Practical alternative synthesis of 1-(8-Fluoro-naphthalen-1-yl)piperazine

Article abstract of DOI:10.1021/op7001535

Convergent synthesis of 8-fluoronaphthalen-1-ylamine (6) was achieved through the reaction of 1H-tauphtho[1,8-de][1,2,3]triazine (15) with HF-pyridine under mild conditions. This new synthesis for the preparation of 6 overcame many scale-up challenges that exist in the methods reported in the literature and provided a practical alternative synthesis of 1-(8-fluoronaphthalen-1-yl) piperazine (1).

Full text of DOI:10.1021/op7001535

Organic Process Research & Development 2007, 11, 907–909
Practical Alternative Synthesis of 1-(8-Fluoro-naphthalen-1-yl)piperazine
Zhijian Zhu,* Norm L. Colbry, Mark Lovdahl, Kenneth E. Mennen, Alison Acciacca, Vladimir G. Beylin, Jerry D. Clark, and
Daniel T. Belmont
Pfizer Global Research and DeVelopment, Pharmaceutical Sciences, Ann Arbor, Michigan 48105, U.S.A.
Scheme 1. Original synthesis of compound 1
Abstract:
Convergent synthesis of 8-fluoronaphthalen-1-ylamine (6) was
achieved through the reaction of 1H-naphtho[1,8-de][1,2,3]triazine
(15) with HF-pyridine under mild conditions. This new synthesis
for the preparation of 6 overcame many scale-up challenges that
exist in the methods reported in the literature and provided a
practical alternative synthesis of 1-(8-fluoronaphthalen-1-yl)
piperazine (1).
Owing to their unique properties, fluoro-organic compounds
are increasingly important in the agrochemical and pharma-
ceutical industry.1 However, selective introduction of fluoro
substituents onto organic molecules continuously represents a
significant challenge.2,3b In connection with our work, prepara-
tion of a significant quantity of 1-(8-fluoronaphthalen-1-yl)pi-
perazine (1) was required as a key intermediate to support one
of our drug discovery/development programs. The original
synthesis3 (Scheme 1) started with very expensive 8-bromo-1-
naphthoic acid (5). The synthesis involved Curtius rearrange-
ment, Balz–Schiemann diazotization/fluoro-dediazotization, and
palladium catalyzed coupling with N-Boc-piperazine. Both of
the Curtius and Balz–Schiemann reactions were highly energetic
and would require considerable evaluation to ensure safe
operation on a large scale. Additionally, a significant amount
of the des-fluoro impurity (1-bromonaphthalene) was generated
from the Balz–Schiemann reaction when the reaction was scaled
up, and careful chromatographic purification was required to
remove the impurity.
Scheme 2. Retroalternative synthesis of 6 from literature
or the use of heat- and shock-sensitive materials such as 12,7
which limited their use for large-scale preparation. It can also
be envisaged that compound 6 be prepared from 8-fluoro-1-
naphthalenecarboxylic acid (7) through Curtis or Hoffmann
rearrangement. However, the preparation of compound 7 took
five steps from ethyl (o-fluorophenyl)acetate (9).2
In looking for a practical and convergent synthesis of 1, our
efforts centered on the use of 1,8-diaminonaphthalene (14),
which is inexpensive and provides the desired 1,8-disubstituted
functionalities on naphthalene. Initial attempts of diazotization
of 14 with 1 equiv of sodium nitrite in hydrogen fluoride–py-
ridine did not give any desired product. Considering the possible
interference of the second amino group during the diazotization,
protection of one of the amino groups of 14 with succinic
anhydride or phthalic anhydride was carried out according to
literature.8 However, diazotization of both monoprotected
derivatives under either aqueous or nonaqueous conditions gave
Alternatively, compound 1 could be prepared from 8-fluo-
ronaphthalen-1-ylamine (6) (Scheme 2). In the literature, 6 was
prepared from 1-fluoro-8-nitronaphthalene (8) by reduction.4
Compound 8 was prepared either by nitration of 1-fluoronaph-
thalene (11)5 or from 8-nitro-1-naphthalylamine (10)4 through
the Balz–Schiemann reaction. However, both routes required
separations of regio-isomeric mixtures through chromatography5,6
* zhijian.zhu@pfizer.com.
(1) (a) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell
Publishing: Oxford, 2004; pp 3–12. (b) Special issue on Fluorine in
Life Science. ChemBioChem 2004, 5, 557–726.
(2) Tagat, J. R.; McCombie, S. W.; Nazareno, D. V.; Boyle, C. D.;
Kozlowski, J. A.; Chackalamannil, S.; Josien, H.; Wang, Y.; Zhou,
G. J. Org. Chem. 2002, 67, 1171–1177.
(3) (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 Application
2005043309, 2005. (b) Repine, J. T.; Johnson D. S.; White, A. D.;
Favor, D. A.; Stier, M. A.; Yip, J.; Rankin, T.; Ding, Q.; Maiati, S.
Tetrahedron Lett. 2007, 48, 5539–5541.
(4) Bassilios, H. F.; Shawky, M.; Salem, A. Y. Bull. Soc. Chim. Belg
1966, 75, 577–581.
(7) Vesely, V.; Rein, E. Collect. Czech. Chem. Commun. 1929, 1, 360–
367.
(5) Lammers, J. G.; Cornelisse, J. Isr. J. Chem 1977, 16, 299–303.
(6) Hodgson, H. H.; Davey, W. J. Chem. Soc. 1939, 348–349.
(8) Al-Khathlen, H; Zimmer, H. J. Heterocycl. Chem. 1988, 25, 1047.
10.1021/op7001535 CCC: $37.00
Published on Web 08/21/2007
2007 American Chemical Society
Vol. 11, No. 5, 2007 / Organic Process Research & Development
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Table 1. Conversion of 15 to 6 using HF–pyridine
Scheme 3. Conversion of 6 to 1 using
bis(2-chloroethyl)amine HCl
temp,
°C
HF-Py/15
(w/w)
6 yield,
entry
time
%
des-fluoroa
1
2
3
4
5
6
120
60
rt
60
rt
rt
16 h
22 (≈0.28 M)
77
97
0.3
NA
16 h
22
22
3
Treatment of 6 with 1.08 equiv of bis(2-chloroethyl)amine
hydrochloride in the presence of 0.5 equiv of tetrabutyl
ammonium iodide in chlorobenzene and 1-hexanol at reflux for
74 h gave directly the HCl salt of 1 in 76% yield with over
96% HPLC purity (Scheme 3).
60 h
16 h
9 days
3–7 days
NAb
83
NA
9.5
0.4
0.3–0.4
3
5
89
87–90
a The amount of des-fluoro impurity was determined by 1H-NMR. b The product
was not isolated, HPLC of the reaction showed complete disappearance of starting
material.
The fluoro group at the 8-position seemed to slow down
considerably the piperazine formation, as the corresponding
reaction with 1-aminonaphthalene under comparable conditions
could be finished within 8 h. The use of 0.5 equiv of
tetrabutylammonium iodide is crucial to speed up the reaction,
as well as allowing the direct isolation of the HCl salt of 1
without the contamination from the iodide salt. N-Arylpipera-
zines are commonly synthesized from the corresponding aryl-
amines by using bis(2-chloroethyl)amine hydrochloride. How-
ever, the potential risk of generation and release of toxic bis
(2-chloroethyl)amine freebase during the reaction and in the
work-up make this methodology less appealing, especially for
large scale operation.12 The above optimized conditions allow
the direct isolation of the product as hydrochloride salt and
maintain acidic mediates throughout the reaction and the work-
up. This should significantly reduce the risk of exposure to bis(2-
chloroethyl)amine freebase during the operation.
In conclusion, a practical alternative synthesis of 1-(8-fluoro-
naphthalen-1-yl)piperazine (1) was developed. This synthesis
starts with inexpensive 1,8-diaminonaphthalene and provides
1 as HCl salt in three steps in up to 60% overall yield. The
discovery, that 1H-naphtho[1,8-de][1,2,3]triazine (15) can be
used as a stabilized diazonium and can be converted to 8-fluoro-
naphthalene-1-ylamine (6) under mild conditions using hydro-
gen fluoride–pyridine, provides a convergent approach to 6 and
overcomes many scale-up challenges present in the literature
methods for the preparation of 6. With an onset temperature of
240 °C, compound 15 should possess sufficient safety margin
for its isolation and subsequent conversion to 6 using HF–pyridine
at room temperature in large-scale operation.
mostly unreacted starting material. The failure of the diazoti-
zations was most likely caused by the steric hindrance of the
succinimidyl or phthalimidyl group at the 8-position.
It was reported9 that 14 can be converted to 1H-naphtho[1,8-
de][1,2,3]triazine (15) by nonaqueous diazotization in ethanol/
acetic acid in high yield (Table 1). Conversion of 15 to 8-chloro-
1-aminonaphthalene in concentrated hydrochloric acid saturated
with hydrogen chloride gas in the presence of copper under
heating was reported in a German patent.10 We postulated that
15 could be converted to the corresponding 1-amino-8-fluo-
ronaphthalene (6) by using a fluoride source under acidic
conditions, particularly hydrogen fluoride–pyridine (HF-Py).
Treatment of 15 with HF-Py (70%/30%, w/w) at 120 °C in
a stainless steel Parr reactor indeed gave 6 cleanly in 77%
isolated yield (entry 1, Table 1). The reaction worked equally
well at 60 °C (entry 2). At room temperature, the reaction went
cleanly, although it took more than 2 days to complete (entry
3). DSC analysis showed that 15 has an onset temperature of
240 °C with 818 J/g. Although still fairly energetic, the high
onset temperature of 15 should provide a good safety margin
for scale-up operation.
In efforts to optimize the reaction for scale up, the ratio of
HF-Py/15 (w/w) was decreased from 22 to 3. However at 60
°C, up to 9.5% of the des-fluoro impurity, 1-aminonaphthalene,
was generated (entry 4, Table 1). This high level of des-fluoro
impurity was not observed with HF-Py/15 (w/w) ratio of 22
even at 120 °C (entry 1). At room temperature with HF-Py/15
ratio of 3 (entry 5, Table 1), the amount of des-fluoro impurity
was significantly reduced. However, the reaction took over 9
days to complete. During the scale-up, the reactions were run
with HF-Py/15 ratio of 5 for 3–7 days to give 6 in 87% to 90%
yields with consistently low levels of the des-fluoro impurity
(entry 6, table 1). The competitive homolytic decomposition
path way of 15 under higher concentration and/or higher
temperature was likely the cause of the des-fluoro impurity
formation.11
Experimental Section
1H-Naphtho[1,8-de][1,2,3]triazine (15). To a 5 L, three-
neck round bottom flask equipped with mechanical stirring,
dropping funnel, and nitrogen outlet, 1,8-diaminonaphthalene
(Aldrich, catalog no. D21405, 250 g, 1.58 mol) was dissolved
in a mixture of acetic acid (500 mL) and ethanol (2500 mL)
under nitrogen at room temperature. Isoamyl nitrite (Aldrich,
catalog no. 150495, 208.1 mL, 1.55 mol, 0.98 equiv) was then
added dropwise over a period of 3.5 h with temperature
controlled between 18 and 21 °C with a cold-water bath. After
(9) Rees, C. W.; Storr, R. C. J. Chem. Soc. C: Organic 1969, 756.
(10) BASF, DE Patent 147852, 1903.
(11) Satyamurthy, N.; Barrio, J. R.; Schmidt, D. G.; Kammerer, C.; Bida,
G. T.; Phelps, M. E. J. Org. Chem. 1990, 55, 4560–4564, and
references therein.
(12) Rudbeck, H. C; Johannsen, I.; Nielsen, O.; Ruhland, T.; Sommer,
M. B.; Tanner, D.; Dancer, R. Synthesis 2005, 3456–3462, and
reference therein.
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the addition, the resulting red suspension was stirred at room
temperature for 19 h. The solid was collected by filtration,
washed with ethanol (2 × 500 mL) and dried under vacuum to
color) was concentrated to give an oil, which was azeotroped
with chlorobenzene twice (2 × 500 mL) to remove residue
water. The oil was solidified after sitting at room temperature
overnight. The solid was further dried under vacuum to give a
red-brown solid (86.1g, 90.4%). 1H NMR (400 MHz,
DMSO-d6) (δ ppm): 7.48 (dd, J ) 8.2 Hz, 0.9 Hz, 1H), 7.27
(m, 1H), 7.19 (t, J ) 7.8 Hz, 1H), 7.03 (m, 2H), 6.65 (dd, J )
7.6 Hz, 1.2Hz, 1H), 5.66 (s, 2H). Anal. Calcd for C10H8FN: C,
74.52; H, 5.00; N, 8.69. Found: C, 74.36; H, 4.92; N, 8.79.
1-(8-Fluoro-naphthalen-1-yl)piperazine Hydrochloride
(1). 8-Fluoro-1-aminonaphthalene (168.86 g, 1.048 mol), bis(2-
chloroethyl)amine hydrochloride (Aldrich, catalog no. B38503,
202.0 g, 1.13 mol, 1.08 equiv), tetrabutylammonium iodide
(Aldrich, catalog no. 140775, 193.5 g, 0.524 mmol, 0.5 equiv),
and hexyl alcohol (Aldrich, 100 mL) in anhydrous chloroben-
zene (Aldrich, 1950 mL) was stirred in a 3 L, three-neck round
bottom flask equipped with mechanical stir, Dean–Stark trap
(50 mL), and condenser. The mixture was degassed by bubbling
nitrogen for 20 min. The mixture was then heated to reflux
under nitrogen for 74 h to give a light brown suspension. The
progress of the reaction was checked by HPLC (after 23 h,
product/starting material ) 70.5/27.6; after 74 h, product/starting
material ) 93.8/0). The suspension was slowly cooled to room
temperature and gently stirred overnight to give a brown
suspension. The solid was collected by filtration, washed with
chlorobenzene (300 mL) and toluene (300 mL), and dried under
vacuum at room temperature for 24 h to give a yellow solid
(232.19 g). The crude HCl salt of 1 was slurried twice in
acetonitrile (500 mL) for 5 h. The solid was collected by
filtration, washed with acetonitrile (70 mL), and dried under
vacuum to give the HCl salt of 1 as a yellow solid (213.52 g,
1
give a red crystalline solid (235.86 g, 88%). H NMR (400
MHz, DMSO-d6) (δ ppm): 13.24 (s, 1H), 7.24 (m, 2H), 7.11
(m, 1H), 7.01 (d, J ) 8.4 Hz, 1H), 6.86 (dd, J ) 5.4 Hz, 2.6
Hz, 1H), 6.10 (d, J ) 7.2 Hz, 1H). Anal. Calcd for C10H7N3:
C, 70.99; H, 4.17; N, 24.84. Found: C, 70.62; H, 4.06; N, 24.46.
8-Fluoro-naphthalen-1-ylamine (6). To a 4000 mL Nal-
gene bottle with magnetic stirring, hydrogen fluoride–pyridine
(Aldrich, catalog no. 18422-5, 70% HF/30% pyridine, 400 g)
was added and cooled in an ice bath. (Caution: To reduce the
risk of exposure to hydrogen fluoride, people inVolVed in
handling the reaction are recommended to wear Viton gloVes
or SilVer Shield/4H gloVes, SilVer Shield/4H apron, SilVer
Shield/4H sleeVes, and safety face-shield.) 1H-Naphtho[1,8-
de][1,2,3]triazine (100 g, 0.59 mol) was added slowly in about
five portions. After the addition, the Nalgene bottle was rinsed
with additional 100 g of hydrogen fluoride–pyridine to wash
down the solid sticking on the sidewall of the bottle (total
hydrogen fluoride–pyridine used: 500 g, 17.5 mol, 30 equiv).
The Nalgen bottle was capped. The bottle was vented through
Tygon tubing attached to a small hole on the cap. The reaction
solution was stirred at room temperature for 7 days. HPLC
showed that all starting material disappeared, with 94% product
purity. The reaction bottle was cooled in an ice bath, and ice
chips (total 500 g) were added. Once the temperature was below
10 °C, KOH (45 wt %, 1.35 L) was slowly added with
temperature controlled below 35 °C. During the neutralization
period, 500 g of ice chips was added occasionally for effective
cooling (about 1.5 h for the addition). The final pH of the
mixture was about 11. The mixture was diluted with EtOAc
(500 mL) and stirred for 20 min. The mixture was then
transferred to a 6 L separatory funnel through suction. The
aqueous layer was separated and removed. The organic layer
and emulsion interface were filtered through Celite to remove
solid. The filtering cake was washed with ethyl acetate (2 ×
200 mL). The bilayer filtrate (now nicely separated) was
separated. The organic layer was washed twice with a mix of
saturated sodium chloride (300 mL), water (300 mL) and
saturated sodium bicarbonate (300 mL) (directly wash the
organic layer with saturated sodium bicarbonate generated
emulsion) and then saturated sodium chloride (300 mL). The
organic layer was then degassed by bubbling nitrogen for 20
min to remove oxygen and prevent oxidation of the product.
The solution was stirred under nitrogen with activated carbon
(Sigma-Aldrich, 242276, Darco, G-60, 100 mesh, 50 g) for 5 h
and additional activated carbon (50 g) overnight. The activated
carbon was removed by filtration through Celite; the solid cake
was washed with EtOAc (2 × 300 mL). The filtrate (red-wine
1
76.4%). H NMR (400 MHz, DMSO-d6) (δ ppm): 9.34 (bs,
2H), 7.70 (dd, J ) 8.2 Hz, 0.8Hz, 1H), 7.62 (m, 1H), 7.43 (m,
2H), 7.22 (m, 1H), 7.10 (dd, J ) 7.5 Hz, 0.8 Hz, 1H), 3.33 (m,
4H), 3.11 (m, 2H), 3.00 (m, 2H). HPLC: 96.4% purity (Tr )
10.28 min, wavelength at 215 nm; YMC PackPre C18, 150 ×
4.6 mm, 3 µm; solvent A, 0.2% HClO4 in 90:10 water/ACN;
solvent B, ACN; gradient, 90% A to 5% A in 30 min, then
hold for 5 min; flow rate, 1.0 mL/min). Anal. Calcd for
C14H15FN2 ·1.05HCl·0.6H2O: C, 60.19; H, 6.22; N, 10.03; Cl,
13.32. Found: C, 59.95; H, 6.09; N, 10.16; Cl, 13.62.
ACKNOWLEDGMENT
The authors thank Anne Akin, Eric Nord, and Megan Wang
for analytical support and Donald J. Knoechel for DSC analysis
of compound 15.
Received for review July 2, 2007.
OP7001535
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