Synthesis of triazolopyridines as conformationally constrained tertiary amides

Article abstract of DOI:10.1016/S0040-4039(00)00632-8

Amide derivatives of cyclic amines are common templates for biologically active chemical entities. To constrain the tertiary amide moiety of N- acylpiperidine-based GPIIb/IIIa antagonists for further structure-activity study, we have prepared new 1,2,4-triazolo[4,3-a]pyridines. The syntheses of two classes of triazolopyridines are reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00632-8

Tetrahedron Letters 41 (2000) 4533±4536
Synthesis of triazolopyridines as conformationally constrained
tertiary amides
Edward C. Lawson, Bruce E. Maryano€* and William J. Hoekstra*,
y
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA
Received 16 March 2000; revised 30 March 2000; accepted 31 March 2000
Abstract
Amide derivatives of cyclic amines are common templates for biologically active chemical entities. To
constrain the tertiary amide moiety of N-acylpiperidine-based GPIIb/IIIa antagonists for further structure-
�activity study, we have prepared new 1,2,4-triazolo[4,3-a]pyridines. The syntheses of two classes of
triazolopyridines are reported. # 2000 Elsevier Science Ltd. All rights reserved.
Piperidine-based amides are important templates in biologically active chemical systems.1
�4
Some of their prominent therapeutic applications have been in the areas of kappa-opioid
5
6
7
analgesics, antiin¯ammatory agents, and antithrombotic agents. We identi®ed a novel series of
8
antithrombotic agents based on nipecotic acid as a peptidomimetic sca€old, from which elaro®ban
�11
(
RWJ-53308) was selected for clinical evaluation in humans (Eq. (1)).9
Thus, as a follow-up,
we sought to incorporate an element of planar, geometric rigidi®cation into the key tertiary
amide group. Possible improvements in the bioactivity and, especially, the pharmacokinetics of
these ®brinogen receptor (GPIIb/IIIa) antagonists were envisioned by the use of such ring-fused
analogues. In this letter, we report the synthesis of bicyclic triazolopyridines bearing functionality
8
on both rings to accommodate the structure±activity relationship. Besides providing a basis
for novel ®brinogen receptor antagonists, our results suggest a general annulation strategy for the
preparation of variably functionalized, fused triazole sca€olds suitable for chemical library
preparation by high-throughput organic synthesis.
ꢀ1†
*
y
Corresponding author. Tel: 215-628-5530; fax: 215-628-4985; e-mail: bmaryano@prius.jnj.com
Present address: Glaxo Wellcome, Research Triangle Park, NC 27709, USA.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00632-8

4
534
Fusion of a ®ve-membered ring at the N-1/C-2 position of nipecotic acid would elaborate a
new bicyclic ring system and thereby remove a potentially metabolically labile tertiary amide
(Eq. (1)). A synthetic conversion of 2-pyrrolidinones and acylhydrazides to substituted triazolo-
pyrroles reported by Rigo et al. provided a precedent for our nipecotic acid-type system.
12,13
In
Rigo's three-step procedure, 5-carboxy-2-pyrrolidinone was O-methylated with dimethyl sulfate,
treated with N-acetylhydrazide, and warmed to give an amidrazone intermediate, which was
heated with chlorotrimethylsilane/triethylamine to a€ord the bicyclic triazole.
Disubstituted tetrahydrotriazolopyridines14 were prepared in a similar fashion. A reliable,
high-yielding method utilizing existing 3-(4-piperidine)propionic acid and enantiomerically enriched
b-amino acid intermediates (R=aryl) was desired to synthesize a number of analogues on a gram
scale.15 To this end, commercially available piperidone 1 was methylated with trimethyloxonium
tetra¯uoroborate in dichloromethane and treated with Boc-protected acylhydrazide 2 in methanol
to give an amidrazone intermediate 3 (Eq. (2)). Rigo's annulation method, which had required
basic, chlorotrimethylsilane-mediated conditions at high temperatures, produced a complex
mixture of products in our hands when starting with the ®ve-membered ring system, ethyl 2-oxo-
3
-pyrrolidine carboxylate. By contrast, simply warming the corresponding six-membered ring
amidrazone 3 in methanol under neutral conditions for an extended period of time (18±24 h)
a€orded tetrahydrotriazolopyridine 4 in good yield. The corresponding N-benzyloxycarbonyl-
protected analogue of 4 was prepared in a similar fashion.
ꢀ2†
A triazolopyridine ring system with six-membered ring unsaturation16 was also prepared to
introduce further conformational rigidi®cation of the central sca€old. To address this modi®cation,
17
intermediate ester 9 was prepared in three steps starting with chloronicotinate 6 (Eq. (3)). Initial
attempts to add hydrazide 2 directly to 6 (as in Eq. (2)) to provide acylhydrazide 8 proved
unsuccessful. Alternatively, compound 6 was treated with hydrazine in warm dioxane followed by
water soluble carbodiimide-mediated (EDC) formation of acylhydrazide 8. Generation of tria-
zolopyridine 9 by cyclization of acylhydrazide 8 utilizing neutral methanol conditions was
unsuccessful in this case. Instead, the hydrazide was cyclized under acidic conditions (acetic acid/
toluene, re¯ux) to a€ord key intermediate 9.

4
535
ꢀ3†
In conclusion, we have described concise syntheses of two novel, disubstituted 1,2,4-tri-
azolo[4,3-a]pyridines. Given the straightforward, three-step assembly from a key pyridyl±acyl-
18
hydrazide intermediate, this methodology represents a general approach to new peptidomimetics
of tertiary amides. As an application of this chemistry, esters 4 and 9 were carried forward to the
biologically interesting antithrombotic compounds 5 and 10.1
9,20
Acknowledgements
We thank David F. McComsey for helpful discussions.
References
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4
536
1
4. For a patent on 1,2,4-triazolo[4,3-a]pyridine-8-acetic acids as angiotensin II receptor antagonists, see: Manning,
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1
solution of ethyl 2-oxo-3-piperidine carboxylate (6.31 g, 36.9 mmol) in CH
stirred for 18 h. N-Boc-3-(4-piperidine)propionic hydrazide (10.0 g, 36.9 mmol) in CH Cl (62 mL) was added.
2 2
Cl (62 mL) and the reaction was
2
2
The resulting mixture was stirred for 24 h, diluted with CH
organic layer was dried (Na SO ) and evaporated to give a white solid, which was dissolved in MeOH (365 mL)
Cl
2 2
(150 mL), and washed with brine (2Â50 mL). The
2
4
and heated at re¯ux for 24 h. The mixture was cooled, concentrated in vacuo, and puri®ed by ¯ash
chromatography (CH Cl :MeOH:NH OH, 97:2:1) to give 4 as a white solid (7.79 g, 52% yield, >98% purity).
2
2
4
1H NMR (CDCl
H); ES/MS m/z 407.4 (MH+).
6. Jones, G.; Sliskovic, R. Adv. Heterocycl. Chem. 1983, 34, 79.
) ꢀ 4.1 (q, 2H), 3.9 (m, 4H), 2.7 (m, 2H), 2.0 (m, 6H), 1.6 (m, 6H), 1.6 (s, 9H), 1.2 (t, 3H), 1.1 (m,
3
2
1
1
7. Ester 9 was synthesized from 6 as follows: Ethyl 2-chloronicotinate (2.1 g, 11.3 mmol) and anhydrous hydrazine
ꢁ ꢁ
(0.4 mL, 12.7 mmol) were heated in dioxane (54 mL) at 60 C for 2 h. The mixture was cooled to 23 C and
concentrated in vacuo to give ethyl 2-hydrazinenicotinate (2.0 g, 97%). N-Boc-3-(4-piperidine)propionic acid (7;
ꢁ
2
propylcarbodiimide HCl (2.55 g, 13.3 mmol), N-methylmorpholine (1.5 mL, 13.6 mmol), and 1-hydroxy-
.85 g, 11.1 mmol) was dissolved in CH
.
2
Cl
2
(55 mL), cooled to 0 C, and treated with ethyl 3-dimethylamino-
benzotriazole (0.15 g, 1.11 mmol). Ethyl 2-hydrazinenicotinate (2.0 g, 11.0 mmol) was added and the reaction
ꢁ
ꢁ
was brie¯y stirred at 0 C, warmed to 23 C, and stirred for 17 h. The mixture was diluted with CH Cl (100 mL)
2
2
and washed with water (3Â50 mL). The organic layer was dried (MgSO
4
) and concentrated in vacuo to give 8 as a
white solid (2.24 g, 48%), which was heated with acetic acid (6.0 mL, 105 mmol) in toluene (106 mL) at re¯ux for
Ê
2 h using a Dean±Stark trap containing 4 A molecular sieves. The mixture was concentrated in vacuo and ¯ash
2
chromatographed (CH
1
2
2
Cl :MeOH, 98:2) to give 9 as a white powder (1.54 g, 77% yield, >98% purity). H NMR
(
CDCl
m, 2H), 1.8 (m, 4H), 1.6 (s, 9H), 1.3 (t, 3H); ES/MS m/z 403.4 (MH ).
3
) ꢀ 8.6 (d, 1H), 8.1 (d, 1H), 7.4 (dd, 1H), 4.6 (m, 2H), 4.4 (q, 2H), 4.1 (q, 2H), 3.5 (m, 1H), 3.2 (t, 2H), 2.7
+
(
8. Kelly, J. W. Bioorg. Med. Chem. 1999, 7, 1.
1
1
2
9. The biological results will be reported separately.
0. Hoekstra, W. J.; Lawson, E. C.; Maryano€, B. E. WO 00/06570.