Practical and scalable synthesis of ethyl (R)-piperidine-3-acetate

Article abstract of DOI:10.1080/00397911.2010.536293

A practical and scalable synthesis of ethyl (R)-piperidine-3-acetate was achieved from commercially available 3-pyridylacetic acid in 76% overall yield. The practical synthesis was demonstrated on 100-g scale. One-pot reductive N-ethylation of the pyridinium salt with acetonitrile gave an N-ethyl piperidine derivative. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.536293

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Practical and Scalable Synthesis of Ethyl
(R)-Piperidine-3-acetate
Ying-Guang Zhu a , Hong-Zhu Kan a , Li-Qin Jiang a & Wen-Hao Hu a
a Shanghai Engineering Research Center of Molecular Therapeutics
and New Drug Development, East China Normal University, Shanghai,
China
Available online: 07 Oct 2011
To cite this article: Ying-Guang Zhu, Hong-Zhu Kan, Li-Qin Jiang & Wen-Hao Hu (2012): Practical and
Scalable Synthesis of Ethyl (R)-Piperidine-3-acetate, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:8, 1137-1145
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Synthetic Communications1, 42: 1137–1145, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.536293
PRACTICAL AND SCALABLE SYNTHESIS OF ETHYL
(R)-PIPERIDINE-3-ACETATE
Ying-Guang Zhu, Hong-Zhu Kan, Li-Qin Jiang, and
Wen-Hao Hu
Shanghai Engineering Research Center of Molecular Therapeutics and New
Drug Development, East China Normal University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract A practical and scalable synthesis of ethyl (R)-piperidine-3-acetate was achieved
from commercially available 3-pyridylacetic acid in 76% overall yield. The practical syn-
thesis was demonstrated on 100-g scale. One-pot reductive N-ethylation of the pyridinium
salt with acetonitrile gave an N-ethyl piperidine derivative.
Keywords Ethyl (R)-piperidine-3-acetate; hydrogenation; L-(þ)-mandelic acid; reductive
N-ethylation; resolution
INTRODUCTION
Piperidine derivatives exhibit a broad range of biological activities such as
antitumor, antiinflammatory, anxiolytic, and anti-epileptic activity.[1] For instance,
optically active ethyl (R)-piperidine-3-acetate (R-1) is presented as a key skeleton
in a number of bioactive compounds that are under active pharmaceutical research
(Fig. 1).[2–4]
Because of its potential applications, many research groups have been studying
the synthesis of (R)-1 and its derivatives. It was reported that (R)-1 was easily
resolved from racemic 1 with L-(þ)-mandelic acid in good yield.[5] However, prep-
aration of racemic 1 required rather harsh reaction conditions and=or expensive
reagents. For example, rhodium-catalyzed hydrogenation of ethyl 3-pyridylacetate
(6) was reported to afford racemic 1 in good yields, but this procedure is not suitable
for scale-up because of the expensive rhodium catalyst as well as elevated reaction
Received September 21, 2010.
Address correspondence to Wen-Hao Hu, Shanghai Engineering Research Center of Molecular
Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China.
E-mail: whu@chem.ecnu.edu.cn
1137

1138
Y.-G. ZHU ET AL.
Figure 1. Selected illustrative examples of the importance of (R)-piperidine-3-acetate (1) motifs in drug
discovery.
temperature and relatively long reaction time.[6] Alternatively, expensive PtO2 also
has been successfully used for the hydrogenation of 6.[7] To avoid using the expensive
rhodium and platinum catalysts,[8] reductions of some other pyridine derivatives
such as corresponding N-oxide[9] or pyridinium salts[10] have been reported. For
example, transfer hydrogenation of a pyridine N-oxide with ammonium formate
in the presence of Pd=C was accomplished at room temperature.[9] We report here
our efforts to achieve a practical and scalable synthesis of (R)-1 under mild reaction
conditions using 5% Pd=C as a catalyst. During the research, we found that CH3CN
can be used as a reductive N-ethylation reagent for the preparation of N-ethyl-
piperidine-3-acetate (9). The modified practical and scalable procedures for the prep-
aration of 1 and 9 have been demonstrated on a 100-g scale without using any
column chromatographic purification during the whole processes.
RESULTS AND DISCUSSION
The synthetic route for the synthesis of (R)-1 is outlined in Scheme 1. Commer-
cially available 3-pyridylacetic acid hydrochloride (5) was used as the starting
material. Esterification of 5 with SOCl2 in ethanol gave 6 in 93% yield.[11] The chal-
lenge in the next step is to reduce the pyridine functionality under mild and practical
reaction conditions. We first tried transfer hydrogenation of N-oxide of pyridine 6 in
the presence of Pd=C catalyst according to a similar procedure reported in the litera-
ture.[9] Unfortunately, the reaction failed to give the desired piperidine rac-1. Instead,

SYNTHESIS OF PIPERIDINE DERIVATIVES
1139
Scheme 1. Synthetic route of (R)-piperidine-3-acetate [(R)-1].
only the N-O bond was reduced back to the pyridine 6. We were gratified to find that
the reduction of 6 was successfully achieved through hydrogenation of corresponding
N-benzyl pyridinium salt. Thus, treatment of 6 with benzyl chloride in acetonitrile
gave the corresponding N-benzyl pyridinium salt 7 in 95% yield. Hydrogenation of
7 was carried out in EtOH under 10 bar H2 pressure at room temperature in the pres-
ence of 5% Pd=C to cleanly afford the desired rac-1 in 98% yield (Table 1, entry 3).
Lower yield of the hydrogenation was observed when lower hydrogen pressure was
applied (Table 1, entries 1 and 2). Other Pd catalysts such as Pd(OAc)2 and
Pd(OH)2=C were less effective than Pd=C in the hydrogenation (entries 4 and 5).
Among the solvents screened, EtOH was found to be the best (entry 3 vs. entries
6–9). When using methanol as the solvent, a significant amount of transesterification
product leading to methyl piperidine-3-acetate was obtained (entry 6).
The hydrogenation of 7 was successfully scaled up to 200 g with the same yield.
During the process development for the scale-up, we found that residual solvent acet-
onitrile from the previous step has to be totally excluded before the hydrogenation.
Otherwise, in the presence of CH3CN, N-ethyl piperidine 9 was formed as a side pro-
duct. Formation of 9 is proposed in Scheme 2. Hydrogenation of 7 should give rac-1.
Nucleophilic addition of 1 to CH3CN affords an amidine intermediate. Complete
hydrogenation of the amidine intermediate results in N-ethyl piperidine 9 together
with the formation of one molecule of NH3. Similar reaction of N-ethylation from
CH3CN with both primary aromatic or aliphatic amines under Rh=C-catalyzed
hydrogenation has been described in the literature before.[12]
This N-ethylation method is particularly attractive because those toxic and
corrosive alkylating agents such as alkyl halides and carbonyl compounds are
avoided. We decided to carry out a large-scale reaction to demonstrate the usefulness
of the reaction. Thus, the one-pot reduction and N-ethylation of N-benzyl pyridi-
nium salt 7 with 2 equiv. of CH3CN was carried out on a 250-g scale under 10 bar
H2 pressure in the presence of Pd=C catalyst to afford N-ethyl piperidine 9 in 96%
yield (Scheme 3).

1140
Y.-G. ZHU ET AL.
Table 1. Reaction condition optimization for the hydrogenation of N-benzyl pyridinium salt 7a
Entry
H2 (bar)
Solvent
Catalyst
Yield (%)b
1
2
3
4
5
6
7
8
9
1
5
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
EtOAc
AcOH
THF
5% Pd=C
5% Pd=C
5% Pd=C
30
75
10
10
10
10
10
10
10
98
Pd(OAc)2
5% Pd(OH)2=C
5% Pd=C
—
42
<10c
85
5% Pd=C
5% Pd=C
5% Pd=C
89
40
aThe hydrogenation was carried out with 7 (1 g, 3 mmol) in the corresponding solvent (10 mL) at
ambient temperature for 8 h in the presence of 5 mol% catalyst.
bIsolated yield.
cMethyl piperidine-3-acetate was isolated in 94% yield.
Finally, resolution of rac-1 with L-(þ)-mandelic acid was achieved in EtOAc
to give (R)-1 (>99% ee) in 88% yield according to a similar procedure reported in
literature.[5] The optical purity of (R)-1 was determined to be 99.2% ee by HPLC
analysis. Under the same resolution conditions, (S)-1 was also obtained in 81% yield
with greater than 99% ee using D-(ꢀ)-mandelic acid as the resolution agent. For easy
storage and transportation, oily 1 was converted to corresponding HCl salt form as a
white solid.
Scheme 2. Proposed pathway for the formation of N-ethyl piperidine 9.

SYNTHESIS OF PIPERIDINE DERIVATIVES
1141
Scheme 3. Scale-up of one-pot reduction and N-ethylation of 7.
In conclusion, we have reported a practical and scalable synthesis of (R)-1 from
commercially available 3-pyridylacetic acid hydrochloride (5) in four steps with 76%
overall yield. (S)-1 can also be made similarly. The practical protocol was demon-
strated on a 100-g scale. The key step in the synthesis is the successful hydrogenation
of N-benzyl pyridinium salt of ethyl 3-pyridylacetate using relatively cheap Pd=C as
a catalyst under mild reaction conditions. A one-pot reduction and N-ethylation of
the N-benzyl pyridinium salt with acetonitrile was demonstrated on a large scale to
give the corresponding N-ethyl piperidine derivative in good yield.
EXPERIMENTAL
All reagents were obtained commercially and were used without further purifi-
cation unless otherwise noted. 1H and 13C NMR spectra were recorded on a Bruker
500-MHz spectrometer. Chemical shifts (d) are reported in parts per million (ppm)
1
relative to the internal standard tetramethylsilane (TMS, d ¼ 0 ppm) for H NMR
and deuteriochloroform (CDCl3, d ¼ 77.00 ppm) or deuteriodimethyl sulfoxide
(DMSO-d6, d ¼ 39.5 ppm) for 13C NMR spectroscopy. Mass spectra were recorded
on a Bruker microTOF II mass spectrometer for both low-resolution and high-
resolution mass spectra (HRMS). Optical rotations were measured with a Perkin-
Elmer 241 MC polarimeter. Melting points were determined with a Zeiss Axiolab
microscope apparatus and are uncorrected.
Ethyl 3-Pyridylacetate (6)
SOCl2(35 mL, 0.43 mol) was added to a solution of 5 (250.0 g, 1.44 mol) in
EtOH (2.5 L) in 15 min at 0–5 ꢁC. After completion of the addition, the reaction
was heated under reflux for additional 16 h. EtOH was evaporated under reduced
pressure. To the residue was added 2 M aqueous Na2CO3 (300 mL), and the resulting
mixture was extracted with EtOAc (3 ꢂ 400 mL). The combined organic layers were
washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated to give 6 as a colorless liquid (222.0 g, 93% yield). 1H NMR (500 MHz,
CDCl3): d 1.26 (t, J ¼ 6.7 Hz, 3 H), 3.62 (s, 2 H), 4.17 (q, J ¼ 6.7 Hz, 2 H),
7.27–7.28 (m, 1 H), 7.64–7.65 (m, 1 H), 8.53 (m, 2 H). 13C NMR (125 MHz, CDCl3):
d 14.02, 38.39, 61.07, 123.27, 129.75, 136.67, 148.40, 150.27, 170.59. MS (ESI):
m=z ¼ 165 [Mþ]. HRMS (ESI): m=z [M þ H]þ calcd. for C9H12NO2: 166.0863;
found: 166.0882.

1142
Y.-G. ZHU ET AL.
1-Benzyl-3-ethoxycarbonylmethyl-pyridinium Chloride (7)
PhCH2Cl (185 mL, 1.61 mol) was added to a solution of 6 (222.0 g, 1.35 mol) in
CH3CN (2.3 L) at room temperature. The resulting mixture was stirred for 12 h under
reflux. The reaction mixture was evaporated under reduced pressure to remove
CH3CN. The residue was washed with ether (2 ꢂ 400 mL) and completely dried in
vacuo. N-Benzyl pyridinium salt 7 was obtained as a light yellow solid (372.5 g,
95% yield), mp 131–132 ꢁC. 1H NMR (500 MHz, CDCl3): d 1.25 (t, J ¼ 7.1 Hz, 3 H),
3.99 (s, 2 H), 4.16 (q, J ¼ 7.1 Hz, 2 H), 6.28 (s, 2 H), 7.36–7.38 (m, 3 H), 7.69–7.71 (m,
2 H), 7.92–7.95 (m, 1 H), 8.33 (d, J ¼ 7.9 Hz, 1 H), 9.57 (d, J ¼ 5.9 Hz, 1 H), 9.79 (s, 1 H).
13C NMR (125 MHz, CDCl3): d 14.03, 37.26, 62.02, 64.24, 127.49, 129.60, 129.65,
129.95, 132.97, 135.86, 143.42, 145.72, 146.11, 168.92. MS (ESI): m=z ¼ 256 [M ꢀ
Cl]þ. HRMS (ESI): m=z [M ꢀ Cl]þ calcd. for C16H18NO2: 256.1332; found: 256.1332.
(ꢃ)-Ethyl 3-Piperidylacetate (Rac-1)
A mixture of 7 (200.0 g, 0.68 mol), EtOH (1.4 L), and 5% Pd=C (65.0 g) was stir-
red under 10 bar H2 pressure at room temperature for 8 h. After completion of the
hydrogenation, the catalyst was removed by filtration, and the filtrate was concen-
trated under reduced pressure. The resulting residue was added to 2 M aqueous
Na2CO3 (400 mL), and the resulting mixture was extracted with EtOAc (3 ꢂ 400 mL).
The combined organic layers were washed with brine (400 mL), dried over Na2SO4,
filtered, and concentrated to give racemic 1 as a colorless liquid (115.0 g, 98% yield).
1H NMR (500 MHz, CDCl3): d 1.08–1.09 (m, 1 H), 1.20 (t, J ¼ 7.1 Hz, 3 H), 1.41–1.44
(m, 1 H), 1.58–1.61 (m, 1 H), 1.77–1.80 (m, 1 H), 1.86–1.89 (m, 1 H), 2.10–2.27 (m, 4
H), 2.47–2.49 (m, 1 H), 2.93 (d, J ¼ 12.1 Hz, 1 H), 3.01 (d, J ¼ 12.1 Hz, 1 H), 4.07 (q,
J ¼ 7.1 Hz, 2 H). 13C NMR (125 MHz, DMSO-d6): d 14.00, 21.48, 27.72, 29.97, 37.23,
43.02, 47.06, 59.89, 171.09. MS (ESI): m=z ¼ 171 [Mþ]. HRMS (ESI): m=z [M þ H]þ
calcd. for C9H18NO2: 172.1332; found: 172.1339.
(R)-Ethyl Piperidine-3-acetate (R-1)
L-(þ)-Mandelic acid (80 g, 0.53 mol) was added to a solution of rac-1 (90.0 g,
0.53 mol) in EtOAc (800 mL). The resulting mixture was refluxed under stirring
for 4 h. The resulting solution was allowed to cool to room temperature and stand
at room temperature for an additional 12 h. The formed mandelic acid salt was
filtered to give a white solid (160 g). The salt was recrystallized twice from EtOAc
until enantiomeric excess (ee) of (R)-1 free base reaches 99%. The mandelic acid salt
was added to 2 M aqueous Na2CO3 (200 mL), and the resulting mixture was
extracted with EtOAc (3 ꢂ 300 mL). The combined organic layers were washed with
brine (200 mL), dried over Na2SO4, filtered, and concentrated to give (R)-1 as a
yellow oil (39.6 g, 88% yield) with 99.2% ee determined by HPLC analysis (Daicel
Chirapak AD-H, detection wavelength ¼ 210 nm, flow rate ¼ 1.0 mL=min, n-hexane=
EtOH=diethylamine ¼ 95:5:0.1, tR ¼ 5.04 min).
(R)-Ethyl Piperidine-3-acetate Hydrochloride (8)
Dry hydrogen chloride was continuously bubbled into a solution of (R)-1
(39.6 g, 0.23 mol) in ether (300 mL) at 0 ꢁC for 2 h until thin-layer chromatography

SYNTHESIS OF PIPERIDINE DERIVATIVES
1143
(TLC) showed the free base (R)-1 was completely consumed. Then, the mixture was
stirred for an additional 2 h at ambient temperature. The precipitated solid was
isolated by filtration and dried to afford a white solid 8 (46.6 g, 97% yield), mp
20
1
132–134 ꢁC. ½aꢄD ꢀ 9:7ꢁ (c 1.00, MeOH). H NMR (500 MHz, DMSO-d6): d 1.18
(t, J ¼ 7.1 Hz, 3 H), 1.16–1.19 (m, 1 H, overlap), 1.64–1.68 (m, 1 H), 1.70–1.74 (m,
2 H), 2.10–2.13 (m, 1 H), 2.22–2.27 (m, 1 H), 2.32–2.36 (m, 1 H), 2.56 (t, J ¼ 11.9 Hz,
1 H), 2.67–2.70 (m, 1 H), 3.13–3.16 (m, 2 H), 4.07 (q, J ¼ 7.1 Hz, 2 H), 8.93 (br, s, 2 H).
MS (ESI): m=z ¼ 207 [Mþ]. HRMS (ESI): m=z [M þ Na]þ calcd. for C9H18
ClNNaO2: 230.0918; found: 230.0930.
N-Ethyl-Piperidine-3-acetate (9)
In a 2-L autoclave, a mixture of 7 (250.0 g, 0.85 mol), CH3CN (89.0 mL,
1.70 mol), EtOH (1.6 L), and 5% Pd=C (90.4 g) was stirred under 10 bar H2 pressure
at room temperature for 12 h. After completion of the hydrogenation, the catalyst
was removed by filtration through a celite pad. The filtrate was concentrated under
reduced pressure. H2O (400 mL) and EtOAc (400 mL) were added to the resulting
mixture. The organic layer was separated, and the aqueous layer was extracted with
EtOAc (2 ꢂ 400 mL). The combined organic layers were washed with brine (400 mL),
dried over Na2SO4, filtered, and concentrated to give 9 as a colorless liquid (163.8 g,
96% yield). 1H NMR (500 MHz, CDCl3): d 0.93–1.00 (m, 1 H), 1.07 (t, J ¼ 7.2 Hz, 3
H), 1.25 (t, J ¼ 7.1 Hz, 3 H), 1.56–1.69 (m, 3 H) 1.75–1.79 (m, 1 H), 1.84–1.88 (m, 1
H), 2.06–2.11 (m, 1 H), 2.20–2.23 (m, 2 H), 2.38 (q, J ¼ 7.2 Hz, 2 H), 2.83–2.88 (m, 2
H), 4.13 (q, J ¼ 7.1 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d 13.35, 15.63, 26.46,
32.25, 34.68, 40.92, 54.02, 54.91, 60.62, 61.58, 173.94. MS (ESI): m=z ¼ 199 [Mþ].
HRMS (ESI): m=z [M þ H]þ calcd. for C11H22NO2: 200.1645; found: 200.1613.
ACKNOWLEDGMENT
Financial support from the Science and Technology Commission of Shanghai
Municipality (10XD1401700) is gratefully acknowledged.
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yield) was obtained by treatment of (R)-1 (100 mg, 0.6 mmol) with benzyl chloride (75 mg,

SYNTHESIS OF PIPERIDINE DERIVATIVES
1145
0.6 mmol) in the presence of K2CO3 (165 mg, 1.2 mmol) in CH3CN (5 mL) under reflux for
4 h. N-benzyl derived (S)-1 was also made similarly. HPLC analysis results from the
N-benzyl derivatives of (R)-1 and (S)-1: (R)-1: 99.2% ee, retention time: tR ¼ 5.04 min;
(S)-1: 100% ee, retention time: tR ¼ 4.14 min. Daicel Chirapak AD-H, detection wave-
length ¼ 210 nm, flow rate ¼ 1.0 mL=min, n-hexane:EtOH:diethylamine ¼ 95:5:0.1.