Efficient synthesis of 1,4-diaryl-5-methyl-1,2,3-triazole, a potential mglur1 antagonist, and the risk assessment study of arylazides

Article abstract of DOI:10.1021/op900062p

A concise and practical synthesis of a 1,4-diaryl-5-methyl-1,2,3-triazole is described. A mGluR1 antagonist 1 was prepared with one-pot operation by the Negishi coupling reaction between two building blocks, 5-bromophthalimidine (2) and 1-aryl-5-methyl-4-

Full text of DOI:10.1021/op900062p

Organic Process Research & Development 2009, 13, 1407–1412
Efficient Synthesis of 1,4-Diaryl-5-methyl-1,2,3-triazole, A Potential mGluR1
Antagonist, and the Risk Assessment Study of Arylazides
Takayuki Tsuritani,*,† Hiroo Mizuno,*,† Nobuaki Nonoyama,† Satoshi Kii,† Atsushi Akao,† Kimihiko Sato,†
Nobuyoshi Yasuda,‡ and Toshiaki Mase†
Process Research, PreClinical Department, Banyu Pharmaceutical Co. Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan, and
Process Research, Merck Research Laboratories, Merck & Co. Inc., Rahway, New Jersey 07065, U.S.A.
Scheme 1. Retrosynthetic analysis
Abstract:
A concise and practical synthesis of a 1,4-diaryl-5-methyl-
1,2,3-triazole is described. A mGluR1 antagonist 1 was
prepared with one-pot operation by the Negishi coupling
reaction between two building blocks, 5-bromophthalimidine
(2) and 1-aryl-5-methyl-4-triazolylzinc (3-Zn). Bromide 2 was
synthesized via N-selective cyclization of o-hydroxymethyl-
benzamide 8 easily prepared from phthalide 4. Zinc species
3-Zn was generated in situ by transmetalation of 1-aryl-4-
magnesio-5-methyltriazole (3-Mg), which in turn was gener-
ated by the regioselective click chemistry between 2,4-
difluorophenylazide (5) and propynylmagnesium bromide.
The risk assessment of potentially explosive arylazides is also
mentioned.
1. Introduction
efficient approach to 1 appeared to be the coupling reaction
between N-isopropyl-5-bromophthalimidine (2) and 1-aryl-4-
metala-5-methyltriazole 3. As to the preparation of N-isopropyl-
5-bromophthalimidine (2), phthalide 4 is thought to be an
appropriate raw material. And the other coupling partner, 1-aryl-
4-metala-5-methyltriazole 3 would be prepared by regioselective
click chemistry between 2,4-difluorophenylazide (5) and pro-
pynylmetal reagent. Herein we wish to report the process
development of compound 1. As handling of a large amount
of potentially explosive aryazides is a serious risk factor, we
carried out a risk assessment study and the results are described.
Schizophrenia is one of the most common psychiatric
diseases. Prevalence of the disease is about 1% of the total
population over the age of 18. The patient population is 2.2
million in the US and 51 million worldwide with an incidence
of 100,000 patients/year in US and 1.5 million patients/year
worldwide. About $65 billion a year is spent for direct treatment,
social and family costs (30% being direct costs). Atypical
antipsychotics such as clozapine, risperidone and olanzapine
which share D2/5HT2A antagonism dominate the market. While
the introduction of atypical antipsychotics has greatly improved
symptoms of schizophrenia, 20-30% of patients do not respond
well to these drugs and over one-third has a relapse of symptoms
following chronic use. Atypical antipsychotics are relatively
extrapyramidal motor side effect-free, however, long-term
treatment increases the risk of motor depression and body
weight gain. Therefore, there is still a significant need for a
new class of antipsychotics. Recently we found the triazole
compound 1 which was identified as a potent and selective
mGluR1 antagonist1 could be a novel target to treat schizo-
phrenia.2
2. Results and Discussion
Following our synthetic strategy (Scheme 1), we began to
establish efficient and robust procedures for each reaction. Also,
the risk assessment study of potentially explosive arylazides
was conducted to develop safe enough procedures for a large-
scale synthesis.
(1) (a) Satow, A.; Maehara, S.; Ise, S.; Hikichi, H.; Fukushima, M.; Suzuki,
G.; Kimura, T.; Tanaka, T.; Ito, S.; Kawamoto, H.; Ohta, H.
J. Pharmacol. Exp. Ther. 2008, 326, 577. (b) Suzuki, G.; Kimura, T.;
Satow, A.; Kaneko, N.; Fukuda, J.; Hikichi, H.; Sakai, N.; Maehara,
S.; Kawagoe-Takaki, H.; Hata, M.; Azuma, T.; Ito, S.; Kawamoto,
H.; Ohta, H. J. Pharmacol. Exp. Ther. 2007, 321, 1144, and references
cited therein.
Compound 1 consists of phthalimidine unit 2 and triazole
moiety 3 connected with sp2-sp2 carbon bond. The most
(2) (a) Ohta, H.; Sato, A.; Kimura, T.; Suzuki, G.; Kawamoto, H. PCT
Int. Appl. WO 2007007909 A1 20070118, 2007. (b) Kawamoto, H.;
Ito, S.; Satoh, A.; Nagatomi, Y.; Hirata, Y.; Kimura, T.; Suzuki, G.;
Sato, A.; Ohta, H. PCT Int. Appl. WO 2005085214 A1 20050915,
2005.
* Corresponding authors. Telephone: +81-29-877-2215. Fax: +81-29-877-
2173. E-mail: takayuki_tsuritani@merck.com; hiroo_mizuno@merck.com.
† Banyu Pharmaceutical Co. Ltd.
‡ Merck & Co. Inc.
10.1021/op900062p CCC: $40.75  2009 American Chemical Society
Published on Web 05/12/2009
Vol. 13, No. 6, 2009 / Organic Process Research & Development
•
1407

Scheme 2. Preparation of N-isopropyl-5-bromophthalimidine
Table 1. Thermal analysis study of arylazidesa
2.1. Preparation of N-Isopropyl-5-bromophthalimidine
(2). The synthesis of the targeted phthalimidine 2 was achieved
by N-selective cyclization of o-hydroxymethylbenzamide 8
which was recently reported by our group.3 The elaboration of
the o-hydroxymethylbenzamide 8 was readily accomplished by
aminolysis of phthalide 4 in the presence of MsOH at mild
temperature.4 It was found that the amount of MsOH greatly
affected the aminolysis. For instance, when an excess of MsOH
(2.0 equiv) was employed, phthalide 4 was recovered quanti-
tatively as a result of hydrolysis of imino-ester which was
formed by O-cyclization of the o-hydroxymethylbenzamide 8.
Thus, phthalide 4 was treated with 5.0 equiv of isopropylamine
in the presence of 1.2 equiv of MsOH in 1,3-dimethyl-2-
imidazolidinone (DMI) at 60 °C for 3 h to give o-hydroxym-
ethylbenzamide 8 in 88% isolated yield. The o-hydroxymeth-
ylbenzamide 8 was then treated with 2.25 equiv of isopropyl-
magnesium chloride followed with 1.3 equiv of ClP(O)(OEt)2
in DMI to give the phthalimidine 2 in 70% isolated yield.
2.2. Synthesis of Triazole Moiety and Risk Assessment
Study of Arylazides. After establishing the efficient synthetic
method for 5-bromophthalimidine 2, we next focused on the
synthesis of 1,2,3-triazole 3. For the construction of 1,2,3-
triazoles, 1,3-dipolar cycloaddition of organic azides and alkynes
is quite often used.5 However, employing organic azides raises
safety concerns since organic azides are known to be heat- and
shock-sensitive compounds of varying degrees of stability and
sensitive to traces of strong acids and metallic salts which may
catalyze explosive decomposition.6 For example, phenylazide
is a distillable compound at considerably reduced pressure;
however, phenylazide explodes when heated at ambient pressure
and, occasionally, at lower pressure.7 Thus, a risk assessment
study of 2,4-difluorophenylazide (5) was necessary prior to the
large-scale synthesis.
entry
R1
R2
R3
init. temp. [°C]
size [kcal/mol]
1
2
F
H
H
H
F
H
H
H
H
H
F
115
140
125
135
130
120
140
110
75, 200
100
85
56
H
H
H
H
F
46
3
F
84
4
H
69
5
H
80
6
Cl
H
H
Cl
Cl
H
77
7
79
8
Cl
NO2
F
69
9
30, 80
66
10
11
Cl
46
a Exothermic activity was evaluated up to a minimum of 300 °C in the closed
Tantalum cell (Heat rate: 5 °C/min).
identify an approximate exothermic initiation temperature with
differential scanning calorimetry (DSC) measurement. Other
arylazide compounds8 were also assessed for comparison (Table
1). It was found that arylazides had a potentially very large
exothermic energy which initiated above 100 °C with a rapid
rate of heat release (entry 1, Table 1).
2.2.2. Drop Weight Testing. We next performed drop weight
testing, or an impact resistance test where weights are dropped
on the specimen from varying heights, to determine the
possibility of shock sensitivity of arylazides (Table 2). Most of
the arylazides including 2,4-difluorophenylazide (5) (entry 1,
Table 2) showed positive results; explosion occurred with a blast
sound, smoke, smell and discoloration (entries 1-7, Table 2).
A more detailed study of the 2,4-difluorophenylazide (5)
proved that 5 is a highly shock sensitive compound (Table
3). The positive result was observed even at 5 kg · cm
impact (entry 6, Table 3). However, when the azide 5 was
diluted with organic solvents, it was found that the
solutions had a safe enough operational window of shock
tolerance (entries 7-9, Table 3).
2.2.1. Thermal Analysis Study of Arylazides. We first
assessed the thermal stability of 2,4-difluorophenylazide (5) to
(3) Tsuritani, T.; Kii, S.; Akao, A.; Sato, K.; Nonoyama, N.; Mase, T.;
Yasuda, N. Synlett 2006, 801.
(4) For AlCl3-catalyzed aminolysis of lactone, see: Lesimple, P.; Bigg,
D. C. H. Synthesis 1991, 306.
(5) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; pp 1-176. (b) Padwa, A. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991;
Vol. 4, pp 1069-1109. (c) Fan, W.-Q.; Katritzky, A. R. In Compre-
hensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 4, pp 101-
126.
2.2.3. AdVanced ReactiVe System Screening Tool (ARSST)
Test. 2,4-Difluorophenylazide (5) proved to have a potentially
very large exothermic energy and be a highly shock sensitive.
(6) Boyer, J. H.; Moriarty, R.; de Darwent, B.; Smith, P. A. S. Chem.
Eng. News 1964, 42, 6.
(8) All arylazides were synthesized with Sandmeyer reaction from the
corresponding arylamines.
(7) Lindsay, R. O.; Allen, C. F. H. Org. Synth. 1942, 22, 96.
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Vol. 13, No. 6, 2009 / Organic Process Research & Development

Table 2. Drop weight testinga
entry
R1
R2
R3
stateb
resultsc
1
F
H
H
H
F
H
H
H
H
H
F
L
L
L
L
L
L
L
S
S
S
S
+
+
+
+
+
+
+
-
-
-
-
2
H
H
H
H
F
3
F
4
H
Figure 2. Time vs pressure (neat 5).
5
H
6
Cl
H
H
Cl
Cl
H
7
8
Cl
NO2
F
9
10
11
Cl
a Test conditions: volume 20 mg (solid) or 30 µg (liquid), temp. ambient
temperature, height 60 cm (solid) or 30 cm (liquid), weight 5 kg, impact 300
kg·cm (solid) or 150 kg ·cm (liquid). b L: liquid, S: solid. c +: positive, -:
negative.
Figure 3. Time vs temperature (MTBE solution 5).
Table 3. Drop weight testing of 2,4-difluorophenyazidea
entry
state
impact [kg ·cm] resultsb
1
2
3
4
5
6
7
8
9
neat
150
100
50
+
+
+
+
+
+
-
-
-
20
10
5
150
150
150
THF solution (25.9 wt %)
heptane solution (26.4 wt %)
MTBE solution (29.4 wt %)
a Test conditions: volume 30 µg, temp. ambient temperature, weight 5 kg. b +:
positive, -: negative.
Figure 4. Time vs pressure (MTBE solution 5).
Table 4. ARSST test (temperature scanning mode) results of
5a
initial peak MAX.
MAX.
MAX.
residual
pressure
pressure temp
dT/dt
dP/dt
pressure
sample
[psi]
[°C] [°C/min] [psi/min] increase [psi] [psi]
neat
MTBE solution
(29.4 wt %)
15
298
>500b 338,194 90,736
294 3,682 6,144
NAc
122
NAc
9.4
a Conditions; sample mass 5.6 mL (neat) or 7.0 mL (MTBE solution), heating
rate 2 °C/min, acquisition frequency 1 °C or 1 psi or 0.5 min, heater shut off 500
°C or 500 psi or 500 min. b A full measurement of temperature could not be
detected due to heater shutdown criteria. c A full measurement of pressure and
residual pressure could not be detected due to rupture of rupture disk.
Figure 1. Time vs temperature (neat 5).
nature. Although relatively high temperature and pressure
increase were also observed around 200 °C, the temperature
and pressure were decreased after the culmination without an
explosion (Figure 3 and 4, and Table 4). Isothermal ages test
proved that the MTBE solution of 5 was relatively stable at
50-110 °C range; max dT/dt was less than 2.0 °C/min, max
dP/dt was less than 0.3 psi/min and max pressure increase was
less than 30 psi (Table 5).
2.2.4. Synthesis of 2,4-Difluorophenylazide in Large Scale.
On the basis of the results of the risk assessment studies (Vide
supra), we focused on the synthesis of 5 on a large scale. For
the synthesis of arylazides, the Sandmeyer reaction of 2,4-
difluoroaniline was adopted.10 The Sandmeyer reaction was
superior to other approaches such as hydrazine chemistry11 and
copper-catalyzed azidation12 in view of yield, purity, and milder
Thus an ARSST test9 was conducted to obtain more informa-
tion. ARSST data yielded critical experimental knowledge of
the rates of temperature and pressure increases during the
exothermic decomposition of 5, thereby providing reliable
energy and gas release rates which can be applied directly to
full scale process conditions. ARSST results are summarized
in Figures 1, 2, 3, and 4 and Tables4 and5. Temperature
scanning mode test showed that neat 2,4-difluorophenylazide
(5) had a potential to explode upon heating with significant rapid
temperature and pressure increase around 200 °C (Figures 1
and 2, and Table 4). On the other hand, the MTBE solution of
2,4-difluorophenylazide (5) was proved not to have an explosive
(9) Burelbach, J. P.; Miller, A. E. Proc. NATAS Annu. Conf. Therm. Anal.
Appl. 2001, 29, 567.
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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1409

Table 5. ARSST test (isothermal age mode) results of the
MTBE solution of 5
Table 6. Regioselective [3 + 2] annulationa
initial
age
MAX.
MAX.
MAX. pressure residual
pressure temp
dT/dt
dP/dt
increase
[psi]
pressure
[psi]
entry
[psi]
[°C] [°C/min] [psi/min]
1
2
3
4
301
302
303
301
50
70
90
1.45
1.99
1.99
1.77
0.21
0.21
0.26
0.24
5.56
11.90
19.05
26.71
1.37
5.79
7.82
entry
electrophile
E+
yieldb [%]
110
12.51
1
H2O
H2O
D2O
NBS
H+
H+
D+
Br+
95
96
91
89
a Conditions; sample mass 7.0 mL (MTBE solution), hours aged 16 h,
acquisition frequency 1 °C or 1 psi or 0.5 min, heater shut off 500 °C or 500 psi
or 500 min.
2c
3
4
a The reaction was performed with 1.05 equiv of a THF solution of prop-
ynylmagnesium bromide. b Isolated yield. c A MTBE solution of 2,4-difluoro-
phenylazide (5) (25.5 wt %) was used instead of neat one.
Scheme 3. Synthesis of 2,4-difluorophenylazide (5)
the following coupling reaction.15 Thus, we examined consecu-
tive reactions for the construction of triazole moiety and
subsequent C-C bond formation.
reaction conditions although it entailed the use of the toxic
reagent, NaN3. It was found that the reaction should be
conducted in the presence of MTBE to prevent potentially
hazardous separation of the highly hydrophobic 2,4-difluo-
rophenylazide (5) from the aqueous media. Eventually we were
able to establish an efficient procedure for the synthesis of 2,4-
difluorophenylazide (5) under the company criteria for judging
safety of operations (for the company criteria, see Experimental
Section and references cited there). 2,4-Difluoroaniline (9) was
treated with 1.0 equiv of 15% NaNO2 aq in 1.5 N HCl aq and
MTBE at between -10 to 5 °C (initial addition temperature
-10 °C) followed with 1.05 equiv of 12% NaN3 aq at between
-10 to 5 °C (initial addition temperature -10 °C) to give a
MTBE solution of 2,4-difluorophenylazide (5) in 90% assay
yield (Scheme 3).
2.3. Regioselective Synthesis of 4-Metallatriazole and Its
Application to Palladium-Catalyzed C-C Bond-Coupling
Reaction. After establishing the safe-enough protocol for the
synthesis of 2,4-difluorophenylazide (5),13 we turned our
attention to the regioselective synthesis of 4-metallatriazole 3.
Sharpless et al., had already reported that regioselective 1,3-
dipolar addition of azide and alkynyl Grignard reagent pro-
ceeded smoothly at ambient temperature.14 Accordingly, 1,3-
dipolar addition of 1-propynylmagnesium bromide and 2,4-
difluorophenylazide (5) was examined (Table 6). The reaction
proceeded smoothly at ambient temperature, and afforded the
corresponding triazole in high yield as a single regioisomer.
The reaction with crude MTBE solution of azide 5 also resulted
in acceptable yield of triazole (entry 2). Triazole 3-Mg still has
active magnesium at the 4-position which can be utilized for
After extensive investigation, we found the Pd2(dba)3-
Xantphos catalyst system to work very well for this one-pot
reaction.16 However, when this developed method was applied
to the reaction of 3-Mg and phthalimidine 2, the lactam moiety
of 2 was not tolerant of the reaction conditions. It was
discovered that this issue was able to be circumvented by the
use of less nucleophilic 3-Zn reagent which was easily prepared
from 3-Mg. Thus, the MTBE solution of 2,4-difluoropheny-
lazide (5) was treated with 1.07 equiv of propynylmagnesium
bromide in THF at ambient temperature for 2 h followed with
1.10 equiv of ZnCl2 to give the intermediate 3-Zn. The resulting
3-Zn was treated with 0.98 equiv of the phthalimidine 2 in the
presence of 1.5 mol % of Pd2(dba)3 and 3.0 mol % of Xantphos
at 55 °C for 6 h to give the desired 1,4-diaryl-5-methyltriazole
1 in 89% assay yield (Scheme 4). Crystallization from MTBE
furnished the crude 1 as a pale-yellow colored crystal with
98.5% purity on HPLC, residual palladium 66 ppm and the
undesired kinetically favored crystal form. Recrystallization
from AcOEt/heptane in the presence of PBu3 (5.0 equiv with
respect to palladium catalyst) to reduce palladium content and
control crystal form furnished the pure 1 as a white crystal with
99.0% purity on HPLC, residual palladium 18 ppm and the
desired thermodynamically favored crystal form.
3. Conclusion
In conclusion, a concise and practical synthesis of 1,4-diaryl-
5-methyl-1,2,3-triazole has been established. For the synthesis
of 5-bromophthalimidine intermediate 2 and 1,4-diaryl-5-
methyl-1,2,3-triazole 1, we successfully developed a new and
concise procedure. Both developed reactions are adaptable not
only for a large-scale synthesis but also for a wide variety of
substrates.3,16 The risk assessment study of arylazide 5 proved
that neat arylazides have a very large exothermic energy, are
highly shock sensitive, and have potential to explode upon
heating, whereas a diluted solution of 5 was safe enough to
handle.
(10) Odlo, K.; Hentzen, J.; dit Chabert, J. F.; Ducki, S.; Gani, O. A.; Sylte,
I.; Skrede, M.; Florenes, V. A.; Hansen, T. V. Bioorg. Med. Chem.
2008, 16, 4829.
(11) Iranpoor, N.; Firouzabadi, H.; Nowrouzi, N. Tetrahedron Lett. 2008,
49, 4242.
(12) Jacob, A.; Ulf, M.; Fredrik, B.; Xifu, L. Synlett 2005, 2209.
(13) The obtained 2,4-difluorophenyazide (5) was labile against oxygen
and light. The solution of azide 5 took on deep black color unless it
was stored under light shielding, nitrogen atmosphere and low
temperature. For the photochemistry of fluorinated aryl azides, see:
Leyva, E.; Munoz, D.; Platz, M. S. J. Org. Chem. 1989, 54, 5938.
(14) (a) Krasin˜ski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6,
1237. (b) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A. Zh. Org.
Khim. 1967, 3, 968. (c) Akimova, G. S.; Chistokletov, V. N.; Petrov,
A. A. Zh. Org. Khim. 1967, 3, 2241. (d) Akimova, G. S.; Chistokletov,
V. N.; Petrov, A. A. Zh. Org. Khim. 1968, 4, 389.
(15) The reactions of the resulting 4-magnesiotriazole 3-Mg with various
electrophiles has already reported by Sharpless (ref 14); however, the
transition metal-catalyzed reactions of 3-Mg with arylhalides were
unexplored.
(16) For detailed information of this one-pot coupling reaction, see: Akao,
A.; Tsuritani, T.; Kii, S.; Sato, K.; Nonoyama, N.; Mase, T.; Yasuda,
N. Synlett 2007, 31.
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Vol. 13, No. 6, 2009 / Organic Process Research & Development

Scheme 4. Coupling reaction of N-isopropyl-5-bromophthalimidine with 4-zincio-1,2,3-triazole 3-Zn
4. Experimental Section
heated at 50 °C. The resulting solution was cooled down to 41
4.1. General. All reagents were purchased and used without
°C, and then 6.8 g of seed (phthalimidine 2) was added. After
stirring for 1 h at 41 °C, the suspension was slowly cooled down
to -6 °C over about 5 h, and stirred for 1 h. The desired product
was collected by filtration, washed with heptane (17.2 L), and
dried under vacuum at 60 °C for 20 h. to give 4.8 kg of 2 in
64.8% yield. 1H NMR (CDCl3) 7.70 (d, J ) 7.9 Hz, 1H), 7.61
(s, 1H), 7.60 (d, J ) 7.9 Hz, 1H), 4.65 (septet, J ) 6.8 Hz,
1H), 4.32 (s, 2H), 1.29 (d, J ) 6.8 Hz, 6H). 13C NMR (CDCl3)
166.89, 142.96, 132.37, 131.44, 126.12, 125.64, 124.99, 44.60,
42.76, 20.77. IR (neat, cm-1) 1674, 1609, 1449, 1406, 1275,
1236, 1174, 1060, 867, 839, 768, 674, 620.
1
any further purification. H and 13C NMR spectra were taken
in CDCl3 at 400 and 100 MHz, respectively.
4.2. N-Isopropyl-4-bromo-2-hydroxymethylbenzamide (8).
To an 80 L reactor were charged DMI (16.0 L) and phthalide
4 (8.0 kg, 37.6 mol). The resulting slurry was cooled to 0 °C,
and then i-PrNH2 (16.1 L, 187.8 mol) was added to the slurry.
MsOH (2.9 L, 45.1 mol) was slowly added over about 1.5 h,
keeping the temperature range between 0 to 15 °C during the
addition. The slurry was heated at 60 °C for 3 h, and then the
resulting solution was allowed to cool to ambient temperature.
To a 150 L vessel was charged half the volume of the above
crude solution, water (12.0 L) and MeCN (32.0 L). To the
solution was added 12.0 g (amide 8) of seed. After stirring for
1 h, water (64.0 L) was added dropwise over 1 h to the resulting
suspension and stirred for 3 h. The same operations were
conducted with the rest of the crude solution. The amide 8 was
collected by filtration, washed with water (20.0 L), and dried
under vacuum at 60 °C for 36 h to give 9.0 kg of 8 in 87.7%
4.4. 2,4-Difluorphenylazide (5). The reaction was con-
ducted with a 50 L vessel (2 batches). Arylazide 5 must not
be isolated since it is highly shock sensitive and thermally
unstable. Considering the perilousness for the explosive
nature of arylazide 5 with metal and heat, the reaction
temperature was controlled by an oil bath, not an internal
heating/cooling pipe, and was limited to temperatures lower
than 40 °C. The reaction vessel was covered with aluminum
foil to obscure light since arylazide 5 is decomposed by
light.13 To a 50 L vessel were added 1.5 N HCl aq (14 L),
MTBE (3.5 L), and 2,4-difluoroaniline (900 g, 6.97 mol). The
mixture was cooled down to -10 °C. NaNO2 aq (480 g, 6.97
mol in 2.70 L water) was added carefully, keeping the
temperature range between -10 to 5 °C during the addition.17
After completion of the addition, the mixture was stirred for
15 min at between 0 to 5 °C. NaN3 aq (480 g, 7.32 mol in 3.60
L water) was added carefully keeping the temperature range
between -10 to 5 °C.18 After completion of the addition, the
mixture was stirred for 30 min at between 0 to 5 °C. To the
1
yield. H NMR (CDCl3) 7.56 (s, 1H), 7.49 (d, J ) 8.2 Hz,
1H), 7.37 (d, J ) 8.2 Hz, 1H), 6.20-6.13 (bs, 1H), 4.56 (s,
2H), 4.26 (septet, J ) 6.5 Hz, 1H), 1.27 (d, J ) 6.5 Hz, 6H).
4.3. N-Isopropyl-5-bromophthalimidine (2). To a 150 L
vessel equipped with dropping funnel were charged DMI (40.0
L) and amide 8 (8.0 kg, 29.4 mol). The resulting solution was
cooled to -10 °C, and then 1.98 M of i-PrMgCl (33.1 L, 65.5
mol, 2.23 equiv to amide 8) was added dropwise over 1.5 h,
keeping the temperature range between -10 to 5 °C during
the addition. The resulting solution was warmed to ambient
temperature and stirred for 0.5 h. The solution was cooled to 0
°C, and then ClP(O)(OEt)2 (6.6 kg, 38.2 mol, 1.3 equiv to amide
8) was added dropwise over about 50 min, keeping the
temperature range between 0 to 14 °C during the addition. The
mixture was warmed to ambient temperature and stirred for
14 h. The resulting solution was quenched by slow addition of
2 N HCl aq (40.0 L) at between 10 to 25 °C. The mixture was
extracted with i-PrOAc (40.0 L × 2), and the combined i-PrOAc
extracts were washed with water (40.0 L × 2) and 20% brine
(8.0 L). The combined organic layer was assayed by HPLC
measurement (6.8 kg assay, 90.5% yield). Azeotropic dehydra-
tion with i-PrOAc was conducted until the water content was
below 500 ppm, and then i-PrOAc (3.4 L) was added. To the
suspension was added heptane (45.6 L), and the suspension was
(17) The addition of the sodium nitrite aqueous solution should be
controlled with stirring and cooling throughout due to the moderate
size of heat generation,-18.6 kcal/mol (aniline) of aniline with an
adiabatic temperature rise of +6.4 K.
(18) Sodium azide in water is in equilibrium with hydrogen azide, a highly
volatile and shock sensitive material. Aqueous solutions greater than
15 wt % NaN3 could pose a thermal hazard. Therefore, it is
recommended to prepare a more dilute sodium azide aqueous solution,
the temperature of the sodium azide aqueous solution must be
maintained cold,-5 °C to avoid volatilization of hydrogen azide
(boiling point of hydrogen azide is 36-38 °C), and the addition of
the sodium azide aqueous solution should be controlled with stirring
and cooling throughout due to the moderate size of heat generation,-
52.0 kcal/mol (aniline) of aniline with an adiabatic temperature rise
of + 17.0 K. The appropriate venting capacity must be calculated to
deal with nitrogen gas generation during addition of sodium azide
aqueous solution.
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mixture was added MTBE (6.98 L). After phase separation,19
the organic layer was washed with 1 N NaOH (4.50 L) and
water (4.50 L) successively. Azeotropic dehydration with
MTBE (∼22.50 L)20 was conducted until the water content
became lower than 500 ppm. 2,4-Difluorophenylazide (5) was
obtained in 970 g assay, 90% assay yield with 86.24 area %
purity on HPLC. The product solution should be stored away
from sources of heat, under light shielding and nitrogen gas
atmosphere. It should be stored refrigerated if it is not used
immediately. It should not be stored for a prolonged period of
then with water (13.62 kg) and analyzed by HPLC (1.97 kg
assay, 89% yield from phthalimidine 2).
The obtained solution was combined with an another batch
of 1 and treated with Darco KB-100 mesh (850 g) for 1 h. After
a filtration of the mixture, the residual charcoal was washed
with THF (22.3 kg). The solution was switched to MTBE with
addition-and-concentration. During the course of solvent switch-
ing, seed of 1 (7.4 g) was added. The resultant slurry was heated
to 50-55 °C, PBu3 (344 g, 1.70 mol, 5 equiv with respect to
palladium catalyst) was added, and the batch aged for 3 h. Then
the slurry was cooled to ambient temperature and stirred for
overnight. The mixture was filtered, and the collected solid was
washed with ice-cold MTBE and dried under a nitrogen
atmosphere. The coupled product 1 was obtained as pale-yellow
colored crystals (2471 g, 70% recovery, 98.5 area % purity on
HPLC, 66 ppm of Pd content, undesired crystal form). Loss in
mother liquid was 716 g assay (20%) and rinsed solution was
163 g assay (4.6%). To control the crystal form and reduce Pd
content, the following recrystallization was performed. The
obtained crystals were dissolved in EtOAc (55.75 kg) and stirred
for 1 h. The solution was concentrated under reduced pressure,
and the resulted slurry was heated to 90 °C for dissolution of
crystals, then PBu3 (84.9 mL, 0.34 mol, 0.05 equiv to the crude
crystals) was added. The slurry was cooled to 65-70 °C, and
seed of 1 (15.7 g) was added. The slurry was stirred for 1 h,
and heptane (28.75 kg) was slowly added with over 80 min.
Then the resulting slurry was stirred for 1 h., and was cooled
gradually to ambient temperature and stirred for overnight. The
slurry was filtered, and the collected solid was washed with
heptane/EtOAc (9:1, 13.19 L) and dried under vacuum at 50
°C overnight. The desired compound 1 was obtained as almost
colorless crystals (2293 g, 93% recovery, 99.0 area % purity
on HPLC, 18 ppm of Pd content, desired crystal form). 1H NMR
(CDCl3) δ 8.00 (s, 1H), 7.94 (d, J ) 7.6 Hz, 1H), 7.81 (dd, J
) 7.6, 1.2 Hz, 1H), 7.61-7.55 (m, 1H), 7.16-7.09 (m, 2H),
4.72 (septet, J ) 6.8 Hz, 1H), 4.42 (s, 2H), 2.45 (d, J ) 1.2
Hz, 3H), 1.33 (d, J ) 6.8 Hz, 6H). 13C NMR (CDCl3) δ 167.35,
164.89, 164.78, 162.36, 162.25, 157.88, 157.76, 155.33, 155.20,
143.64, 141.82, 133.87, 132.73, 131.94, 129.87, 129.76, 126.46,
123.70, 121.39, 120.44, 120.40, 120.30, 120.26, 112.70, 112.66,
112.47, 112.43, 105.58, 105.35, 105.32, 105.09, 44.99, 42.63,
20.72, 9.50, 9.47. IR (neat, cm-1) 1679, 1662, 1625, 1519, 1456,
1411, 1264, 1144, 963, 850, 811, 780, 610. HRMS [M + H]+
m/z calcd for C20H18N4OF2 + H 369.1527; Found, 369.1531.
1
time. H NMR (CDCl3) 7.05-7.00 (m, 1H), 6.90-6.85 (m,
2H). 13C NMR (CDCl3) 124.22, 121.63, 121.56, 112.01, 111.97,
111.83, 111.79, 105.49, 105.30, 105.27, 105.09. IR (neat, cm-1)
2137, 2104, 1604, 1504, 1436, 1333, 1270.
4.5. 1H-Isoindol-1-one, 5-[1-(2,4-difluorophenyl)-5-meth-
yl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-2-(1-methylethyl) (1).
The reaction was performed with an 80 L vessel (two batches).
To the stirred THF solution of 8.9 wt % propynylmagnesium
bromide (12.35 kg, 6.61 mol), was added a MTBE solution of
azide 5 (25.5 wt %, 3.76 kg, 958 g assay, 6.18 mol) over 20
min.21 The combined mixture was stirred for 2 h at around 25
°C. Then, THF solution of 17.3 wt % ZnCl222 (water content
412 ppm, 5.35 kg, 926 g assay, 6.79 mol) was added over 30
min, keeping the temperature range between 20 to 30 °C23 and
stirred overnight. To the resulting dark-brown solution were
added phthalimidine 2 (1.54 kg, 6.05 mol) and an active
palladium catalyst solution which was prepared by mixing of
Pd2(dba)3 (84.8 g, 0.0926 mol) and Xantphos (107 g, 0.185
mol) in THF (2.55 kg) then by degassed by vacuum/N2-fill
cycles 3 times, and stirred for 2 h. The reaction mixture was
degassed and stirred at 55 °C for 6 h. Then the reaction mixture
was cooled to ambient temperature. To the solution, was added
1 N HCl (13.48 L).24 The organic layer was extracted by MTBE
(8.60 kg). The organic extract was washed successively with 1
N HCl (13.53 L) and water (13.27 kg). The organic layer was
extracted against the combined acidic aqueous layers by THF/
MTBE (THF 2.87 L + MTBE 2.40 kg). The combined organic
layers were washed with 5% NaHCO3 (13.22 and 6.64 kg) and
(19) The aqueous waste before aqueous NaOH wash operations must be
treated by aqueous NaOH.
(20) The batch temperature during the concentration must be kept as low
as possible and not approach temperatures above 40 °C as there is a
large exotherm present in the concentrate. A high alarm set at 50 °C
should be provided for the reactor. Emergency cooling should be
applied if the alarm goes off. Dilution of batch with cold MTBE is to
be done if the batch temperature approaches 70 °C. The product
solution may not be concentrated to a level significantly higher than
that tested (29.4 wt % MTBE solution).
(21) The addition of MTBE solution of arylazide 5 to the vessel should be
controlled with stirring and cooling throughout. The heat release was
measured to be-37.1 kcal/mol (azide) of the arylazide with an
adiabatic temperature rise of +32.9 K. A high temperature alarm of
50 °C should be set on the reactor.
Acknowledgment
We thank Drs. T. P. Vichery and T. T. Lam, Merck & Co.
Inc., for their helpful advice on the safety assessment studies
of arylazides.
(22) Preparation for the THF solution of ZnCl2: To a 20 L vessel, THF
(6.20 kg) was charged, and ZnCl2 (1300 g) was added keeping the
temperature range between 20 to 30 °C. To the solution, molecular
sieves 4 Å (1300 g) was added. The resultant solution was left at rest
for overnight at ambient temperature, and its supernatant solution was
used for the coupling reaction.
(23) The addition of zinc chloride THF solution to the vessel should be
controlled with stirring and cooling throughout. The heat release was
measured to be-8.4 cal/g (batch) with an adiabatic temperature rise
of +19.9 K.
(24) The addition of 1 N HCl to the vessel should be controlled with stirring
and cooling throughout. The heat release was measured to be-5.6
cal/g (batch) with an adiabatic temperature rise of +9.5 K.
Supporting Information Available
Detailed ARSST study results and spectra chart of compound
1. This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review March 16, 2009.
OP900062P
1412
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Vol. 13, No. 6, 2009 / Organic Process Research & Development