An improved synthesis of 5,6,7,8-tetrahydro-1,7-naphthyridine - A conformationally-restricted analog of 2-(3-pyridyl)ethylamine

Article abstract of DOI:10.1002/jhet.5570380241

The 5,6,7,8-tetrahydro-1,7-naphthyridine (7) pharmacophore has the potential to serve as a conformationally-locked analog of the pharmacologically active 2-(3-pyridyl)ethylamine (1) core structure. This paper describes the synthesis of 5,6,7,8-tetrahydro-

Full text of DOI:10.1002/jhet.5570380241

Mar-Apr 2001
An Improved Synthesis of 5,6,7,8-Tetrahydro-1,7-naphthyridine -
A Conformationally-Restricted Analog of 2-(3-Pyridyl)ethylamine
535
∗
Robert L. Dow and Steven R. Schneider
Pfizer Global Research and Development, Pfizer Inc, Groton, CT 06340
Received October 23, 2000
The 5,6,7,8-tetrahydro-1,7-naphthyridine (7) pharmacophore has the potential to serve as a confor-
mationally-locked analog of the pharmacologically active 2-(3-pyridyl)ethylamine (1) core structure. This
paper describes the synthesis of 5,6,7,8-tetrahydro-1,7-naphthyridine (7) via a five-step sequence, which
affords a significant improvement over previously reported syntheses.
J. Heterocyclic Chem., 38, 535 (2001).
Introduction.
The 2-(3-pyridyl)ethylamine pharmacophore (1) has
been documented to possess a range of pharmacological
activities, including potent binding to members of the
dopaminergic [1] and cholinergic [2] receptor families. Of
particular interest is the suggestion that 1 is bioisosteric to
the 3-hydroxyphenylethylamine pharmacophore found in
many dopamine agonists [1]. This replacement of
3-hydroxyphenyl with pyridyl could potentially lead to
agents with improved pharmacokinetic properties, given
the low bioavailability and short in vivo half-lives
associated with the former functionality. In addition,
replacement of the aromatic ring of phenylethylamines
with the 3-pyridyl functionality has been shown to
improve aqueous partitioning [3], thus improving the
"drug-like" potential of the resultant analogs. Though
pharmacological studies have been carried out on
compounds in which the 2-(3-pyridyl)ethylamine pharma-
cophore is constrained within a pyrido[3,4-d]azepine ring
[2], there have not been any reports on analogs containing
conformationally restrained 5,6,7,8-tetrahydro-1,7-naph-
thyridine (7) core structure.
In contrast to the previously reported syntheses of 7, the
approach described herein (Scheme I) is based on appending
the pyridine ring to a commercially available 3-piperidone
(2). This was envisioned to occur through incorporation of a
three-carbon aldehyde equivalent into the 4-position of the
piperidone backbone followed by decarboxylation and
cyclization/aromatization with N-hydroxylamine to from the
tetrahydronaphthyridine core (6). Towards this end,
alkylation of the β-ketoester 2 with 2-(2-bromoethyl)-1,3-
dioxolane afforded 4a in 55% yield, along with 12% of the
corresponding O-alkylated product. Attempts to hydrolyze
and decarboxylate 4a under a variety of conditions (e.g.
To date there have been only two reported syntheses of
the 5,6,7,8-tetrahydro-1,7-naphthyridine (7) [4] or its
N-benzyl derivative 6 [5], both of which are based on
elaboration of a 2,3-disubstituted pyridine core. The first
of these routes relies upon a partial reduction of 1,7-naph-
thyridine that affords a 1:1 mixture of 7 and 1,2,3,4-
tetrahydro-1,7-naphthyridine, which require separation by
preparative gas chromatography or multiple thin-layer
chromatographies [4]. Preparation of the requisite
1,7-naphthyridine proceeds via a six-step synthesis in a
low overall yield (<10%). The other reported synthesis [5]
of a 5,6,7,8-tetrahydro-1,7-naphthyridine core proceeds
via a nine-step sequence, affording 6 in low overall yield.
NaOH, LiCl/H O or MgCl /HMPA) afforded a significant
2
2
number of side products in addition to desired ketone 5.
Presumably, formation of the undesired reaction products is
at least in part mediated via a reverse Dieckmann reaction.

536
As a means of circumventing this problem, benzyl ester
3 was prepared (92%) by transesterification of 2 catalyzed
by 4-dimethylaminopyridine [6]. Alkylation of the
potassium enolate of 3 with the dioxolane-based bromide
afforded 4b in 65% yield. Selective hydrogenolysis
Vol. 38
R. L. Dow and S. R. Schneider
1-Benzyl-4-(2-[1,3]dioxolan-2-yl-ethyl)-3-piperidone-4-
carboxylic Acid Benzyl Ester (4b).
To a cooled (0 °C), stirred solution of 1-benzyl-3-piperidone-
4-carboxylic acid benzyl ester (3) (13.6 g, 42.0 mmol) in
dimethylformamide (84 mL) was added potassium tert-butoxide
(5.2 g, 46.2 mmol). After 5 minutes, the cooling bath was
removed and the resulting solution was allowed to stir at ambient
temperature for an additional 30 minutes. Freshly distilled 2-(2-
bromoethyl)-1,3-dioxolane (15.2 g, 84.1 mmol) and sodium
iodide (3.2 g, 21.0 mmol) were added and the resulting mixture
was heated at 80 °C for 2 hours. After cooling, the reaction
mixture was diluted with ethyl ether (1 L), washed with water
(3 x 50 mL), brine (50 mL), dried over sodium sulfate and
concentrated in vacuo to afford a brown oil. Chromatography
through a pad of silica gel (300 g) employing a gradient of 5% to
20% ethyl acetate/hexanes afforded the title compound as a
golden oil, 11.5 g (65%). H nmr (deuteriochloroform): δ
1.51-1.72 (m, 4H, CH -CH ), 1.95 (dt, 1H, CH ), 2.57-2.70 (m,
3H, CH , CH ), 3.02 (AB quartet, 2H, CH -N, J = 15.8, ∆ν =
66.0 Hz), 3.44 (AB quartet, 2H, CH -N), 3.78-3.92 (AB pattern,
4H, O-CH CH -O), 4.81 (t, 1H, O-CH-O), 5.13 (AB quartet, 2H,
O-CH ), 7.20-7.33 (m, 10H, Ar-H); ms (CI) m/z 424 (M+1,
100%). This compound slowly polymerizes (~20% degradation
after 1 month at 5 °C) to an insoluble white solid/red oil mixture.
(Pd/carbon, 15 p.s.i. H in ethyl acetate) of the benzyl ester
2
followed by concomitant decarboxylation produced
ketodioxolane 5. Cyclodehydration of this 1,5-dicarbonyl
equivalent with hydroxylamine hydrochloride in either
acetic acid [7] or ethanol [8] provided the tetrahydronaph-
thyridine nucleus. From a limited set of experiments,
heating in ethanol at 70 °C for 16 hours afforded the
highest yield (34%) of 6. Finally, N-debenzylation was
achieved by hydrogenolysis (Pd/carbon) in acidic
methanol to afford the dihydrochloride salt of 5,6,7,8-
tetrahydro-1,7-naphthyridine (7) in 78% recrystallized
yield.
In summary we have developed a five-step synthesis of
5,6,7,8-tetrahydro-1,7-naphthyridine, which provides
improved access to this conformationally-restrained,
pharmacophore structure and its corresponding N-substi-
tuted derivatives.
1
2
2
2
2
2
2
2
2
2
2
1-Benzyl-4-(2-[1,3]dioxolan-2-yl-ethyl)-3-piperidone (5).
EXPERIMENTAL
A slurry of 1-benzyl-4-(2-[1,3]dioxolan-2-yl-ethyl)-3-piperi-
done-4-carboxylic acid benzyl ester (4b) (1.3 g, 3.1 mmol) and
10% palladium-on-carbon (0.65 g) in ethyl acetate (15 mL) was
treated with 15 p.s.i. of hydrogen on a Parr apparatus for 2
hours. The reaction slurry was filtered through a short pad of
Celite, washing with dichloromethane and ethyl acetate. The
filtrate was concentrated in vacuo to afford the title compound as
a tan oil, 0.73 g (82%). This material was utilized in the next
General.
Melting points were determined on a Thomas Hoover
melting point apparatus and are uncorrected. H nmr spectra
1
were recorded on a Varian Inova 400 MHz Spectrometer. Low
resolution mass spectral data were obtained on a Micromass
ZMD2000 utilizing flow injection and APcI ionization.
Microanalyses were obtained from Schwarzkopf
Microanalytical Laboratory, Inc. Silica gel column chromatog-
raphy was performed on a Biotage Flash 40i chromatography
module. All commercial reagents were used without further
purification.
1
reaction without further purification. H nmr (deuterio-
chloroform): δ 1.33-1.42 (m, 1H, CH ), 1.57-1.71 (m, 3H, CH ,
2
2
CH ), 1.90-2.03 (m, 1H, CH ), 2.04-2.09 (m, 1H, CH ), 2.24-2.32
2
2
2
(m, 1H, CH ), 2.42-2.48 (m, 1H, CH ), 2.89-2.94 (m, 1H, CH),
2
2
3.19 (AB quartet, 2H, CH -N, J = 13.7, ∆ν = 157.3 Hz), 3.56
2
(s, 2H, CH -N), 3.77-3.97 (AB pattern, 4H, O-CH CH -O), 4.83
2
2
2
(t, 1H, O-CH-O), 7.22-7.32 (m, 5H, Ar-H); ms (CI) m/z 290
(M+1, 100%).
1-Benzyl-3-piperidone-4-carboxylic Acid Benzyl Ester (3).
A stirred solution of 1-benzyl-3-piperidone-4-carboxylic
acid ethyl ester (2) (23.3 g, 89 mmol) [9], benzyl alcohol
(45 mL) and 4-dimethylaminopyridine (1.1 g, 8.9 mmol) in
toluene (400 mL) was heated at reflux temperature for
48 hours, with an additional portion of 4-dimethylamino-
pyridine (1.1 g, 8.9 mmol) being added at the 24 hour time
point. The solvent and excess benzyl alcohol were removed by
distillation under reduced pressure (5 - 10 Torr). The resulting
oil was purified by elution through a pad of silica gel (400 g)
employing 5% ethyl acetate/hexanes to afford the title
7-Benzyl-5,6,7,8-tetrahydro-1,7-naphthyridine (6).
A slurry of 1-benzyl-4-(2-[1,3]dioxolan-2-yl-ethyl)-3-piperi-
done (5) (0.73 g, 2.5 mmol) and hydroxylamine hydrochloride
(1.8 g, 25 mmol) in anhydrous ethanol (25 mL) was stirred at
70 °C for 16 hours. The resulting brown solution was cooled,
concentrated in vacuo, diluted with half-saturated aqueous
sodium carbonate and extracted twice with dichloromethane. The
combined organic layers were dried over sodium sulfate, filtered
and concentrated in vacuo. The resulting brown oil was
chromatographed on a Biotage Flash 40S eluting with a gradi-
ent of 0%-1.5% methanol in dichloromethane to afford the title
1
compound as a yellow oil, 26.6 g (92%). H nmr (deuterio-
chloroform): δ 2.38 (t, 2H, CH ), 2.59 (t, 2H, CH ), 3.11
2
2
1
(s, 2H, CH -N), 3.61 (s, 2H, CH -N), 5.20 (s, 2H, O-CH ),
compound as a golden oil, 0.19 g (34%). H nmr (deuterio-
2
2
2
7.31-7.35 (m, 10H, Ar-H), 11.82 (s, 0.3H, enol); ms (CI) m/z
324 (M+1, 100%).
chloroform): δ 2.74 (t, 2H, CH -pyridyl), 2.87 (t, 2H, CH -N),
2
2
3.72 (s, 2H, CH -N), 3.74 (s, 2H, CH -N), 7.03-7.06 (m, 1H,
2
2
Anal. Calcd. for C H N O : C, 74.28; H, 6.55; N, 4.33.
Found: C, 74.17; H, 6.71; N, 4.38.
pyridyl-H), 7.23-7.40 (m, 6H, Ar-H and pyridyl-H), 8.33 (d, 1H,
pyridyl-H); ms (CI) m/z 325 (M+1, 100%).
20 21
1 3

Mar-Apr 2001
An Improved Synthesis of 5,6,7,8-Tetrahydro-1,7-naphthyridine
537
The bis-hydrochloride salt was recyrstallized from
.
Anal. Calcd. for C H N Cl 0.25H 0: C, 45.41; H, 5.95; N,
8
12
2
2
2
methanol/ethyl acetate; mp 231-233 °C (significant darkening of
13.24. Found: C, 45.15; H, 6.04; N, 12.98. A portion of the
dihydrochloride salt was free-based (CH Cl /aq. Na CO ) and
the H nmr spectrum of the isolated oil was consistent with that
previously reported [4].
1
solid above 225 °C); H nmr (methanol-d ): δ 3.43 (br t, 2H,
4
2
2
2
3
CH -pyridyl), 3.78 (br s, 2H, CH -N), 4.66 (s, 2H, CH -N), 4.71
1
2
2
2
(s, 2H, CH -N), 7.53-7.55 (m, 3H, Ar-H), 7.66-7.69 (m, 2H,
2
Ar-H), 7.89 (dd, 1H, pyridyl-H), 8.39 (d, 1H, pyridyl-H), 8.73
(d, 1H, pyridyl-H), 9.78 (br s, 2H, HCl).
REFERENCES AND NOTES
Anal. Calcd. for C H N Cl : C, 60.62; H, 6.10; N, 9.42.
15 18
2
2
Found: C, 60.44; H, 6.13; N, 9.42.
[1] F. Claudi, G. M. Cingolani, G. Giorgioni, M. Cardellini, F.
Amenta, and C. Polidori, Eur. J. Med. Chem., 30, 415 (1995).
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I. Damaj and R. A. Glennon, Eur. J. Med. Chem., 34, 177 (1999).
[3] J. M. Mayer, B. Testa, H. van de Waterbeemd and A.
Bornand-Crausaz, Eur. J. Med. Chem. – Chim. Ther., 17, 461 (1982).
[4] W. L. F. Armarego, J. Chem. Soc. C, 377 (1967).
[5] Y. Sato, T. Iwashige and T. Miyadera, Chem. Pharm. Bull. 8,
427 (1960).
[6] D. F. Taber, J. C. Amedio, Jr. and T. K. Patel, J. Org. Chem.,
50, 3618 (1985).
[7] G. Chelucci, F. Soccolini and C. Botteghi, Syn. Commun., 15,
807 (1985).
5,6,7,8-Tetrahydro-1,7-naphthyridine, Bis-hydrochloride (7).
A slurry 7-benzyl-5,6,7,8-tetrahydro-1,7-naphthyridine (6)
(170 mg, 0.76 mmol) and 10% palladium-on-carbon (0.85 mg) in
methanol (4 mL)/4 N HCl in dioxane (0.8 mL) was treated with
50 p.s.i. of hydrogen on a Parr apparatus for 6 hours. The
reaction slurry was filtered through a short pad of Celite,
washed with methanol and concentrated in vacuo. The resulting
solids were azeotroped with toluene (2x) and dried in vacuo
(0.1 torr) to afford an off-white solid. Recrystallization from
methanol/ethyl acetate and drying in vacuo (0.1 torr, 60 °C)
afforded the title compound, 123 mg (78%), mp 251-253 °C
(significant darkening of solid above 180 °C). Alternatively, 7 can
be prepared by palladium-on-carbon catalyzed hydrogenolysis of
[8] J. R. Huff, J. J. Baldwin, S. J. deSolms, J. P. Guare Jr., C. A.
Hunt, W. C. Randall, W. W. Sanders, S. J. Smith, J. P. Vaccs and M. M.
Zrada, J. Med. Chem. 31, 641 (1988).
6 in the presence of di-t-butyl dicarbonate (MeOH, 50 p.s.i. H )
2
and subsequent N-BOC cleavage with methanol/HCl in ~90%
[9] The free base was obtained from the corresponding
hydrochloride salt (Aldrich Chemical Co.) by partitioning between ethyl
acetate and half-saturated aqueous sodium bicarbonate, drying the
organic phase over sodium sulfate and concentrating in vacuo to afford a
brown oil.
1
overall yield. H nmr (dimethylsulfoxide-d ): δ 3.09 (t, 2H,
6
Ar-CH ), 3.36-3.38 (m, 2H, CH -N), 4.38 (s, 2H, pyridyl-CH -
2
2
2
N), 7.58 (dd, 1H, pyridyl-H), 8.01 (d, 1H, pyridyl-H), 8.57 (d, 1H,
pyridyl-H), 10.12 (br s, 2H, HCl); ms (CI) m/z 135 (M+1, 100%).