Highly selective synthesis of 2-(2H-1,2,3-Triazol-2-yl)benzoic acids

Article abstract of DOI:10.1021/acs.oprd.8b00349

A selective and scalable synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoic acid starting from 1-fluoro-2-nitrobenzene derivatives is presented. The four-step synthesis introduces the triazole at the start via N²-arylation of 4,5-dibromo-2H-1,2,3- triazole. A sequence of consecutive functional group transformations, namely hydrogenation, Sandmeyer iodination, and Grignard carboxylation, provides the target molecules in a reliable and scalable manner. The usefulness of this method is demonstrated by the synthesis of di- or tri(2H-1,2,3-triazol-2-yl)benzene derivatives, which are difficult to produce by other methods.

Full text of DOI:10.1021/acs.oprd.8b00349

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Highly Selective Synthesis of 2‑(2H‑1,2,3-Triazol-2-yl)benzoic Acids
Remo Roth,† Gunther Schmidt,* Alice Prud’homme, and Stefan Abele
Chemistry Process R&D, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH−4123 Allschwil, Switzerland
S
* Supporting Information
ABSTRACT: A selective and scalable synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoic acid starting from 1-fluoro-2-nitrobenzene
derivatives is presented. The four-step synthesis introduces the triazole at the start via N2-arylation of 4,5-dibromo-2H-1,2,3-
triazole. A sequence of consecutive functional group transformations, namely hydrogenation, Sandmeyer iodination, and
Grignard carboxylation, provides the target molecules in a reliable and scalable manner. The usefulness of this method is
demonstrated by the synthesis of di- or tri(2H-1,2,3-triazol-2-yl)benzene derivatives, which are difficult to produce by other
methods.
KEYWORDS: orexin, 2H-1,2,3-triazoles, Sandmeyer reaction, Grignard reaction, scale-up
Halogen−magnesium exchange and trapping of the Grignard
species with CO2 should afford the desired products. These
procedures should be safe, robust, and suitable for a further
scale-up to 10 kg.
INTRODUCTION
■
Dual orexin antagonists (DORA), like suvorexant, are used to
treat primary insomnia. A patent screen in 2016 by Roch and
Boss showed that many patents were filed in the field of DORA
demonstrating the high interest in this topic.1 Many Active
Pharmaceutical Ingredients (APIs) described in this screen
have a common structural element: a 2-(2H-1,2,3-triazol-2-
yl)benzamide (Figure 1). Therefore, an efficient and general
synthesis of triazole benzoic acids is of high interest. A one step
synthesis to prepare these compounds via copper catalyzed
arylation of 1,2,3-triazole with 2-iodo- or 2-bromobenzoic
acids was described by Buchwald et al.2 A mixture of N-1 and
N-2 isomers is formed, which had to be separated by
crystallization or by column chromatography. This approach
was employed successfully for the synthesis of Suvorexant by
Merck.3 The regioisomers of the benzoic acid were separated
via crystallization of the corresponding sodium benzoate. A
highly N2-selective palladium catalyzed arylation of 1,2,3-
triazoles was introduced by Buchwald et al.4 Yields of 46−91%
and excellent N2-selectivity of >95% were obtained. Since the
triazole is a good directing group, these derivatives could
straightforwardly be converted to benzoic acids via C−H
activation. Palladium catalyzed halogenation,5 ethoxycarbony-
lation,6 and rhodium catalyzed cyanation were the key steps in
these transformations.7 Barth et al. produced the benzoic acid
of Suvorexant by deprotonating 2-(p-tolyl)-2H-1,2,3-triazole
with tert-butyllithium at −80 °C and trapping the anion with
CO2.8 The precursor was produced via copper catalyzed
cyclization of glyoxal toluylosazone.9
RESULTS AND DISCUSSION
■
Synthesis of 2-(2H-1,2,3-Triazol-2-yl)benzoic Acids
5a−d. The synthesis started with the 1-fluoro-2-nitrobenzene
derivatives 6a−d, which are available on kilogram scale, and
with dibromo triazole, which was prepared in high yield from
triazole, bromine, and sodium hydroxide in water (Scheme
1).11 The N-arylation was performed with potassium carbonate
as base in DMF at elevated temperatures according to the
literature procedure.10 The products 7a−d were precipitated
by addition of water and isolated by filtration. The yields were
high (78−95%), and purity by LC-MS was greater than 98%
area percent (% a/a). The N − 1 isomers could not be
observed. The hydrogenation of the nitro compounds 7a−d
was performed in a 3 L double jacketed autoclave. EtOAc was
chosen as solvent and Pd/C as catalyst. The reduction of the
nitro group was fast at the beginning, but the reaction stalled
due to catalyst poisoning by the generated HBr. In the
presence of triethylamine, the nitro reduction was sluggish. If
potassium or sodium acetate (2.1 equiv) was present from the
beginning, the nitro reduction and debromination proceeded
smoothly. The hydrogenation was exothermic and conversion
was complete after 1−2 h to cleanly produce the desired
anilines. The exothermicity of the reaction could easily be
controlled by adjusting the stirrer speed. Filtration of the
catalyst, aqueous work up, and precipitation of the anilines as
sulfates salts from isopropanol afforded the desired products
8a−d in high yields and purities. The sulfate salts were chosen
since the subsequent Sandmeyer reaction was run in aqueous
sulfuric acid. At first, the aryl bromide was targeted.
Diazotization was performed with tert-butyl nitrite in
For the Idorsia Orexin program, different triazole benzoic
acids 5a−8a on gram to kilogram scale were on demand
(Figure 2). A selective, general approach was chosen for their
synthesis. These procedures should further scale-up to 10 kg.
The strategy described by Wang et al., who found that 4,5-
dibromo-1,2,3-triazole was arylated highly selectively at the N-
2 position, seemed attractive to us:10 2-fluoronitrobenzenes
reacted with dibromotriazole in >90% yield to single
regioisomers, and further reduction by hydrogenation afforded
the ortho triazole anilines. Our intention was to convert the
anilines into iodobenzenes via a Sandmeyer reaction.
12
acetonitrile in the presence of CuBr2 or in water with
Received: October 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Figure 1. Selection of DORA APIs (2−4) from a patent screen of 2016 and Suvorexant 1.
temperature provided the product 9a in high purity 97% a/a as
a yellow oil. The iodide 9a was still contaminated by the 2-
phenyl-2H-1,2,3-triazole. In the final step, 9a was reacted with
iPrMgCl in THF at −20 °C. An aliquot was treated with
ammonium chloride and analyzed by LC-MS, proving a
complete I/Mg-exchange. CO2 was bubbled through the
reaction mixture at −20 to −10 °C. The addition was
exothermic, and the color changed from brown to yellow. The
exothermicity of the reaction was controlled by the feeding rate
of the CO2. After the exotherm had ceased, the mixture was
treated with aqueous HCl. THF was removed by distillation,
and the product was extracted into DCM. The crude product
was crystallized from toluene, and 5a was obtained in a yield of
78% as a yellow solid with a purity of >99% a/a. The overall
yield of the four-step sequence was 41%, and 22 g of the
benzoic acid 5a was produced.
For 5b, the procedure was similar to that for 5a, except the
Sandmeyer reaction produced the iodide 9b in a much cleaner
fashion. The reduced product was not observed and the purity
of the crude product was >98% a/a. In addition, the purity of
the product could be further upgraded by recrystallization from
iPrOH. Benzoic acid 5b was produced on 1 kg scale in an
overall yield of 48%. The procedure was further scaled up at a
custom manufacturer to 10 kg without issues.
The synthesis of benzoic acid 5c held similar challenges as
the synthesis of 5a. The iodination of 8c delivered an oily
product which was not clean enough for the following step.
Again, a purification by distillation was necessary. In total ca. 3
kg of crude material was produced which was distilled on a
short path distillation apparatus with a recovery of 2.5 kg. The
jacket temperature was adjusted to 120 °C and the vacuum to
0.004 mbar. The yield of the Sandmeyer reaction was 78%.
The benzoic acid 5c was produced once more on 1 kg scale
and on 10 kg with an external partner without issues. The
isomer 5d was made on 100 g scale. Interestingly, the
Sandmeyer product 9d was isolated as an orange solid in
Figure 2. 2-(2H-1,2,3-Triazol-2-yl)benzoic acid 5a−d.
sodium nitrite in the presence of CuBr. In general, the reaction
provided the products in 60−95% yield after purification, but
the work ups were challenging due to insoluble copper salts.
Therefore, we focused on the synthesis of the iodides 9a−d as
they are accessible without Cu salts. Instead, water-soluble
potassium iodide as halogen source was used. Sulfate 8a was
dissolved in aqueous sulfuric acid and treated with 1 equiv of
sodium nitrite at 0−5 °C. The diazonium salt was stable over a
period of 24 h at room temperature, as judged by LC-MS. In
addition, no gas evolution could be observed over this period.
Therefore, the diazonium salt solution was deemed stable at
0−5 °C and safe for a scale-up to 10 kg. For a further scale-up,
more safety investigation should be carried out. A solution of
potassium iodide in water was heated to 60−70 °C, and the
diazonium salt solution was added carefully in a dosed
controlled fashion. The conversion of the diazonium salt to
the product 9a directly after addition was >95%, as judged by
LC-MS. After aging at 60−70 °C for 20 min the reaction
provided the product in a purity of ca. 80% a/a. As a minor
impurity, 2-phenyl-2H-1,2,3-triazole was present with 2% a/a.
This impurity was easily removed in the next step. Two
impurities with 9 respectively 6% a/a with a mass of 415 g/mol
[M + 1] were problematic, because they were also converted
into carboxylic acids in the subsequent step. We were not able
to purify acid 5a by crystallization. Fortunately, distillation of
the iodophenyl triazole at 4 × 10−3 mbar and 84 °C head
Scheme 1. Synthesis of Triazole Benzoic Acids 5a−d from 1-Fluoro-2-nitrobenzenes 6a−d
B
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
a
Scheme 2. Preparation of 2,4-Di(2H-1,2,3-triazol-2-yl)benzoic Acid 15a and Benzaldehyde 15b
a
Reagents and conditions: (a) 11 (1.0 equiv), 10 (2.5 equiv), DMF, K2CO3 (3 equiv), 50 °C, 96%; (b) 10% Pd/C, H2, KOAc (5.0 equiv), EtOAc,
H2O, 60 °C, 80%; (c) (i) 2 M HCl, MeCN, NaNO2 (1.1 equiv), 5−15 °C, (ii) potassium iodide, 70 °C, 81%; (d) iPrMgCl (1.05 equiv), THF, 3
°C, (ii) CO2, −20 °C, 97%; (e) iPrMgCl (1.05 equiv), THF, −4 °C, (ii) DMF (2.0 equiv), −4 °C, 91%.
a
Scheme 3. Preparation of 2,6-Di(2H-1,2,3-triazol-2-yl)benzoic Acid 20a and Benzaldehyde 20b
a
Reagents and conditions: (a) 16 (1.0 equiv), 10 (2.2 equiv), DMF, K2CO3 (2.2 equiv), 50 °C, 99%; (b) (i) 10% Pd/C, H2, KOAc (5.0 equiv),
EtOAc, H2O, 60 °C, 86%; (c) (i) 2 M HCl, MeCN, NaNO2 (1.1 equiv), 0 °C, (ii) potassium iodide, 75 °C, 91%; (d) iPrMgCl (1.05 equiv), THF,
5 °C, (ii) CO2, −25 °C, 87%; (e) iPrMgCl (1.05 equiv), THF, −6 °C, (ii) DMF (4.0 equiv), 22 °C, 36%.
Scheme 4. Preparation of 2,4,6-Tri(2H-1,2,3-triazol-2-yl)benzoic Acid 25a, Benzaldehyde 25b, and 1,3,5-Tri(2H-1,2,3-triazol-
a
2-yl)benzene 25c
a
Reagents and conditions: (a) 21 (1.0 equiv), 10 (3.5 equiv), DMF, K2CO3 (3.4 equiv), 70 °C, 95%; (b) 10% Pd/C, H2, KOAc (7.0 equiv),
EtOAc, H2O, 60 °C, 69%; (c) (i) 2 M HCl, MeCN, NaNO2 (1.3 equiv), 5 °C, (ii) potassium iodide, 68 °C, 79%; (d) iPrMgCl (1.05 equiv), THF,
4 °C, (ii) CO2, −25 °C, 97%; (e) iPrMgCl (1.05 equiv), THF, −5 °C, (ii) DMF (4.0 equiv), 22 °C, 10%; (f) iPrMgCl (1.05 equiv), THF, 5 °C,
(ii) NH4Cl, 5 °C, 100%.
excellent purity. In summary, four benzoic acids 5a−d were
produced in a general and simple manner in an overall yield
between 40 and 55% and with high purities. The most difficult
operation for scale-up is the purification by distillation, which
is required for 9a and 9c.
The iodo compounds 9a−d are valuable building blocks for
further diversification. I−Mg exchange and trapping of the
Grignard species with an electrophile could deliver new 1,2,3-
triazole compounds. Many ortho-fluoro nitrobenzenes are
commercially available and should be compatible with this
synthetic sequence to prepare other triazole benzoic acids on
scale. Hence, we engaged to explore the synthesis of benzene
derivatives decorated with two or three 2H-1,2,3-triazole
moieties.
moieties attached. These compounds are difficult to access by
other methods, and not many examples are described in the
literature.13 We have chosen three examples: the 2,4 and the
2,6 disubstituted benzene derivatives (Scheme 2 and 3) and in
addition the 2,4,6 trisubstituted benzene derivatives (Scheme
4).
The N2 arylation of 10 with fluoro nitrobenzenes 11, 16, or
21 in DMF and K2CO3 worked as described in the literature in
high yields (>95%).10 The reaction temperatures were between
50 and 70 °C. The conversion was not easy to monitor by LC-
MS due to the low solubility of the products. In general, the
reaction was run for 15−24 h. After this time, water was added
and the products were isolated by filtration with high purities.
Compound 22 was almost insoluble in DMSO, DCM, MeCN,
acetone, or ethyl acetate. We identified only deutero DMF as a
suitable solvent for the measurement of NMR spectra.
The hydrogenation was carried out in ethyl acetate with
KOAc/water and 10% Pd/C. The hydrogenation of 12
proceeded in an exothermic mode at 3 bar of hydrogen and
Synthesis of Di- and Tri-2-(2H-1,2,3-triazol-2-yl)-
benzene Derivatives 15, 20, and 25. The highly selective
N2 arylation of dibromotriazole 10, followed by the
demonstrated reaction sequence, should allow for the facile
synthesis of benzene derivatives with two or three triazole
C
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
60 °C on 50 g scale. After the consumption of ca. 50% of the
theoretical amount of hydrogen, a thick suspension formed.
We speculated that some intermediate aniline prior debromi-
nation precipitated. The reaction was completed after 3 h, and
a nicely stirrable suspension was formed. The reaction mixture
was filtered at room temperature, and product 13 was isolated
after crystallization from iPrOH in a yield of 80%.
With the iodides 14, 19, and 24 available, the iodine−
magnesium exchange followed by quench with electrophiles
could be investigated. The 2,4-bis-triazole iodide 14 converted
cleanly to the corresponding benzoic acid 15a (97% yield) and
the benzaldehyde 15b (91% yield). While 2,6-substituted
benzoic acid 20a was produced in 87% yield, the benzaldehyde
20b was only formed in 36% yield. When DMF was added to
the Grignard species, ca. 20% of 1,3-di(2H-1,2,3-triazol-2-
yl)benzene was formed. Two crystallizations from iPrOH and
acetone were necessary to purify 20b. The tris-triazole
derivative 24 reacted with iPrMgCl in THF, but the Grignard
species precipitated. Nevertheless, the formation of benzoic
acid 25a was accomplished in a yield of 97%. The production
of the benzaldehyde 25b was troubled by the formation of ca.
30% of the reduced product 25c. 25c was even less soluble
than 25b, and purification via crystallization was difficult. 25b
could be isolated in a yield of 10% and a purity of 98% from
the mother liquor. 25c was produced on purpose by simple
addition of saturated ammonium chloride solution to the
reactive Grignard intermediate. Aqueous HCl was added to the
reaction mixture, and the product was collected by filtration in
excellent yield. The off-white product showed a melting point
of 398 °C (DSC). Analysis of the highly symmetrical
compound was difficult due to solubility issues. The product
was not sufficiently soluble in DCM, THF, EtOAc, acetone,
DMF, or DMSO even at elevated temperatures. Strong acids
were identified as good solvents. The product was well soluble
in sulfuric acid, TFA, or trifluoromethanesulfonic acid.
Unfortunately, reasonable NMR spectra in D2SO4 or in
deutero TFA could not be obtained. In the end, it was possible
to dissolve 25c in deutero TFA and dilute the mixture with
The 2,6-substituted nitrobenzene 17 was reduced with
similar reaction conditions, but once more a thick suspension
formed after the consumption of 33% of hydrogen. Again at
the end of the reaction the suspension was better stirrable. The
usual work up afforded 18 in a yield of 86%. Based on these
observations the reduction of the triple substituted nitro
compound 22 should be challenging with regard to the low
solubility of the aniline intermediate. Hence, the external
temperature was increased to 70 °C, the amount of EtOAc
increased from 10 to 20 volumes, and 60% more catalyst was
used. In practice, more than 500 g of nitrobenzene 22 was
reduced in 5 batches.14 The reaction mixtures (thick
suspensions) were combined and filtered. The usual work up
afforded the product in a yield of ca. 5%: it turned out that
aniline 23 precipitated in EtOAc and was filtered off with the
catalyst. The filter cake was rinsed with copious amounts of
THF, acetonitrile, and DCM. Finally, 52 g of 23 was isolated in
a yield of 30%. The aniline 23 was suspended in iPrOH (10
vol) and treated with sulfuric acid (1.05 equiv). The sulfate salt
was not formed, instead 23 was recovered from this mixture
with 98% by filtration. The reduction of the nitro compound
22 was repeated on 50 g scale. This time the mixture was
filtered over paper, the filtrate was discarded, and the cake was
suspended in 6 vol of TFA. The suspension was filtered over
Celite, the filtrate was concentrated, and the residue was taken
up in iPrOH. Aniline 23 was isolated with an improved yield of
69%.
1
CDCl3. This sample preparation was successful and H and
13C spectra were obtained. A LC-MS chromatogram was
recorded and a purity of 98.8% a/a was determined and a mass
of 280 g/mol [M + 1] was detected.
The Sandmeyer reaction was checked on 5 g scale with the
sulfate salt of 13. The salt did not dissolve in 10 vol of aqueous
sulfuric acid and upon addition of sodium nitrite the
diazonium salt formed but precipitated. The suspension was
added to an aqueous solution of potassium iodide at elevated
temperatures and the product 14 was formed in 81% yield.
The reaction was scaled up to 60 g and delivered 14 with a
reduced yield of 57%. Some sulfate salt of 13 was not
converted due to the low solubility in the reaction mixture.
Despite these issues, 40 g of iodide 14 was produced. For the
synthesis of 2,6-substituted iodide 19 the same problems
occurred. The yield of 19 was only 19% on 14 g scale. Since
the sulfate salt of tritriazole substituted aniline 23 was
impossible to form, the Sandmeyer reaction seemed challeng-
ing. Indeed, the reaction in sulfuric acid with sodium nitrite
showed no conversion to the diazonium salt by LC-MS.
Finally, 2 M HCl (10 vol) and acetonitrile (20 vol) were tried.
As expected the starting material did not dissolve, but upon
addition of sodium nitrite a clear solution was formed. The
iodide 24 was formed in 86% yield. Two more runs on 10 and
31.5 g went smoothly with reproducible yields of 85 and 81%,
respectively. The products were combined and recrystallized
from iPrOH, and a total of 46 g of 24 was produced. With this
improved procedure in hand, the Sandmeyer reaction with the
2,4-ditriazole aniline 13 and the 2,6-ditriazole aniline 18 was
repeated. The yield was 81% for iodide 14 and 91% for 19, but
most importantly no issues with precipitated diazonium salts
were encountered.
CONCLUSION
■
Four ortho (2H-1,2,3-triazol-2-yl)benzoic acids 5a−d have
been synthesized in four steps to support our in-house orexin
program. The aim was to prepare the different compounds
with a general method, which should be suitable to produce
gram and several kilogram quantities in a reliable and safe
manner. Several methods are described in the literature (vide
supra) to install the triazole moiety, and we opted for the
selective and high yielding procedure via 4,5-dibromo-2H-
1,2,3-triazole from Wang et al.10 Hence, the anilines 8a−d
were straightforwardly produced and further derivatized to the
iodides and finally to the benzoic acids in excellent yields and
purities. The general method was employed for the synthesis of
compounds bearing two or three triazole moieties (15, 20, and
25). In addition, the highly symmetric 1,3,5-tri(2H-1,2,3-
triazol-2-yl)benzene 25c was produced on gram scale.
EXPERIMENTAL SECTION15
■
1
General. Compounds are characterized by H NMR (500
MHz, Bruker) or 13C NMR (125 MHz, Bruker). Details for
the LC−MS methods are listed in the Supporting Information.
The purity is given in area percent (% a/a). Unless stated
otherwise, yields are given as is without correcting for purity.
4,5-Dibromo-2H-1,2,3-triazole (10). 1H-1,2,3-Triazole
(1347 g, 19.5 mol) and water (6.7 L) were charged to a 30
L glass lined reactor. The solution was heated to 45 °C. To the
D
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
solution was added bromine (1 L, 19.5 mol) at 45−48 °C over
a period of 20 min (exothermic addition). After five minutes a
white suspension was formed. To the suspension was dosed
simultaneously 50% aqueous NaOH solution (2027 mL, 38
mol) and bromine (1 L, 19.5 mol) at 40−52 °C over a period
of 30 min (very exothermic addition). The suspension was
cooled to 20 °C and treated with 40% aqueous bisulfite
solution (350 mL). The suspension was filtered, and the cake
was washed with water (6 L). The product was dried on a 20 L
rotavap at 60 °C under reduced pressure for one hour to yield
an off white solid. Yield: 4.23 kg (96%). Purity (LC-MS
method 2): 100% (210 nm), tR 0.66 min, mp 192 °C (DSC
(onset), decomposition); 13C NMR (125 MHz, D6-DMSO) δ:
124.2.
at 3 × 10−3 mbar (head temperature: 85−95 °C) to afford a
yellow oil as product. Yield: 6.7 g (64%). Purity (LC-MS
1
method 2): 97% (210 nm), tR0.86 min; H NMR (500 MHz,
CDCl3) δ: 7.99 (m, 1H), 7.89 (m, 2H), 7.47 (m, 2H), 7.18
(m, 1H), 13C NMR (125 MHz, CDCl3) δ: 143.2, 140.4, 135.6,
130.9, 128.9, 127.8, 92.8.
2-(2H-1,2,3-Triazol-2-yl)benzoic Acid (5a). Iodide 9a (41.2
g, 0.152 mol) was dissolved in THF (300 mL), and the
solution was cooled to −20 °C. Isopropylmagnesium chloride
(80 mL as a 2 M solution in THF, 0.160 mol) was added
slowly at −20 °C. The mixture was stirred for 20 min. CO2
(gas) was bubbled through the reaction mixture until no
exotherm was observed. Temperature was kept between −20
°C and −10 °C. One M HCl (100 mL) was added to the
mixture. THF was removed under reduced pressure. The
residue was diluted with iPrOAc (300 mL) and H2O (50 mL).
Layers were separated, and the pH of the aqueous layer was
adjusted to 1 with 2 M HCl (50 mL). The aqueous layer was
extracted consecutively with iPrOAc (100 mL), TBME (100
mL), and DCM (300 mL). Organic layers were combined and
concentrated under reduced pressure to give a yellow solid as
crude material (25.8 g). The benzoic acid was recrystallized
from toluene (200 mL) to yield a yellow solid. Yield: 22.3 g
(78%). Purity (LC-MS method 1): 100% (220 nm), tR0.81
min; [M + 1]+ = 190, mp 138 °C (DSC); 1H NMR (500 MHz,
D6-DMSO) δ: 13.08 (m, 1H), 8.09 (s, 2H), 7.77 (m, 2H), 7.71
(m, 1H), 7.60 (td, J1 = 1.3 Hz, J2 = 7.5 Hz, 1H), 13C NMR
(125 MHz, D6-DMSO) δ: 168.1, 137.9, 136.8, 132.2, 130.0,
129.3, 128.6, 124.8.
4,5-Dibromo-2-(2-nitrophenyl)-2H-1,2,3-triazole (7a). A
mixture of fluoro-2-nitrobenzene 6a (100 g, 0.709 mol),
K2CO3 (97.9 g, 0.709 mol), DMF (450 mL), and 4,5-dibromo-
2H-1,2,3-triazole 10 (161 g, 0.709 mol) was stirred at 80 °C
overnight. The suspension was diluted with H2O (1.5 L) at 50
°C and filtered at 22 °C. The cake was rinsed with H2O (500
mL) and iPrOH (500 mL). The product was dried under
reduced pressure at 50 °C to yield an off-white solid. Yield:
234 g (95%). Purity (LC-MS method 2): 100% (210 nm), tR
1
1.00 min, mp 124 °C (DSC); H NMR (500 MHz, D6-
DMSO) δ: 8.18 (d, J = 8.1 Hz, 1H), 8.02 (m, 1H), 7.96 (m,
1H), 7.84 (m, 1H), 13C NMR (125 MHz, D6-DMSO) δ:
143.3, 134.9, 131.8, 131.2, 128.7, 126.6, 126.0.
2-(2H-1,2,3-Triazol-2-yl)aniline Sulfate (8a). Nitro com-
pound 7a (213 g, 0.612 mol), KOAc (127 g, 1.29 mol) and
10% Pd/C (50% wet, 32.6 g), EtOAc (1 L), and H2O (100
mL) were charged to a 3 L double jacketed autoclave equipped
with a hollow shaft stirrer, equipped with a hydrogen pressflow.
The reaction mixture was pressurized 3 times to 3 bar with
nitrogen and two times with hydrogen to 3 bar. The
suspension was stirred under hydrogen (1 bar) for 2 h at 65
°C. The reaction mixture was cooled to 22 °C and filtered over
paper. Layers were separated, and the organic layer was washed
with 16% aqueous NaOH (320 mL) and H2O (2 × 250 mL).
The organic layer was concentrated to dryness under reduced
pressure. The residue was diluted with iPrOH (1 L) and
heated to 60 °C. Concentrated H2SO4 (60 g, 0.612 mol) was
added. The suspension was cooled to 20 °C and filtered. The
product was dried under reduced pressure at 60 °C to yield a
white solid. Yield: 135.8 g (86%). Purity (LC-MS method 2):
100% (210 nm), tR0.68 min; [M + 1]+ = 161, mp 195 °C
(DSC); 1H NMR (500 MHz, D2O) δ: 7.96 (m, 2H), 7.89 (d, J
= 8.0 Hz, 1H), 7.49 (m, 2H), 13C NMR (125 MHz, D2O) δ:
136.8, 132.5, 130.1, 129.6, 125.2, 123.6, 122.2.
2-(2-Iodophenyl)-2H-1,2,3-triazole (9a). Aniline 8a (10 g,
0.039 mol) was dissolved in 2 M H2SO4 (50 mL), and the
solution was cooled to 0 °C. A solution of sodium nitrite (2.67
g, 0.039 mol) in H2O (15 mL) was added, keeping the internal
temperature below 10 °C. The solution was stirred for 10 min.
In another flask, potassium iodide (9.64 g, 0.058 mol) was
dissolved in H2O (15 mL) and the solution was heated up to
70 °C. The diazonium salt solution was added over 10 min.
The dark foaming mixture was stirred for two hours at 70 °C.
The mixture was cooled to 22 °C. Isopropyl acetate (100 mL)
was added, and the layers were separated. The organic layer
was washed with H2O (100 mL), sat. aqueous thiosulfate
solution (100 mL), and H2O (100 mL). The organic layer was
concentrated under reduced pressure to give a brown oil as
crude material (9.8 g). The product was purified by distillation
4,5-Dibromo-2-(4-methoxy-2-nitrophenyl)-2H-1,2,3-tria-
zole (7b). A mixture of 4-fluoro-3-nitroanisole 6b (80 g, 0.453
mol), 4,5-dibromo-2H-1,2,3-triazole 10 (108 g, 0.476 mol),
K2CO3 (68.9 g, 0.499 mol), and DMF (560 mL) was heated to
120 °C for 21 h. The reaction mixture was cooled to 10 °C and
diluted with H2O (1.2 L). The resulting suspension was
filtered, and the cake was washed with H2O (200 mL). The
product was dissolved in iPrOAc (1 L). The organic layer was
washed with H2O (700 and 500 mL) and evaporated under
reduced pressure. To the residue was added iPrOH (500 mL).
The resulting suspension was filtered and the off-white solid
was dried under reduced pressure. Yield: 133 g (78%). Purity
(LC-MS method 2): 100% (210 nm), tR 1.03 min, mp 118 °C
1
(DSC); H NMR (500 MHz, D6-DMSO) δ: 7.91 (d, J = 8.9
Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.48 (dd, J1 = 2.8 Hz, J2 =
9.0 Hz, 1H), 3.94 (s, 3H), 13C NMR (125 MHz, D6-DMSO)
δ: 160.9, 144.5, 128.3, 127.8, 124.5, 120.0, 111.1, 57.2.
5-Methoxy-2-(2H-1,2,3-triazol-2-yl)aniline Monosulfate
(8b). Nitro compound 7b(100 g, 0.265 mol), NaOAc (76 g,
0.556 mol), and 10% Pd/C (50% water wet, 10.1 g) were
suspended in EtOAc (1 L) and H2O (100 mL). The reaction
mixture was pressurized with nitrogen three times to 3 bar and
two times with hydrogen to 3 bar. The mixture was heated to
50 °C and set under hydrogen (2 bar) for one hour. The
reaction mixture was filtered at 23 °C. The cake was rinsed
with H2O (400 mL). Layers were separated, and the organic
layer was washed with a 10% aqueous citric acid solution (400
mL) and with H2O (500 mL). The organic layer was
concentrated under reduced pressure to give an oil (52 g).
The crude aniline was dissolved in iPrOH (350 mL), and conc.
H2SO4 (14.6 mL, 0.273 mol) was added below 40 °C. The
suspension was cooled to 22 °C and filtered. The cake was
washed with iPrOH (50 mL) and TBME (150 mL). The solid
was dried under reduced pressure to obtain a white solid.
E
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Yield: 70.4 g (89%). Purity (LC-MS method 2): 100% (210
= 0.7 Hz, J2 = 8.3 Hz, 1H), 2.54 (s, 3H), 13C NMR (125 MHz,
D6-DMSO) δ: 146.4, 141.2, 132.0, 131.3, 128.4, 127.1, 126.0,
21.3.
4-Methyl-2-(2H-1,2,3-triazol-2-yl)aniline Monosulfate
(8c). Nitro compound 7c (300 g, 0.276 mol), NaOAc
trihydrate (282 g, 2.07 mol), and 5% Pd/C (50% water wet,
30.9 g) were suspended in EtOAc (1.5 L). The reaction
mixture was pressurized with nitrogen three times to 3 bar and
two times with hydrogen to 3 bar. The mixture was heated to
40−50 °C and stirred under hydrogen (1 bar) in an autoclave
for 2 h.
1
nm), tR 0.71 min; [M + 1]+ = 191, mp 216 °C (DSC); H
NMR (500 MHz, D2O) δ: 7.97 (d, J = 1.3 Hz, 2H), 7.75 (d, J
= 9.0 Hz, 1H), 7.03 (m, 2H), 3.83 (s, 3H), 13C NMR (125
MHz, D6-DMSO) δ: 160.1, 142.2, 135.0, 124.8, 119.5, 103.1,
101.4, 55.5.
2-(2-Iodo-4-methoxyphenyl)-2H-1,2,3-triazole (9b). Ani-
line 8b (200 g, 0.694 mol) was dissolved in 2 M H2SO4 (1.4 L)
and cooled to −5 °C. To the mixture was added a solution of
sodium nitrite (62 g, 0.902 mol) in H2O (600 mL) at −5 to 0
°C. The mixture was stirred at 0 °C for 30 min and then added
carefully to a solution of potassium iodide (161 g, 0.971 mol)
in H2O (700 mL) at 65 °C. The mixture was stirred at 60 °C
for 20 min, cooled to 22 °C, and treated with a solution of
sulfamic acid (27 g, 0.278 mol) in H2O (120 mL). The mixture
was extracted with iPrOAc (2 L). The organic layer was
washed with a mixture of 2 N NaOH (500 mL) and 40%
aqueous bisulfite solution (100 mL), 1 M HCl (50 mL) and
H2O (500 mL). The organic layer was concentrated to dryness
under reduced pressure to yield 204 g of a red solid. The
residue was dissolved in iPrOH (700 mL) at 70 °C and cooled
to 2 °C. The suspension was filtered. The yellow solid was
rinsed with iPrOH (150 mL) and dried under reduced
pressure. Yield: 164 g (79%). Purity (LC-MS method 1):
100% (210 nm), tR 1.54 min; [M + 1]+ = 302; 1H NMR (500
MHz, CDCl3) δ: 7.87 (s, 2H), 7.49 (d, J = 2.7 Hz, 1H), 7.38
(d, J = 8.8 Hz, 1H), 7.00 (dd, J1 = 2.7 Hz, J2 = 8.8 Hz, 1H),
3.87 (s, 3H), 13C NMR (125 MHz, CDCl3) δ: 160.4, 136.8,
135.3, 128.3, 125.0, 114.5, 93.7, 55.9.
Five more batches with 300 g and one with 212 g were
hydrogenated (total input of 7c:2.012 kg, 5.56 mol). The
combined reaction mixtures were filtered over paper. The
filtrate (ca. 10 L) was washed with H2O (8 L), 1 M NaOH (4
L), and 50% aqueous NaOH (250 mL) and finally with H2O
(3 × 2 L). The organic layer was concentrated in a 30 L glass
lined reactor at 80 °C under reduced pressure (ca. 9 L solvent
was distilled off). iPrOH (12 L) was added to the residue. The
solution was again concentrated under reduced pressure, and
ca. 3 L solvent was removed. To the residue was added conc.
H2SO4 (573 g, 5.84 mol) below 50 °C. The suspension was
cooled to 20 °C and filtered. The cake was washed with iPrOH
(3 L). The product was dried at 60 °C to obtain a beige solid.
Yield: 1.298 kg (86%). Purity (LC-MS method 2): 100% (210
1
nm), tR 0.65 min; [M + 1]+ = 175, mp 219 °C (DSC); H
NMR (500 MHz, D6-DMSO) δ: 8.22 (s, 2H), 7.73 (d, J = 1.1
Hz, 2H), 7.59 (m, 4H), 7.31 (m, 1H), 7.25 (m, 1H), 2.36 (s,
3H), 13C NMR (125 MHz, D6-DMSO) δ: 136.7, 134.8, 130.1,
130.1, 127.4, 123.9, 123.1, 20.7.
5-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic Acid (5b). Io-
dide 9b (200 g, 0.664 mol) was dissolved in THF (2 L) and
cooled to 0 °C. Isopropylmagnesium chloride (350 mL as a 2
M solution in THF, 0.697 mol) was added at 0 °C. The
mixture was cooled to −20 °C, and CO2 (gas) was bubbled
into the solution over 30 min. To the mixture was added 2 N
HCl (600 mL) at 8 °C. THF was removed under reduced
pressure at 60 °C (2.4 L solvent removed). The residue was
extracted with TBME (1.6 L). The organic layer was washed
with 1 M HCl (200 mL). The product was extracted into the
aqueous layer with 1 M NaOH (600 and 200 mL). The
aqueous layer was filtered over activated charcoal (15 g,
DARCO), diluted with H2O (200 mL), and treated with 32%
aqueous HCl (160 mL). The resulting suspension was filtered
and washed with H2O (200 mL). The product was dried at 60
°C and reduced pressure to yield an orange solid. The
obtained product can be crystallized from toluene or H2O.
Yield: 127 g (87%). Purity (LC-MS method 1): 100% (210
2-(2-Iodo-5-methylphenyl)-2H-1,2,3-triazole (9c). Aniline
8c (1553 g, 5.7 mol) was dissolved in 1 M aqueous H2SO4
solution (11 L) and cooled to −5 °C. To the mixture was
added a solution of sodium nitrite (433 g, 6.27 mol) in H2O (4
L) at −5 to 0 °C. The mixture was stirred at 0 °C for 30 min
and then added to a mixture of potassium iodide (1325 g, 7.99
mol) in H2O (4 L) at 55−70 °C. The resulting dark mixture
was stirred at 60 °C for 20 min, cooled to 20 °C, and treated
with a solution of sulfamic acid (220 g, 2.28 mol) in H2O (900
mL). The mixture was extracted with iPrOAc (13 L). The
organic layer was washed with a mixture of 2 N NaOH (3.5 L)
and 40% aqueous sodium bisulfite solution (330 g), and a
mixture of 1 M HCl (280 mL) in H2O (3.5 L). The organic
layer was concentrated to dryness under reduced pressure at 60
°C to afford a brown oil. Yield: 1580 g (97%). Purity (LC-MS
method 1): 91% (210 nm), tR 1.59 min; [M + 1]+ = 286.
The crude product, together with a second batch (1411 g,
96%), was purified by distillation on a short path distillation
equipment at 120 °C jacket temperature, feeding tank (70 °C),
cooling finger (20 °C) and at a pressure of 0.004 mbar. Yield:
2.544 kg (78%). Purity (LC-MS method 1): 100% (210 nm),
1
nm), tR 1.07 min; [M + 1]+= 220, mp 130 °C (DSC); H
NMR (500 MHz, D6-DMSO) δ: 12.99 (bs, 1H), 8.02 (s, 2H),
7.65 (d, J = 8.8 Hz, 1H), 7.26 (m, 2H), 3.87 (s, 3H), 13C NMR
(125 MHz, D6-DMSO) δ: 167.5, 159.5, 136.2, 131.6, 130.4,
126.9, 117.5, 114.8, 56.3.
1
tR 1.59 min; [M + 1]+= 286; H NMR (500 MHz, CDCl3) δ:
4,5-Dibromo-2-(5-methyl-2-nitrophenyl)-2H-1,2,3-triazole
(7c). A mixture of 3-fluoro-4-nitrotoluene 6c (1.367 kg, 8.81
mol), 4,5-dibromo-2H-1,2,3-triazole 10 (1.999 kg, 8.81 mol),
K2CO3 (1.340 kg, 9.69 mol), and DMF (11 L) was heated to
75 °C for 15 h. The reaction mixture was cooled to 22 °C,
diluted with H2O (18 L), and filtered. The product cake was
washed with H2O (4 L) and iPrOH (5 L). The solid was dried
under reduced pressure to give an off white solid. Yield: 2811 g
(88%). Purity (LC-MS method 1): 100% (210 nm), tR 1.88
min; mp 123 °C (DSC); 1H NMR (500 MHz, D6-DMSO) δ:
7.87 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 0.8 Hz, 1H), 7.43 (dd, J1
7.85 (s, 2H), 7.81 (d, J = 8.1 Hz, 1H), 7.30−7.30 (m, 1H),
6.98 (m, 1H), 2.33 (s, 3H), 13C NMR (125 MHz, CDCl3) δ:
143.0, 140.0, 139.4, 135.5, 131.8, 128.5, 88.4, 20.8.
4-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid (5c). Iodide
9c (1250 g, 4.38 mol) was dissolved in THF (13 L) and cooled
to 0 °C. Isopropylmagnesium chloride (2.2 L as a 2 M solution
in THF, 4.38 mol) was added at 0 °C. The mixture was cooled
to −25 °C and CO2 (gas) was bubbled into the solution over
60 min until the exothermicity was ceased. Two N HCl (5 L)
was added at 4 °C, and the mixture was concentrated under
reduced pressure to remove 14.5 L solvent. The residue was
F
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
extracted with TBME (10 L). The organic layer was extracted
with 1 M NaOH (6 and 3 L). The combined aqueous layers
were treated with 32% aqueous HCl (1.23 L). The resulting
suspension was filtered and washed with H2O (5 L). The
yellow solid was dried at 60 °C and reduced pressure. Yield:
796 g (89%). Purity (LC-MS method 1): 100% (210 nm), tR
for 10 min. iPrOAc (800 mL) was added followed by 2 N
NaOH (180 mL) and a 40% aqueous solution of sodium
bisulfite (17 g). The pH was adjusted to 12 with 32% aqueous
NaOH (50 mL). Layers were separated, and the organic phase
was washed with H2O (200 mL) and 1 M HCl (20 mL). The
organic phase was concentrated to dryness to afford an orange
solid as crude material (82 g). The crude product was
dissolved in iPrOH (600 mL) at 70 °C. The solution was
cooled to 5 °C, and n-heptane (200 mL) was added. The
suspension was filtered, and the cake was rinsed with cold
iPrOH (150 mL). The yellow solid was dried under reduced
pressure at 65 °C. Yield: 67 g (80%). Purity (LC-MS method
2): 100% (210 nm), tR 0.83 min; mp 113 °C (DSC); 1H NMR
(500 MHz, CDCl3) δ: 7.89 (s, 2H), 7.85 (d, J = 1.0 Hz, 1H),
7.37 (m, 1H), 7.28−7.30 (m, 1H), 2.42 (s, 3H), 13C NMR
(125 MHz, CDCl3) δ: 141.4, 140.9, 140.7, 135.4, 129.6, 127.3,
92.7, 20.7.
5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid (5d). Io-
dide 9d (153 g, 0.54 mol) was dissolved in THF (1.5 L),
and the solution was cooled to −5 °C. Isopropylmagnesium
chloride (290 mL as a 2 M solution in THF, 0.58 mol) was
added over 20 min. The solution was further cooled down to
−25 °C, and CO2 (gas) was bubbled into the reaction mixture
over a period of 30 min. Two N HCl (400 mL) was added, and
the mixture was concentrated at 60 °C under reduced pressure.
To the residue was added TBME (1.4 L). Layers were
separated, and the organic phase was washed with 1 M HCl
(400 mL). The organic phase was extracted with 1 M NaOH
(400 and 200 mL). The organic layer was discarded, and the
combined basic aqueous phases were treated with activated
charcoal (3 g, DARCO) for 10 min. The suspension was
filtered over paper. To the filtrate was added 32% aqueous HCl
(55 mL), and the resulting suspension was filtered. The cake
was rinsed with H2O (150 mL). The solid was dried under
reduced pressure at 60 °C. The benzoic acid (92.3 g) was
crystallized from toluene (600 mL) to yield a yellow solid.
Yield: 87.1 g (80%). Purity (LC-MS method 2): 100% (210
nm), tR 0.66 min; [M + 1]+ = 204, mp 172 °C; 1H NMR (500
MHz, D6-DMSO) δ: 12.99 (s, 1H), 8.05 (s, 2H), 7.63 (m,
1H), 7.58 (d, J = 1.5 Hz, 1H), 7.50−7.52 (m, 1H), 2.43 (s,
3H), 13C NMR (125 MHz, D6-DMSO) δ: 168.1, 139.2, 136.5,
135.8, 132.5, 130.3, 128.7, 124.8, 20.9.
1
1.10 min; [M + 1]+= 204, mp 125 °C (DSC); H NMR (500
MHz, D6-DMSO) δ: 12.90 (bs, 1H), 8.06 (s, 2H), 7.68 (d, J =
7.9 Hz, 1H), 7.56 (d, J = 0.5 Hz, 1H), 7.41 (ddd, J1 = 0.7 Hz,
J2 = 1.6 Hz, J3 = 7.9 Hz, 1H), 2.44 (s, 3H), 13C NMR (125
MHz, D6-DMSO) δ: 167.9, 142.7, 138.2, 136.5, 130.2, 129.9,
126.2, 125.6, 21.2.
4,5-Dibromo-2-(4-methyl-2-nitrophenyl)-2H-1,2,3-triazole
(7d). A mixture of 4-fluoro-3-nitrotoluene 6d (90 g, 0.58 mol),
K2CO3 (80.2 g, 0.58 mol), 4,5-dibromo-2H-1,2,3-triazole 10
(132 g, 0.58 mol), and DMF (700 mL) was stirred at 85 °C for
20 h. After cooling to 22 °C, H2O (1.2 L) was added and the
resulting yellowish suspension was filtered. The cake was
rinsed with H2O (200 mL). The solid was stirred in iPrOH
(500 mL), filtered, and dried at 60 °C under reduced pressure.
Yield: 185.3 g (88%). Purity (LC-MS method 2): 98% (220
1
nm), tR 0.96 min; mp 155 °C (DSC); H NMR (500 MHz,
CDCl3) δ: 7.74 (d, J = 1.1 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H),
7.55 (ddd, J1 = 0.6 Hz, J2 = 1.8 Hz, J3 = 8.2 Hz, 1H), 2.53 (m,
3H), 13C NMR (125 MHz, CDCl3) δ: 143.1, 141.4, 133.8,
129.7, 127.9, 125.6, 125.5, 21.2.
5-Methyl-2-(2H-1,2,3-triazol-2-yl)aniline Sulfate (8d).
Nitro compound 7d (185 g, 0.51 mol) was suspended in
EtOAc (900 mL) in an autoclave equipped with a hollow shaft
stirrer. To the suspension was added NaOAc (105 g, 1.28 mol)
and 5% Pd/C (50% water wet, 19 g). The reaction mixture was
pressurized with nitrogen three times to 3 bar and two times
with hydrogen to 3 bar. The mixture was hydrogenated at 30
°C jacket temperature at 1 bar pressure. After 90 min the
hydrogen uptake stalled and triethylamine (140 mL, 1 mol)
and 5% Pd/C (50% water wet, 5 g) were added and the
reaction was continued until hydrogen (ca. 56.5 L) was
consumed. The suspension was filtered and the cake was rinsed
with H2O (1 L). 32% aqueous NaOH (20 mL) was added to
reach pH 10, and layers were separated. The organic phase was
washed twice with H2O (500 mL). The organic phase was
concentrated to dryness at 60 °C to give a red oil as crude
product (83.9 g). This oil was dissolved in iPrOH (1 L) and
heated to 50 °C. Concentrated H2SO4 (28.6 mL, 0.537 mol)
was added. The thick white suspension was stirred overnight at
22 °C and then filtered. The cake was rinsed with iPrOH (300
mL). The obtained white solid was dried at 60 °C under
reduced pressure. Yield: 119 g (86%). Purity (LC-MS method
2): 100% (210 nm), tR 0.70 min; [M + 1]+ = 175, mp 237 °C
(DSC); 1H NMR (500 MHz, D2O) δ: 7.98 (s, 2H), 7.78 (d, J
= 8.3 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.34 (d, 1H), 2.34 (s,
3H), 13C NMR (125 MHz, D2O) δ: 141.0, 136.7, 130.6, 130.2,
125.4, 123.5, 122.1, 20.0.
2,2′-(4-Nitro-1,3-phenylene) Bis(4,5-dibromo-2H-1,2,3-tri-
azole) (12). A mixture of 2,4-difluoronitrobenzene 11 (25 g,
0.157 mol), K2CO3 (65.2 g, 0.471 mol), 4,5-dibromo-2H-
1,2,3-triazole 10 (89.1 g, 0.393 mol), and DMF (250 mL) was
stirred overnight at 50 °C. To the suspension was added H2O
(500 mL) at 20 °C. The suspension was filtered and the cake
was rinsed with H2O (500 mL), iPrOH (500 mL) and TBME
(250 mL). The solid was dried under reduced pressure and 60
°C to afford an off-white product. Yield: 86.6 g (96%). Purity
(LC-MS method 2): 100% (210 nm), tR 1.21 min; mp 247 °C
1
(DSC); H NMR (500 MHz, D6-DMSO) δ: 8.42 (d, J = 2.3
2-(2-Iodo-4-methylphenyl)-2H-1,2,3-triazole (9d). Aniline
8d (80 g, 0.294 mol) was suspended in 1 M H2SO4 (560 mL)
and cooled to −5 °C. A solution of sodium nitrite (22.3 g,
0.323 mol) in H2O (240 mL) was added. The reaction mixture
was stirred at 2 °C for 20 min. In another vessel potassium
iodide (68.3 g, 0.411 mol) was dissolved in H2O (280 mL) at
85 °C. To this solution was added the diazonium solution over
20 min. Thirty min after the addition the reaction mixture was
cooled to 30 °C. A solution of sulfamic acid (11.4 g, 0.118
mol) in H2O (50 mL) was added, and the mixture was stirred
Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.30 (dd, J1 = 2.3 Hz, J2 =
8.9 Hz, 1H), 13C NMR (125 MHz, D6-DMSO) δ: 141.5,
141.2, 132.3, 130.1, 129.3, 128.5, 119.8, 115.4.
2,4-Di(2H-1,2,3-triazol-2-yl)aniline (13). Nitro compound
12 (50 g, 0.0873 mol), 10% Pd/C (50% water wet, 8.45 g),
KOAc (42.8 g, 0.436 mol), EtOAc (500 mL), and H2O (44
mL) were charged into an autoclave equipped with a hollow
shaft stirrer. The reaction mixture was pressurized with
nitrogen three times to 3 bar and two times with hydrogen
to 3 bar. The reaction mixture was stirred at 60 °C under
G
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
hydrogen (3 bar) for 3 h. The mixture was filtered over paper.
The filtrate was washed with H2O (500 mL). The organic layer
was separated and washed with 1 M NaOH (2 × 300 mL) and
H2O (300 mL). The organic layer was dried over MgSO4 and
filtered. The filtrate was concentrated at 60 °C under reduced
pressure. The residue was crystallized from iPrOH (300 mL),
and a white solid was obtained. Yield: 15.8 g (80%). Purity
(LC-MS method 2): 99% (210 nm), tR 0.80 min; [M + 1]+ =
distilled off under reduced pressure. The residue was diluted
with DCM (600 mL) and layers were separated. The organic
layer was washed with 1 M HCl (100 mL) and H2O (100 mL),
dried with MgSO4, filtered, and concentrated to give 6.86 g of
an off-white solid. The product was recrystallized from acetone
(75 mL), and a white solid was obtained. Yield: 6.47 g (91%);
Purity (GC-MS): 100%, tR 4.46 min; [M + 1]+ = 241, mp 211
1
°C (DSC); H NMR (500 MHz, D6-DMSO) δ: 10.27 (d, J =
1
228; H NMR (500 MHz, D6-DMSO) δ: 8.39 (d, J = 2.5 Hz,
0.7 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.35 (s, 2H), 8.31 (s,
2H), 8.27 (ddd, J1 = 0.7 Hz, J2 = 2.1 Hz, J3 = 8.6 Hz, 1H), 8.11
(d, J = 8.6 Hz, 1H), 13C NMR (125 MHz, D6-DMSO) δ:
190.1, 142.9, 141.6, 138.6, 138.6, 131.4, 127.2, 118.1, 112.6.
2,2′-(2-Nitro-1,3-phenylene) Bis(4,5-dibromo-2H-1,2,3-tri-
azole) (17). A mixture of 4,5-dibromo-2H-1,2,3-triazole 10
(119 g, 0.525 mol), 2,6-difluoronitrobenzene 16 (38 g, 0.239
mol), K2CO3 (72.6 g, 0.525 mol), and DMF (250 mL) was
stirred at 90 °C overnight. The suspension was cooled to 22
°C, and H2O (1.2 L) was added. The brown suspension was
filtered, and the cake was rinsed with H2O (1 L) and iPrOH
(500 mL). The solid was dried under reduced pressure to give
a light green solid. Yield: 136 g (99%). Purity (LC-MS method
2): 95% (210 nm), tR 1.17 min; mp 235 °C (DSC); 1H NMR
(500 MHz, D6-DMSO) δ: 8.22 (m, 2H), 8.08 (dd, J1 = 8.7 Hz,
J2 = 7.9 Hz, 1H), 13C NMR (125 MHz, D6-DMSO) δ: 135.3,
134.1, 131.2, 129.7, 126.4.
2,6-Di(2H-1,2,3-triazol-2-yl)aniline (18). Nitro compound
17 (82 g, 0.143 mol), 10% Pd/C (50% water wet, 13.9 g),
KOAc (70.3 g, 0.716 mol), EtOAc (1.0 L), and H2O (72 mL)
were charged into an autoclave equipped with a hollow shaft
stirrer. The reaction mixture was pressurized with nitrogen
three times to 3 bar and two times with hydrogen to 3 bar. The
mixture was stirred at a jacket temperature of 60 °C under
hydrogen (3 bar) for one hour. The mixture was filtered over
paper. The cake was rinsed with EtOAc (300 mL). The layers
were separated. The organic layer was washed with 16%
aqueous NaOH (100 mL) and H2O (2 × 100 mL). The
organic layer was filtered through a Whatman filter (4.5 μm).
The filtrate was concentrated to dryness under reduced
pressure to afford a yellow solid (33.7 g). The aniline 17
was crystallized from iPrOH (250 mL) to yield a white solid.
Yield: 28 g (86%). Purity (LC-MS method 2): 98% (210 nm),
tR0.82 min; [M + 1]+ = 228, mp 84 °C (DSC), 1H NMR (500
MHz, D6-DMSO) δ: 8.20 (s, 4 H), 7.78 (d, J = 8.1 Hz, 2 H),
6.92 (t, J = 8.1 Hz, 1 H), 6.58 (brs, 2 H), 13C NMR (125
MHz, D6-DMSO) δ: 136.1, 134.2, 127.0, 124.3, 116.2.
1H), 8.19 (s, 2H), 8.05 (s, 2H), 7.82 (dd, J1 = 2.5 Hz, J2 = 8.9
Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.43 (s, 2H), 13C NMR
(125 MHz, D6-DMSO) δ: 140.1, 136.1, 135.8, 129.6, 124.0,
119.7, 118.4, 113.4.
2,2′-(4-Iodo-1,3-phenylene) Bis(2H-1,2,3-triazole) (14).
Aniline 13 (5 g, 0.022 mol) was suspended in 2 M HCl (50
mL) and acetonitrile (50 mL). The suspension was cooled to 5
°C. A solution of sodium nitrite (1.67 g, 0.024 mol) in H2O
(10 mL) was added. The reaction mixture was warmed to 15
°C. In another flask, potassium iodide (11 g, 0.066 mol) was
dissolved in H2O (12.6 mL) at 70 °C. The first solution was
added dropwise to the potassium iodide solution. The reaction
mixture was stirred at 70 °C for 20 min. The mixture was
cooled to 20 °C. Sulfamic acid (0.214g, 0.0022 mol) was
added to the mixture as well as 40% bisulfite solution (10 mL).
Layers were separated, and the aqueous layer was extracted
with iPrOAc (2 × 50 mL). Organic layers were combined and
washed with H2O (2 × 50 mL). The organic layer was
concentrated under reduced pressure to yield a yellow solid as
crude material (7.2 g). The solid was recrystallized from
iPrOH (70 mL). Yield: 6 g (81%). Purity (LC-MS method 2):
1
100% (210 nm), tR 0.92 min; mp 132 °C (DSC); H NMR
(500 MHz, D6-DMSO) δ: 8.27 (d, J = 8.6 Hz, 1H), 8.21 (m,
4H), 8.11 (d, J = 2.5 Hz, 1H), 7.97 (dd, J1 = 2.5 Hz, J2 = 8.6
Hz, 1H), 13C NMR (125 MHz, D6-DMSO) δ: 143.9, 142.1,
140.0, 137.9, 137.0, 121.5, 117.5, 92.2.
2,4-Di(2H-1,2,3-triazol-2-yl)benzoic Acid (15a). Iodide 14
(10 g, 0.030 mol) was dissolved in THF (100 mL), and the
solution was cooled to 3 °C. Isopropylmagnesium chloride
(15.6 mL as a 2 M solution in THF, 0.031 mol) was added at 5
°C. The mixture was cooled to −25 °C. CO2 (gas) was
bubbled into the reaction mixture, which was then stirred for
one hour at −20 °C. Two M HCl (40 mL) was added. THF
was removed under reduced pressure. The residue was diluted
with iPrOAc (100 mL). Layers were separated, and the organic
layer was washed with 1 M HCl (100 mL) and extracted with 1
M KOH (2 × 30 mL). To the combined aqueous layers was
added conc. HCl until a pH of 1 was reached at 0 °C. The
suspension was filtered. The cake was rinsed with H2O (100
mL) and dried under reduced pressure at 55 °C to give an off-
white solid. Yield: 7.33 g (97%). Purity (LC-MS method 2):
100% (210 nm), tR 0.70 min; [M + 1]+ = 257, mp 187 °C
2,2′-(2-Iodo-1,3-phenylene) Bis(2H-1,2,3-triazole) (19).
Aniline 18 (10 g, 0.044 mol) was suspended in 2 M HCl
(50 mL) and MeCN (50 mL). The suspension was cooled to 0
°C, and a solution of sodium nitrite (3.3 g, 0.048 mol) in H2O
(20 mL) was added. The yellow solution was stirred for 1 h at
0 °C. In another flask, potassium iodide (21.9 g, 0.132 mol)
was dissolved in H2O (100 mL) at 70 °C. The diazonium salt
solution was added to this solution at an external temperature
of 75 °C. The mixture was cooled to 22 °C. Sulfamic acid
(0.44 g, 0.004 mol), a 40% aqueous solution of sodium
bisulfite (6 mL), and iPrOAc (200 mL) was added. The layers
were separated. The organic layer was washed with H2O (2 ×
100 mL). The organic layer was concentrated under reduced
pressure to yield a yellow solid (14.5 g). The product was
crystallized from iPrOH (100 mL). Yield: 13.6 g (91%). Purity
(LC-MS): 100%, tR 0.77 min; [M + 1]+ = 339, mp 144 °C
1
(DSC); H NMR (500 MHz, D6-DMSO) δ: 13.31 (bs, 1H),
8.37 (d, J = 2.1 Hz, 1H), 8.26 (s, 2H), 8.21 (dd, J1 = 2.1 Hz, J2
= 8.5 Hz, 1H), 8.18 (s, 2H), 7.97 (d, J = 8.5 Hz, 1H), 13C
NMR (125 MHz, D6-DMSO) δ: 167.5, 141.1, 138.7, 138.2,
137.4, 132.1, 127.2, 118.3, 113.9.
2,4-Di(2H-1,2,3-triazol-2-yl)benzaldehyde (15b). Iodide
14 (10 g, 0.0296 mol) was dissolved in THF (100 mL), and
the solution was cooled to −2 °C. Isopropylmagnesium
chloride (15.6 mL as a 2 M solution in THF, 0.031 mol) was
added at −4 °C. DMF (4.58 mL, 0.059 mol) was added, and
the red solution was stirred at −2 °C for 30 min and then at 20
°C for 1.5 h. Two M HCl (40 mL) was added. THF was
1
(DSC); H NMR (500 MHz, D6-DMSO) δ: 8.19 (m, 4H),
H
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
7.76 (m, 3H), 13C NMR (125 MHz,D6-DMSO) δ: 145.1,
136.8, 130.5, 129.6, 97.9.
H2O (50 mL) were charged into an autoclave equipped with
hollow shaft stirrer. The reaction mixture was pressurized with
nitrogen three times to 3 bar and two times with hydrogen to 3
bar. The reaction mixture was stirred at 60 °C under hydrogen
(3 bar) for one hour. The reaction mixture was cooled to 22
°C and filtered over paper. The cake was washed with H2O
(100 mL). The cake was suspended in TFA (300 mL). The
suspension was filtered over Celite (50 g). The filtrate was
concentrated under reduced pressure. The residue was diluted
with iPrOH (200 mL). The resulting suspension was filtered,
and the product was rinsed with iPrOH (50 mL). The solid
was dried under reduced pressure at 60 °C. Yield: 12.8 g
(69%). Purity (LC-MS method 2): 100% (210 nm), tR 0.95
min; [M + 1]+= 295, mp 276 °C (DSC); 1H NMR (500 MHz,
D6-DMSO) δ: 8.48 (s, 2H), 8.30 (s, 4H), 8.14 (s, 2H), 7.11
(br s, 2H), 13C NMR (125 MHz, D6-DMSO) δ: 136.8, 136.6,
132.9, 128.7, 126.7, 113.5.
2,6-Di (2H-1,2,3-triazol-2-yl)benzoic Acid (20a). Iodide 19
(6.6 g, 0.020 mol) was dissolved in THF (66 mL), and the
solution was cooled to 3 °C. Isopropylmagnesium chloride
(10.3 mL as a 2 M solution in THF, 0.021 mol) was added at 5
°C. The mixture was stirred for 5 min. The reaction mixture
was cooled to −25 °C. CO2 (gas) was bubbled into the
reaction mixture, which was then stirred for one hour at −20
°C. Two M HCl (25 mL) was added, and THF was removed
under reduced pressure. The residue was diluted with iPrOAc
(100 mL). Layers were separated, and the organic layer was
washed with 1 M HCl (100 mL) and extracted with 1 M KOH
(2 × 20 mL). To the combined aqueous layers was added
conc. HCl until a pH of 1 was reached at 0 °C. The suspension
was filtered. The cake was rinsed with H2O (50 mL) and dried
at 55 °C under reduced pressure to give an off-white solid.
Yield: 4.34 g (87%). Purity (LC-MS method 2): 99% (210
2,2′,2’’-(2-Iodobenzene-1,3,5-triyl) Tris(2H-1,2,3-triazole)
(24). Aniline 23 (31.5 g, 0.107 mol) was suspended in 2 M
HCl (315 mL) and acetonitrile (315 mL). The suspension was
cooled to 5 °C. A solution of sodium nitrite (9.59 g, 0.139
mol) in H2O (63 mL) was added at 5−7 °C, and the
suspension was warmed up to 22 °C. In another flask,
potassium iodide (53.3 g, 0.321 mol) was dissolved in H2O
(315 mL) at 58−68 °C. The diazonium salt solution was
added slowly to this solution. The reaction mixture was stirred
10 min at 65 °C. The mixture was cooled to 22 °C. Sulfamic
acid (4.15 g, 0.0428 mol) and iPrOAc (300 mL) were added.
The mixture was filtered over Celite, and layers were separated.
The organic layer was washed with a mixture of 2 M NaOH
(250 mL) and 40% aq. sodium bisulfite solution (50 mL), 1 M
HCl (300 mL), and H2O (300 mL). The organic layer was
concentrated to dryness to afford an orange solid as crude
material (34.9 g, 81%). The crude product was combined with
two other batches, which were produced in a similar fashion
(1.2 g + 11.7 g) and recrystallized in iPrOH (580 mL). Yield:
46.2 g (79%, calculated from 42.5 g aniline 23 (0.144 mol)).
Purity (LC-MS method 2): 98%, tR 0.9 min; [M + 1]+= 406,
1
nm), tR 0.59 min; [M + 1]+ = 257, mp 141 °C (DSC); H
NMR (500 MHz, D6-DMSO) δ: 13.22 (br s, 1H), 8.16 (s,
4H), 7.95 (d, J = 0.6 Hz, 1H), 7.94 (s, 1H), 7.84 (dd, J1 = 7.5
Hz, J2 = 8.7 Hz, 1H), 13C NMR (125 MHz, D6-DMSO) δ:
165.5, 137.9, 137.3, 131.6, 124.6. 124.0.
2,6-Di(2H-1,2,3-triazol-2-yl)benzaldehyde (20b). Iodide
19 (6.47 g, 0.019 mol) was dissolved in THF (65 mL), and
the solution was cooled to −6 °C. Isopropylmagnesium
chloride (10 mL as a 2 M solution in THF, 0.020 mol) was
added at −6 to 0 °C. The mixture was stirred for 5 min. DMF
(2.96 mL, 0.038 mol) was added. The mixture was warmed to
22 °C and stirred for two hours. The reaction mixture was
warmed to 40 °C. After 1.5 h, additional DMF (2.96 mL, 0.038
mol) was added and the reaction mixture was stirred for 1.5 h.
The mixture was quenched with 2 M HCl (25 mL), and THF
was evaporated. The residue was diluted with iPrOAc (100
mL), and layers were separated. The organic layer was washed
with 1 M HCl (100 mL) and H2O (100 mL), and dried over
MgSO4. The filtrate was concentrated under reduced pressure
to afford 4.68 g of an orange solid as crude material. The crude
benzaldehyde was suspended in iPrOH (55 mL) and filtered.
The recovered product (3.3 g) was again suspended in acetone
(50 mL) and filtered. The isolated solid was discarded. The
mother liquor was cooled to 0 °C and filtered. The product
was dried under reduced pressure at 60 °C. Yield: 1.66 g
(36%). Purity (GC-MS): 100%, tR 4.42 min; [M + 1]+ = 240,
mp 145 °C (DSC); 1H NMR (500 MHz, D6-DMSO) δ: 10.51
(s, 1H), 8.22 (s, 4H), 8.07 (d, J = 8.2 Hz, 2H), 7.91 (dd, J1 =
7.8 Hz, J2 = 8.5 Hz, 1H), 13C NMR (125 MHz, D6-DMSO) δ:
165.5, 137.9, 137.3, 131.6, 131.4, 124.6.
2,2′,2′′-(2-Nitrobenzene-1,3,5-triyl) Tris(4,5-dibromo-2H-
1,2,3-triazole) (22). A mixture of 4,5-dibromo-2H-1,2,3-
triazole 10 (112 g, 0.494 mol), K2CO3 (68.3 g, 0.494 mol),
2,4,6-trifluoronitrobenzene 21 (25 g, 0.141 mol), and DMF
(250 mL) was stirred at 70 °C overnight. The mixture was
cooled to 22 °C and H2O (500 mL) was added. The resulting
suspension was filtered, and the cake was rinsed with iPrOH
(500 mL) and TBME (250 mL). The beige solid was dried
under reduced pressure. Yield: 107 g (95%). Purity (LC-MS
method 2): 100% (220 nm), tR 1.33 min; 1H NMR (500 MHz,
D7-DMF) δ: 8.74 (s, 2H), 13C NMR (125 MHz, D7-DMF) δ:
140.0, 133.1, 132.6, 130.2, 130.0, 113.8.
1
mp 168 °C (DSC); H NMR (500 MHz, D6-DMSO) δ: 8.27
(m, 8 H), 13C NMR (125 MHz, D6-DMSO) δ: 145.9, 140.0,
138.5, 137.3, 118.3, 94.5.
2,4,6-Tri(2H-1,2,3-triazol-2-yl)benzoic Acid (25a). Iodide
24 (8 g, 0.020 mol) was dissolved in THF (80 mL), and the
solution was cooled to 4 °C. Isopropylmagnesium chloride
(10.4 mL as a 2 M solution in THF, 0.021 mol) was added at 5
°C and the mixture was stirred for 5 min. The mixture was
cooled to −25 °C. CO2 (gas) was bubbled into the reaction
mixture which was then stirred for one hour at −20 °C. Two
M HCl (25 mL) was added, and THF was removed under
reduced pressure. To the residue was added 1 M KOH until
pH = 14 was reached. The suspension was cooled to 0 °C and
acidified to pH = 1 with 32% aqueous HCl. The suspension
was filtered. The cake was rinsed with H2O (50 mL) and dried
at 55 °C under reduced pressure to give a white solid. Yield:
6.19 g (97%). Purity (LC-MS method 2): 100%, tR 0.73 min;
[M + 1]+= 324, mp 380 °C (DSC); 1H NMR (500 MHz, D6-
DMSO) δ: 13.5 (bs, 1H), 8.52 (s, 2H), 8.31 (s, 2H), 8.25 (s,
4H), 13C NMR (125 MHz, D6-DMSO) δ: 165.0, 140.1, 138.8,
138.5, 137.9, 121.3, 112.8.
2,4,6-Tri(2H-1,2,3-triazol-2-yl)benzaldehyde (25b). Iodide
24 (8.5 g, 0.021 mol) was dissolved in THF (85 mL), and the
solution was cooled to −5 °C. Isopropylmagnesium chloride
(11 mL as a 2 M solution in THF, 0.022 mol) was added at −5
2,4,6-Tri(2H-1,2,3-triazol-2-yl)aniline (23). Nitro com-
pound 22 (50 g, 0.063 mol), 10% Pd/C (50% water wet,
10.4 g), KOAc (43.1 g, 0.439 mol), EtOAc (700 mL), and
I
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
°C. The suspension was stirred at −2 °C for 10 min. DMF
(3.25 mL, 0.042 mol) was added at −10 °C and the mixture
was stirred at 22 °C for 4 h. The reaction was quenched with 2
M HCl (22 mL). THF was removed under reduced pressure,
and the residue was filtered. The cake was rinsed with 1 M
HCl (50 mL) and with H2O (50 mL). The product was dried
at 60 °C under reduced pressure to afford 5.3 g of a yellow
solid with a purity of 93% a/a. The product was suspended in
acetonitrile (640 mL) at reflux. The suspension was filtered at
22 °C, and the mother liquor was concentrated to dryness to
afford 620 mg of a yellow solid. Yield: 620 mg (9.6%). Purity
(LC-MS method 2): 100%, tR 0.94 min; [M + 1]+ = 308, mp
253 °C (DSC); 1H NMR (500 MHz, D6-DMSO) δ: 10.59 (s,
1H), 8.61 (s, 2H), 8.33 (s, 2H), 8.28 (s, 4H), 13C NMR (125
MHz, D6-DMSO) δ: 190.5, 141.0, 139.4, 138.6, 138.1, 122.8,
110.6.
REFERENCES
■
(1) Boss, C.; Roch, C. Orexin research: patent news from 2016.
Expert Opin. Ther. Pat. 2017, 27, 1123−1133.
(2) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L.
Copper-Diamine-Catalyzed N-Arylation of Pyrroles, Pyrazoles,
Indazoles, Imidazoles, and Triazoles. J. Org. Chem. 2004, 69, 5578−
5587.
(3) Baxter, C. A.; Cleator, E.; Brands, K. M.; Edwards, J. S.; Reamer,
R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.; Wallace, D. J. The
First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor
Antagonist for the Treatment of Sleep Disorder. Org. Process Res. Dev.
2011, 15, 367−375.
(4) Ueda, S.; Su, M.; Buchwald, S. L. Highly N2-Selective Palladium-
Catalyzed Arylation of 1,2,3-Triazoles. Angew. Chem., Int. Ed. 2011,
50, 8944−8947.
(5) Tian, Q. H.; Chen, X. M.; Liu, W.; Wang, Z. H.; Shi, S. P.;
Kuang, C. X. Regioselective halogenation of 2-substituted-1,2,3-
triazoles via sp2 C−H activation. Org. Biomol. Chem. 2013, 11, 7830−
7833.
(6) Sang, R.; Zheng, Y.; Zhang, H.; Wu, X.; Wang, Q.; Hai, L.; Wu,
Y. Palladium-catalyzed direct C−H ethoxycarbonylation of 2-aryl-
1,2,3-triazoles and efficient synthesis of suvorexant. Org. Chem. Front.
2018, 5, 648−652.
1,3,5-Tri(2H-1,2,3-triazol-2-yl)benzene (25c). Iodide 24 (9
g, 0.022 mol) was dissolved in THF (90 mL), and the solution
was cooled down to 3 °C. Isopropylmagnesium chloride (11.7
mL as a 2 M solution in THF, 0.0233 mol) was added at 3 °C.
The suspension was stirred for 15 min. The reaction mixture
was poured into a sat. solution of NH4Cl (100 mL) and ice (50
g). The suspension was filtered and the cake rinsed with THF
(20 mL) and H2O (20 mL). The filtrate was concentrated to
remove THF. The suspension was filtered and the solid was
combined with the first solid cake and dried to give an off-
white product. Yield: 6.19 g (100%). Purity (LC-MS method
3): 99.8% (254 nm), tR 10.00 min; [M + 1]+ = 280, mp 398 °C
(7) (a) Zhang, H.; Jing, L.; Zheng, Y.; Sang, R.; Zhao, Y.; Wang, Q.;
Wu, Y. Rhodium Catalyzed ortho Cyanation of 2 Aryl 1,2,3 triazole:
An Alternative Approach to Suvorexant. Eur. J. Org. Chem. 2018,
2018, 723−729. (b) Lv, S.; Li, Y.; Yao, T.; Yu, X.; Zhang, C.; Hai, L.;
Wu, Y. Rhodium-Catalyzed Direct C-H Bond Cyanation in Ionic
Liquids. Org. Lett. 2018, 20, 4994−4997.
̈
(8) Hoferl-Prantz, K.; Barth, R.; Richter, F.; Zupancic, B.
Preparation of a Benzoic Acid Derivative and ist use for the
Preparation of Suvorexant. WO/2016/020403 A1, 2016.
1
(DSC); H NMR (500 MHz, CDCl3 and TFA) δ: 8.75 (s,
3H), 8.05 (s, 6H), 13C NMR (125 MHz, CDCl3 and TFA) δ:
(9) Myachina, G. F.; Ermakova, T. G.; Kuznetsova, N. P.;
Sultangareev, R. G.; Larina, L. I.; Klyba, L. V.; Suchanov, G. T.;
Trofimov, B. A. Optimization of the synthesis of 2-phenyl-1,2,3-
triazole. Chem. Heterocycl. Compd. 2010, 46, 79−81.
(10) Wang, X-j.; Zhang, L.; Lee, H.; Haddad, N.; Krishnamurthy, D.;
Senanayake, C. H. Highly Regioselective N-2 Arylation of 4,5-
Dibromo-1,2,3-triazole: Efficient Synthesis of 2-Aryltriazoles. Org.
Lett. 2009, 11, 5026−5028.
141.0, 136.8, 109.2.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00349.
(11) Iddon, B.; Nicholas, M. Azoles. Part 13. Synthesis and Bromine
lithium exchange reactions of some 1-substituted 4,5-dibromo-1 H-
1,2,3triazoles and 2-substituted 4,5-dibromo-2 H-1,2,3-triazoles. J.
Chem. Soc., Perkin Trans. 1 1996, 1341−1347.
Experimental procedures and analytical data for
compounds 2 and 3; NMR, DSC, and X-ray powder
diffraction for other compounds as well (PDF)
(12) Doyle, M. P.; Siegfried, B.; Dellaria, J. F. Alkyl Nitrite-Metal
Halide Deamination Reactions. 2. Substitutive Deamination of
Arylamines by Alkyl Nitrites and Copper(II) Halides. A Direct and
Remarkably Efficient Conversion of Arylamines to Aryl Halides. J.
Org. Chem. 1977, 42, 2426−2431.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gunther.schmidt@idorsia.com.
(13) (a) Smirnov, O. Y.; Churakov, A. M.; Strelenko, Y. A.;
Tartakovsky, V. A. Benzo-1,2,3,4-tetrazine 1,3-dioxides annulated with
tetraazapentalene systems. Russ. Chem. Bull. 2008, 57, 2180−2184.
(b) Kumar, A. S.; Kommu, N.; Ghule, V. D.; Sahoo, A. K. Synthesis of
trifluoromethyl-substituted N-aryl-poly-1,2,3-triazole derivatives. J.
Mater. Chem. A 2014, 2, 7917−7926. (c) Song, Y.; Xu, Q.; Jia, Z.
J.; Kane, B.; Bauer, M.; Pandey, A. Pyrazine Kinase Inhibitors. US
2013/0131040 A1, 2013. (d) De Lombaert, S.; Goldberg, D. R.;
Brameld, K. A.; Sjogren, E. B. Acylguanidines as Tryptophan
Hydroxylase Inhibitors. WO 2015/089137 A1, 2015.
ORCID
Gunther Schmidt: 0000-0003-2413-4145
Present Address
†(R.R.) ETH Zu
̈
rich HCI H 338, Vladimir-Prelog-Weg 1-5/10,
rich, Switzerland.
CH-8093 Zu
̈
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(14) One trial reaction on 50 g scale in DMF failed, because the
hydrogenation stalled. This mixture was discarded.
(15) Synthesis of 5b and 5c was disclosed in Schmidt, G.;
■
The authors would like to thank Mourad Nabate and Kristina
Kamin for DSC measurements and Boris Mathys for the LC-
MS measurement of 25c. The authors acknowledge Patric
̈
̈
Dorrwachter, P. PCT/EP2018/061172.
̈
̈
Dorrwachter and Marco Tschanz for their work in the
development and scale-up of 5a−d. We are grateful to Dr.
Thomas Weller for the fruitful collaboration with medicinal
̈
chemistry. We are indebted to Dr. Gabriel Schafer for his
valuable feedback regarding this manuscript.
J
DOI: 10.1021/acs.oprd.8b00349
Org. Process Res. Dev. XXXX, XXX, XXX−XXX