Novel convenient synthesis of rivastigmine

Article abstract of DOI:10.1080/00397910802531948

A novel and convenient synthesis of rivastigmine has been reported. This procedure provides high yield and excellent enantiomeric excess (100% ee) starting from the diastereromerically pure (S)-1-(3-methoxyphenyl)-N-[(S)-1- phenylethyl] ethanamine. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802531948

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Novel Convenient Synthesis of
Rivastigmine
Meng Hu a , Fu-Li Zhang a & Mei-Hua Xie a
a Pharmacochemistry Division, Shanghai Institute of
Pharmaceutical Industry, Shanghai, China
Published online: 02 Apr 2009.
To cite this article: Meng Hu , Fu-Li Zhang & Mei-Hua Xie (2009) Novel Convenient
Synthesis of Rivastigmine, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:9, 1527-1533, DOI:
10.1080/00397910802531948
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Synthetic Communications1, 39: 1527–1533, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802531948
Novel Convenient Synthesis of Rivastigmine
Meng Hu, Fu-Li Zhang, and Mei-Hua Xie
Pharmacochemistry Division, Shanghai Institute of Pharmaceutical
Industry, Shanghai, China
Abstract: A novel and convenient synthesis of rivastigmine has been reported.
This procedure provides high yield and excellent enantiomeric excess (100% ee)
starting from the diastereromerically pure (S)-1-(3-methoxyphenyl)-N-[(S)-1-
phenylethyl] ethanamine.
Keywords: Acetyl cholinesterase inhibitor, rivastigmine, synthesis
Rivastigmine (1) [(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-
carbamic acid, phenyl ester, (L)-2,3-dihydroxybutanedioic acid salt] is
an acetyl cholinesterase inhibitor with brain-region selectivity and a long
duration of action.[1] It was approved by the U.S. Food and Drug Admin-
istration for the treatment of Alzheimer’s disease (AD) on April 21, 2000.
Originally, rivastigmine was synthesized by resolving the racemic
rivastigmine with (þ)-di-O,O0-p-toluoyl tartaric acid monohydrate.[2]
However, this method involves three or more recrystallizations to achieve
increased enantiomeric excess. Accordingly, the total yield is at a low
level and high enantiomeric excess cannot be ensured.
Several other syntheses of rivastigmine have been reported,[3–7] which
are either too long or contain unacceptable operations, and thus their are
not suitable for plant-scale operations. Most important of all, none of the
procedures can obtain high enantiomeric excess of rivastigmine.
Received June 18, 2008.
Address correspondence to Meng Hu, Pharmacochemistry Division, Shanghai
Institute of Pharmaceutical Industry, Zhongshanbeiyilu Road 1111, Shanghai,
200437, China. E-mail: humengsipi@yahoo.cn
1527

1528
M. Hu, F.-L. Zhang, and M.-H. Xie
We reported a novel one-pot asymmetric reductive amination of
3-methoxyacetophenone with (S)- or (R)-a-methylbenzylamine using
the combination of Ti(OiPr)4=Raney-Ni=H2 in 2007,[8] and the diastereo-
merically pure (S)-1-(3-methoxyphenyl)-N-[(S)-1-phenylethyl]ethanamine
(2) was obtained in 74.2% yield. Here we extend our earlier work and
report a novel method to synthesize rivastigmine starting from the
diastereomerically pure 2 (Scheme 1).
Compound 2 was subjected to N-methylation using formic acid
and formaldehyde, and (S)-1-(3-methoxyphenyl)-N-methyl-N-[(S)-1-
phenylethyl] ethanamine (3) was obtained. Demethylation of the
methoxy function of 3 in HBr proceeded in 76.8% yield. Processing
4 with N-ethyl-N-methyl carbomoyl chloride gave the compound 5.
The regioselective hydrogenolysis of 5 is very important. Bringmann
et al.[9] described that when the bis(a-methylbenzyl)amine derivatives
have an electron-donating group, which increases the electron den-
sity of the aromatic ring, a highly regioselective hydrogenolysis
may be observed. This observation was consistent with the results
described in this communication. The regioselectivity of the cleavage
was extremely high for the oxygenated compound 5, leading to the
desired product 6 in excellent yield. After N-methylation, the free
base of rivastigmine (7) was obtained in 76.4% yield, which was
finally treated with L-tartaric acid to give rivastigmine (1) in
84.8% yield.
The enantiomeric excess of rivastgmine was determined by chiral
high-performance liquid chromatography (HPLC), and the enantiomer
was not found.
Scheme 1. Synthesis of rivastigmine.

Novel Convenient Synthesis of Rivastigmine
1529
In summary, we present a novel and convenient synthesis of
rivastigmine. The total yield is high (49.7%), and the enantiomeric excess
of rivastgmine is very high (100% ee).
EXPERIMENTAL
1H NMR spectra were recorded on a Varian 400-MHz instrument using
CDCl3 as the solvent with tetramethylsilane (TMS) as an internal
standard. Mass spectra were determined on a Shimadzu LCMS-
2010EV (ESI) instrument. Elemental analyses were performed on a
Carlo-Erba 1106 instrument. Melting points were observed in an open
capillary tube and were uncorrected. Optical rotations were determined
with a Perkin-Elmer 341 automatic polarimeter.
HPLC Methods
Reaction progress was monitored by HPLC with purities being determined
by peak area percent. An Agilent 1100 instrument was used for all ana-
lyses. Parameters were TSK C18 column (250 ꢀ 4.6 mm); mobile phase,
0.01 M (NH4)2HPO4=MeOH ¼ 22:78 (v=v); flow, 1.0 ml=min; detection
wavelength, 230 nm; temperature, 40ꢁC, and injection volume, 10 mL.
Enantiomeric excess of rivastigmine was determined under the
following chiral HPLC analysis conditions: Chromtech, Chiral-AGP col-
umn (100 ꢀ 4.6 mm); mobile phase, 0.03 M NaH2PO4 (pH adjusted to 7.4
with phosphoric acid)=MeOH ¼ 85:15 (v=v); flow, 0.8 ml=min; detection
wavelength, 210 nm; temperature, 25ꢁC, and injection volume, 10 mL.
Retention times for rivastigmine (1) were 17.1 min and for (R)-isomer
of 1 were 15.2 min.
Step A: (S)-1-(3-Methoxyphenyl)-N-methyl-N-[(S)-1-phenylethyl]
Ethanamine (3)
To 2 (25.5 g, 0.1 mol), 98% aqueous formic acid solution (18.9 g, 0.4 mol)
followed by 37% aqueous formaldehyde solution (16.68 g, 0.2 mol) were
added. The reaction mixture was heated to reflux for 4 h. After cooling
to room temperature, 200 ml water were added. The solution was neutra-
lized with Na2CO3 and extracted with ethyl acetate (200 ml ꢀ 2). The
combined organic layer was washed with 40 ml water and dried over
anhydrous MgSO4. The solvent was evaporated under reduced pressure

1530
M. Hu, F.-L. Zhang, and M.-H. Xie
to yield 28.94 g of 7 as oil (99.3% HPLC purity), which was used directly
20
in the next step. ½aꢂD ¼ ꢃ75:6ꢁ (c 2.0, EtOH).
1H NMR (CDCl3) d: 1.31 (d, 3H), 1.33 (d, 3H), 2.01 (s, 3H), 3.82
(s þ m, 5H), 6.78 (m, 1H), 6.95 (m, 2H), 7.25 (m, 2H), 7.33 (m, 4H);
13C NMR (CDCl3) d: 159.6, 146.2, 144.1, 128.9, 128.0, 127.8, 126.6,
120.2, 113.6, 111.8, 59.3, 59.2, 55.1, 32.9, 18.6, 18.4; MS (ESI) m=z:
270.2 (M þ 1).
Step B: 3-[(S)-1-[Methyl-[(S)-1-phenylethyl]amino]ethyl] Phenol (4)
Compound 3 from step A was dissolved in 75 ml 48% solution of HBr,
and the resulting solution was refluxed under stirring for 12 h.
Excess hydrobromic acid was evaporated under normal pressure. The
residue was dissolved in 150 ml water and neutralized with Na2CO3.
The solution was extracted with ethyl acetate (275 ml ꢀ 2). The combined
organic layer was washed with 50 ml water and dried over anhydrous
MgSO4. The solvent was evaporated under reduced pressure to yield
crude 4, which was recrystallized from ethyl acetate=petroleum ether to
afford 4 as a white crystalline solid (19.58 g, 76.8%, 99.5% HPLC purity),
20
½aꢂD ¼ ꢃ82:5ꢁ (c 2.0, EtOH), mp 99–100ꢁC.
1H NMR (CDCl3) d: 1.30 (d, 3H), 1.33 (d, 3H), 1.99 (s, 3H), 3.78
(q, 1H), 3.85 (q, 1H), 6.70 (m, 1H), 6.91 (m, 2H), 7.20 (m, 2H), 7.33
(m, 4H); 13C NMR (CDCl3) d: 155.6, 146.6, 144.0, 129.2, 128.1, 127.9,
126.6, 120.3, 114.7, 113.8, 59.3, 59.2, 32.9, 18.6, 18.4; MS (ESI) m=z:
256.1 (M þ 1). anal. calcd. for C17H21NO: C, 79.96; H, 8.29; N, 5.49.
Found: C, 79.83; H, 8.25; N, 5.47.
Step C: N-Ethyl-N-methyl-3-[(S)-1-methyl-[[(S)-1-
phenylethyl]amino]ethyl]phenyl Carbamate (5)
Under a nitrogen atmosphere, a 60% oil dispersion of NaH (3.14 g,
78.4 mmol) was added slowly to 80 ml tetrahydrofuran (THF). A solu-
tion of 4 (10 g, 39.2 mmol) was added dropwise to the NaH suspen-
sion. The mixture was stirred for 30 min, followed by addition of
N-ethyl-N-methyl carbomoyl chloride[10] (9.53 g, 78.4 mmol), which
was dissolved in 20 ml THF. After 4 h, the solvent was evaporated
under reduced pressure, and the residue was partitioned between
120 ml water and 100 ml ethyl acetate. The organic layer was sepa-
rated, and the aqueous fraction was extracted with additional ethyl
acetate (50 ml ꢀ 2). The combined organic layer was washed with

Novel Convenient Synthesis of Rivastigmine
1531
0.1 N NaOH (60 ml) and dried over anhydrous MgSO4. The solvent
was evaporated under reduced pressure to yield 16.03 g of 5 as an
oil (93.8% HPLC purity), which was used directly in the next step.
20
½aꢂD ¼ ꢃ65:9ꢁ (c 1.0, EtOH).
1H NMR (CDCl3) d: 1.31 (d, 3H), 1.33 (d, 3H), 2.0 (s, 3H), 3.0, 3.07
(2 ꢀ s, 3H), 3.46 (br, 2H), 3.84 (m, 2H), 7.05 (m, 1H), 7.17 (s, 1H), 7.27
(m, 7H); 13C NMR (CDCl3) d: 151.6, 146.1, 144.5, 128.7, 128.1, 127.7,
126.5, 124.4, 120.9, 119.9, 59.3, 58.9, 44.0, 32.9, 18.5, 18.2; MS (ESI)
m=z: 341.2 (M þ 1).
Step D: (S)-N-Ethyl-N-methyl-3-[1-(methylamino)ethyl]-phenyl
Carbamate (6)
Compound 5 from step C was dissolved in 200 ml methanol, and hydro-
genolysis was carried out in the presence of 10% Pd=C (0.7 g) under
10 atm at 60ꢁC. After 12 h, the catalyst was filtered out, and the filtrate
was evaporated under reduced pressure to yield 10.92 g 6 as oil (92.7%
20
HPLC purity), which was used directly in the next step. ½aꢂD ¼ ꢃ32:7ꢁ
(c 1.0, EtOH).
1H NMR (CDCl3) d: 1.21 (br, 3H), 1.40 (d, 3H), 2.32 (s, 3H),
2.99, 3.05 (2 ꢀ s, 3H), 3.45 (br, 2H), 3.68 (q, 1H), 7.01 (d, 1H), 7.09
(s, 1H), 7.14 (d, 1H), 7.30 (m, 1H); 13C NMR (CDCl3) d: 151.7,
146.3, 128.9, 123.2, 120.2, 119.8, 59.8, 43.9, 34.1, 23.3; MS (ESI)
m=z: 237.1 (M þ 1).
Step E: (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl
Carbamate (7)
To compound 6 from step D, 98% aqueous formic acid solution (7.36 g,
156 mmol) followed by 37% aqueous formaldehyde solution (6.36 g,
78.4 mmol) were added. The reaction mixture was heated to reflux
for 4 h. After cooling to room temperature, 70 ml water was added.
The solution was neutralized with Na2CO3 and extracted with ethyl
acetate (80 ml ꢀ 3). The combined organic layer was washed with 20 ml
water and dried over anhydrous MgSO4. The solvent was evaporated
under reduced pressure, and the crude product was vacuum distilled.
Compound 7 (7.49 g, 76.4%, 99.2% HPLC purity) as a viscous oil was
20
collected at 130–135ꢁC=35 Pa. ½aꢂD ¼ ꢃ32:1ꢁ (c 5.0, EtOH) (lit.
20
½aꢂD ¼ ꢃ32:1ꢁ[2]).
1H NMR (CDCl3) d: 1.22 (m, 3H), 1.34 (d, 3H), 2.19 (s, 6H), 2.99,
3.04 (2 ꢀ s, 3H), 3.25 (q, 1H), 3.44 (br, 2H), 6.99–7.12 (m, 3H), 7.27

1532
M. Hu, F.-L. Zhang, and M.-H. Xie
(m, 1H); 13C NMR (CDCl3) d: 154.1, 151.3, 145.5, 128.4, 123.7, 120.3,
119.8, 65.2, 43.7, 42.8, 33.7, 19.6, 12.8; MS (ESI) m=z: 251.1 (M þ 1),
283.2 (M þ 1 þ CH3OH).
Step F: Rivastigmine (1)
L-(þ)-Tartaric acid (2.83 g, 18.9 mmol) was added to 7 (4.72 g, 18.9 mmol)
in 30 ml acetone. The mixture was heated to reflux for 1 h and left to cool to
room temperature. It crystallized at 0ꢁC for 12 h. The precipitated white
crystalline product was sucked off, washed with cold acetone, and vacuum
dried at 40ꢁC. Finally, 6.4 g (84.8% yield, 99.8% HPLC purity) of the
desired product were obtained. Mp 123–124ꢁC (lit. 123–125ꢁC[2]),
20
20
½aꢂD ¼ þ6:0ꢁ (c 5.0, EtOH) (lit. ½aꢂD ¼ þ4:7ꢁ[2]).
IR (KBr), cmꢃ1: 3319.2, 2977.9, 2934.2, 2874.8, 1714.5, 1595.9; H
NMR (CDCl3) d: 1.17, 1.23 (2 ꢀ t, 3H), 1.68 (d, 3H), 2.65 (s, 6H), 2.96,
3.06 (2 ꢀ s, 3H), 3.38, 3.46 (2 ꢀ q, 2H), 4.36 (q, 1H), 4.47 (s, 2H), 7.14
(t, 1H),7.21 (s, 1H), 7.28 (t, 1H), 7.39 (t, 1H), 8.42 (br, 4H); 13C NMR
(CDCl3) d 176.2, 154.3, 154.1, 151.8, 135.1, 130.0, 126.1, 123.1, 122.7,
72.5, 65.0, 44.2, 40.3, 34.2, 33.9, 16.5, 13.2, 12.4; MS (ESI) m=z: 251.08
(M þ 1). Anal. calcd. for C18H28N2O8: C, 53.99; H, 7.05; N, 7.0. Found:
C, 53.91; H, 7.08; N, 6.93.
1
ACKNOWLEDGMENTS
We are grateful to the Social Development Foundation of Shanghai
(No. 05DZ19348) for financial support.
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