An efficient synthesis of the opioid analgesic (R)-phenampromide via an aziridinium ion

Article abstract of DOI:10.1016/j.tetasy.2017.06.001

A simple and efficient synthesis of the opioid analgesic agent (R)-phenampromide with high enantiopurity (>99% ee) via the formation of an aziridinium ion as a key step using commercially available starting material is described.

Full text of DOI:10.1016/j.tetasy.2017.06.001

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient synthesis of the opioid analgesic (R)-phenampromide via
an aziridinium ion
a
a
b
Mohammad Mujahid a,b, , Prashant Mujumdar , Murugesan Sasikumar , Shirish P. Deshmukh ,
⇑
Murugan Muthukrishnan a,
⇑
a Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b P.G. Department of Chemistry, Shri Shivaji College of Arts, Commerce & Science, Akola 444003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthesis of the opioid analgesic agent (R)-phenampromide with high enantiopu-
rity (>99% ee) via the formation of an aziridinium ion as a key step using commercially available starting
material is described.
Received 16 May 2017
Accepted 31 May 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
fer from certain drawbacks, such as low overall yields, the use of
expensive reagents and chemicals, protection and deprotection
There has been an increasing demand for producing and mar-
keting single enantiomer drug substances rather than racemates,
which may contain both the active and inactive enantiomers in
an equimolar ratio.1 Due to the potentially large differences in bio-
logical activities of the two enantiomers of a particular drug sub-
stance, there is a need for producing enantiomerically pure new
drugs and to enantioenrich old ones so that they display high enan-
tiomeric purity.2 Phenampromide 1 is an opioid analgesic, which is
considered to be structurally similar to isomethadone.3 Phenam-
promide belongs to the ampromide family of drugs, which also
include propiram and diampromide (Fig. 1). According to the liter-
ature, (R)-phenampromide has greater analgesic potency than its
(S)-enantiomer.4 Studies also revealed that based on the structure
of phenampromide, U50,488, a highly selective kappa opioid ago-
nist was discovered.5 Few reports are currently available for the
synthesis of the (R)-enantiomer of phenampromide, which mainly
involve resolution processes.3,4
steps. Hence a method, which could provide easy access to opti-
cally active phenampromide and its analogues would be highly
desirable.
Epoxides are considered to be a versatile functional group that
are used for the industrial production of several important com-
pounds and in the synthesis of many intermediates.6 Investigations
in our laboratory have demonstrated the potential utility of these
epoxides for the synthesis of many optically active pharmaceuti-
cals.7,8 Herein we report a concise and simple synthesis of (R)-
phenampromide (R)-1 starting from commercially available (R)-
epichlorohydrin, thereby devising a new approach that would
enable the synthesis of other ampromide families of drugs with
high enantiomeric purity.
2. Results and discussion
The retrosynthetic analysis of (R)-1 is depicted in Scheme 2. In
Route 1, we envisaged that the optically active aziridine (R)-5
would serve as a key intermediate for the synthesis, which could
be transformed into the final product via aziridine ring opening
and amide formation. The key intermediate (R)-5 can be obtained
from (R)-epichlorohydrin (R)-2 via epoxide opening and reduction
protocols. Alternatively, this chiral precursor (R)-2 could be uti-
lized for Route 2 via intermediate (R)-9. Our synthesis commenced
with commercially available (R)-epichlorohydrin, which on treat-
ment with aniline in methanol under reflux condition followed
by LiAlH4 reduction furnished the amino alcohol derivative (S)-4
(Scheme 3). Compound (S)-4 underwent a Mitsunobu reaction
(Table 1, entry 1–4) to afford the optically active aziridine (R)-5,
Wright et al.3 synthesized (R)-1 starting from 2-bromopropi-
onyl bromide, which upon treatment with piperidine followed by
subsequent transformations yielded rac-phenampromide
(Scheme 1). Finally, rac-phenampromide was resolved using
-malic acid. Portoghese4 reported another synthesis of (R)-1
1
L
starting with 2-chloropropionic acid. This method involved the res-
olution of an intermediate using quinine followed by number of
steps to accomplish the synthesis (Scheme 1). These methods suf-
⇑
Corresponding authors. Tel.: +91 9890142969; fax: +91 7242410438
(M. Mujahid); tel.: +91 20 25902284; fax: +91 20 25902629 (M. Muthukrishnan).
E-mail addresses: mmujahidchem@gmail.com (M. Mujahid), m.muthukrishnan@
ncl.res.in (M. Muthukrishnan).
http://dx.doi.org/10.1016/j.tetasy.2017.06.001
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mujahid, M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.06.001

2
M. Mujahid et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
N
N
O
N
O
N
N
phenampromide 1
N
N
Activity
(R)-isomer > (S)-isomer
diampromide
propiram
Figure 1. Examples of few opioid analgesic from ampromide family.
Wright et al. synthesis
O
O
Br
Br
resolution
N
N
N
N
4 steps
O
rac-1
(R)-1
Portoghese synthesis
O
O
Cbz
O
N
OH
N
N
N
4 steps
Cl
(R)-1
Scheme 1. Reported approaches for the synthesis of (R)-1.
The ring opening of (R)-2 was carried out using N-benzylaniline
followed by LiAlH4 reduction to afford (S)-7 in good yield
(Scheme 4). Mesylation of compound (S)-7 went smoothly to pro-
vide the crude mesylate (S)-8 which upon treatment with Et3N and
piperidine in refluxing toluene furnished (R)-9 via ring opening of
the aziridinium ion. It should be noted that the ring opening of
aziridinium ion could be performed using different amines, which
may facilitate a diverse range of phenampromide analogues. N-
debenzylation of compound (R)-9 using catalytic Pd(OH)2 under
H2 pressure, followed by treatment with propionyl chloride in
the presence of a base afforded the target compound (R)-phenam-
promide (R)-1 with high enantiopurity (ee >99%).
O
N
N
1
(R)-
aziridine ring
opening
amide formation
amide formation
N
N
HN
)-9
(R
5
(R)-
3. Conclusion
mesylation
debenzylation
Mitsunobu
Route 1
azirdine ring opening
In conclusion, we have reported an efficient new route for the
synthesis of (R)-phenampromide (R)-1 via aziridinium ring forma-
tion as the key step using simple commercially available starting
materials. The final product has been obtained with high enantiop-
urity (ee >99%). We envisage that this simple protocol may find
application in the synthesis of other ampromides with high enan-
tiomeric purity.
Route 2
OH
OH
H
N
N
regioselective
ring opening
(S)-7
4
(S)-
ring opening
4. Experimental
4.1. General
reduction
reduction
O
Cl
(R)-2
Solvents were purified and dried by standard procedures prior
to use. IR spectra were obtained from Perkin–Elmer Spectrum
one spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on a Bruker AC-200 NMR spectrometer. Spectra were
obtained in CDCl3. Monitoring of reactions was carried out using
TLC plates Merck Silica Gel 60 F254 and visualization with UV light
(254 and 365 nm), I2 and anisaldehyde in ethanol as development
reagents. Optical rotations were measured with a JASCO P 1020
Scheme 2. Retrosynthetic analysis of (R)-phenampromide.
but all our attempts failed to produce the required key intermedi-
ate. Additionally, we tried to mesylate the (S)-4 derivative in order
to convert it into the desired aziridine, but it also failed to proceed
(Table 1, entry 5). Thus, we turned our attention towards Route 2.
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M. Mujahid et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
OH
OH
H
N
H
N
LiAlH4, THF
O
Cl
aniline, MeOH
reflux, 3h
Cl
0
oC- reflux, 5h
78%
(R)-3
(S)-4
60%
(R)-2
O
N
Table 1
N
N
5
(R)-
(R)-1
Scheme 3. Attempted synthesis for (R)-1.
4.13–4.22 (m, 1H), 4.64 (s, 2H), 6.73–6.84 (m, 3H), 7.17–7.35 (m,
7H); 13C NMR (50 MHz, CDCl3) dC 148.2 (C), 137.8 (C), 129.3 (CH,
2 carbons), 128.6 (CH, 2 carbons), 127.0 (CH), 126.8 (CH), 117.9
(CH), 113.4 (CH), 69.0 (CH), 55.7 (CH2), 54.8 (CH2), 47.7 (CH2);
MS: m/z 275 [M+H]+.
Table 1
Attempted conditions for the synthesis of (R)-5
Entry
Conditions
Result
1.
2.
3.
4.
5.
DIAD, Bu3P, toluene, reflux, 4 h
DIAD, Bu3P, THF, reflux, 4 h
DIAD, PPh3, toluene, rt, 12 h
DIAD, PPh3, toluene, reflux, 6 h
MsCl, DCM, 0 °C–rt,12 h
N.R.
N.R.
N.R.
Trace
N.R.
4.1.2. (S)-1-(Benzyl(phenyl)amino)propan-2-ol (S)-7
A solution of (R)-6 (1.4 g, 5.0 mmol) in dry THF (15 mL) was
added dropwise to a suspension of LiAlH4 (0.2 g, 5.7 mmol) in
dry THF (15 mL) at 0 °C. After being stirred at room temperature
for 30 min, the mixture was refluxed for 6 h. After completion of
the reaction, the mixture was allowed to cool to 0 °C and aq KOH
(5 mL) was added slowly followed by the addition of ethyl acetate
(25 mL). The residue was filtered over Celite and the filtrate was
washed with water, brine, dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified over col-
umn chromatography (silica gel, petroleum ether/EtOAc, 80:20)
digital polarimeter. Mass spectra were recorded at ionization
energy 70 eV on API Q Star Pulsar spectrometer using electrospray
ionization. Enantiomeric excess was determined by chiral HPLC.
4.1.1. (R)-1-(Benzyl(phenyl)amino)-3-chloropropan-2-ol (R)-6
To
a stirred solution of (R)-epichlorohydrin (R)-2 (0.98 g,
10.6 mmol) and methanol (8 ml) at room temperature was added
N-benzyl aniline (1.94 g, 10.6 mmol) dissolved in methanol
(10 ml) for 5 min. The reaction mixture was then refluxed for
24 h. After completion of the reaction methanol was evaporated
under reduced pressure and the crude product was purified by col-
umn chromatography (silica gel, petroleum ether/ethyl acetate,
to afford (S)-7 as an oil (1.13 g, 94%); [a]
25 = +8.3 (c 1.02, CHCl3);
D
1H NMR (200 MHz, CDCl3): dH 1.16 (d, J = 6.5 Hz, 3H), 3.20–3.43
(m, 2H), 3.99–4.13 (m, 1H), 4.57 (s, 2H), 6.65–6.76 (m, 3H), 7.09–
7.27 (m, 7H); 13C NMR (50 MHz, CDCl3) dC 156.3 (C), 140.0 (C),
129.2 (CH, 3 carbons), 128.6 (CH, 3 carbons), 126.9 (CH), 126.7
(CH), 113.4 (CH), 113.2 (CH), 65.5 (CH), 59.6 (CH2), 55.3 (CH2),
20.2 (CH3); MS: m/z 242 [M+H]+.
85:15) so as to afford (R)-6 as an oil (1.9 g, 65%); [
a]
25 = À10.8 (c
D
1.06, CHCl3); 1H NMR (200 MHz, CDCl3): dH 3.47–3.71 (m, 4H),
O
b
OH
a
OH
c
Cl
N
N
Cl
2
(R)-
6
(R)-
(S)-7
OMs
d
e
N
N
N+
N
8
(S)-
(R)-9
O
f
N
N
HN
N
1
(R)-phenampromide (R)-
10
(R)-
ee>99%
Scheme 4. Reagents and conditions: (a) N-benzylaniline, MeOH, reflux, 24 h, 65%; (b) LiAlH4, THF (dry), 0 °C to reflux, 6 h, 94%; (c) MsCl, Et3N, DCM, 0 °C, 2 h; (d) piperidine,
Et3N, toluene, reflux, 8 h, 30% (two steps); (e) Pd(OH)2, H2 (60 psi), MeOH, 6 h, 91%; (f) propionyl chloride, K2CO3, toluene, 0 °C to rt, 4 h, 69%.
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4
M. Mujahid et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.1.3. (R)-N-Benzyl-N-(1-(piperidin-1-yl)propan-2-yl)aniline
(R)-9
evaporated under reduced pressure. The crude product was puri-
fied by column chromatography (silica gel, petroleum ether/ace-
To a pre-cooled (0 °C) solution of alcohol (S)-7 (1.1 g, 4.5 mmol)
in dry DCM (50 mL) was added triethylamine (1.9 mL, 13.6 mmol)
followed by the slow dropwise addition of methanesulfonyl chlo-
ride (0.4 mL, 5.9 mmol). The reaction mixture was stirred at 10 °C
for 2 h before quenching with water, more DCM was added and
extracted with water, washed with brine and evaporated under
reduced pressure. The crude product (S)-8 was used for the next
step without purification.
tone, 95:5) to afford (R)-1 as a colorless oil (0.08 g, 69%);
[a]
25 = À28.4 (c 1.05, CHCl3) {lit.3
[
a]
D
25 = À16.3 (c 2, H2O)}; 1H
D
NMR (200 MHz, CDCl3): dH 1.00–1.04 (m, 6H), 1.40–1.43 (m, 2H),
1.52–1.59 (m, 4H), 1.89–1.97 (m, 3H), 2.12–2.24 (m, 3H), 2.49–
2.50 (m, 2H), 5.16–5.18 (m, 1H), 7.08–7.09 (m, 1H), 7.38–7.41
(m, 4H); 13C NMR (50 MHz, CDCl3) dC 173.7 (CO), 138.8 (C), 130.6
(CH, 2carbons), 128.9 (CH), 128.0 (CH, 2carbons), 62.2 (CH2), 54.5
(CH2, 2carbons), 46.5 (CH), 28.4 (CH2), 26.2 (CH2, 2carbons), 24.5
(CH2), 17.4 (CH3), 9.7 (CH3); MS: m/z 297 [M+Na]+; ee >99% [Chiral-
cel OD-H (250 Â 4.6 mm) column; eluent: n-hexane/ethanol
(96:4); flow rate 0.5 mL/min; detector: 254 nm] [(R)-isomer
tR = 9.675 min, (S)-isomer tR = 10.600 min].
To a stirred solution of (S)-8 in dry toluene was added triethy-
lamine (0.6 mL, 4.9 mmol) followed by the addition of piperidine
(0.8 mL, 8.1 mmol). The reaction mixture was refluxed for 8 h
and the solvent was evaporated in vacuo. Next, DCM (25 mL) was
added and the organic layer was washed with water (2 Â 15 mL),
brine, dried over Na2SO4 and evaporated under reduced pressure.
The crude oil obtained was purified over column chromatography
(silica gel, petroleum ether/EtOAc, 80:20) so as to afford (R)-9 as an
Acknowledgements
Financial support from the CSIR – India Network projects
(CSC0130, BSC0121 and CSC0108) is gratefully acknowledged. M.
M & S.P.D thanks Principal Dr. S. G. Bhadange for constant encour-
agement and support.
oil (0.4 g, 30%); [a]
25 = +26.5 (c 1.25, CHCl3); 1H NMR (200 MHz,
D
CDCl3): dH 1.25 (d, J = 6.5 Hz, 3H), 1.39–1.58 (m, 6H), 2.23–2.54
(m, 6H), 4.20–4.30 (m, 1H), 4.42 (s, 2H), 6.61–6.73 (m, 3H), 7.10–
7.34 (m, 7H); 13C NMR (50 MHz, CDCl3) dC 149.2 (C), 140.4 (C),
128.9 (CH, 2carbons), 128.2 (CH, 2carbons), 126.4 (CH, 2carbons),
126.3 (CH), 116.3 (CH), 113.4 (CH, 2 carbons), 62.6 (CH2), 55.2
(CH2, 2carbons), 50.9 (CH), 48.8 (CH2), 26.0 (CH2, 2carbons), 24.3
(CH2), 16.6 (CH3); MS: m/z 331 [M+Na]+.
A. Supplementary data
Supplementary data (copies of 1H NMR, 13C NMR of all the com-
pounds & chiral HPLC chromatograph of the final compound) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetasy.2017.06.001.
4.1.4. (R)-N-(1-(Piperidin-1-yl)propan-2-yl)aniline (R)-10
To a solution of (R)-9 (0.2 g, 0.6 mmol) in methanol (10 mL) was
added palladium hydroxide (0.02 g, 10–20 wt %) and the reaction
mixture was stirred under hydrogen (60 psi) for 6 h. After comple-
tion of the reaction (indicated by TLC), the catalyst was filtered
over a plug of celite bed and the solvent was evaporated under
reduced pressure. The crude product was purified by column chro-
matography (silica gel, petroleum ether/acetone, 80:20) so as to
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afford (R)-10 as a colorless oil (0.12 g, 91%); [
a
]
25 = À22.3 (c 1.28,
D
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CHCl3); 1H NMR (200 MHz, CDCl3): dH 1.20 (d, J = 6.0 Hz, 3H),
1.47–1.59 (m, 6H), 2.23–2.47 (m, 6H), 3.38–3.54 (m, 1H), 6.64–
6.73 (m, 3H), 7.13–7.21 (m, 2H); 13C NMR (50 MHz, CDCl3) dC
148.5 (C), 129.1 (CH, 2carbons), 117.1 (CH), 113.6 (CH, 2carbons),
64.5 (CH2), 54.5 (CH2, 2carbons), 45.6 (CH), 26.0 (CH2, 2carbons),
24.3 (CH2), 19.8 (CH3); MS: m/z 219 [M+H]+.
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4.1.5. (R)-N-Phenyl-N-(1-(piperidin-1-yl)propan-2-yl)
propionamide (R)-1
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To a solution of compound (R)-10 (0.1 g, 0.45 mmol) in dry
toluene (2 ml) was added K2CO3 (0.13 g, 0.9 mmol). The reaction
mixture was cooled to 0 °C and propionyl chloride (0.045 ml,
0.5 mmol) was added slowly and stirred at 10 °C for 4 h. After com-
pletion of the reaction, the solid was filtered and the solvent was
Please cite this article in press as: Mujahid, M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.06.001