Nonchromatographic isolation of 2-Alkyl-2H-1,2,3-triazoles in the synthesis of NK3 receptor antagonists

Article abstract of DOI:10.1021/op900320j

A nonchromatographic isolation of a 2-alkyl-2H-triazole from a 1:1 mixture with the corresponding 1-alkyl-1H isomer was developed in a scalable synthesis of a synthetic intermediate for NK3 receptor antagonists. Based on the fundamental nucleophilicity difference in the isomeric triazoles, this method could be used as a general tactic in the isolation of 2H-triazoles.

Full text of DOI:10.1021/op900320j

Organic Process Research & Development 2010, 14, 474–476
Nonchromatographic Isolation of 2-Alkyl-2H-1,2,3-Triazoles in the Synthesis of NK3
Receptor Antagonists
Huan Wang* and Hao Yin
Chemical DeVelopment, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PennsylVania 19406, U.S.A.
Abstract:
Herein we wish to report a simple yet potentially general,
nonchromatographic method for the isolation of a 2-alkyl 2H-
1,2,3-triazole.
A nonchromatographic isolation of a 2-alkyl-2H-triazole from a
1:1 mixture with the corresponding 1-alkyl-1H isomer was
developed in a scalable synthesis of a synthetic intermediate for
NK3 receptor antagonists. Based on the fundamental nucleophi-
licity difference in the isomeric triazoles, this method could be used
as a general tactic in the isolation of 2H-triazoles.
Results and Discussion
In our synthesis of a group of neurokinin 3 (NK3) receptor
antagonists of general structure 1,8 easy access to the common
intermediate ester 2 was required. The triazole moiety in the
target structure could be conveniently introduced by an SN2
displacement of benzyl bromide 38,9 with the triazole anion
(Scheme 1). However, despite considerable effort, a 1:1 mixture
of 1H and 2H isomers (5 and 2, respectively) was produced in
this alkylation reaction (Table 1). Different solvents (entries
1-6), bases (entries 7-12), or reaction temperature (entry 13)
proved ineffective in further improving the selectivity. Although
separation of the two isomers was achieved by chromatography,
a nonchromatographic isolation of the target 2H product 2 was
deemed more desirable.
It is known that 2-alkyl-2H-1,2,3-triazole and 1-alkyl-1H-
1,2,3-triazole have marked difference in their pKa’s, with N-3
in 1-alkyl-1H-1,2,3-triazole being by far the most basic (Figure
1).10 It was therefore envisioned that after protonation of the
quinoline, protonation of a mixture of 2 and 5 would occur
selectively on N-3 of the 1H isomer 5, thus enabling the
separation of the two isomers by selective salt formation
(Scheme 2).
Introduction
1,2,3-Triazole derivatives are an important class of com-
pounds due to their wide application in medicinal chemistry as
biologically active systems, as well as in the fine chemical
industry as dyestuffs, fluorescent whiteners, corrosion inhibitors,
and photostabilizers.1 N-1-Substituted 1H-1,2,3-triazoles can
usually be synthesized via 1,3-dipolar cycloaddition reactions,2
whereas a general and scalable method for the synthesis of N-2-
substituted 2H-1,2,3-triazoles is still unavailable. There have
been reported selective syntheses of 2-substituted 2H-1,2,3-
triazoles; however, the substituent on N-2 is limited to aryl,3
allyl,4 or hydroxymethyl.5
One of the most convenient ways of preparing 2-substituted
2H-1,2,3-triazole is by alkylation of NH-1,2,3-triazole. A
significant drawback of this method, however, is that a mixture
of regioisomeric 1H and 2H products is produced, and the
product distribution is often unfavorable for the 2H isomer in
the cases of simple alkyls.6,7 This is especially cumbersome in
the context of process development, as it entails undesirable
chromatographic separation to obtain the pure 2H product.
A number of strong acids, including HCl, H2SO4, MsOH,
TsOH, and TfOH were tried in different solvents, and selective
salt formation indeed was observed. However, in most of the
cases the corresponding salt 6 formed as an oil. The only excep-
* To whom correspondence should be addressed. E-mail: huan.2.wang@
gsk.com. Phone: 610-270-5362. Fax: 610-270-4022.
(1) (a) Wamhoff, H. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 5, p 669.
(b) Fan, W.-Q.; Katritzky, A. R. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, U.K., 1996; Vol. 4, p 1.
(6) Finley, K. T. In The Chemistry of Heterocyclic Compounds; Weiss-
berger, A., Taylor, E. C., Eds.; Wiley: New York, 1980; Vol. 39, p 5.
(7) Selective N-1 alkylation can be achieved using 2-trimethylsilyl-2H-
1,2,3-triazole Ohta, S.; Kawasaki, I.; Uemura, T.; Yamashita, M.;
Yoshioka, T.; Yamaguchi, S. Chem. Pharm. Bull. 1997, 45, 1140.
(8) Chan, W. N.; Smith, P. W.; Wyman, P. A. Quinoline 4-Carboxamide
Derivatives and Their Use As Neurokinin 3 (NK-3) Receptor
Antagonists. PCT International Application WO2005014575 A1,
February 17, 2005.
(9) (a) Simpson, R. T.; Kang, J.; Albert, S. J.; Alhambra, C.; Koether,
M. G.; Woods, M. J.; Li, Y. Quinoline Derivatives As NK3
Antagonists. PCT International Application WO2006130080 A2,
December 7, 2006. (b) Smith, P. W.; Wyman, P. A. Compounds
Having Activity at NK3 Receptor and Uses Thereof in Medicine. PCT
International Application WO 2006050992 A1, May 18, 2006. (c)
Porter, R. A.; Smith, P. W. Compounds Having Activity at NK3
Receptor and Uses Thereof in Medicine. PCT International Application
WO 2006050989 A1, May 18, 2006. (d) Bradley, D. M.; Porter, R. A.;
Smith, P. W.; Stead, R. E. A.; Vong, A. K. K. Compounds Having
Activity at NK3 Receptor and Uses Thereof in Medicine. PCT
International Application WO2006050991 A1, May 18, 2006.
(10) (a) Catalan, J.; Abboud, J. L. M.; Elguero, J. AdV. Heterocycl. Chem.
1987, 41, 187. (b) Wamhoff, H. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York,
1984; Vol. 5, p 690.
(2) For recent development in regioselective synthesis of 1,4- and 1,5-
1,2,3-triazoles by 1,3-dipolar addition, see: (a) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (b)
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596. (c) Rodionov, V. O.; Presolski, S. I.;
Gardinier, S.; Lim, Y.; Finn, M. G. J. Am. Soc. Chem. 2007, 129,
12696, and the references cited therein. (d) Zhang, L.; Chen, X.; Xue,
P.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia,
G. J. Am. Chem. Soc. 2005, 127, 15998. (e) Boren, B. C.; Narayan,
S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin,
V. V. J. Am. Chem. Soc. 2008, 130, 8923, and the references cited
therein.
(3) (a) Riebsomer, J. L. J. Org. Chem. 1948, 13, 815. (b) Bhatnagar, I.;
George, M. V. J. Org. Chem. 1967, 32, 2252. (c) Balachandran, K. S.;
Hiryakkanavar, I.; George, M. V. Tetrahedron 1975, 31, 1171, and
the references cited therein.
(4) (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2002,
43, 9707. (b) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 7786.
(5) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008, 10, 3171.
474
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Vol. 14, No. 2, 2010 / Organic Process Research & Development
10.1021/op900320j  2010 American Chemical Society
Published on Web 02/04/2010

Scheme 1
Table 1. N-1/N-2 selectivity in the alkylation of triazole using bromide 3
entry
solvent
base
time/min
conversion/%
5/2a
1
DMF
DMSO
THF
NaH
60
60
60
60
120
60
40
30
30
15
15
15
15
100
100
96
100
60
87
100
50
38
99
1.1
1.2
11.3
1.8
1.1
2.1
1.0
1.0
11.3
1.0
1.0
1.0
1.0
2
NaH
3
NaH
4
MeCN
toluene
Me2CO3
DMF
NaH
5
NaH
6
NaH
7
K2CO3
Na2CO3
Et3N
8
DMF
9
DMF
10
11
12
13
DMF
NaHMDS
LiHMDS
KHMDS
NaHMDSb
DMF
100
100
95
DMF
DMF
a By HPLC peak area ratio. b Run at -40 °C.
The selective salt formation and the selective methylation
provided two potential methods for isolation of the 2H isomer
2. Based on the fundamental pKa/nucleophilicity difference in
the two isomeric triazoles, both methods should be general in
scope and could be used as general tactics in the isolation of
2H-triazoles. The selective salt formation method has the
advantage that it also leaves the 1H isomer intact and recover-
able. However, it does suffer from the fact that an equal amount
of the isomeric 1-alkyl-1H isomer is present and can potentially
act as a crystallization inhibitor, its applicability therefore
depends more on the crystallinity of specific substrates. In the
absence of other nucleophilic sites, the selective methylation
method appears to be more robust and was chosen in our work.
The optimized process proceeded smoothly in scale-up: The
displacement of the bromide was carried out with NaHMDS
in DMF11 to give a 1:1 mixture of regioisomers 2 and 5. The
mixture was treated with Me2SO4 to selectively methylate N-3
in 5, which was removed conveniently in the ensuing aqueous
work-up. The desired 2H-1,2,3-triazole 2 was obtained in 40%
yield over two steps and contained neither 1H isomer 5 nor its
methylation product 8.
Figure 1
tion was when TfOH was used (in dimethyl carbonate at 80
°C), salt 6 could be isolated as a solid. The desired 2H isomer
remained in solution, as well as <3% of the 1H isomer 5.
It was further rationalized that by the same token, selective
alkylation could also be achieved, with N-3 in the 1H isomer
expected to be the most nucleophilic site. Indeed, when the
mixture of 2 and 5 was treated with Me2SO4, methylation took
place on 5 exclusively, providing triazolium 8 and leaving the
2H isomer 2 unreacted. The presence of the quinoline nitrogen
did not interfere with the methylation on the triazole, presumably
due to the steric congestion around it. A solvent screening
showed that this reaction proceeded in a number of solvents
(Table 2). The reaction tended to stall in highly basic solvents
such as DMSO or DMF (entries 1 and 2), whereas in less polar
solvents the conversion was noticeably slower and the cationic
product tended to form an oil (entries 3-5). The reaction was
best conducted in CH3CN where the reaction mixture remained
homogeneous and complete conversion could be easily achieved.
Upon the consumption of the 1H isomer and removal of
CH3CN, a simple aqueous extraction cleanly removed the ionic
8 and left the desired product 2 as the only isomer in the organic
layer (ethyl acetate or TBME).
In summary, a scalable, nonchromatographic isolation of 2,
an intermediate in the synthesis of NK3 receptor antagonists,
was developed. This isolation method was based on the fun-
damental nucleophilicity difference in the isomeric triazoles and
could be used as a general tactic for the isolation of 2H-triazoles.
(11) Although the combination of NaH/DMF gave similar selectivity, it
was not chosen for safety reasons. See amEnde, D. J.; Vogt, P. F.
Org. Process Res. DeV. 2003, 7, 1029, and references cited therein.
Vol. 14, No. 2, 2010 / Organic Process Research & Development
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475

Scheme 2
Table 2. Solvent effect in the selective methylation of 1H-isomer
entry
solvent
methylation of 5/%a
entry
solvent
methylation of 5/%a
1
2
3
4
DMSO
DMF
EtOAc
butanone
41b
14b
86
5
6
7
8
Me2CO3
CH2Cl2
CHCl3
84
10c
99d
99
79
CH3CN
a Conversion by HPLC peak area ratio. b Conversion at 3 h, reaction stalled. c rt, 14 h. d 60 °C, 20 h.
Experimental Section
Methyl 2-(3-Fluorophenyl)-3-(1H-1,2,3-triazol-1-ylmethyl)-
4-quinolinecarboxylate (5). The 1H isomer could be purified
by chromatography from the reaction mixture in the triazole
alkylation reaction. ES-MS: m/z, 363 (M + H+). 1H NMR (300
MHz, CDCl3) δ 8.12 (dm, J ) 8.3 Hz, 1 H), 7.85-7.71 (m, 2
H), 7.66-7.56 (m, 1 H), 7.55 (d, J ) 1.0 Hz, 1 H), 7.44-7.32
(m, 1 H), 7.28 (d, J ) 1.0 Hz, 1 H), 7.18-7.03 (m, 3 H), 5.69
(s, 2 H), 3.96 (s, 3 H). 13C NMR (75 MHz, CDCl3) δ 48.38,
53.02, 115.67 (d, JFC ) 22.4 Hz), 115.91 (d, JFC ) 20.7 Hz),
121.86, 123.00, 123.53, 124.07 (d, JFC ) 2.8 Hz), 124.79,
128.24, 129.68, 130.30 (d, JFC ) 8.3 Hz), 131.11, 133.47,
140.64 (d, JFC ) 7.5 Hz), 141.14, 147.36, 158.43 (d, JFC ) 1.9
Hz), 162.43 (d, JFC ) 248 Hz), 166.81. 19F NMR (282 MHz,
CDCl3) δ -111.6.
Methyl 2-(3-Fluorophenyl)-3-(2H-1,2,3-triazol-2-ylmethyl)-
4-quinolinecarboxylate (2). 1H-[1,2,3]Triazole (6.42 g, 92.9
mmol, 1.2 equiv) was dissolved in 145 mL of DMF and cooled
to 0 °C. NaHMDS (1.0 M in THF, 93 mL, 93 mmol, 1.2 equiv)
was slowly added to the solution. The resultant mixture was
stirred at 0 °C for 1 h. Bromide 3 (29.0 g, 77.5 mmol) in 140
mL of DMF was slowly added to the triazole anion at 0 °C.
The mixture was stirred at 0 °C for 1 h and quenched with
water (290 mL). The mixture was extracted with EtOAc (290
mL + 145 mL). The combined organic layers were washed
with water (290 mL × 2). The organic solution was concen-
trated to minimum stir, and the residue was diluted with
acetonitrile to a total volume of 270 mL. Me2SO4 (5.87 g, 46.5
mmol, 0.6 equiv) was added to the mixture of 2 and 5, and the
resultant solution was heated to 80 °C for 4 h. LC analysis of
the reaction mixture showed that methylation of 1H isomer was
complete. The reaction mixture was cooled to rt, concentrated
to minimum stir, and the residue was diluted with EtOAc to
300 mL. H2O (300 mL) was added. The two layers were
separated, and the organic layer was washed with H2O (240
mL). The organic solution was concentrated. Heptane (130 mL)
and EtOAc (15 mL) were added. The resultant slurry was heated
at 60 °C for 40 min, cooled slowly to 0 °C, and stirred at 0 °C
for 1 h. The product was collected by filtration and dried at 50
°C under vacuum to give a beige-colored solid: 11.3 g, 31.2
mmol, 40% over 2 steps. Purity by HPLC peak area: 96.2%.
Electrospray-mass spectrometry (ES-MS): m/z, 363 (M + H+).
1H NMR (300 MHz, CDCl3) δ 8.24 (d, J ) 8.5 Hz, 1 H),
7.77-7.86 (m, 2 H), 7.62 (ddd, J ) 8.3, 7.0, 1.2 Hz, 1 H),
7.57 (s, 2 H), 7.43 (m, 2 H), 7.36 (dm, J ) 9.7 Hz, 1 H), 7.17
(m, 1 H), 5.82 (s, 2 H), 3.97 (s, 3 H). 13C NMR (75 MHz,
CDCl3) δ 52.74, 53.02, 115.92 (d, JFC ) 21.3 Hz), 116.23 (d,
JFC ) 22.9 Hz), 122.62, 123.37, 124.71 (d, JFC ) 2.8 Hz),
124.89, 128.15, 129.50, 130.15 (d, JFC ) 8.3 Hz), 131.10,
134.40, 140.73 (d, JFC ) 7.5 Hz), 141.40, 147.11, 158.59 (d,
JFC ) 2.2 Hz), 162.50 (d, JFC ) 247 Hz), 168.67. 19F NMR
(282 MHz, CDCl3) δ -112.2.
1-({2-(3-Fluorophenyl)-4-[(methyloxy)carbonyl]-3-
quinolinyl}methyl)-3-methyl-1H-1,2,3-triazol-3-ium Meth-
ylsulfate (8). The 1H isomer 5 (24.8 mg, 0.0684 mmol) was
dissolved in CD3CN (1 mL): 1H NMR (300 MHz, CD3CN) δ
8.10 (d, J ) 8.4 Hz, 1 H), 7.96-7.81 (m, 2 H), 7.77-7.64 (m,
1 H), 7.52 (s, 1 H), 7.50-7.37 (m, 2 H), 7.27-7.17 (m, 2 H),
7.14 (d, J ) 9.6 Hz, 1 H), 5.69 (s, 2 H), 3.98 (s, 3 H). Dimethyl
sulfate (7.0 µL, 0.074 mmol, 1.1 equiv) was added. The mixture
was heated to 70 °C for 17.5 h, and HPLC analysis showed
1
the reaction was complete. ES-MS: m/z, 377 (M+). H NMR
(300 MHz, CD3CN) δ 8.34 (d, J ) 1.4 Hz, 1 H), 8.29 (ddd, J
) 0.6, 1.1, 8.5 Hz, 1 H), 8.18 (d, J ) 1.4 Hz, 1 H), 8.08 (ddd,
J ) 0.7, 1.3, 8.5 Hz, 1 H), 8.02 (ddd, J ) 1.4, 7.0, 8.5 Hz, 1
H), 7.85 (ddd, J ) 1.3, 7.0, 8.4 Hz, 1 H), 7.59-7.49 (m, 1 H),
7.37-7.17 (m, 3 H), 5.93 (s, 2 H), 4.12 (s, 3 H), 4.11 (s, 3 H),
3.45 (s, 3 H). The triazole Hs shifted from 7.45 and 7.52 ppm
in 5 to 8.18 and 8.34 ppm in 8.
Received for review December 9, 2009.
OP900320J
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Vol. 14, No. 2, 2010 / Organic Process Research & Development