Synthesis of 3-vinylphenyl ethyl(methyl)carbamate: A potential human metabolite of rivastigmine

Article abstract of DOI:10.14233/ajchem.2013.13473

Convenient and efficient syntheses of 3-vinylphenyl ethyl (methyl) carbamate, one of potential metabolites from rivastigmine, has been developed. The overall yield is higher than 30% and represents the first direct synthesis of this metabolite from rivast

Full text of DOI:10.14233/ajchem.2013.13473

Asian Journal of Chemistry; Vol. 25, No. 6 (2013), 3499-3500
http://dx.doi.org/10.14233/ajchem.2013.13473
NOTE
Synthesis of 3-Vinylphenyl Ethyl(methyl)carbamate:
A Potential Human Metabolite of Rivastigmine
1
1
2
1
1
1,*
GUANHONG XU , TENG MA , JING YANG , FENGLIANG WANG , HONGJUAN ZHANG , XIUZHEN WANG and FEI LI
1School of Pharmacy, Nanjing Medical University, Nanjing 210029, P.R. China
2Chireach Biomedical Technology (Group) Co., Ltd., Suzhou 215128, P.R. China
*Corresponding author: Fax: +86 25 86863165; Tel: +86 25 86863175; E-mail: kldlf@njmu.edu.cn
(Received: 19 January 2012;
Accepted: 28 December 2012)
AJC-12624
Convenient and efficient syntheses of 3-vinylphenyl ethyl (methyl) carbamate, one of potential metabolites from rivastigmine, has been
developed. The overall yield is higher than 30 % and represents the first direct synthesis of this metabolite from rivastigmine.
Key Words: Rivastigmine, Synthesis, Metabolite, Alzheimer's disease.
H3C
CH3
INTRODUCTION
OH
CH3
N
COOH
H3C
N
O
Alzheimer's disease (AD) is the most common cause
of progressive mental deterioration in people of advanced age.
It is characterized by impaired neuronal signaling, leading
to multiple cognitive deficits and often accompanied by
behavioural disturbances1,2. Acetylcholine (ACh) is the pri-
mary neurotransmitter that facilitates learning and increases
attention.
HOOHC
C
CH3
H2
OH
O
1
CH3
N
CH3
CH3
H
C
H3C
HO
H3C
N
O
C
H2
CH2
The deficiency of acetylcholine is considered to be respon-
sible for cognitive, behavioural and functional impairment3.
Rivastigmine hydrogen tartrate (Exelon, 1), (S)-N-ethyl-3-[(1-
dimethylamino) ethyl]-N-methyl-phenyl carbamate hydrogen
tartrate, is a reversible acetylcholinesterase inhibitor of the
carbamate type approved for the treatment of alzheimer's
disease4. Rivastigmine was approved as cholinergic agent by
many countries and regions including all the members of the
European Union and the US5.
O
2
3
Fig. 1. Rivastigmine (1), NAP 226-9 (2) and 3-vinylphenyl ethyl(methyl)-
carbamate (3)
In this paper, we report the highly efficient synthesis of 3
and the synthetic routes are described in Scheme-I. The target
compound was synthesized by using ethyl(methyl)carbamic
chloride (4) and 1-(3-hydroxyphenyl)ethanone (5) as the
starting materials.
In pre-clinical and clinical studies, the metabolic mecha-
nism and reaction of rivastigmine (1) have been studied in
human. Analytical evaluation using liquid chromatography-
tandem mass spectrometry (LC-MS/MS) suggested that NAP
226-90 (2) and the potential metabolite, 3-vinylphenyl ethyl
(methyl) carbamate (3) existed in human plasma6. Among
them, the synthesis of 2 has been reported7. Rivastigmine is
relatively a novel drug and perhaps for that particular reason,
few synthesis methods of 3 have been reported in the literature.
Prompt and convenient synthesis of 3 was required for an
urgent request for providing the standard on quality control
during drug production.
Preparation of 3-acetylphenyl ethyl(methyl)carbamate
(6): Acetone (150 mL) was charged in a 250 mL three necked
flask equipped with a reflux condenser and a mechanical
stirrer. 5 (5 g, 36.76 mmol) was added with stirring at ambient
temperature. K2CO3 (15 g, 108 mmol) was added in one lot.
Then 4 (6.7 g, 55 mmol) was added dropwise in 15 min. Then
the mixture was refluxed for 3 h. Cooled, filtered and evapo-
rated in vacuum. The obtained mixture was dissolved in CH2Cl2
(100 mL). The organic phase was washed with 1 N NaOH

3500 Xu et al.
Asian J. Chem.
O
O
CH3
CH3
(50 mL × 2), brine and dried with Na2SO4. After evaporated
in vacuum, 8.12 g of light yellow oil, 3-acetylphenyl ethyl
(methyl)carbamate (6) was obtained in 99 % yield8. 1H NMR
(CDCl3, 400 MHz, ppm) δ 7.78 (d, 1H, J = 7.7 Hz), 7.69 (s,
1H), 7.45 (t, 1H, J = 7.9 Hz), 7.34 (d, 1H, J = 8.0 Hz), 3.45
(qd, 2H, J = 7.1 Hz, J = 18.5 Hz), 3.04 (d, 3H, J = 33.8 Hz),
2.60 (s, 3H), 1.23 (td, 3H, J = 7.1 Hz, J = 23.0 Hz).
a
N
Cl
HO
N
O
H3
C
H3C
+
C
H2
CH3
C
H2
CH3
O
O
4
5
6
CH3
CH3
OH
CH3
c,d
H
C
b
H3C
N
O
H3C
N
O
C
H2
CH2
C
H2
O
O
7
3
3-(1-Hydroxyethyl) phenyl ethyl(methyl)carbamate
(7): NaBH4 (0.31 g, 8.2 mmol) was added to a cooled (0 ºC)
solution of 6 (3 g, 13.57 mmol) in dried EtOH 25 mL and then
the resultant mixture was stirred for 1 h at room temperature.
The reaction was quenched with saturated aqueous NH4Cl
(20 mL) and then diluted with water (50 mL). The resultant
solution was extracted with CH2Cl2 (30 mL × 2 mL) and the
organic phase was washed with brine, dried and evaporated.
2.36 g of yellow oil, 3-(1-hydroxyethyl) phenyl ethyl (methyl)
carbamate (7) was obtained, in 78 % yield9. 1H NMR (CDCl3,
400 MHz, ppm) δ 7.33 (t, J =7.83 Hz, 1H), 7.20-7.15 (m,
2H), 7.02 (d, J = 7.77 Hz, 1H), 4.89 (q, J = 6.48 Hz, 1H),
3.51-3.38 (m, 2H), 3.03 (d, J = 23.25 Hz, 3H), 1.49 (d, J =
6.45 Hz, 3H), 1.27-1.17 (m, 3H).
Scheme-I: Synthetic route of 3-vinylphenyl ethyl(methyl)carbamate (3).
Reagents and conditions:(a) K2CO3, acetone; (b) NaBH4,
MeOH; (c) TsCl, Py; (d)DBU, reflux
Conclusion
An efficient synthetic approach is reported for the 3-vinyl-
phenyl ethyl(methyl)carbamate in an overall yield 30 % in
three steps form the commercially available materials. With
satisfactory yields and mild conditions, this route is able to be
used a large scale to provide the standard samples of metabolite
of rivastigmine.
ACKNOWLEDGEMENTS
3-Vinylphenyl ethyl(methyl)carbamate (3): 7 (1.5 g,
6.7 mmol) was dissolved in 10 mL of pyridine and the solution
was cooled to 0 ºC and then TsCl (1.92 g, 0.01 mol) was added.
The mixture was stirred at room temperature overnight. Then
the mixture was evaporated in vacuum. The resultant was
dissolved in 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 5 mL)
and refluxed at 140 ºC for 3 h. After being cooled to room
temperature, the reaction mixture was poured into ice-chilled
EtOAc. The organic layer was washed with 1 N HCl until the
aqueous phase became less than pH 3 then 5 % NaHCO3 and
saturated NaCl three times, respectively and dried over Na2SO4.
The residual yellow oil was purified by column chromato-
graphy on silica and 0.42 g of colourless oil 3 was obtained in
30 % yield10. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.29 (t, 1H,
J = 7.8 Hz), 7.21 (d, 1H, J = 7.7Hz), 7.16 (s, 1H), 7.01 (d, 1H,
J = 7.8 Hz), 6.68 (dd, 1H, J = 10.9 Hz, J = 17.6 Hz), 5.73 (dd,
1H, J = 0.8Hz, J = 17.6Hz), 5.25 (dd, 1H, J = 0.6 Hz, J = 10.9
Hz), 3.43 (m, 2H), 3.02 (d, 3H, J = 29.4 Hz), 1.21 (td, 3H, J =
7.2Hz, J = 20.1 Hz). ESI-MS m/z: 206.1 [M + H]+.
The authors gratefully acknowledged the support of this
work by the Natural Science Foundation of China (No. 21172108),
Jiangsu Science and Technology Promotion Foundation (No.
08KJD310004) and NJMU Science and Technology Promotion
Foundation (No. 06NMUM023) for the support.
REFERENCES
1. J.L. Cummings and G. Cole, J. Am. Med. Assoc., 287, 2335 (2002).
2. P.T. Francis, A.M. Palmer, M. Snape and G.K. Wilcock, J. Neurol.
Neurosur. Psychiatry, 66, 137 (1999).
3. G. Lefèvre, M. Büche, G. Sedek, S. Maton, A. Enz, U. Lorch, C. Sagan
and S. Appel-Dingemanse, J. Clin. Pharmacol., 49, 430 (2009).
4. B.R. Williams,A. Nazarians and M.A. Gill, Clin. Ther., 25, 1634 (2003).
5. J. Bhatt, G. Subbaiah and S. Kambli, J. Chromatogr. B, 852, 115 (2007).
6. F. Pommier and R. Frigola, J. Chromatogr. B, 784, 301 (2003).
7. F. Zhang, M. Hu, M. Xie, A. Lai, R. Sun, D. Chen, R. Bao and H. Bai,
Prepatation Method of Rivastigmine, Its Intermediates and Preparation
Method of the Intermediates, US Patent 0286437 A1 (2010).
8. A. Gaitonde and M. Mangle, GB Patent 2409453A.
9. F. Deng, J.J. Lu, H.Y. Liu, L.P. Lin, J. Ding and J.S. Zhang, Chin.
Chem. Lett., 22, 28 (2011).
10. Y. Hayashi, S. Orikasa, K. Tanaka, K. Kanoh andY. Kiso, J. Org. Chem.,
65, 8402 (2000).