Practical synthesis of ethyl cis-4-amino-3-methoxy-1-piperidine carboxylate, a key intermediate of cisapride

Article abstract of DOI:10.1081/SCC-100103541

A practical synthesis of ethyl cis-4-amino-3-methoxy-1piperidinecarboxylate 1, a key intermediate of cisapride as a potent gastrointestinal stimulant, has been accomplished from 1-methyl-1,2,3,6-tetrahydropyridine 2 via an efficient formation of cis-fused oxazolidinopiperidine 7.

Full text of DOI:10.1081/SCC-100103541

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PRACTICAL SYNTHESIS OF
ETHYL CIS-4-AMINO-3-
METHOXY-1-PIPERIDINE
CARBOXYLATE, A KEY
INTERMEDIATE OF CISAPRIDE
Bong J. Kim a , Do K. Pyun a , Hee J. Jung a , Hyun
J. Kwak a , Jae H. Kim a , Eun J. Kim a , Won J.
Jeong a & Cheol H. Lee b
a Korea Research Institute of Chemical Technology,
P.O. Box 107, Yusung, Taejon, 305-343, Korea
b Korea Research Institute of Chemical Technology,
P.O. Box 107, Yusung, Taejon, 305-343, Korea
Version of record first published: 09 Nov 2006.
To cite this article: Bong J. Kim , Do K. Pyun , Hee J. Jung , Hyun J. Kwak , Jae H.
Kim , Eun J. Kim , Won J. Jeong & Cheol H. Lee (2001): PRACTICAL SYNTHESIS OF
ETHYL CIS-4-AMINO-3-METHOXY-1-PIPERIDINE CARBOXYLATE, A KEY INTERMEDIATE
OF CISAPRIDE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:7, 1081-1089
To link to this article: http://dx.doi.org/10.1081/SCC-100103541
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SYNTHETIC COMMUNICATIONS, 31(7), 1081–1089 (2001)
PRACTICAL SYNTHESIS OF ETHYL
CIS-4-AMINO-3-METHOXY-1-PIPERIDINE
CARBOXYLATE, A KEY INTERMEDIATE OF
CISAPRIDE
Bong J. Kim, Do K. Pyun, Hee J. Jung, Hyun J. Kwak,
Jae H. Kim, Eun J. Kim, Won J. Jeong, and
Cheol H. Lee*
Korea Research Institute of Chemical Technology,
P.O. Box 107, Yusung, Taejon 305-343, Korea
ABSTRACT
A practical synthesis of ethyl cis-4-amino-3-methoxy-1-
piperidinecarboxylate 1, a key intermediate of cisapride
as a potent gastrointestinal stimulant, has been accomplished
from 1-methyl-1,2,3,6-tetrahydropyridine 2 via an efficient
formation of cis-fused oxazolidinopiperidine 7.
Ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate 1 has been used
as a key intermediate for the synthesis of cisapride as a potent gastrointest-
inal stimulant. The intermediate 1 was synthesized from N-benzyl-4-piper-
idone by Van Daele et al.1,7 Their synthetic strategy involved O-alkylation
and reductive amination steps, which were dangerous and explosive in
large-scale process.
* Corresponding author. Fax: 82-42-860-1291; E-mail: cheolhl@pado.krict.re.kr
1081
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1082
KIM ET AL.
Reported herein is our highly efficient and stereoselective synthesis
of ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate 1 from 1-methyl-
1,2,3,6-tetrahydropyridine 2 in 10 steps. We envisioned that compound 1
could be synthesized through the selective ring opening of cis-fused N-ben-
zoyloxazolidinopiperidine 7, followed by O-methylation as shown in the
following retrosynthetic plan. The requisite oxazolidinone 7 could be
obtained from the bromohydrin 5, which in turn could be regioselectively
prepared from epoxide 4.
Known and inexpensive starting material 2 was converted into ethyl
1,2,3,6-tetrahydropiperidine-1-carboxylate 3 by reaction with ethyl chloro-
formate in refluxing toluene.2,3 Epoxide 4 was readily prepared by the reac-
tion of 3 with N-bomosuccinimide and aqueous DMSO, followed by
treatment of the resulting mixture of bromohydrin with potassium carbo-
nate in high overall yield. Exposure of epoxide 4 to 48% hydrobromic acid
exclusively afforded the desired bromohydrin 5 in quantitative yield4
(Scheme 1).
Scheme 1. Preparation of trans-4-bromo-3-hydroxypiperidine 5: (a) (i) K2CO3/
toluene, rt, (ii) EtOCOCl, toluene, reflux; (b) (i) NBS, DMSO, H2O, rt, (ii)
K2CO3, MeOH, rt; (c) 48% HBr/CHCl3, À40ꢀC.

CISAPRIDE INTERMEDIATE
1083
With multigrams of 5 in hand, we developed a one-pot synthesis of
cis-fused bicyclic oxazolinopiperidine 8, as summarized in Scheme 1. Thus,
bromohydrin 5 was reacted with benzoyl isocyanate in THF to give the
corresponding benzolyated compound 6. Further treatment of 6 with potas-
sium tert-butoxide, followed by the selective deprotection of the benzoyl
group of compound 7 with lithium hydroxide in an aqueous solution
afforded cis-fused bicyclic oxazolidinopiperidine 8.5 To open the oxazolidi-
none ring in a regioselective fashion, crude 8 was converted into N-Boc-
protected oxazolidinone 9 to provide cis-N-Boc-oxazolidinopiperidine 9 in
51% yield from 5 (Scheme 2).
Scheme 2. Preparation of cis-N-Boc-oxazolidinopiperidine 9: (a) benzoyl isocya-
nate, THF, rt; (b) t-BuOK, THF, reflux; (c) LiOH, THF, H2O, rt; (d) Boc2O,
Et3N, DMAP(cat.), CH2Cl2, 30ꢀ–35ꢀC.
By the reaction with a catalytic amount of cesium carbonate, the
oxazolidinone ring of 9 was cleaved to N-Boc-amino alcohol 10 in a regio-
selective manner,5 which was further converted into the corresponding
O-methylated piperidine 117 by treatment with dimethylsulfate in aqueous
NaOH. Exposure of the crude 11 to 13% hydrogen chloride in ethyl acetate
gave the desired ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate
hydrochloride 1 in 71% yield from the cis-N-Boc-oxazolidinopiperidine 9
as a white solid8 (Scheme 3). The spectroscopic and physical properties of 1
1
such as H and 13C NMR, IR, MS, and m.p. were in excellent agreement
with authentic material.1

1084
KIM ET AL.
Scheme 3. Preparation of cis-4-amino-3-methoxy-1-piperidine carboxylate hydro-
chloride 1: (a) cesium carbonate, MeOH, rt; (b) dimethylsulfate, aq. 50% NaOH, rt;
(c) 13% HCl in EtOAc, rt; (d) (i) ArCOOH, EtOCOCl, Et3N, CHCl3, 0ꢀC; (ii) KOH,
i-PrOH, reflux; (iii) RX, Et3N, DMF.
The key intermediate 1 could be converted into cisapride in three steps
by known methods.1,6 In summary, we have accomplished the synthesis of
ethyl cis-4-amino-3-methoxy-1-piperidine carboxylate 1 on a large scale
from inexpensive 1-methyl-1,2,3,6-tetrahydropyridine 2 by featuring an effi-
cient, stereoselective, one-pot preparation of cis-oxazolidinopiperidine 8
from trans-bromohydrin 5 and a regioselective oxazolidinone ring opening
of N-Boc protected oxazolidinone 9 as key steps.
EXPERIMENTAL
General
1H and 13C NMR spectra were recorded on a Varian Gemini 200
1
(200 MHz H, 50 MHz 13C). Chemical shifts are reported in ppm (ꢀ) units
relative to tetramethylsilane. Infrared (IR) spectra were recorded on a
Unicam mattson Genesis II FT-IR spectrometer. Mass spectral data were
taken on a HP 1000 LC-MSD mass spectrometer an electrospray (ES)
mode. Melting points were determined on a Thomas Hoover capillary melt-
ing point apparatus and were uncorrected. Column chromatography was
performed using silica gel (0.05–0.2 mm, Merck).
Ethyl 1,2,3,6-Tetrahydropiperidine-1-carboxylate (3)
1-Methyl-1,2,3,6-tetrahydropiridine hydrochloride 2 (200 g, 1.5 mol)
was dissolved in 500 mL of water and to this mixture was added

CISAPRIDE INTERMEDIATE
1085
potassium carbonate (207 g, 1.5 mol). After being stirred for 10 min, the
mixture was extracted with three times of toluene and the combined organic
layers were dried over MgSO4. After filtration, to the filtrate was added
potassium carbonate (20 g) and the mixture was heated to refluxing tem-
perature. To this was slowly added ethyl chloroformate (280 mL, 3 mol)
during 1 h and the mixture was refluxed for 2 h. The resulting solution was
cooled to room temperature, washed with water and brine, and dried over
MgSO4. Filtration and concentration in vacuo provided the oily residue,
which was distilled under water pump vacuum to give 3 in 75% (174 g)
yield as a colorless oil: b.p. 105ꢀ–110ꢀC/15 mm; 1H NMR (CDCl3,
200 MHz) ꢀ 1.24 (t, J ¼ 7.1 Hz, 3H), 1.90–2.20 (m, 2H), 3.16–3.28 (m, 4H),
3.45 (br, 1H), 3.68–3.76 (m, 1H), 3.86 (m, 1H), 4.09 (q, J ¼ 7.2 Hz, 2H); IR
(film, cmÀ1) 1430, 1472, 1699, 2873, 2923, 3515; MS (70 eV) m/z 171 (Mþ),
154, 142, 128, 115.
Ethyl 3-Oxo-1-piperidinecarboxylate (4)
To a solution of ethyl 1,2,3,6-tetrahydropiridine-1-carboxylate 3
(155 g, 1 mol) in dimethyl sulfoxide (2 L) was gradually added N-bromosuc-
cinimide (356 g, 2 mol) over 10 min. The reaction mixture was maintained
to 40ꢀ–50ꢀC for an additional 10 min. The mixture was poured into ice water
and extracted three times with ethyl acetate. The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was treated
with potassium carbonate (138 g, 2 mol) in 95% aqueous methanol (2.5 L)
for 30 min. Insoluble materials were filtered off, and the filtrate was diluted
with H2O. The resulting mixture was extracted twice with ethyl acetate
and dried over MgSO4. Filtration and concentration in vacuo provided
oily residue, which was distilled under water pump vacuum to give 4
in 86% (148 g) yield as a colorless oil: b.p. 80ꢀ–85ꢀC/15 mm; H NMR
1
(CDCl3, 200 MHz) ꢀ 2.16 (t, J ¼ 7.2 Hz, 3H), 2.13 (bs, 2H), 3.53
(t, J ¼ 5.7 Hz, 2H), 3.92 (t, J ¼ 2.5 Hz, 3H), 4.13 (q, J ¼ 5.6 Hz, 2H), 5.67
(m, 1H), 5.81 (m, 1H); IR (film, cmÀ1) 1432, 1703, 2843, 2916, 2987, 3038;
MS (70 eV) m/z 155 (Mþ), 126, 110, 96.
Ethyl trans-4-Bromo-3-hydroxy-1-piperidinecarboxylate (5)
To a solution of ethyl 3-oxo-1-piperidinecarboxylate 4 (147 g,
0.86 mol) in chloroform (3 L) was added dropwise 48% hydrobromic acid
(289 mL) at À40ꢀC. After being stirred for 30 min at the same temperature,
the mixture was treated with 5% aqueous sodium bicarbonate (1 L) and

1086
KIM ET AL.
extracted twice with ethyl acetate. The combined extracts were washed with
dilute HCl, H2O, and brine. The organic phase was dried over MgSO4,
evaporated in vacuo to obtain 5 in quantitative yield as a yellowish oil,
which was pure enough to be used for the next step without further pur-
1
ification: H NMR (CDCl3, 200 MHz) ꢀ 1.26 (t, J ¼ 7.1 Hz, 3H), 1.92–2.06
(m, 1H), 2.26–2.38 (m, 1H), 2.67 (bs, 1H), 3.71–3.75 (m, 1H), 3.92–3.99 (m,
2H), 4.08 (q, J ¼ 7.2 Hz, 2H), 4.25 and 4.28 (dd, J ¼ 1.8, 3.6 Hz, 1H); IR
(film, cmÀ1) 1246, 1430, 1699, 2870, 2931; MS (70 eV) m/z 252 (Mþ), 236,
222, 172.
cis-1-tert-Butyloxycarbonyl-5-ethoxycarbonyl-2-oxo-hexahydro-
oxazolo[5,4-c]pyridine (9)
Benzoyl isocyanate (14.4 mL, 0.14 mol) was added to a solution of
ethyl trans-4-bromo-3-hydroxy-1-piperidinecarboxylate 5 (28 g, 0.12 mol)
in THF (30 mL) and stirred for 1 h. The reaction mixture was diluted with
THF (300 mL) and added potassium tert-butoxide (13.4 g, 0.12 mol). After
refluxing for 1 h, the mixture was cooled and insoluble materials were fil-
tered off. The resulting ethyl cis-1-benzoyl-2-oxo-hexahydro-oxazolo[5,4-c]-
pyridine-5-carboxylate 7 solution was diluted with H2O (300 mL) and
treated with lithium hydroxide monohydrate (4.78 g, 0.12 mol) for 1 h.
The mixture was extracted twice with ethyl acetate and dried over
MgSO4. Filtration and concentration in vacuo provided ethyl cis-2-oxo-
hexahydro-oxazolo[5,4-c]pyridine-5-carboxylate 8, which was dissolved in
methylene chloride (300 mL). To the resulting solution of 8 was added
di-tert-butyldicarboxylate (24.6 g, 0.11 mol), triethylamine (15.7 mL,
0.112 mol), and 4-dimethylaminopyridine (2 g, 1.6 mmol). After being stirred
for 2 h at 30ꢀ–35ꢀC, the mixture was evaporated in vacuo. The residue was
chromatographed on silica gel (n-hexane:ethyl acetate ¼ 2:1) to afford 9 in
51% (18.2 g) as a syrup.
Ethyl trans-4-Bromo-3-benzoylaminocarbonyloxy-1-piperidine-
carboxylate (6)
1H NMR (CDCl3, 200 MHz) ꢀ 1.29 (t, J ¼ 7.1 Hz, 3H), 1.90–2.03
(m, 1H), 2.27–2.40 (m, 1H), 3.58 (m, 2H), 3.94 (m, 1H), 4.13 (q,
J ¼ 7.2 Hz, 2H), 4.27 (d, J ¼ 15 Hz, 1H), 4.80 (bs, 2H), 7.34–7.84 (m, 5H);
IR (film, cmÀ1) 1425, 1690, 1785, 2980; MS (70 eV) m/z 400 (Mþ), 355,
319, 268.

CISAPRIDE INTERMEDIATE
1087
Ethyl cis-1-Benzoyl-2-oxo-hexahydro-oxazolo[5,4-c]pyridine-5-
carboxylate (7)
1H NMR (CDCl3, 200 MHz) ꢀ 1.29 (t, J ¼ 7.1 Hz, 3H), 2.19–2.22 (m,
2H), 3.35 (m, 1H), 3.40–3.47 (m, 2H), 3.60–3.79 (m, 1H), 4.17 (q, J ¼ 7.2 Hz,
2H), 4.00 (m, 1H), 5.0 (m, 1H), 7.34–7.84 (m, 5H), 8.25 (br, 1H); 13C NMR
(CDCl3, 50.0 MHz) ꢀ 14.4, 23.2, 38.2, 40.7, 51.5, 61.6, 71.7, 127.8, 128.8,
132.4, 132.7, 150.7, 152.5, 169.4; IR (film, cmÀ1) 1442, 1684, 1784, 2934,
2984; MS (70 eV) m/z 318 (Mþ).
Ethyl cis-2-Oxo-hexahydro-oxazolo[5,4-c]pyridine-5-carboxylate (8)
1H NMR (CDCl3, 200 MHz) ꢀ 1.26 (t, J ¼ 7.1 Hz, 3H), 1.76–1.94 (m,
2H), 3.42–3.51 (m, 3H), 4.13 (q, J ¼ 7.1 Hz, 2H), 4.04–4.20 (m, 2H), 4.78 (bs,
1H), 5.70 (bs, 1H); 13C NMR (CDCl3, 50.0 MHz) ꢀ 14.12, 25.4, 37.1, 41.3,
47.9, 61.0, 73.2, 155.5, 159.0; IR (film, cmÀ1) 1427, 1692, 1747, 2978, 3293;
MS (70 ev) m/z 215 (Mþ), 185, 169, 153, 141.
cis-1-tert-Butyloxycarbonyl-5-ethoxycarbonyl-2-oxo-hexahydro-
oxazolo[5,4-c]pyridine (9)
1H NMR (CDCl3, 200 MHz) ꢀ 1.27 (t, J ¼ 7.1 Hz, 3H), 1.55 (s, 9H),
2.09 (m, 2H), 3.35 (m, 2H), 3.60 (m, 1H), 4.13 (q, J ¼ 7.2 Hz, 2H), 4.15 (m,
1H), 4.24 (m, 1H), 4.40 (m, 1H); 13C NMR (CDCl3, 50.0 MHz) ꢀ 13.8, 24.3,
27.2, 37.4, 40.3, 51.0, 60.9, 70.1, 83.3, 148.3, 150.7, 155.0; IR (film, cmÀ1
1382, 1698, 1812, 2980; MS (70 eV) m/z 315 (Mþ), 299, 258, 213.
)
Ethyl cis-4-Amino-3-methoxy-1-piperidinecarboxylate hydrochloride
(1)
To a solution of cis-1-tert-butyloxycarbonyl-5-ethoxycarbonyl-2-oxo-
hexahydro-oxazolo[5,4-c]pyridine (12.8 g, 40.7 mmol) in methanol
9
(180 mL) was added cesium carbonate (2.65 g, 8.1 mmol) and stirred for
4 h. After evaporation of solvent in vacuo, the residue was dissolved in
toluene (100 mL) and insoluble materials were filtered off. To this crude
ethyl cis-4-tert-butyloxycarbonylamino-3-hydroxy-1-piperidinecarboxylate
10 solution was added aqueous 50% of sodium hydroxide (60 mL),
dimethylsulfate (4.63 mL, 48.8 mmol), and benzyl triethylammonium chlor-
ide (100 mg, 0.3 mmol). After being stirred for 5 h, the mixture was diluted

1088
KIM ET AL.
with ice water (70 mL) and extracted twice with ethyl acetate. The combined
organic phases were dried over MgSO4. Filtration and concentration
in vacuo provided crude ethyl cis-4-tert-butyloxycarbonylamino-3-meth-
oxy-1-piperidinecarboxylate 11, which was further treated with 13% hydro-
gen chloride solution in ethyl acetate (130 mL). The mixture was stirred for
6 h. The white solids formed were collected and washed with ethyl ether to
give desired ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate hydro-
chloride 1 in 71% (6.88 g) yield as a whie solid.
Ethyl cis-4-tert-Butyloxycarbonylamino-3-hydroxy-1-piperidine-
carboxylate (10)
M.p. 116ꢀ–117ꢀC; H NMR (CDCl3, 200 MHz) ꢀ 1.18 (t, J ¼ 7.1 Hz,
1
3H), 1.37 (s, 9H), 1.61 (m, 2H), 2.71–2.95 (m, 3H), 3.60 (m, 1H), 3.82 (bs,
1H), 4.03 (q, J ¼ 7.2 Hz, 2H), 4.04–4.10 (m, 2H), 5.01 (d, J ¼ 8.2 Hz, 1H);
13C NMR (CDCl3, 50.0 MHz) ꢀ 14.1, 26.3, 28.3, 42.7, 48.9, 50.5, 61.5, 66.7,
79.4, 150.8, 155.3; IR (film, cmÀ1) 1467, 1526, 1685; MS (70 eV) m/z 289
(Mþ), 233, 213, 185, 141.
Ethyl cis-4-tert-Butyloxycarbonylamino-3-methoxy-1-piperidine-
carboxylate (11)
1H NMR (CDCl3, 200 MHz) ꢀ 1.23 (t, J ¼ 7.2 Hz, 3H), 1.42 (s, 9H),
1.61–1.67 (m, 2H), 2.71–2.80 (m, 3H), 3.32 (m, 1H), 3.36 (s, 3H), 3.65 (m,
1H), 4.08 (m, 1H), 4.09 (q, J ¼ 7.2 Hz, 2H), 4.04 (m, 1H), 5.01 (d, J ¼ 8.2 Hz,
1H); 13C NMR (CDCl3, 50.0 MHz) ꢀ 14.7, 26.9, 28.2, 42.5, 43.6, 50.1, 56.5,
61.1, 75.6, 79.2, 155.1, 155.7; IR (film, cmÀ1) 1435, 1497, 1702, 2978, 3344,
3454; MS (70 eV) m/z 302 (Mþ), 270, 246, 214, 185.
Ethyl cis-4-Amino-3-methoxy-1-piperidinecarboxylate hydrochloride
(1)
M.p. 217ꢀ–218ꢀC; H NMR (CD3OD, 200 MHz) ꢀ 1.13 (t, J ¼ 7.2 Hz,
1
3H), 1.57–1.67 (m, 2H), 2.68–2.83 (m, 2H), 3.16 (m, 1H), 3.30 (s, 3H), 3.42
(m, 1H), 3.96 (q, J ¼ 7.2 Hz, 2H), 3.96–4.06 (m, 1H), 4.31–4.38 (m, 1H), 4.72
(bs, 3H); 13C NMR (CDCl3, 50.0 MHz) ꢀ 15.8, 26.5, 43.8, 45.0, 58.2, 63.7,
75.3, 158.5; IR (film, cmÀ1) 1237, 1442, 1523, 1698, 2902; MS (70 eV) m/z
238 (Mþ).

CISAPRIDE INTERMEDIATE
ACKNOWLEDGMENTS
1089
We would like to thank Dong Wha Pharmaceutical Industry Co., Ltd,
for financial support.
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Received in Japan April 7, 2000