Pyridine metallations in the synthesis of triazole based NK-1 antagonists

Article abstract of DOI:10.3987/COM-05-S(T)64

Regioselective pyridine metallation chemistry was used to produce N-(3-chloropyridin-4-ylmethyl)-N-methyl-1-(3,5-bis-trifluoromethylbenzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxamide (9a) and [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]t

Full text of DOI:10.3987/COM-05-S(T)64

HETEROCYCLES, Vol. 67, No. 2, 2006
543
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 543 - 547. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd August, 2005, Accepted, 17th November, 2005, Published online, 18th November, 2005. COM-05-S(T)64
PYRIDINE METALLATIONS IN THE SYNTHESIS OF TRIAZOLE
BASED NK-1 ANTAGONISTS
K. Jeff Thrasher, Erik J. Hembre, Kevin M. Gardinier, Kenneth A. Savin,
Jian Eric Hong, and Louis N. Jungheim*† (MS Word Style “02 Het-Author’s
name”)
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis IN 46285, USA
Abstract – Regioselective pyridine metallation chemistry was used to produce
N-(3-chloropyridin-4-ylmethyl)-N-methyl-1-(3,5-bis-trifluoromethylbenzyl)-5-
phenyl-1H-[1,2,3]triazole-4-carboxamide (9a) and [1-(3,5-bis-trifluoromethyl-
benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(3-chloropyridin-4-yl)-5-
hydroxymethylisoxazol-4-yl]methanone (16a), which exhibit NK-1 antagonist
activity.
In recent years, there has been significant interest in the discovery and development of NK-1 antagonists.1
Currently, Merck’s NK-1 antagonist (MK-869) is approved for the treatment of emesis.2 NK-1 antagonists
have been studied in the clinic as treatment for stress related disorders. We recently disclosed some of our
work on a triazole based platform represented by compounds (1) and (2) (Figure 1).3 These compounds
demonstrated potent NK-1 antagonist activity in in vitro and in vivo models but issues of solubility and
CF3
Cl
Cl
N
O
Me
HO
Me
N
CF3
O
N
O
N
O
O
N
N
N
N
N
N
O
CF3
CF3
N
F
HN
NH
F3C
1
F3C
MK-869
O
Figure 1
† Dedicated to Professor Barry M. Trost on the occasion of his 65th birthday.

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HETEROCYCLES, Vol. 67, No. 2, 2006
metabolism limited drugability. Our goal was to improve the aqueous solubility of these compounds by
replacing the chloro-phenyl moiety with a chloro-pyridyl moiety without reducing intrinsic NK-1
antagonist activity.
Synthesis of the triazole template is accomplished regioselectively through the condensation of an azide(4)
with an appropriately substituted ß-keto ester (3) following the method of Cottrell.4 Base-catalyzed
hydrolysis provided the desired triazole acid (5). Coupling of the triazole acid (5) with (2-chlorobenzyl)-
methylamine (6) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxy-
7-azabenzotriazole (HOAT) in DMF provided compound (1) (Scheme 1).
O
HO
N
O
N3
N
EtO
1. K2CO3, DMSO
N
CF3
+
2. aq NaOH, THF
80%
O
CF3
F3C
5
4
3
F3C
HOAT
Cl
EDC
DMF
1
6
NHMe
77%
Scheme 1
In order to prepare the appropriately substituted pyridines we took advantage of the directing ability of
halogen to selectively metallate halopyridines. We used LDA/THF deprotonation conditions to achieve
“thermodynamic” lithiation as described by Queguiner.5 Quench of the anions with DMF produced the
desired aldehydes (7a-c). Our results metallating chloropyridines to produce pyridyl aldehydes (7a-c) are
summarized in Figure 2 and parallel results described by Queguiner using fluoro pyridines.5
Cl
Cl
CHO
Cl
Cl
CHO
LDA, THF
DMF
2.2 eq. LDA, THF
DMF
- 70oC
62%
- 70oC
85%
N
N
N
N
HCl
7a
7b
CHO
LDA, THF
- 70oC
41%
DMF
Cl
N
N
Cl
7c
Figure 2

HETEROCYCLES, Vol. 67, No. 2, 2006
545
To complete construction of the desired pyridyl amide derivatives, for example, pyridyl aldehyde (7a) was
subjected to reductive amination conditions with methylamine to produce the amine (8a) (Scheme 2).
Subsequent amide coupling to the previously described triazole acid (5) provided the desired chloropyridyl-
triazole amide (9a). This sequence was successfully accomplished with aldehydes (7b) and (7c) to
provide the regioisomeric pyridyl amide derivatives (9b) and (9c). We were pleased to find that the
pyridyl analogs displayed improved aqueous solubility and retained their activity as NK-1 receptor
antagonists (compound 9a, Ki = 0.10 nM; compound 9b, Ki = 50.80 nM; compound 9c, Ki = 2.90 nM).6,8
N
Cl
Me
O
CHO
NHMe
Cl
N
Cl
MeNH2
NaBH4
5
EDC
N
MeOH
DMF
HOAT
N
N
N
N
89%
70%
8a
7a
CF3
9a
F3C
Scheme 2
Another aspect of our investigation involved the use of isoxazoles as potentially more metabolically stable
amide isosteres. Using the method of Buckle,7 reaction of an azide (4) with diethyl malonate produced the
5-hydroxytriazole derivative (10). Conversion to the 5-chlorotriazole derivative (11) using PCl5 in toluene
set the molecule up for late stage substitution at the triazole C-5 position (Scheme 3). In preparation for
isoxazole construction, the 5-chlorotriazole ester (11) was reduced with LiBH4 in THF followed by
Dess-Martin oxidation to the triazole aldehyde (12). Alkynyl Grignard addition to the triazole aldehyde
(12) followed with MnO2 oxidation in toluene produced the keto alkyne intermediate (13).
O
O
EtO
EtO
N
N
N3
N
Cl
N
HO
N
N
diethyl malonate
NaOEt
PCl5
toluene
70%
EtOH
87%
CF3
CF3
CF3
F3C
F3C
4
F3C
11
10

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HETEROCYCLES, Vol. 67, No. 2, 2006
TBDMSO
O
O
MgBr
THF
Cl
N
N
N
TBDMSO
N
1. LiBH4, THF
1.
N
Cl
N
2. Dess-Martin
periodinane
2. MnO2, toleune
CF3
CF3
CH2Cl2
F3C
88%, 2 steps
91%, 2 steps
F3C
13
12
Scheme 3
To prepare for cycloaddition with the keto alkyne (13), the pyridyl-substituted nitrile oxide precursor (14)
was produced by conversion of the pyridyl aldehyde (7a) to the oxime followed by oxidation with
N-chlorosuccinimide (Scheme 4). Reaction of 14a with the keto alkyne intermediate (13) in diethyl ether
using triethylamine (TEA) as base resulted in formation of the desired isoxazole ring (15a). Substitution at
C-5 of the triazole was accomplished, for example, by heating the 5-chlorotriazole derivative (15a) with
morpholine followed by acid catalyzed hydrolysis of the silyl ether protecting group to give the desired
pyridyl-isoxazole-triazole-ketone (16a) (Scheme 4). Similarly this sequence was carried out with each of
the pyridyl aldehydes (7b-c). These compounds demonstrated good NK-1 antagonist activity (analog 16a,
Ki = 0.16 nM; analog 16b, Ki = 2.59 nM; analog 16a, Ki = 0.24 nM)6.8 as well as improved solubility and
metabolic properties.
Cl
N
O
N
TBDMSO
OH
N
Cl
CHO
O
N
Cl
N
Cl
13
1. NH2OH, aq EtOH
2. NCS, DMF
88%
Cl
N
Et2O, TEA
67%
N
N
CF3
7a
15a
14a
F3C
Cl
N
O
N
HO
50oC
1. morpholine
O
N
N
N
N
2. TsOH, MeOH
50%, 2 steps
O
CF3
16a
Scheme 4
F3C

HETEROCYCLES, Vol. 67, No. 2, 2006
547
In conclusion, we have used directed pyridine metallation chemistry to produce various pyridyl triazole
amides and pyridyl isoxazole-triazole-ketones. These derivatives demonstrated comparable biological
activity to the phenyl substituted analogs (1) and (2). Further disclosure of additional aspects of our
triazole based structure activity relationships will occur in due course.
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