Synthesis of fluorinated 1,8-naphthyridinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.09.090

Processes for the synthesis of fluorinated 1,8-naphthyridinone derivatives including 6,7-difluoro-1,8-naphthyridin-2-one are described.

Full text of DOI:10.1016/j.tetlet.2007.09.090

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8189–8191
Synthesis of fluorinated 1,8-naphthyridinone derivatives
a,
a
a
Joseph T. Repine,a,* Douglas S. Johnson, Timothy Stuk, Andrew D. White,
*
Michael A. Stier,a Tingsheng Li,b Zhixiang Yangb and Samarendra N. Maitib
aPfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
bNaeja Pharmaceuticals, 4290-91a Street, Edmonton, Alberta, Canada T6E 5V2
Received 13 June 2007; revised 12 September 2007; accepted 13 September 2007
Available online 18 September 2007
Abstract—Processes for the synthesis of fluorinated 1,8-naphthyridinone derivatives including 6,7-difluoro-1,8-naphthyridin-2-one
are described.
Ó 2007 Elsevier Ltd. All rights reserved.
The 1,8-naphthyridine core is a versatile template for
drug discovery. This structure is incorporated in numer-
ous biologically active compounds and drugs which act
by various mechanisms for diverse indications. Among
these are compounds useful as antibacterials,1 anticon-
vulsants,2 antihypertensives,3 and inhibitors of both
ACAT4 and platelet aggregation.5 Compounds contain-
ing the 1,8-naphthyridin-2(1H)-one (1) skeleton can illi-
cit phosphodiesterase6 and kinase activities7 which have
been indicated as treatments for asthma, proliferative
and inflammatory disorders. In our laboratory, the
1,8-naphthyridin-2(1H)-one fragment has provided
compounds which are potentially useful for the treat-
ment of schizophrenia and bipolar disorder.8
hydrogen bonding interactions.9c An example of a drug
containing a fluoro substituted naphthyridine core is the
fluoroisoquinolone antibiotic enoxacin. Therefore, the
incorporation of fluorine in a variety of naphthyridines
would be expected to provide highly desirable intermedi-
ates for the synthesis of new drug candidates.
We describe herein the synthesis of a series of
fluorinated 1,8-naphthyridinone fragments including
6-fluoro-7-(4-hydroxybutoxy)-3,4-dihydro-1,8-naphthyri-
din-2(1H)-one (2), 6-fluoro-7-(4-hydroxybutoxy)-1,8-
naphthyridin-2(1H)-one (3), 3-fluoro-7-(4-hydroxybut-
oxy)-1,8-naphthyridin-2(1H)-one (4), and 6,7-difluoro-
1,8-naphthyridin-2(1H)-one (5).
X
Y
From the above examples, structural changes surround-
ing a lead molecule with a 1,8-naphthyridine core are
often desired in order to optimize the potency and selec-
tivity against receptors and modulate the physical and
ADME (absorption, distribution, metabolism, and
elimination) properties of the molecule. The incorpora-
tion of fluorine into a lead molecule can alter its chem-
ical properties (Pauling electronegativity of fluorine is
3.98 versus 2.20 for hydrogen), pharmacokinetic and
pharmacodynamic properties (metabolic stability and
absorption), and biological activity.9a It has been recog-
nized that fluorine substitution on aromatic rings can be
used to redirect metabolism while often preserving or
improving receptor binding of medicinal compounds.9b
Furthermore, aromatic fluorine can participate in
W
N
N
H
O
Cmpd.
W
H
X
H
F
F
H
F
Y
H
H
H
F
1
2
3
4
5
unsat.
sat.
HO(CH2)4O
HO(CH2)4O
HO(CH2)4O
F
unsat.
unsat.
unsat.
H
The synthesis of 6-fluoro-dihydronaphthyridinone
analog 2 began with the synthesis of intermediate 10
as shown in Schemes 1 and 2. Regioselective displace-
ment of the 6-chloro of 2,6-dichloro-5-fluoronicotino-
nitrile (6) by the alkoxide formed from 4-benzyloxy-1-
butanol (7) proceeded in good yield to give 8. This
was the same regiochemical preference as observed by
*
Corresponding authors. E-mail addresses: aarepinej@comcast.net;
doug.johnson@pfizer.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.090

8190
J. T. Repine et al. / Tetrahedron Letters 48 (2007) 8189–8191
F
CN
Cl
F
CN
F
CHO
NH2
F
CN
Cl
a
b
a
b
BnO(CH2)4O
N
10
NH2
BnO(CH2)4O
N
14
BnO(CH2)4O
N
Cl
N
6
8
F
F
CO2Et
CO2Et
F
CN
F
CN
N3
c
d
c
BnO(CH2)4O
N
15
NH2
BnO(CH2)4O
N
16
NH2
BnO(CH2)4O
N
10
NH2
BnO(CH2)4O
N
9
F
F
Scheme 1. Reagents and conditions: (a) BnO(CH2)4OH (7), t-BuOK,
THF, À78 °C to rt, 3 h, 70–80%; (b) NaN3, DMF, 70 °C, 84%; (c)
(Me3Si)2S, MeOH, rt, 86%.
e
HO
BnO(CH2)4O
N
N
H
O
O
N
N
H
O
17
2
Scheme 3. Reagents and conditions: (a) DIBAL-H, THF, 0 °C,
10 min, 66–79%; (b) Ph3P@CHCO2Et, THF, reflux, 50%; (c) H2
(40 psi), RaNi, THF, rt, 1 h; (d) p-toluenesulfonic acid, i-PrOH, 80 °C,
30 min, 92% over two steps; (e) H2 (60 psi), Pd–C, EtOH, rt, 1 h, 88%.
F
CN
F
F
F
CN
F
a
b
BnO(CH2)4O
N
N
11
12
F
CN
NHPMB
F
CN
F
c
F
COOEt
a
BnO(CH2)4O
N
13
BnO(CH2)4O
N
10
NH2
BnO(CH2)4O
N
N
H
O
BnO(CH2)4O
N
15
NH2
18
Scheme 2. Reagents and conditions: (a) BnO(CH2)4OH (7), t-BuOK,
THF, À70 °C to À50 °C, 1 h, reaction mixture carried to next step; (b)
p-methoxybenzylamine, À70 °C to rt, 70% over two steps; (c) TFA,
À8 °C to rt, 1.5 h, 67%.
F
b
HO
O
N
N
H
O
3
Miyamoto et al.10 Conversion of the 2-chloro of 8 to an
amino group was accomplished by either of the two
methods. The first method involved the displacement
of the chloro group with sodium azide to give azide 9
followed by reduction to the amine using hexamethyldi-
silathiane in methanol11 to give the amine intermediate
10 in 86% yield.
Scheme 4. Reagents and conditions: (a) 3 N HCl, dioxane, reflux, 1 h,
53%; (b) H2 (50 psi), Pd–C, EtOH, rt, 2 h, 87%.
The synthesis of the 3-fluoro substituted naphthyridi-
none 4 started from the pivaloyl protected intermediate
19 (Scheme 5).12 Similar to the preparation of 8, reaction
of the alkoxide of 4-(tetrahydro-2H-pyran-2-yloxy)-
butan-1-ol13 (20) with 19 gave 21 in 46% yield. With
the aldehyde already in place, a Wittig reaction with
triethyl-2-fluoro-2-phosphonoacetate was performed to
give a cis/trans mixture of 22. Unpurified 22 was cyc-
lized under acidic conditions which also resulted in the
removal of the THP protecting group to yield 4.
In Scheme 2, an alternate introduction of the C2-amine
started with the more reactive intermediate 2,5,6-tri-
fluoropyridin-3-carbonitrile
(11,
source:
ABCR
F07832MF). Addition of the alkoxide of 7 at low
temperature proceeded with high selectivity at C6 to
give 12. Subsequent addition of p-methoxybenzylamine
in a one-pot sequence resulted in the displacement of
the fluoro group at the activated C2 site to give the
desired product 13 in 70% yield. The p-methoxybenzyl
group was removed using TFA to give 10 in 67% yield.
As we wished to avoid additional synthetic and depro-
tection steps in the synthesis of compounds containing
the 1,8-naphthyridin-2(1H)-one core, we prepared 6,7-
difluoro-1,8-naphthyridin-2(1H)-one (5) to serve as a
more general synthetic intermediate (Scheme 6). Previ-
ously in the literature, 2,5,6-trichloronicotinic acid was
Scheme 3 continues with the reduction of the nitrile in
compound 10 to aldehyde 14 with DIBAL-H. Wittig
reaction of aldehyde 14 with (carbethoxymethylene)-tri-
phenylphosphorane provided 15 as a mixture of cis and
trans isomers. The mixture was hydrogenated in the
presence of Raney nickel to give 16 which was easily cyc-
lized under acidic conditions to give dihydronaphthyrid-
inone 17. A more rigorous hydrogenation removed the
benzyl protecting group to give 2.
CHO
CHO
a
b
THPO(CH2)4O
N
NHPiv
Cl
N
NHPiv
19
21
F
CO2Et
F
c
HO
In Scheme 4, the analogous 3,4-dehydro compound 3
was prepared from the common intermediate 15. Treat-
ment of 15 with 3 N HCl in refluxing dioxane resulted in
cyclization to provide 18 in 50% yield. Conditions were
selected for the hydrogenation to affect selective removal
of the benzyl protecting group without reducing the
naphthyridinone ring system to give 3.
O
N
N
O
THPO(CH2)4O
N
NHPiv
H
4
22
Scheme 5. Reagents and conditions: (a) THPO(CH2)4OH (20), NaH,
DMF, 0 °C, 1.5 h, 46%; (b) 2 equiv (EtO)2P(O)CHFCO2Et, 2 equiv
LiCl, 2 equiv DBU, CH3CN, rt; (c) 3 N HCl, dioxane, reflux, 2 h, 26%
over two steps.

J. T. Repine et al. / Tetrahedron Letters 48 (2007) 8189–8191
8191
Aoki, M.; Niwa, A. Chem. Pharm. Bull. 2002, 50, 1050–
1059.
F
F
CO2H
Cl
b
a
H2N
N
NH2
7. (a) Boehm, J. C.; Callahan, J. F.; Hall, R. F.; Lin, X.
Widdowson, K. L. PCT Int. Appl. WO2004073628, 2004;
(b) Adams, N. D.; Darcy, M. G.; Dhanak, D.; Duffy, K.
J.; Fitch, D. M.; Knight, S. D.; Newlander, K. A.; Shaw,
A. N. PCT Int. Appl. WO2006113432, 2006.
Cl
N
23
24
F
F
c
8. (a) Clark, J. D.; Davis, J. M.; Favor, D.; Fay, L. K.;
Franklin, L.; Henegar, K. E.; Johnson, D. S.; Nichelson,
B. J.; Ou, L.; Repine, J. T.; Walters, M. A.; White, A. D.;
Zhu, Z. U.S. Patent Appl. US 2005043309, 2005; (b)
Johnson, D. S.; Singer, J. M.; White, A. D. PCT Int. Appl.
WO2006090273, 2006; (c) Favor, D. A.; Johnson, D. S.;
Repine, J. T.; White, A. D. PCT Int. Appl.
WO2006090272, 2006.
H2N
N
N
O
F
N
N
O
H
H
25
5
Scheme 6. Reagents and conditions: (a) 28% NH4OH, 150 °C
(pressure vessel), 24 h, 43%; (b) D,L-malic acid, concd H2SO4,
115 °C, 1 h, 97%; (c) 70% HF-pyridine, KNO2, 20 °C, 2 h, 43%.
decarboxylated during reaction with aqueous ammonia
to give 3-chloro-2,6-diamino-pyridine.14 By analogy,
2,6-dichloro-5-fluoro-nicotinic acid (23) upon heating
with ammonia gave 2,6-diamino-3-fluoropyridine (24).
Treatment of 24 with D,L-malic acid in concentrated sul-
furic acid afforded 7-amino-6-fluoro-1,8-naphthyridin-
2-one (25) in high yield similar to that reported in the
literature for the conversion of 2,6-diaminopyridine to
7-amino-1,8-naphthyridin-2-one.15 Finally, diazotiza-
tion of 25 in the presence of HF-pyridine gave the
desired 6,7-difluoro-1,8-naphthyridin-2-one (5).16 Com-
pound 5 bears an activated fluorine at the 7 position
which is easily displaced by amines or alkoxides and
thus, provides a useful intermediate for further investi-
gation of the 6-fluoro-1,8-naphthyridin-2-one series.
9. (a) Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27–33;
(b) Park, B. K.; Kitteringham, N. R.; O’Neill, P. M. Ann.
Rev. Pharmacol. Toxicol. 2001, 41, 443–470; (c) Razgulin,
A. V.; Mecozzi, S. J. Med. Chem. 2006, 49, 7902–7906.
10. Miyamoto, T.; Egawa, H.; Shibamori, K.; Matsumoto, J.
J. Heterocycl. Chem. 1987, 24, 1333–1339.
11. Capperucci, A.; Degl’Innocenti, A.; Funicello, M.; Mau-
riello, G.; Scafato, P.; Spagnolo, P. J. Org. Chem. 1995,
60, 2254–2256.
12. Turner, J. A. J. Org. Chem. 1990, 55, 4744–4750.
13. Petroski, R. J. Synth. Commun. 2003, 33, 3251–3259.
14. (a) Mutterer, Francis; Weis, C. D. Helv. Chim. Acta 1976,
59, 222–229; (b) Laeckmann, D.; Rogister, F.; Dejardin, J.
V.; Prosperi-Meys, C.; Geczy, J.; Delarge, J.; Masereel, B.
Bioorg. Med. Chem. 2002, 10, 1793–1804.
15. Carboni, S.; De Settimo, A.; Pirisino, G. Ann. Chim. 1964,
54, 883–890.
16. Experimental procedure for the synthesis of 5: A mixture of
2,6-dichloro-5-fluoronicotinic acid (23) (140 g, 670 mmol,
Alfa Aesar) in NH4OH (1.2 L, 28–30%, Caledon) was
heated to 150 °C in a commercial grade stainless steel
pressure vessel (2 L volume) for 24 h, cooled to room
temperature, and diluted with EtOAc (2 L). The mixture
was washed with brine, dried over sodium sulfate, and
concentrated to give 3-fluoropyridine-2,6-diamine (24) as
a dark solid (36.5 g, 287 mmol, 43%). 1H NMR (400 MHz,
d ppm): 7.03 (dd, 1H), 5.85 (dd, 1H), 4.34 (br s, 2H), 4.07
(br s, 2H).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
09.090.
References and notes
D,L-Malic acid (112.7 g, 842 mmol, Alfa Aesar) was added
to a solution of 24 (40 g, 314 mmol) in concd H2SO4
(154 mL, Caledon). The mixture was heated to 115 °C for
1 h. Adequate ventilation should be maintained to avoid
inhalation of the carbon monoxide by-product of this
reaction. The mixture was cooled to room temperature, ice
was added, and the pH was adjusted to ꢀ7 by adding
NH4OH (28–30%, Caledon) to give a precipitate, which
was filtered and dried at 40 °C to afford 7-amino-6-fluoro-
1,8-naphthyridin-2(1H)-one (25) as a yellow solid (55 g,
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1
307 mmol, 97%). H NMR (400 MHz, d ppm): 11.65 (s,
1H), 7.62 (M, 2H), 7.07 (br s, 2H), 6.15 (d, 1H).
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HF-pyridine complex (187 mL, containing 70% HF, Alfa
Aesar) was added to 25 (64.2 g, 358 mmol) at ꢀ5 °C. After
25 dissolved, KNO2 (42.6 g, 501.2 mmol, Alfa Aesar) was
added in portions at 20 °C. The mixture was stirred
continuously for 2 h at 20 °C (yellow solid formed) and
put into ice to give a solid. The solid was collected and
then washed with ether to give the desired compound as
the hydrofluoride salt. This solid was suspended in water
again, adjusted to pH ꢀ8 by the addition of sat. NaHCO3,
filtered, washed with water followed by ether, and dried at
40 °C to give 6,7-difluoro-1,8-naphthyridin-2(1H)-one (5)
as a yellow solid (28 g, 153 mmol, 43%). 1H NMR
(400 MHz, d ppm): 12.39 (s, 1H), 8.35 (dd, 1H), 7.90 (d,
1H), 6.18 (d, 1H).
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