Practical synthesis of p-aminophenethylspiperone (NAPS), a high-affinity, selective D2-dopamine receptor antagonist

Article abstract of DOI:10.1080/00397910701821135

Because attempts to scale up the published synthetic preparation of p-aminophenethylspiperone (NAPS) by N-alkylation of spiperone with 4-nitrophenethyl bromide followed by reduction gave poor yields and difficulties during purification, an alternative synthetic approach has been developed. Use of 4-(N-tert-butyloxycarbonyl) aminophenethyl bromide to alkylate spiperone followed by the Boc group deprotection gave NAPS in 56% yield. This procedure provides an improved and efficient synthesis of the important high-affinity, selective D2-dopamine receptor antagonist NAPS. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701821135

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Practical Synthesis of
p‐Aminophenethylspiperone (NAPS), a
High‐Affinity, Selective D2‐Dopamine
Receptor Antagonist
Chunyang Jin a , Louise D. Mayer a , Anita H. Lewin a , Kenneth S. Rehder a
George A. Brine a
&
a Center for Organic and Medicinal Chemistry, RTI International, North
Carolina, USA
Published online: 15 Feb 2008.
To cite this article: Chunyang Jin , Louise D. Mayer , Anita H. Lewin , Kenneth S. Rehder & George A. Brine
(2008) Practical Synthesis of p‐Aminophenethylspiperone (NAPS), a High‐Affinity, Selective D2‐Dopamine
Receptor Antagonist, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:5, 816-823, DOI: 10.1080/00397910701821135
To link to this article: http://dx.doi.org/10.1080/00397910701821135
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Synthetic Communicationsw, 38: 816–823, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701821135
Practical Synthesis of
p-Aminophenethylspiperone (NAPS), a
High-Affinity, Selective D2-Dopamine
Receptor Antagonist
Chunyang Jin, Louise D. Mayer, Anita H. Lewin, Kenneth
S. Rehder, and George A. Brine
Center for Organic and Medicinal Chemistry, RTI International, North
Carolina, USA
Abstract: Because attempts to scale up the published synthetic preparation of
p-aminophenethylspiperone (NAPS) by N-alkylation of spiperone with 4-nitrophenethyl
bromide followed by reduction gave poor yields and difficulties during purification, an
alternative synthetic approach has been developed. Use of 4-(N-tert-butyloxycarbonyl)
aminophenethyl bromide to alkylate spiperone followed by the Boc group deprotection
gave NAPS in 56% yield. This procedure provides an improved and efficient synthesis of
the important high-affinity, selective D2-dopamine receptor antagonist NAPS.
Keywords: D2-dopamine receptor, NAPS, N-alkylation
INTRODUCTION
p-Aminophenethylspiperone (NAPS) is a high-affinity, selective antagonist of
the D2-dopamine receptor, which is predominantly present in the central
nervous system (CNS) and plays a crucial role in regulation of cognitive
function and motor control.[1] Radiolabeled[2,3] and fluorophor-labeled[4–7]
NAPS ligands have important uses in the development of radioreceptor
assays, for histological localization of receptors, and for applications in
Received in the USA September 5, 2007
Address correspondence to Chunyang Jin, Center for Organic and Medicinal
Chemistry, RTI International, P. O. Box 12194, Research Triangle Park, NC 27709,
USA. E-mail: cjin@rti.org
816

Synthesis of NAPS
817
experimental or clinical brain-imaging techniques. To date, two synthetic
approaches have been followed to prepare this class of N-substituted
spiperone analogues. One[8–10] utilizes N-alkylation of spiperone with a
suitable alkyl halide or tosylate, and the other[10] involves N-alkylation of
8-tert-butyloxycarbonyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one followed
by acid removal of the tert-butyloxycarbonyl (Boc) group and subsequent alky-
lation with 4-chloro-40-fluorobutyrophenone. The specific synthesis of NAPS,
carried out on a small (1-g) scale in moderate yield, is reported by the N-alky-
lation of spiperone with 4-nitrophenethyl bromide using NaH/dimethylforma-
mide (DMF)[8] or KOH/K2CO3/TBAB/toluene[9] followed by reduction of
the nitro group with Fe/HCl. In our hands, attempted scale-up of the
published procedure gave poor yields, and purification of the intermediate
nitro compound, as well as of the final product (NAPS), was difficult.
Therefore, alternative synthetic approaches were investigated. We here report
an improved and efficient synthetic pathway, useful for the preparation of
multigram amounts of NAPS.
RESULTS AND DISCUSSION
To synthesize NAPS (6) following the literature procedure[9] (Scheme 1), the
required starting material, spiperone (3), was prepared in 74% yield from com-
mercially available 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1) and
4-chloro-40-fluorobutyrophenone (2).[10] Treatment of 3 (2.5 g) with 2 equiva-
lents of 4-nitrophenethyl bromide (4) using the biphasic conditions (KOH/
K2CO3/TBAB/toluene) at 908C for 2 h gave the desired N-alkylation
product 5 in 12% yield, along with a 21% of recovered spiperone. Use of
longer reaction times did not improve the yield, leading instead to apparent
Scheme 1.

818
C. Jin et al.
decomposition of the starting material 3. Attempted N-alkylation of 3 using
KOH in CH2Cl2 or NaH in DMF also resulted in poor yields of 5.
In light of these unsatisfactory results, an alternative synthetic route
(Scheme 2) based on a reported synthesis of p-nitrobenzylspiperone[10] was
investigated. The key intermediate, 8-tert-butyloxycarbonyl-1-phenyl-1,3,8-
triazaspiro[4.5]decan-4-one (7), was obtained in 95% yield by treatment of
1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1) with di-tert-butyl dicarbonate
in methylene chloride. The N-alkylation reaction of 7 with 4 using sodium
hydride was probed under a variety of solvent (DMF, tetrahydrofuran (THF),
or toluene), temperature, and reaction time conditions. Unfortunately, similar
to the reaction of spiperone (3) with 4-nitrophenethyl bromide (4), N-alkylation
of 7 with 4 gave poor yields of desired 8. The best condition was the use of
sodium hydride in anhydrous toluene at 908C and 8 was obtained in 8%
yield. Proton NMR analyses of the reaction mixtures showed the presence of
vinylic hydrogens, suggesting that elimination had occurred. This observation
prompted us to re-examine N-alkylation of spiperone (3) with 4-nitrophenethyl
bromide (4) using the biphasic conditions, carefully monitored by high perform-
ance liquid chromatography (HPLC) which we hoped would shed some light on
the cause of the low yield of 5. HPLC analysis of the reaction mixture revealed
the formation of 4-nitrostyrene, presumably by elimination of the hydrogen
bromide from 4, immediately upon addition of 4 to the reaction mixture. The
implication was that 4 was consumed at a rate that competed favorably with
the relatively sluggish N-alkylation of spiperone (3) with 4. The formation of
4-nitrostyrene was also confirmed by proton NMR analysis of the crude
product mixture, an observation that is consistent with the usual findings for
reported alkylations[11–14] using 4 with other nucleophiles. Eventually, it was
found that use of 12 equivalents of 4 under the biphasic conditions improved
the yield of 5 to 30%. However, the addition of this large excess of 4 was
impractical for the large-scale synthesis of NAPS because of both the
expense of 4 and the formation of multiple by-products, which made
Scheme 2.

Synthesis of NAPS
819
purification of 5 difficult. Similar results (i.e., multiple products) were noted
when we attempted to prepare 5 in a Mitsunobo reaction of spiperone (3)
with 4-nitrophenethyl alcohol. No product was formed in quantities justifying
isolation and identification.
The elimination reaction of 4-substituted 2-phenylethyl bromides is
strongly accelerated by electron-withdrawing substituents.[11] Accordingly,
N-alkylation of spiperone (3) using N-protected 4-amino-2-phenylethyl
bromide was examined (Scheme 3). Hydrogenation[15] of 4 at atmospheric
pressure over platinum(IV) oxide in ethanol and hydrochloric acid afforded
intermediate 9, which was then treated with di-tert-butyl dicarbonate in the
presence of N,N-diisopropylethylamine (DIEA) to give the required 4-(N-
tert-butyloxycarbonyl)aminophenethyl bromide (10) in 70% yield. We were
gratified to find that N-alkylation of spiperone (3) using 2 equivalents of 10
and the biphasic conditions reported[9] at 908C for 2 days produced 11 in
90% yield. Subsequent removal of the Boc protecting group using trifluoroa-
cetic acid (TFA) in methylene chloride provided NAPS (6) in 62% yield after
1
purification. The H NMR spectrum of 6 was in good agreement with the
published data of NAPS,[8] and HPLC analysis indicated the product to be
99% pure. Similar results were obtained in two separate runs starting from
3 g and 8 g of spiperone, respectively.
In summary, we have developed an improved and efficient synthesis of
NAPS (6) in 41% overall yield from commercially available 1-phenyl-
1,3,8-triazaspiro[4.5]decan-4-one (1). Our synthetic approach to NAPS is
amenable to scaling without compromising either the yield or the purity.
Scheme 3.

820
C. Jin et al.
EXPERIMENTAL
Melting points were determined on a Mel-Temp II capillary melting-point
apparatus and are uncorrected. NMR (1H and 13C) spectra were obtained
using a Bruker Avance DPX 300-MHz NMR spectrometer. Chemical shifts
are reported in parts per million (ppm) with reference to internal solvent.
HRMS (high-resolution mass spectrometry) were recorded on a Waters
Autospec Ultima mass spectrometer and were performed at the University
of Michigan, Ann Arbor, MI. Elemental analysis was done by Atlantic
Microlab Inc., Norcross, GA. Analytical thin-layer chromatography (TLC)
was carried out using EMD silica-gel 60 F254 TLC plates. Flash-column
chromatography was done on a CombiFlash Companion system using Isco
prepacked silica-gel columns. Reagents were obtained from Sigma-Aldrich
Chemical Company and used as received unless otherwise noted.
8-[3-(4-Fluorobenzoyl)propyl]-1-phenyl-1,3,8-
triazaspiro[4.5]decan-4-one (spiperone) (3)
A stirred mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1) (25.0 g,
0.11 mol), 4-chloro-40-fluorobutyrophenone (2) (16.7 mL, 0.10 mol), KI
(17.9 g, 0.11 mol), and Et3N (16.9 mL, 0.12 mol) in anhydrous CH3CN
(200 mL) was refluxed under nitrogen for 20 h. The reaction mixture was con-
centrated in vacuo. The residue was taken up in CH2Cl2 (200 mL), washed
with NaHCO3 (3 ꢀ 50 mL), dried (Na2SO4), and concentrated in vacuo.
Recrystallization of the crude solids from CH2Cl2–hexanes gave 3 (30.8 g,
1
74%) as a white crystalline solid: mp 208–2098C (lit.[16] 2098C); H NMR
(300 MHz, DMSO-d6) d 1.53 (2H, d, J ¼ 13.2 Hz), 1.76–1.87 (2H, m),
2.32–2.52 (4H, m), 2.60–2.78 (4H, m), 3.03 (2H, t, J ¼ 6.8 Hz), 4.55 (2H,
s), 6.68–6.82 (3H, m), 7.17 (2H, t, J ¼ 7.8 Hz), 7.35 (2H, t, J ¼ 8.9 Hz),
8.02–8.12 (2H, m), 8.60 (1H, s). The product was found to be identical to
an authentic sample obtained from Sigma-Aldrich Chemical Company.
4-(N-tert-Butyloxycarbonyl)aminophenethyl Bromide (10)
A mixture of 4-nitrophenethyl bromide (4) (25.0 g, 0.11 mol), PtO2 (1.25 g),
and 37% HCl (44.0 mL) in EtOH (390 mL) was hydrogenated overnight at
room temperature under atmospheric pressure. The reaction mixture was
filtered through a short pad of Celitew, and the filtrate was concentrated in
vacuo. The residue was precipitated from toluene (500 mL) to give crude 9
(20.5 g, 80%), which was used in the next step without further purification.
DIEA (32.3 mL, 0.19 mol) was added to a stirred solution of crude 9
(20.5 g, 0.087 mol) in anhydrous THF (760 mL) at room temperature under
nitrogen, followed by di-tert-butyl dicarbonate (22.7 g, 0.10 mol). The

Synthesis of NAPS
821
resultant reaction mixture was stirred 4 days at room temperature. The mixture
was filtered, and the filtrate was concentrated in vacuo. The residue was
dissolved in EtOAc (500 mL), washed with 10% citric acid (3 ꢀ 100 mL)
and brine (3 ꢀ 100 mL) and dried (Na2SO4), and concentrated in vacuo.
Recrystallization of the crude solids from hexanes gave 10 (22.7 g, 87%) as
1
a white crystalline solid: mp 104–1068C; H NMR (300 MHz, CDCl3) d
1.50 (9H, s), 3.07 (2H, t, J ¼ 7.7 Hz), 3.49 (2H, t, J ¼ 7.7 Hz), 6.72 (1H, br
s), 7.06 (2H, d, J ¼ 6.0 Hz), 7.23 (2H, d, J ¼ 6.0 Hz); 13C NMR (75 MHz,
CDCl3) d 28.4, 33.3, 38.8, 80.5. 118.9, 129.3, 133.5, 137.3, 152.9; EI
HRMS calcd. for C13H18BrNO2 [M þ Na]þ: 322.0419. Found: 322.0409.
p-Aminophenethylspiperone (NAPS) (6)
A mixture of 3 (8.00 g, 0.02 mol), powdered KOH (0.56 g, 0.01 mol),
powdered K2CO3 (11.1 g, 0.08 mol), and tetrabutylammonium bisulfate
(TBAB) (2.04 g, 0.006 mol) in anhydrous toluene (432 mL) was stirred
30 min at 908C under nitrogen. A solution of 10 (12.0 g, 0.04 mol) in
anhydrous toluene (50 mL) was then added slowly over 30 min. After the
addition, the resultant reaction mixture was stirred 2 days at 908C.
Afterward, the mixture was allowed to come to room temperature, washed
with brine (3 ꢀ 50 mL), dried (Na2SO4), and concentrated in vacuo. Flash-
column chromatography on silica gel using 0 ! 3% MeOH in CH2Cl2 gave
11 (11.3 g, 90%) as a white foam. Although this sample still contained
minor impurities, it was used in the next step without further purification.
1H NMR (300 MHz, CDCl3) d 1.50 (9H, s), 1.51–1.60 (2H, m), 1.90–2.02
(2H, m), 2.45–2.62 (4H, m), 2.70–2.85 (4H, m), 2.89 (2H, t, J ¼ 7.2 Hz),
3.00 (2H, t, J ¼ 7.1 Hz), 3.63 (2H, t, J ¼ 7.2 Hz), 4.51 (2H, s), 6.59 (1H,
bs.), 6.77–6.87 (3H, m), 7.08–7.33 (8H, m), 7.98–8.08 (2H, m); 13C NMR
(75 MHz, CDCl3) d 21.1, 28.5, 28.9, 29.8, 33.2, 36.4, 42.3, 49.4, 57.4, 60.3,
63.9, 115.6, 115.7, 115.9, 119.0, 119.3, 129.3, 129.4, 130.8, 130.9, 132.6,
137.3, 142.9, 152.9, 164.2, 167.5, 174.2, 198.3; EI HRMS calcd. for
C36H43FN4O4 [M þ Na]þ: 615.3347. Found: 615.3352.
Trifluoroacetic acid (66 mL) was added to a stirred solution of 11 (11.3 g)
in CH2Cl2 (66 mL) at room temperature under nitrogen. After stirring for 2 h,
the reaction mixture was poured into ice water and carefully made basic using
saturated NaHCO3. The layers were separated, and the aqueous layer was
further extracted with CH2Cl2 (3 ꢀ 50 mL). The combined CH2Cl2 extract
was washed with brine (3 ꢀ 50 mL), dried (Na2SO4), and concentrated in
vacuo. Flash-column chromatography (330-g Isco silica-gel column) using
0 ! 4% MeOH in CH2Cl2 gave 3.70 g of pure 6 and 3.63 g of less pure
product. Recrystallization of the less pure product from acetone–hexanes
afforded 2.17 g of pure 6 as a white crystalline solid, for a combined yield
of 62%: mp 94–968C; 1H NMR (300 MHz, CDCl3) d 1.54 (2H, d,
J ¼ 13.8 Hz), 1.89–2.01 (2H, m), 2.42–2.51 (4H, m), 2.71–2.89 (6H, m),

822
C. Jin et al.
3.01 (2H, t, J ¼ 7.2 Hz), 3.52–3.65 (4H, m), 4.51 (2H, s), 6.62 (2H, d,
J ¼ 8.4 Hz), 6.76–6.86 (3H, m), 7.01 (2H, d, J ¼ 8.4 Hz), 7.13 (2H, t,
J ¼ 8.6 Hz), 7.22 (2H, t, J ¼ 8.6 Hz), 8.01 (2H, dd, J ¼ 5.4, 9.0 Hz); 13C
NMR (75 MHz, CDCl3) d 22.1, 29.4, 33.0, 36.5, 42.5, 49.7, 57.7, 60.7,
63.9, 115.4, 115.5, 115.8, 118.9, 127.9, 129.2, 129.6, 130.7, 130.8, 133.8,
143.2, 145.2, 164.0, 167.4, 174.4, 198.7. Anal. calcd. for C31H35FN4O2: C,
72.33; H, 6.86; N, 10.89. Found: C, 72.08; H, 6.96; N, 10.74.
ACKNOWLEDGMENT
This work was supported by the National Institute of Mental Health under
contract N01-MH-32005.
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