International Journal of Organic Chemistry, 2011, 1, 26-32
doi:10.4236/ijoc.2011.12005 Published Online June 2011 (http://www.SciRP.org/journal/ijoc)
A Simple and Highly Efficient Enantioselective Synthesis of
(S)-Rivastigmine
Veera R. Arava1*, Laxminarasimhulu Gorentla1, Pramod K. Dubey2
1R&D Laboratory, Suven Life Sciences Ltd., Hyderabad, India
2Department of Chemistry, J. N. T. University, Hyderabad, India
Received April 1, 2011; revised May 17, 2011; accepted May 28, 2011
Abstract
A highly efficient and convenient procedure for the enantioselective synthesis of (S)-Rivastigmine, a cho-
linergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to
Parkinson’s disease, is accomplished by the treatment of versatile, readily accessible (S)-(-)-2-methyl-
2-propanesulfinamide with 3-hydroxyacetophenone. This protocol provides high yield and excellent enan-
tiomeric excess in short step synthesis.
Keywords: Cholinergic Agent, Enantioselective, Highly Efficient, (S)-(-)-2-Methyl-2-Propane Sulfinamide,
(S)-Rivastigmine
1. Introduction
Alzheimer’s disease (AD) is the most common form of
dementia, a severe human health threat with more than
30 million sufferers worldwide [1]. Rivastigmine, (S)-3-
[1-(dimethylamino)ethyl] phenyl ethyl (methyl) car-
bamate 1, is the first USFDA approved drug in the form
of capsules and patches for the treatment of mild to
moderate dementia of the Alzheimer’s type [2-5] and for
mild to moderate dementia related to Parkinson’s disease
[6]. In the year 2006, it has been used in more than 6
million patients worldwide. Rivastigmine works by in-
hibiting both butyrylcholinesterase (BuChE) and acetyl-
cholinesterase (AChE) with the same potency, unlike
donepezil 2 (which selectively inhibits acetylcholines-
terase), mimantine 3 and galanthamine 4. Its pharmacol-
ogical effect is selectively on the central nervous system,
preferentially on the monomeric G1 isoform of AChE
(selectivity for different isoforms of BuChE have not yet
been investigated). The metabolism of rivastigmine is by
the enzyme cholinesterase and do not depend on the
P450 system in the liver, which reduces the risk of inter-
actions with other medications [7]. The other stigmine
products are pyridostigmine 5, physostigmine 6 and neo-
stigmine 7 (Figure 1).
Rivastigmine has one chiral center with amine func-
tionality. Therefore, attention needs to be paid to the
synthesis of the correct enantiomer. (S)-enantiomer ex-
hibits the desired cholinesterase inhibition, which re-
quires the drug in enantiomerically pure form.
The insertion of chiral amine functionality through
N-sulfinylimines is a major breakthrough endeavor due
to the exceptional behavior of the chiral sulfinyl group in
N-sulfinylimines, as an activator, chiral controller and
useful protective group and finally recyclability [8]
makes the sulfinamides extremely versatile chiral re-
agents (Figure 2) [9].
2. Results and Discussion
Our research group has been interested in utilization of
these sulfinamides in industrial perspective for the de-
velopment of facile chemical processes for active phar-
maceutical ingredients (API’s) [10]. Although several
methods for the synthesis of rivastigmine and phenyl-
carbamate derivatives have been reported (Scheme 1),
these methods suffer from limitations. Initial approaches
have been developed via resolution of recemate using
chiral acids [11-14] and transition metal catalysis [15,16].
Recent approaches are based on lipase catalyzed kinetic
resolution [17-19], chemoenzymatic asymmetric synthe-
sis [20] and asymmetric transfer hydrogenation [21].
In order to circumvent these difficulties and provide
access to feasible industrial process, we have devised a
highly efficient enantioselective synthetic route based on
the report that enantiopure tert-butane-sulfinamides take

V. R. ARAVA ET AL.27
ON NH
3
C
CH
3
CH
3
H
CH
3
CH
3
O
(S)-Rivastigmine. 1
N
ON
O
Pyrid osti g mine. 5
N
N
O
H
N
OH
Physostigmine . 6
O N
O
N
Neostigmine. 7
O
O
O
N
Donepezil. 2
H
2
N
Mimantine. 3Galanthamine. 4
OH
O
NCH
3
H
3
CO
Figure 1. Acetylcholinesterase inhibitors.
SNH
2
O
SNH
2
O
(R)-tert-butanesulfinamide (S)-tert-butanesulfinamide. 8
Figure 2. Chiral tert-butanesulfinamides.
ON NH
3
C
CH
3
CH
3
H
CH
3
CH
3
O
(S)-Rivastigmine. 1
HO
O
9
O
NS
O
11
H
3
COH
2
CO
O
12
O
O
N
O
10
Path A
Path B
Path C
Path D
resolution using chiral acids
and transition metal catalysis
lipase catalyzed
kinetic resolution
asymmetric transfer
hydrogenation
chemoenzymatic
asymmetric synthesis
Scheme 1
part in the direct and enantioselective addition to alde-
hydes and ketones [9].
Initially we have synthesized 1 starting from 3-meth-
oxyacetophenone 13 [22] via four step synthesis. The

V. R. ARAVA ET AL. 28
procedure includes, insitu preparation of N-sulfiny-
limine 11 from 13 and (S)-8 using Ti(OEt)4 as Lewis
acid and water scavenger in tetrahydrofuran. Imine on
reduction with sodium borohydride at –48˚C furnished
14. Hydrolysis of the sulfinyl group in 14 with dry
methanolic hydrogen chloride gives the HCl salt 15 in
pure form which on alkali treatment yields the chiral
amine intermediate 16 in 65% yield with > 99% ee. 16
was subjected to N,N-dimethylation using formic acid
and formaldehyde results 17 in 90% isolated yield. De-
methylation of 17 in 48% aq.HBr proceeded in 87%
yield of 18. Finally treatment of 18 with N-ethyl-N-
methyl carbamoyl chloride in the presence of sodium
methoxide furnished the free base of 1 in 93% isolated
yield with an enantiomeric excess of >99% (Scheme 2).
Still not satisfied with this yield and chiral purity, we
set out to investigate the alternate possibilities for opti-
mization of the reaction conditions and found great im-
provement in yield and also achieved the excellent enan-
tiomeric excess of the desired product (100% ee). This
time we chose 9 as starting material and synthesized 1 in
two different routes. One is by condensing 1.25 equiv of
N-ethyl-N-methylcarbamoyl chloride with 9 in the pres-
ence of K2CO3 (2.0 equiv) as base and ethyl acetate as
solvent medium resulted 10 in 98.5% yield. 10 on con-
densation with 8 (S-isomer) furnished the imine interme-
diate 19 insitu, which was reduced with sodium boro-
hydride at –48˚C to get 20. Hydrolysis of the sulfinyl
group in 20 and alkali treatment at room temperature
afforded the desired chiral amine 21 in 81% yield
(Scheme 3). N,N-dimethylation of the amine with 98%
formic acid and 35% formaldehyde solution liberates
free base of 1 in 95% yield with 100% ee (Scheme 4).
And the other route proceeded by the treatment of 9 with
+
S
O
NH
2
8 (S)-tbs
Ti(OEt)
4
NaBH
4
-48°C
H
3
CO
O
H
3
CO NS
O
H
3
CO
H
NS
O
H
3
CO NH
2.
HCl
11 14
15
THF
reflux
13
ON NH
3
C
CH
3
CH
3
H
CH
3
CH
3
O
HCHO
HCOOH
C
O
Cl N
NaOMe
H
3
CO NH
2
H
3
CO N
CH
3
CH
3
HO N
CH
3
CH
3
1
17
18
16 base
K
2
CO
3
HCl
MeOH
–
48˚C
Aq.HBr
65%
90%
87%
93%
Scheme 2
C
O
Cl N
HO
O
9
ONH
2
NH
3
C
CH
3
CH
3
H
O
21
NaBH
4
-48°C
HO N
S
O
HO
H
N
S
O
22 23 K
2
CO
3
O
H
NS
O
O
N
20
OO
O
NON
O
N
SOOHN
O
N
SO
Route 1
Route 2
10
19 20
O
98.5% 81%
76%
95%
Scheme 3. Current routes of asymmetric synthesis of 21 from 9.
–
48˚C
19 20
10
O
N
O

V. R. ARAVA ET AL.29
ONH
2
NH
3
C
CH
3
CH
3
H
O
21
ON NH
3
C
CH
3
CH
3
H
CH
3
CH
3
O
1
HCHO
HCOOH
Scheme 4
8 (S-isomer) first, then reduction of the N-sulfinylimine
22 followed by amido-ester formation with N-ethyl-N-
methyl carbamoyl chloride to afford 20 in 76% yield.
Hydrolysis of sulfinyl group with dry methanolic hydro-
gen chloride and alkali treatment gives 21 base with
chiral purity > 94% in 95% yield (Scheme 3). Finally
N,N-dimethylation of amine 21 with formic acid and
35% formaldehyde solution furnished 1 (free base) with
98% chiral purity in 95% yield (Scheme 4). The chiral
purity is then improved to 100% by tartarate salt prepa-
ration with L-(+)-tartaric acid.
3. Experimental Section
Experiments are conducted under nitrogen atmosphere
unless stated otherwise. All solvents and reagents are
reagent grade pure and used without further purification.
All melting points are determined on Polmon MP_96
melting point apparatus. 1H & 13C NMR spectra are re-
corded using a Bruker 400 MHz spectrometer (400 &
100 MHz respectively) with TMS as internal standard.
Mass spectra are recorded on a Perkin-Elmer mass spec-
trometer operating at an ionization potential of 70 eV. IR
spectra are recorded on Perkin Elmer spectrophotometer
as KBr pellets or neat. Analytical TLC is conducted on
E-Merck 60F254 aluminum-packed silicagel plates (0.2
mm). Developed plates are visualized under UV light or
Iodine chamber. Chiral HPLC spectra are recorded on
Waters alliance 2695 with 2487 U. V. detector.
Typical procedure for the preparation of (S)-Rivasti-
gmine (1)
Route A.
Synthesis of 3-acetylphenyl ethyl (methyl) car-
bamate (10): a mixture of 9 (50.0 g, 0.367 mol), K2CO3
(101.5 g, 0.734 mol) and N-ethyl-N-methyl carbamoyl
chloride (56.0 g, 0.46 mol) in ethyl acetate (500 ml) is
refluxed for 4 hours. (Completion of reaction is moni-
tored by TLC). The reaction mixture is cooled to room
temperature and washed with water (3 × 250 mL), then
dried over anhydrous Na2SO4, filtered and evaporated to
get pale yellow oil of 10. Wt 80.0 g, 98.5% yield; HPLC
Purity: 97%; IR (Neat, νmax, cm–1): 1724 (C = O), 1686
(C = O), 2974 (aliphatic CH); 1H-NMR (400MHz,
CDCl3): δH 7.74 (d, 1H, J = 7.6 Hz, ArH), 7.65 (s, 1H,
ArH), 7.40 (t, 1H, J = 7.9 Hz, ArH), 7.30 (d, 1H, J = 7.5
Hz, ArH), 3.42 (q, 1H, J = 7.0 Hz, rotamer1 CH2), 3.37
(q, 1H, J = 7.0 Hz, rotamer2 CH2), 3.04 (s, 1.5H, ro-
tamer1 CH3), 2.95 (s, 1.5H, rotamer2 CH3), 2.55 (s, 3H,
CH3), 1.21 (t, 1.5H, J = 7.0 Hz, rotamer1 CH3), 1.15 (t,
1.5H, J = 7.0 Hz, rotamer2 CH3); 13C NMR (100MHz,
CDCl3): δC 197.08 (1C, C=O), 153.99 (d, J = 15.0 Hz,
1C, C=O), 151.64 (Caryl), 138.19 (Caryl), 129.26 (Caryl),
126.57 (Caryl), 124.93 (Caryl), 121.47 (Caryl), 43.98 (1C,
CH2 of carbamoyl), 34.14 (rotamer1 Mecarbamoyl), 33.70
(rotamer2 Mecarbamoyl), 26.56 (1C, CH3), 13.10 (rotamer1
Mecarbamoyl), 12.29 (rotamer2 Mecarbamoyl); ESI-MS m/z
(%): 222.0 (M+, 100), 223.1 (M+ + H, 20).
Synthesis of (S)-Ethyl-methyl-carbamic acid
3-(1-aminoethyl) phenyl ester (21): compound 10 (80.0
g, 0.36 mol) is refluxed with (S)-tert-butanesul-
finamide 8 (48.2 g, 0.39 mol), titanium tetra ethoxide
(164.26 g, 0.72 mol) in tetrahydrofuran (800.0 ml) for 30
hours. Cool to ambient temperature and further to –48 to
–52˚C. Add NaBH4 (20.5 g, 0.54 mol) in 5 portions. Stir
for 3 hours to complete the reduction of imine intermedi-
ate 19. Gradually warm to –5˚C, add methanol (80 ml)
drop wise at –5˚C to 0˚C and stir for 30 minutes. Add
ethyl acetate (400 ml) and water (500 ml). Stir for 30
minutes to warm to rt and filter off the salts. Separate the
organic layer and aqueous layer is washed with ethyl
acetate (200 ml). Combined organic layers are washed
successively with water (2 × 250 ml) and brine solution
(200 ml). The organic layer is dried over anhydrous
Na2SO4 and evaporated under reduced pressure to get
yellow oil of crude 20, which is hydrolyzed with 13%
methanolic HCl (126 ml) and then alkali treatment with
aq.NaOH at rt, extraction into ethyl acetate and concen-
tration of the solvent afford pale yellow oil. Wt 65.0 g,
yield 81%; [α]D
20 – 16.5˚ (c 1.0, CHCl3); Chiral HPLC
Purity: 99.9%, Column: chiral cel OD-H 250 × 4.6
(SRC-583), mobile phase A: n-hexane:IPA:DEA (90:10:
0.1), Iso: 100%, concentration: 10 mg/10mL, diluent:
ethanol, run time: 20 min, temperature: 25˚C, flow rate:
1 mL/min, UV: 225nm, retention time: (S)-isomer: 12.8
min and (R)-isomer: 11.66 min; HPLC Purity: 98.8%; IR
(Neat, νmax, cm–1): 1716 (C=O), 2974 (aliphatic CH),
3365 (NH2); 1H-NMR (400MHz, CDCl3): δH 7.31 (t, 1H,
J = 7.8 Hz, ArH), 7.27 (s, 1H, ArH), 7.16 (d, 1H, J = 7.7
Hz, ArH), 6.99 (d, 1H, J = 7.7 Hz, ArH), 4.12 (q, 1H, J =
3.4 Hz, CH), 3.46 (q, 1H, J = 7.2 Hz, rotamer1 CH2),

V. R. ARAVA ET AL. 30
3.41 (q, 1H, J = 7.1 Hz, rotamer2 CH2), 3.07 (s, 1.5H,
rotamer1 CH3), 2.99 (s, 1.5H, rotamer2 CH3), 1.61 (s, 2H,
NH2), 1.38 (d, 3H, J = 6.6 Hz, CH3), 1.24 (t, 1.5H, J =
6.1 Hz, rotamer1 CH3), 1.19 (t, 1.5H, J = 6.0 Hz, ro-
tamer2 CH3); 13C-NMR (100MHz, CDCl3): δC 154.45 (d,
J = 18.0 Hz, 1C, C=O), 151.57 (Caryl), 149.22 (Caryl),
129.10 (Caryl), 122.39 (Caryl), 120.02 (Caryl), 118.95 (Caryl),
50.95 (1C, CH), 43.94 (1C, CH2 of carbamoyl), 34.11
(rotamer1 Mecarbamoyl), 33.68 (rotamer2 Mecarbamoyl), 25.40
(1C, CH3), 13.10 (rotamer1 Mecarbamoyl), 12.35 (rotamer2
Mecarbamoyl); ESI-MS m/z (%): 206.0 (M-NH2, 100),
207.1 (M+ – NH2, 20), 223.1 (M+ + H, 15).
The intermediate stages have also isolated for confir-
mation by analytical and spectral data.
2-Methyl propane-2-sulfinic acid [1-(3-methoxy-
phenyl)ethylidene]amide (19): yellow oil, yield 87%;
[α]D
20 – 0.5˚ (c 1.0, CHCl3); HPLC Purity: 96.8%; IR
(Neat, νmax, cm–1): 1089 (S-O), 1723 (C=O), 1575 (C=N),
2975 (aliphatic CH); 1H NMR (400MHz, CDCl3): δH
7.71 (d, 1H, J = 7.5 Hz, ArH), 7.59 (s, 1H, ArH), 7.40 (t,
1H, J = 7.9 Hz , ArH), 7.25 (d, 1H, J = 8.0 Hz, ArH),
3.48 (q, 1H, J = 7.0 Hz, rotamer1 CH2), 3.41 (q, 1H, J =
7.0 Hz, rotamer2 CH2), 3.08 (s, 1.5H, rotamer1 CH3),
2.99 (s, 1.5H, rotamer2 CH3), 2.74 (s, 3H, CH3), 1.30 (s,
9H, C(CH3)3), 1.24 (t, 1.5H, J = 7.0 Hz, rotamer1 CH3),
1.19 (t, 1.5H, J = 7.0 Hz, rotamer2 CH3); 13C NMR
(100MHz, CDCl3): δC 175.27 (1C, C=N), 154.12 (d, J =
18.0 Hz, 1C, C=O), 151.52 (Caryl), 139.93 (Caryl), 129.11
(Caryl), 125.12 (Caryl), 123.96 (Caryl), 120.53 (Caryl), 57.55
(1C, Ct-butyl), 44.02 (1C, CH2 of carbamoyl), 34.19 (ro-
tamer1 Mecarbamoyl), 33.76 (rotamer2 Mecarbamoyl), 22.46
(3C, Ct-butyl), 19.77 (1C, Me), 13.14 (rotamer1 Mecarbamoyl),
12.34 (rotamer2 Mecarbamoyl); ESI-MS m/z (%): 346.9 (M+
+ Na, 100), 325.0 (M + H, 45), 306.9 (20), 291 (65),
250.9 (47), 243.0 (45).
2-Methyl propane-2-sulfinic acid [1-(3-methoxy-
phenyl) ethyl]amide (20): yellow oil, yield 98%; [α]D
20
+ 26.0˚ (c 1.0, CHCl3); Chiral HPLC Purity: 99.95%,
Column: chiral cel AD-H 250 × 4.6 mm/5 µm (SRC-
581), mobile phase A: n-hexane:IPA:TFA (90:10:0.1),
Iso: 100%, concentration: 10 mg/10 mL, diluent: ethanol,
run time: 35 min, temperature: 25˚C, flow rate: 0.8
mL/min, UV: 215 nm, retention time: (S)-isomer: 12.78
min and (R)-isomer: 7.72 min; HPLC Purity: 92%; IR
(Neat, νmax, cm–1): 1055 (S-O), 1718 (C = O), 2978 (ali-
phatic CH), 3234 (NH); 1H NMR (400MHz, CDCl3): δH
7.32 (t, 1H, J = 7.8 Hz, ArH), 7.18 (d, 1H, J = 7.6 Hz ,
ArH), 7.08 (s, 1H, ArH), 7.04 (d, 1H, J = 7.0 Hz, ArH),
4.54 (q, 1H, J = 3.7 Hz, CH), 3.51 (s, 1H, NH), 3.47 (q,
1H, J = 7.0 Hz, rotamer1 CH2), 3.41 (q, 1H, J = 7.1 Hz,
rotamer2 CH2), 3.06 (s, 1.5H, rotamer1 CH3), 2.98 (s,
1.5H, rotamer2 CH3), 1.50 (d, 3H, J = 6.5 Hz, CH3), 1.25
(t, 1.5H, J = 7.0 Hz, rotamer1 CH3), 1.20 (s, 9H,
C(CH3)3), 1.19 (t, 1.5H, J = 7.0 Hz, rotamer2 CH3); 13C
NMR (100MHz, CDCl3): δC 154.20 (d, J = 18.0 Hz, 1C,
C=O), 151.59 (Caryl), 145.27 (Caryl), 129.39 (Caryl),
123.28 (Caryl), 121.12 (Caryl), 119.85 (Caryl), 55.33 (1C,
Ct-butyl), 53.51 (1C, CH), 43.92 (1C, CH2 of carbamoyl),
34.08 (rotamer1 Mecarbamoyl), 33.68 (rotamer2 Mecarbamoyl),
29.14 (1C, Me), 22.48 (3C, Ct-butyl), 13.09 (rotamer1 Me-
carbamoyl), 12.32 (rotamer2 Mecarbamoyl); ESI-MS m/z (%):
348.9 (M+ + Na, 90), 327.0 (M + H, 100), 293.0 (23),
252.9 (54), 245.0 (26), 194.0 (80).
Route B.
Synthesis of 2-Methyl propane-2-sulfinic acid [1-(3-
hydroxyphenyl)ethyl]amide (23):
3-Hydroxyacetophenone (10.0 g, 0.066 mol) is re-
fluxed with (S)-8 (8.07 g, 0.066 mol), titanium tetra eth-
oxide (30.4 g, 0.133 mol) in THF (100 ml) for 30 hr.
Cool to ambient temperature and further to –48 to –52˚C
and added NaBH4 (3.8 g, 0.099 mol) in 4 portions. Stir
for 3 hours to complete the reduction of imine intermedi-
ate 22. Gradually warm to –5˚C and added methanol (10
ml) drop wise at –5˚C to 0˚C. Stir for 30 minutes, added
ethyl acetate (50 ml) and water (100 ml). Stir for 30
minutes to warm to rt and filtered off the salts. Separate
organic layer and aqueous layer is washed with ethyl
acetate (50 ml). Combined organic layers are washed
successively with water (2 × 50 mL) and brine solution
(30 ml). The organic layer is dried over anhydrous
Na2SO4 and evaporated to afford pale yellow solid of 23.
Wt 13.7 g; yield 77.6%; mp 140˚C - 144˚C; [α]D
23 +
25.5˚ (c 1.0, MeOH); Chiral HPLC: 94.76%, Column:
chiral pak AD-H 0.46cm × 25cm (SRC-581), mobile
phase A: n-hexane:IPA:DEA (90:10:0.1), Iso: 100%,
concentration: 50 mg/10mL, diluent: ethanol, run time:
45 min, temperature: 25˚C, flow rate: 1 mL/min, UV:
230nm, retention time: (S)-isomer: 24.87 min and
(R)-isomer: 8.13 min; IR (KBr, cm–1): 3277 (NH), 3086
(OH), 2972 (aliphatic CH), 1017 (S-O); 1H NMR
(400MHz, CDCl3): δH 8.2 (br s, 1H, OH), 7.15 (t, 1H, J
= 8.0 Hz, ArH), 6.81 (d, 1H, J = 7.7 Hz, ArH), 6.77 (s,
1H, ArH), 6.76 (d, 1H, J = 7.5 Hz, ArH), δ 4.41 (q, 1H, J
= 3.5 Hz, CH), δ 3.64 (s, 1H, NH), 1.46 (d, 3H, J = 6.5
Hz, CH3), 1.26 (s, 9H, C(CH3)3); 13C NMR (100MHz,
DMSO-d6): δC 157.57 (1C, Caryl), 147.13 (1C, Caryl),
129.41 (1C, Caryl), 117.50 (1C, Caryl), 114.07 (1C, Caryl),
113.77 (1C, Caryl), 55.44 (1C, Ct-butyl), 54.47 (1C, CH),
24.50 (1C, CH3), 22.97 (3C, Ct-butyl); ESI-MS m/z (%):
242.4 (M + H, 100), 168.3 (50), 125.1 (10).
The intermediate stages have also isolated for confir-
mation by analytical and spectral data.
2-Methyl propane-2-sulfinic acid [1-(3-hydroxy-
phenyl)ethylidene]amide (22): yellow crystals, yield
77.6%; mp 137˚C - 142˚C; [α]23
D + 3.0˚ (c 1.0, MeOH);
Chiral HPLC purity: 99.98%, Column: chiral pak AD-H

V. R. ARAVA ET AL.31
0.46cm × 25cm (SRC-581), mobile phase A: n-hexane:
IPA:DEA (90:10:0.1), Iso: 100%, concentration: 5
mg/10mL, diluent: ethanol, run time: 35 min, temperature:
25˚C, flow rate: 1 mL/min, UV: 254nm, retention time:
(S)-isomer: 16.16 min and (R)-isomer: 12.55 min; IR (KBr,
cm–1): 3180 (OH), 2987 (aliphatic CH), 1597 (C=N), 1028
(S-O); 1H NMR (400MHz, CDCl3): δH 7.72 (br s, 1H,
OH), 7.43 (s, 1H, ArH), 7.32 (d, 1H, J = 7.4 Hz, ArH),
7.23 (t, 1H, J = 7.9 Hz, ArH), 7.01 (d, 1H, J = 7.9 Hz,
ArH), 2.68 (s, 3H, CH3), 1.32 (s, 9H, C(CH3)3); 13C NMR
(100MHz, DMSO-d6): δC 176.82 (1C, C=N), 157.78 (1C,
Caryl), 140.01 (1C, Caryl), 129.98 (1C, Caryl), 119.34 (1C,
Caryl), 118.52 (1C, Caryl), 113.92 (1C, Caryl), 57.08 (1C,
Ct-butyl), 22.37 (3C, Ct-butyl), 20.03 (1C, CH3); ESI-MS m/z
(%): 240.3 (M + H, 65), 184.2 (100), 166.1 (82).
Synthesis of (S)-Ethyl methyl carbamic acid 3-(1-
aminoethyl)phenyl ester (21): a mixture of 23 (13.0 g,
0.053 mol), K2CO3 (14.9 g, 0.107 mol) and N-ethyl-
N-methyl carbamoyl chloride (8.18 g, 0.067 mol) in ethyl
acetate (130 ml) is refluxed for 4 hours. Cool to room
temperature and washed with water (3 × 130 mL), dried
over anhydrous Na2SO4, filtered and evaporated under
reduced pressure to get pale yellow oil of 20 (17.37 g,
99% yield), which is hydrolyzed with 13% methanolic
HCl (18 ml) and then alkali treatment with aq.NaOH at rt,
extraction into ethyl acetate and evaporation of the sol-
vent under reduced pressure afford pale yellow oil of 21.
Wt 11.25 g, yield 95%.
Synthesis of (S)-Rivastig mine (1): the pale yellow oil
21 (65.0 g, 0.43 mol) is dissolved in formic acid (198.0 g,
4.3 mol), formaldehyde (44.0 g, 3.4 mol (35% solution in
water) and water (650 ml). Heated to reflux temperature
(95˚C - 100˚C) and stirred for 5 hr. Cool to ambient
temperature; wash with ethyl acetate (2 × 130 ml) to re-
move the impurities. Aqueous layer is separated, ad-
justed pH to 10 with 20% aq. NaOH solution (758 ml)
and extracted with ethyl acetate (2 × 325 ml). The com-
bined organic layers are washed with brine solution (100
ml), dried over anhydrous sodium sulfate and evaporated
under reduced pressure at 45˚C - 50˚C to get pale yellow
oil. Wt 78.4 g; yield 95%; [α]D
20 – 35.2˚ (c 1.0, CHCl3)
(lit [6]: [α]D
20 – 33.9˚ (c 1.0, CHCl3); Chiral HPLC Pu-
rity 100%, Column: chiral pak OD-H 250 × 4.6 mm,
mobile phase A: n-hexane:IPA:TFA (80:20:0.1), Iso:
100%, concentration: 10 mg/25mL, diluent: ethanol, run
time: 25 minutes, temperature: 25˚C, flow rate: 0.8
mL/min, UV: 215 nm, retention time: (S)-isomer: 14.41
min and (R)-isomer: 9.54 min;; IR (Neat, νmax, cm–1):
2975 (aliphatic CH), 1725 (C=O); 1H NMR (400MHz,
CDCl3): δH 7.28 (t, 1H, J = 7.8 Hz, ArH), 7.10 (d, 1H, J
= 7.8 Hz, ArH), 7.05 (s, 1H, ArH), 7.00 (d, 1H, J = 7.8
Hz, ArH), 3.44 (q, 1H, J = 7.5 Hz, CH2 rotamer 1), 3.41
(q, 1H, J = 7.5 Hz, CH2 rotamer 2), 3.23 (q, 1H, J = 6.6
Hz, –CH), 3.05 (s, 1.5H, CH3 rotamer 1), 2.97 (s, 1.5H,
CH3 rotamer 2), 2.19 (s, 6H, N(CH3)2), 1.34 (d, 3H, J =
6.7 Hz, CH3), 1.23 (t, 1.5H, J = 7.2 Hz, CH3 rotamer 1),
1.17 (t, 1.5H, J = 7.2 Hz, CH3 rotamer 2) ; 13C NMR
(100 MHz, CDCl3): δC 154.41 (d, J = 18.0 Hz, 1C, C =
O), 151.41 (Caryl), 145.63 (Caryl), 128.77 (Caryl), 124.11
(Caryl), 120.60 (Caryl), 120.14 (Caryl), 65.53 (1C, CH),
43.92 (1C, CH2 of carbamoyl), 43.11, 34.09 (rotamer1
Mecarbamoyl), 33.67 (rotamer2 Mecarbamoyl), 19.98 (1C, Me),
13.12 (rotamer1 Mecarbamoyl), 12.37 (rotamer2 Mecarbamoyl);
ESI-MS m/z (%): 251.2 (M + H, 100), 206.2 (60).
Preparation of (S)-(+)-rivastigmine hydrogentar-
tarate (1): (S)-(-)-rivastigmine 1 (4.5 g) and L-(+)-
tartaric acid (2.7 g) are dissolved in anhydrous ethanol
(12.5 mL) at 60˚C. Ethyl acetate (63 mL) is added at the
same temperature and stirred for 10 minutes. Cool the
solution to room temperature and to crystallize at +5˚C
for a period of 12 hours. The precipitated solid is col-
lected through filtration and washed the cake with ethyl
acetate (10 mL). Dry the solid at 50˚C under vacuum to
afford 6.7 g of the desired product. Yield 92%; [α]D
20 +
4.6˚ (c 5.0, ethanol); mp 117˚C - 120˚C; Chiral HPLC
Purity: 100% ee.
4. Conclusions
In summary, a high yielding stereoselective and short
synthesis of (S)-Rivastigmine is described in two ways
with an overall isolated yield of 76% and 70% respec-
tively via 3 step procedure starting from 3-hydroxyaceto-
phenone, a commercially available intermediate. [23]
5. Acknowledgements
We greatly acknowledge our thanks to Mr. Venkat Jasti,
CEO for his excellent support, Mr. K. R. S. Sharma for
Chiral HPLC method development and the analytical
group of SUVEN for providing spectral data.
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