 2,4-difluorobenzoic acid hydrazide 2 with ethyl chlorooxoacetate 3, followed by
cyclization of 4 with Lawesson’s reagent (Scheme 1). The overall yield and throughput of
this early route was high and delivered 1 in multigram amounts to prepare an array of
different thiadiazole-containing compounds for biological testing. However, the route also
suffered from certain drawbacks with regards to scale up: a) the use of malodorous
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Lawesson’s reagent was assessed to be very challenging to handle in our kilolab; b) the
lipophilic Lawesson’s reagent byproducts were challenging to remove by crystallization
and the final product had to be purified by column chromatography (CC); c) the use of
high volumes of undesired CH Cl (15−20 vol.) in the first acylation step. For these
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reasons, we wanted to develop a new synthetic route from a commercially available
thiadiazole starting material, which would supersede the use of Lawesson’s reagent in
our laboratories.
Scheme 1: First Generation Synthesis of 1 using Lawesson’s reagent
F
O
F
O
O
F
O
H
NEt3 (2.0 eq.)
Lawesson's reagent (1.1 eq.)
THF, reflux, 2 h
F
O
NH2
N
Cl
N
N
H
OEt
S
Cl
H
CH2Cl2, 0 °C to rt, 1 h
O
OEt
O
F
F
N N
7
0-75% yield
60-75% yield
purified by CC
2
3
4
1
purified by CC
INITIAL EXPERIMENTS. After considering many different potential starting materials,
we found ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (5) to be a suitable candidate due
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to its commercial availability on kg-scale and its ease of handling as a bench-stable solid.3
We envisioned that the starting material could be converted into the desired building block
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1
by a sequence of Sandmeyer bromination and subsequent Suzuki-Miyaura coupling
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with 2,4-difluorophenyl boronic acid (7) (Scheme 2).
Scheme 2: Retrosynthetic Analysis of 1 starting from commercially available 5
Suzuki-Miyaura
coupling
Sandmeyer
reaction
F
O
O
F
O
S
N N
6
S
N N
5
S
Br
H2N
OEt
OEt
OEt
F
N N
B(OH)2
1
F
7
Perfluorophenyl boronic acids are known to undergo rapid protodeboronation under the
5
traditional basic aqueous conditions of Suzuki-Miyaura couplings. Therefore, the stability
of 2,4-difluorophenyl boronic acid (7) under basic conditions was assessed at the start of
the project. The boronic acid was found to be stable in a 1:1 v/v-mixture of THF and 1 M
aq. NaOH at room temperature and no protodeboronation could be observed after 24 h.
However, in the same solvent system, protodeboronated product 8 started to be observed
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by LC/MS after gradual heating to 55 °C (Figure 2). Therefore, it was apparent that room-
temperature Suzuki-Miyaura coupling conditions needed to be developed, preferably
employing a mild base to further reduce the risk of protodeboronation. In addition, it was
known that the free carboxylic acid of 1 is highly unstable and instantaneously
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decarboxylates, further highlighting the necessity to use a mild base in the Suzuki-
Miyaura coupling to avoid saponification of the ethyl ester.
F
F
8
B(OH)2
Protodeboronation
H
F
F
7
2
00 mg (1.27 mmol) 7,
THF/1 M aq. NaOH (1:1, 4 mL)
a) rt, 24 h, 0% a/a 8
b) 55 °C, 5 h, 20% a/a 8
Figure 2: Protodeboronation of 7 to 8 (ratio determined by LC/MS).
PROCESS DEVELOPMENT. After establishing the stability of the fluorinated boronic
acid at room temperature, we started with the development of the Sandmeyer bromination
7
8
of 5. After initial screenings with different bromide and nitrite sources, the dosing of tert-
butyl nitrite to a mixture of CuBr and the starting material in MeCN at room temperature
2
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was found to be optimal with regards to reaction conversion and impurity profile. With
regards to process safety, differential scanning calorimetry (DSC) analysis of tert-butyl
nitrite showed a highly energetic, autocatalytic decomposition (2175 KJ/kg) at 180 °C.
Therefore, the Sandmeyer bromination was studied in a Systag reaction calorimeter (10
g scale, addition time of tert-butyl nitrite: 30 min). The reaction with tert-butyl nitrite was
found to be dose-controlled at 23 °C with release of an exotherm of 92.9 kJ/kg and a heat
production per unit mass of ca. 45 W/Kg, leading to a MTSR (maximum temperature of
the synthesis reaction) of 65 °C. The intermediate diazonium species was never detected
by LC/MS, and after complete addition of tert-butyl nitrite, the starting material was
normally fully converted (>98% conversion). In addition, analysis of the reaction mixture
after addition of tert-butyl nitrite by thermal screening unit (TSU) showed no sudden gas-
release or exothermic event below 120 °C. Taking all these experiments into
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consideration, we deemed the reaction safe to be run on 1-2 kg scale. The excess nitrite
was destroyed by quenching the reaction mixture with aqueous sulfamic acid (H NSO )
3
3
solution,10 followed by addition of iPrOAc and phase-split. The resulting green organic
phase was repeatedly washed with 20% aq. NH Cl and brine to remove excess copper
4
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(
Figure 3). After removal of the organic solvent under reduced pressure, a dark yellow
crude solid with good chemical purity (ca. 95% a/a) was obtained.
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Addition of
.6 eq. H3NSO3
in H2O (10 vol.)
Addition of
iPrOAc
(10 vol.)
Washing of OP
with 20% aq. NH4Cl
(5 vol.)
Washing of OP
with 20% aq. NH4Cl
(5 vol.)
Washing of OP
with 15% aq. NaCl
(5 vol.)
0
RM
Phase split
Phase split
Phase split
Phase split
OP
(at rt)
(at rt)
(at rt)
(at rt)
(at rt)
(iPrOAc/MeCN)
Discard AP1
Discard AP2
Discard AP3
Discard AP4
Figure 3: Flow diagram of aqueous workup and aspect of aqueous phases after each
phase split. RM = reaction mixture; rt = room temperature; OP = organic phase; AP =
aqueous phase.
However, ICP/MS analysis showed that the crude product was contaminated with high
levels of residual copper (> 1000 ppm). Recrystallization of the crude product proved to
be challenging due to its high solubility in a wide range of organic solvents (TBME, EtOH,
iPrOH, iPrOAc, toluene). The low-melting solid (mp: 81 °C by DSC) also showed the
tendency to oil-out from highly nonpolar solvents such as heptane or methylcyclohexane.
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On the other hand, the crude product was completely insoluble in H O. After many
2
crystallization attempts, it was found that the crude product could be successfully
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recrystallized from a 2:1-mixture of H O and EtOH to isolate the product as an off-white
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solid. In order to avoid concentration of the organic phase to dryness to isolate the crude
product, a solvent swap from iPrOAc/MeCN to EtOH was introduced after the aqueous
workup, followed by addition of H O to induce crystallization of the product. This solvent
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swap-crystallization procedure was demonstrated on 5-25 g scale and led to the isolation
of bromo thiadiazole 6 in good yield (70-75%) and purity (97% a/a) (Scheme 3). The
residual copper content was found to be 50-100 ppm for these batches and hence
drastically reduced compared to the crude material.
Scheme 3: Gram-Scale Sandmeyer reaction
CuBr (1.5 eq.)
tBu-ONO (1.5 eq.)
2
O
O
S
S
H N
Br
2
OEt
OEt
MeCN (10 vol.), rt, 1 h
N N
N N
7
0-75% yield
5
6
5
-25 g scale reactions
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For the screening of the Suzuki-Miyaura coupling, we decided that it was best to
additionally purify the bromo thiadiazole 6 by column chromatography to exclude any
possible interference of residual Cu with the Pd-catalyst system. Many of our initial efforts
were fruitless, and using Pd(PPh ) , Pd(OAc) /SPhos or Pd(OAc) /XPhos in combination
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not provide any trace of coupling product 1, and mainly unreacted and/or hydrolyzed
bromo thiadiazole 6 was observed. More promising was the use of bidentate phosphine
ligands such as dppf or Xantphos. In particular, Pd(OAc) /Xantphos proved to be a highly
2
active catalyst system, and full conversion of 6 was achieved with different bases and
solvent combinations (entries 4-9). The major difference between the individual reactions
was the degree at which the starting material 6 was hydrolyzed over the course of the
reaction. Conditions that enhance the saponification of the ethyl ester in the starting
material, e.g. water-miscible THF with strong inorganic bases (K PO or Cs CO entries
3
4
2
3,
4-5), led to a diminished overall purity of the final IPC (in-process control), as 6 was mainly
converted into its corresponding carboxylate salt. On the other hand, a biphasic system
of toluene and H O protected the starting material 6 from hydrolysis (entries 7-9). By
2
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employing a mild organic base such as N-methylmorpholine (NMM, entry 9), the
hydrolysis was almost completely suppressed, and a clean reaction profile was obtained
after stirring overnight at room temperature.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 1. Suzuki-Miyaura Coupling Screening at Room Temperature
Entry
Pd/L
Solvent
Base
Conversiona
Overall
Purityb
1
2
3
4
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
THF/H O
K PO
66%
25%
18%
28% a/a
16% a/a
8% a/a
2
3
4
THF/H O
K CO
2 3
2
THF/H O
Cs CO
2
2
3
Pd(OAc)2/
THF/H O
K PO
4
>98%
>98%
>98%
>98%
>98%
>98%
19% a/a
47% a/a
57% a/a
2
3
Xantphos
5
6
7
8
9
Pd(OAc)2/
THF/H O
Cs CO
2
2
3
3
3
Xantphos
Pd(OAc)2/
MeTHF/H O
Cs CO
2
2
Xantphos
Pd(OAc)2/
77% a/a
toluene/H O
Cs CO
2
2
Xantphos
Pd(OAc)2/
Toluene/H O
NEt3
73% a/a
90% a/a
2
Xantphos
Pd(OAc)2/
Toluene/H O NMM
2
Xantphos
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7
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Conditions: 100 mg 6 (0.42 mmol, 1.0 eq.), 7 (1.2 eq.), base (2.0 eq.), Pd/L (3.0 mol%),
a
organic solvent/H O (2:1, 12 vol.), 23 °C. Conversion was judged by consumption of 6
2
b
relative to the formation of 1 by LC/MS at 230 nm. Overall purity refers to area/area (a/a)-
percentage of 1 in final IPC by LC/MS at 230 nm.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
On 25 g scale, the catalyst loading could be further reduced to 1.0 mol% and full
conversion was achieved after 5 h at room temperature. After phase split and solvent
swap to iPrOH, the product crystallized as off-white crystalline needles. The isolated yield
(85%) and purity of the product (99% a/a) were both excellent (Scheme 4).
Scheme 4: Gram-Scale Suzuki Coupling
Pd(OAc) (1.0 mol%)
2
Xanthphos (1.0 mol%)
NMM (2.0 eq.)
F
O
F
F
F
O
S
Br
S
OEt
B(OH)2
Toluene (8 vol.)
H O (4 vol.), rt, 5 h
2
OEt
N N
N N
6
7
1
8
5% yield
(1.2 eq.)
2
5 g scale reaction
SCALE UP. The Sandmeyer reaction performed well on 1.1 kg scale from a conversion
and impurity profile point-of-view (Scheme 5). The isolated yield (74%) and purity (96%
a/a, 96% w/w) were also in line with the results from small scale trials. However, the
aqueous washings proved to be much less effective in removing the excess copper, and
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the crystallized product was still intensely yellow and contained 820 ppm Cu. The
differences between the copper content of the gram-scale batches and the kg-batch can
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
most likely be explained by different O contents during the aqueous workup when using
2
laboratory or scale up equipment, respectively. On laboratory scale, the presence of
oxygen during the workup was most likely sufficient to convert all Cu(I) species into Cu(II).
However, in the 30 L reactor in our kilolab the O level is consistently lower - especially
2
during the aqueous workup - and a higher concentration of Cu(I) species are present,
11
which are known to be more challenging to remove by aqueous washings. A Suzuki-
Miyaura coupling use test of the material obtained from the kg-run revealed that the
conversion was sluggish and additional portions of Pd(OAc) /Xantphos needed to be
2
added to reach full conversion of 6. We concluded that interference of residual Cu with
the Pd-catalyst system was the most likely reason for the sluggish conversion. Due to the
high time pressure on the project, we decided to move on with the scale up, without
additional purification of the batch. In addition, by extrapolating the yield from the Suzuki-
Miyaura coupling use test, we estimated that we will get more than sufficient material for
the production of the preclinical candidate. Not surprisingly, the Suzuki-Miyaura coupling
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was very slow on 1.0 kg scale, and we added a total of 3.0 mol% of catalyst to reach full
conversion at 20-25 °C after 24 h (Scheme 5). The extended reaction time also led to
partial hydrolysis of 6, and the isolated product yield dropped to 61%. Nevertheless, the
amount (0.70 kg) and quality (95% a/a, 96% w/w. Main contaminant was Xantphos: 3.6%
a/a) of 1 were sufficient and allowed for the timely production of the final compound.
Scheme 5: Kg-Scale Synthesis of 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F
F
B(OH)2
7
(1.2 eq.)
CuBr (1.5 eq.)
Pd(OAc)2/Xanthphos (3.0 mol%)
NMM (2.0 eq.)
2
F
O
O
tBu-ONO (1.5 eq.)
MeCN (7 vol.), rt, 1 h
74% yield
F
O
S
S
H N
Br
S
2
OEt
OEt
Toluene (8 vol.), H2O (4 vol.), rt, 24 h
OEt
N
N
N
N
6
N
N
61% yield
1.0 kg scale
5
1
1.1 kg scale
After successful production of the final compound, we went back and improved the
isolation and purification procedure of the Sandmeyer reaction. We realized that a simple
charcoal treatment dramatically lowered the residual Cu content of the isolated product.
Therefore, after completed aqueous workup (an additional brine washing was also
implemented), the dark yellow organic phase was circulated through an inline charcoal
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cartridge system until the solution was light yellow, followed by crystallization from
EtOH/H O. Using this procedure on 250 g scale, the isolated product (72% yield, 99% a/a
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
purity, >98% w/w) was now light off-white and residual Cu was found to be 16 ppm. This
material performed very well in the Suzuki reaction, and on 200 g scale full conversion
could be achieved with 1.0 mol% catalyst after 7 h at room temperature, and the product
was isolated as light-yellow needles in high yield (85%) and purity (99% a/a, >98% w/w)
(Scheme 6).
Scheme 6: Improved Synthesis of 1 with Charcoal Treatment of 6
F
F
B(OH)2
7
(1.2 eq.)
CuBr (1.5 eq.)
tBu-ONO (1.5 eq.)
Pd(OAc)2/Xanthphos (1.0 mol%)
NMM (2.2 eq.)
2
F
O
O
F
O
S
S
H N
Br
S
2
OEt
OEt
MeCN (10 vol.), rt, 1 h
Toluene (8 vol.), H2O (4 vol.), rt, 7 h
OEt
N
N
N
N
6
N
N
71% yield
85% yield
200 g scale
5
1
250 g scale
CATALYST SYSTEM. We were curious why the Pd(OAc) /Xantphos catalyst system
2
showed such a remarkable high reactivity in the Suzuki-Miyaura coupling. A recent report
by Eastgate and Blackmond on a Pd/Xantphos-catalyzed C–H arylation reaction
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
suggested that under their reaction conditions, the active ligand was not Xantphos or
Xantphos bisphosphine oxide, but the bisphosphine monoxide form of Xantphos (Figure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
4
). This previously unknown hemilabile, bidentate ligand for palladium was identified by
several experiments to be responsible for the catalytic activity. They also proved that
addition of excess free Xantphos relative to the Pd-source significantly inhibited the
coupling. It was concluded that non-oxidized Xantphos has a higher binding strength to
Pd as the bisphosphine monoxide form (and the bisphosphine oxide) and therefore the
Pd-centre would be saturated with free Xantphos, resulting in the formation of an inactive
catalyst. We observed the same phenomenon: when a 3-fold excess of Xantphos relative
to Pd(OAc) was used, the reaction basically shut down and only 7% conversion of bromo
2
thiadiazole 6 was obtained after 2 h at room temperature (ca. 20% after 18 h).13 In
addition, analyzing an equimolar mixture of 6, Xantphos and Pd(OAc)2 in d8-
toluene/D O/NMM by 31P-NMR showed two phosphorus resonances at 15.7 and 26.7
2
ppm, which is most likely in accordance with the formation of a highly active Xantphos
mono-oxide complex of Pd (X = Br or NMM) in our Suzuki-coupling (signal at 26.5 ppm
corresponds to Xantphos bis-oxide).14
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b)
EtO
N
O
S
N
X
a)
Pd
O
(Ph) P
P(Ph)2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd
O
P(Ph)2
P(Ph)2
(Ph) P
P(Ph)2
O
2
O
Pd(OAc) , base
2
O
H2O
Me Me
Me Me
Me Me
hemilabile ligand
Figure 4: a) Schematic representation of Xantphos mono-oxide as hemilabile ligand. b)
31P-NMR spectrum of proposed Pd-Xantphos mono-oxide complex in Suzuki coupling of
6.
FORMATION OF CARBOXYLATE SALT. The next synthetic step towards our final
compound was an amide coupling on the carboxyl moiety of 1. As mentioned before, the
free acid of 1 was found to be completely unstable and decarboxylated in minutes at room
temperature. Therefore, we envisioned two strategies for this key amide bond formation:
a) Direct amidation of the ethyl ester, or b) finding a stable carboxylate salt and employ it
in the amide coupling. Our medicinal chemistry colleagues found an initial solution by
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
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5
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5
5
5
5
5
5
5
6
mixing 1 in THF/aq. NaOH and then removal of the organic solvent and water under
reduced pressure to give the stable sodium salt 9-Na. With regards to a potential scale
up, this procedure was not optimal, as the 9-Na did not crystallize from THF. Therefore,
large amounts (> 20 vol.) of an aqueous organic solvent mixture would have needed to
be removed to isolate the product. In order to circumvent this problem, we initially found
that potassium salt 9-K was conveniently formed when 1 was treated with potassium
trimethylsilanolate (KOTMS) in TBME/THF. The reaction with a THF-solution of KOTMS
was dose-controlled and 9-K crystallized directly from the reaction mixture. However, 9-
K showed poor filterability and was also completely insoluble in any organic solvent and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H O, and even recording a standard NMR was difficult. Therefore, we turned our attention
2
to the synthesis of lithium salt 9-Li. After many screenings, we found that the lithium salt
could be prepared by heating a THF mixture of 1, LiOH monohydrate (1.2 eq.) and H O
2
(2.5 eq.) to 45 °C. 9-Li nicely crystallized over the course of the reaction and could be
collected by filtration in quantitative yield and excellent purity (>99% a/a) (Scheme 7).
This salt form had much better physicochemical properties and nicely dissolved in DMF
to successfully perform the subsequent amide coupling. Finally, heavy metal content was
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measured for 9-Li, and without the use of any expensive scavengers during the whole
reaction sequence, both residual Pd and Cu were found to be below 10 ppm.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7: Formation of 9-K and 9-Li Carboxylate Salts.
LiOH·H2O (1.2 eq.)
H2O (2.5 eq.)
F
F
F
F
O
TMSOK (1.1 eq.)
TBME (8 vol.), rt, 5 min
94% yield
F
O
F
O
S
S
S
-
+
-
+
O K
OEt
THF (7 vol.), 45 °C, 16 h
O Li
N
N
N
N
N N
1
99% yield
150 g scale
9-Li
9-K
50 g scale
In summary, a robust and scalable route towards key thiadiazole building block 1 has
been developed. In order to avoid the use of Lawesson’s reagent on scale in the in-house
kilolab, commercially available 5 was converted into the desired product via a sequence
of Sandmeyer bromination and Suzuki-Miyaura coupling. Due to the hydrolytic instability
of bromo thiadiazole 6 and the propensity of the fluorinated phenylboronic acid 7 to
protodeboronate at higher temperature, mild Suzuki-Miyaura coupling conditions needed
to be found. Identifying Pd(OA) /Xantphos as highly active catalyst system, in
2
combination with NMM as mild base, allowed us to perform the key Suzuki-Miyaura
coupling at room temperature and to isolate the product in high yield and excellent quality.
The residual Cu content in the starting material was crucial for the success of the Suzuki-
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Miyaura coupling, as severe catalyst poisoning was observed when the content was too
high. Inline charcoal treatment during the workup of the Sandmeyer reaction solved the
problem, and the Suzuki-Miyaura coupling reliably worked with this “purified” material,
using only 1.0 mol% of catalyst. Finally, due to the instantaneous decarboxylation of free
acid 9, a stable carboxylate salt needed to be found. Lithium carboxylate 9-Li is a bench-
stable solid, which was formed from 1 in THF and LiOH monohydrate and crystallized
directly from the reaction mixture.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION. General information.
All commercially available materials and solvents were used as received. All small scale
reaction screenings were performed in 4 mL screw-cap vials under nitrogen atmosphere.
All other reactions were run in double-jacketed glass reactors flushed with nitrogen.
Reaction temperatures are expressed as ET = external temperature (e.g. reactor jacket)
or IT = internal temperature (temperature of reaction mixture). In-process control (IPC)
analyses by LC/MS for intermediates and final product were conducted on a Waters
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Acquity UPLC instrument using an Agilent Zorbax RRHD SB-aq column (2.1 x 50 mm,
1.8 µm). The mobile phase consisted of two eluents: A:Water/TFA 100:0.04 (v/v) and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
eluent B: Acetonitrile. For the formation of the carboxylate salt 9-Li, a basic eluent system
was used: Waters BEH C18 column (2.1 x 50 mm, 2.5 m). The mobile phase consisted
1
of two eluents: A: Water/NH [c(NH ) = 13 mmol/l] and eluent B: Acetonitrile. H NMR and
3
3
13
19
C NMR were measured on a Bruker Ultrashield 400 MHz, 101 MHz. F NMR spectra
1
were recorded with H decoupling in CDCl or D O referenced to TFA (-76.53 ppm).
3
2
Chemical shifts are expressed in parts per million (ppm) downfield from residual solvent
peaks and coupling constants are reported in Hertz (Hz). Splitting patterns are indicated
as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet.
Melting points were determined by differential scanning calorimetry (DSC).
Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (6). A 30 L double-jacketed glass-lined
reactor was charged with ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (5) (1.12 kg, 6.47
mol, 1.0 eq.) and CuBr (2.20 kg, 9.70 mol, 1.5 eq.). MeCN (7.7 L, 7.0 vol.) was added at
2
IT = 20−25 °C. Then, tert-butyl nitrite (1.15 L, 9.70 mol, 1.5 eq.) was added dropwise over
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0−90 minutes, keeping IT between 20−33 °C during addition. The reaction mixture was
stirred at IT = 20−25 °C for 30 min. A solution of H NSO (314 g, 3.23 mol, 0.50 eq.) in
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0
1
2
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H O (8.8 L, 8.0 vol.) was added slowly while maintaining IT between 20−30 °C. After
2
complete addition, iPrOAc (9.9 L, 9.0 vol.) was added and the phases were separated.
The organic phase was washed twice with 20% aq. NH Cl solution (2 x 5.5 L) and once
4
with 15% aq. NaCl (1 x 5.5 L). A slight vacuum was applied to the reactor and the organic
phase was concentrated at ET = 75 °C until a minimal stirring volume was reached. Then,
EtOH (total amount used for solvent switch: 12.5 L) was continuously added and the
distillation continued. Final EtOH content in the reactor after distillation: ca. 5.5 L (5.0
vol.). The mixture was kept at IT = 60−70 °C and H O (11 L, 10 vol.) was added over 15
2
min. The resulting suspension was cooled to IT = 20−25 °C over 1 h and then aged at IT
= 20−25 °C for 1 h. The solid was collected by filtration, washed with H O (3 x 2 L) and
2
then dried at 65 °C under vacuum for 5 h to give 6 (1.13 kg, 4.76 mol, 74% yield) as a
1
dark yellow crystalline solid. LC/MS purity: 96% a/a. m.p. 81 ºC (DSC); H NMR (400
13
MHz, d6-DMSO) 4.43 (q, J = 7.0 Hz, 2H), 1.34 (d, J = 7.0 Hz, 3H); C NMR (101 MHz,
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d6-DMSO) 163.6, 157.1, 144.7, 63.2, 39.5, 13.9. HRMS (ESI) m/z calcd for C H N O BrS
5
6
2
2
+
(
[M+H] ): 236.9328. Found: 236.9333.
1
1
1
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Ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (1). A 30 L double-jacketed
glass-lined reactor was charged with ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (6)
(1.0 kg, 4.22 mol, 1.0 eq.), 2,4-difluorophenylboronic acid (0.80 kg, 5.06 mol, 1.2 eq.),
Pd(OAc) (18.9 g, 84.4 mmol, 2.0 mol%) and Xantphos (48.8 g, 84.4 mmol, 2.0 mol%). A
2
solution of NMM (0.94 L, 8.44 mol, 2.0 eq.) in toluene (8 L, 8.0 vol.) was added at IT =
20−25 °C, followed by addition of H O (4 L, 4.0 vol.). The reaction mixture was strongly
2
stirred (250 rpm) at IT = 20−25 °C for 10 h, after which a second portion of Pd(OAc)2
(9.47 g, 42.2 mmol, 1.0 mol%) and Xantphos (24.4 g, 42.2 mmol, 1.0 mol%) was added.
The reaction mixture was continued to be stirred (250 rpm) at IT = 20−25 °C for 14 h.
Then, iPrOAc (2.5 L, 2.5 vol.) was added and the phases were separated. The aqueous
phase was extracted once with iPrOAc (5.0 L, 5.0 vol.). The combined organic phases
were recharged to the reactor, a slight vacuum was applied and the organic phase
concentrated at ET = 80 °C until a minimal stirring volume was reached. Then, iPrOH
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6
(
total amount used for solvent switch: 15 L) was continuously added and the distillation
continued. Final iPrOH content in the reactor after distillation: ca. 7 L (7.0 vol.). The
mixture was kept at IT = 65−75 °C and then slowly cooled to IT = 20−25 °C over 2 h. The
resulting suspension was aged for an additional hour at IT = 20−25 °C. The solid was
collected by filtration, washed with iPrOH (3 x 1 L) and dried at 65 °C under vacuum for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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0
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0
3
9
h to give 1 (0.70 kg, 2.59 mol, 61% yield) as yellow crystalline needles. LC/MS purity:
1
6% a/a. m.p. 122 ºC (DSC); H NMR (400 MHz, d6-DMSO) 8.42 (q, J = 7.8 Hz, 1H),
13
7.66 (m, 1H), 7.39 (m, 1H), 4.45 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); C NMR
(101 MHz, CDCl ) 165.1 (dd, J = 257, 12 Hz), 163.5 (dd, J = 8, 1 Hz), 160.6 (d, J = 5 Hz),
3
160.6 (dd, J = 256, 12 Hz), 158.8, 130.9 (dd, J = 10, 3 Hz), 114.3 (dd, J = 12, 4 Hz), 113.0
19
(dd, J = 22, 3 Hz), 104.8 (t, J = 26 Hz), 63.4, 14.2. F NMR (376 MHz, CDCl ) -102.60
3
(d, J = 11.1 Hz), -106.03 (d, J = 11.1 Hz). HRMS (ESI) m/z calcd for C H F N O S
11
9
2
2
2
+
([M+H] ): 271.0347. Found: 271.0350.
Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (6). Procedure with charcoal treatment:
a 10 L double-jacketed glass reactor was charged with ethyl 5-amino-1,3,4-thiadiazole-
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-carboxylate (5) (250 g, 1.44 mol, 1.0 eq.) and CuBr (484 g, 2.17 mol, 1.5 eq.). MeCN
2
(2.5 L, 10 vol.) was added at IT = 20−25 °C. Then, tert-butyl nitrite (260 mL, 2.17 mol, 1.5
1
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1
1
1
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0
eq.) was added dropwise over 45−60 minutes, keeping IT between 20−33 °C during
addition. The reaction mixture was stirred at IT = 20−25 °C for 60 min. A solution of
H NSO (86.1 g, 0.866 mol, 0.60 eq.) in H O (2.5 L, 10 vol.) was added slowly while
3
3
2
maintaining IT between 20−30 °C. After complete addition, iPrOAc (2.5 L, 10 vol.) was
added and the phases were separated. The organic phase was washed twice with 20%
aq. NH Cl solution (2 x 1.25 L) and twice with 15% aq. NaCl (2 x 1.25 L). The organic
4
phase was circulated through an inline charcoal filter system from 3M (ZetaCarbon
R55SP) until the aspect was light yellow (ca. 30 min circulation time). A slight vacuum
was applied to the reactor and the organic phase was concentrated at ET = 75 °C until a
minimal stirring volume was reached. Then, EtOH (total amount used for solvent switch:
3.0 L) was continuously added and the distillation continued. Final EtOH content in the
reactor after distillation: ca. 1.25 L (5.0 vol.). The mixture was kept at IT = 60−70 °C and
H O (2.5 L, 10 vol.) was added over 15 min. The resulting suspension was cooled to IT =
2
20−25 °C over 1 h and then aged at IT = 20−25 °C for 1 h. The solid was collected by
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filtration, washed with H O (3 x 0.5 L) and dried at 65 °C under vacuum for 3 h to give 6
2
(247 g, 1.04 mol, 72% yield) as a light off-white crystalline solid. LC/MS purity: 99% a/a.
0
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2
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0
Ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (1). A 10 L double-jacketed
glass reactor was charged with ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (6) (200 g,
0.844 mol, 1.0 eq.), 2,4-difluorophenylboronic acid (160 g, 1.01 mol, 1.2 eq.), Pd(OAc)2
(1.89 g, 8.44 mmol, 1.0 mol%) and Xantphos (4.88 g, 8.44 mmol, 1.0 mol%). A solution
of NMM (204 mL, 1.86 mol, 2.2 eq.) in toluene (1.6 L, 8.0 vol.) was added at IT = 20−25
°C, followed by addition of H O (0.8 L, 4.0 vol.). The reaction mixture was strongly stirred
2
(300 rpm) at IT = 20−25 °C for 7 h. Then, iPrOAc (0.6 L, 3.0 vol.) was added and the
phases were separated. The aqueous phase was extracted once with iPrOAc (1.0 L, 5.0
vol.). The combined organic phases were recharged to the reactor, a slight vacuum was
applied and the organic phase concentrated at ET = 80 °C until a minimal stirring volume
was reached. Then, iPrOH (total amount used for solvent switch: 4 L) was continuously
added and the distillation continued. Final iPrOH content in the reactor after distillation:
ca. 1.2 L (6.0 vol.). The mixture was kept at IT = 65−75 °C and then slowly cooled to IT =
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0−25 °C over 2 h. The resulting suspension was aged for an additional hour at IT =
0−25 °C. The solid was collected by filtration, washed with iPrOH (2 x 0.4 L) and dried
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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2
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5
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0
1
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0
1
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9
0
1
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9
0
at 65 °C under vacuum for 3 h to give 1 (193 g, 0.714 mol, 85% yield) as light-yellow
crystalline needles. LC/MS purity: 99% a/a.
Lithium 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (9-Li). A 4 L double-
jacketed glass reactor was charged with ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-
carboxylate (1) (150 g, 0.555 mol, 1.0 eq.) and THF (1.05 L, 7.0 vol.). LiOH monohydrate
(27.9 g, 0.666 mol, 1.2 eq.) and H O (25 mL, 1.39 mol, 2.5 eq.) were added and the
2
reaction mixture heated to IT = 43−45 °C and stirred for 24 h. The reaction mixture turned
from a clear solution into a suspension over the course of the reaction. The resulting
suspension was cooled to IT = 20−25 °C and was aged for 1 h at this temperature. The
solid was collected by filtration, washed with THF (2 x 0.25 L) and dried at 65 °C under
vacuum for 3 h to give 9-Li (138 g, 0.555 mol, quantitative yield) as an off-white crystalline
1
solid. LC/MS purity: >99% a/a. m.p. 155 ºC (DSC); H NMR (400 MHz, D O) 7.74 (m, 1
2
13
H), 6.89 (m, 2H); C NMR (101 MHz, D O) 168.0 (d, J = 5 Hz), 164.6 (dd, J = 254, 13
2
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