Chemoenzymatic synthesis of rivastigmine via dynamic kinetic resolution as a key step

Article abstract of DOI:10.1021/jo9027374

A practical and efficient procedure for the synthesis of rivastigmine was developed. This procedure includes dynamic kinetic resolution using a polymer-bound ruthenium complex and a lipase in combination as a key step. Enantiopure (-)-rivastigmine was obtained from commercially available 3′-hydroxyacetophenone via five steps in overall 57% yield.

Full text of DOI:10.1021/jo9027374

pubs.acs.org/joc
1987.5 Later, asymmetric syntheses of rivastigmine were
Chemoenzymatic Synthesis of Rivastigmine via
Dynamic Kinetic Resolution as a Key Step
reported.6 Herein, we wish to report an alternative asym-
metric synthetic procedure for rivastigmine, which includes
the dynamic kinetic resolution of a secondary alcohol inter-
mediate as a key step.
Kiwon Han, Cheolwoo Kim, Jaiwook Park,* and
Mahn-Joo Kim*
Dynamic kinetic resolution (DKR), in which in situ metal-
catalyzed racemization is coupled with enzymatic resolution,
is an attractive strategy to obtain enantiomerically enriched
products from racemic substrates with high yields and
excellent enantiomeric excesses, both approaching 100%.7
Several groups including ours have developed racemization
catalysts that are compatible with the enzymatic systems
for the DKR of secondary alcohols.8 However, most of them
are soluble in the reaction medium so that recovering them
is not easy after the reaction is complete. Recently, we
reported the use of a polymer-bound racemization catalyst
(2) in the DKR of alcohols (Figure 1).9,10 In this work, we
used its modified analogue 3 which was more practical to
prepare.11
Department of Chemistry and Bionanotechnology Center,
Pohang University of Science and Technology,
San-31 Hyojadong, Pohang 790-784, Korea
mjkim@postech.ac.kr
Received December 31, 2009
The polymer-bound racemization catalyst 3 was prepared
by heating a mixture of polystyrene-attached benzoyl chlor-
ide (4) and [Ph4(η4-C4CO)]Ru(CO)3 (5) in toluene for 1 d
(Scheme 1). Ruthenium content in 3was estimated to 4.25 wt %
by ICP analysis. The activity and reusability of 3 were examined
in the racemization of optically active 1-phenylethanol ((S)-6,
>99% ee) (Table 1). The racemization of (S)-6 in the presence
^ ꢀ
(6) (a) Boezio, A. A.; Pytkowicz, J.; Cote, A.; Charette, A. B. J. Am. Chem.
ꢀ
Soc. 2003, 125, 14260–14261. (b) Mangas-Sanchez, J.; Rodrıguez-Mata,
´
ꢀ
M.; Busto, E.; Gotor-Fernandez, V.; Gotor, V. J. Org. Chem. 2009, 74, 5304–
5310. (c) Hu, M.; Zhang, F.-L.; Xie, M.-H. Synth. Commun. 2009, 39, 1527–
1533.
A practical and efficient procedure for the synthesis of
rivastigmine was developed. This procedure includes
dynamic kinetic resolution using a polymer-bound ruthe-
nium complex and a lipase in combination as a key step.
Enantiopure (-)-rivastigmine was obtained from com-
mercially available 30-hydroxyacetophenone via five steps
in overall 57% yield.
(7) (a) Kim, M.-J.; Ahn, Y.; Park, J. Curr. Opin. Biotechnol. 2002, 13, 578–
€
587. (b) Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247–3262.
(c) Kim, M.-J.; Ahn, Y.; Park, J. Bull. Korean Chem. Soc. 2005, 26, 515–
522. (d) Kim, M.-J.; Park, J.; Ahn, Y. In Biocatalysis in the Pharmaceutical and
Biotechnology Industries; Patel, R. N., Ed.; CRC Press: Boca Raton, 2007; pp
€
249-272. (e) Martín-Matute, B.; Backvall, J.-E. Curr. Opin. Chem. Biol. 2007,
11, 226–232.
(8) (a) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.; Park,
J. Angew. Chem., Int. Ed. 2002, 41, 2373–2376. (b) Kim, M.-J.; Chung, Y. I.;
Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J. J. Am. Chem. Soc. 2003, 125,
ꢀ €
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n-Matute, B.; Edin, M.; Bogar, K.; Backvall, J.-E.
11494–11495. (c) Martı
Angew. Chem., Int. Ed. 2004, 43, 6535–6539. (d) Kim, M.-J.; Kim, H. M.;
Kim, D. H.; Park, J. Green Chem. 2004, 6, 471–474. (e) Martın-Matute, B.;
´
ꢀ
€
Rivastigmine (1) is an acetylcholinesterase inhibitor of the
carbamate type, which is selective in the brain region and has
a long duration of action.1 It improves cognition, participa-
tion in daily activities, and global evaluation of patients with
mild to moderate Alzheimer’s disease.2 In addition, it is
supposed to be effective in the treatment of dementia caused
by Parkinson’s disease3 and Lewy body.4 Now, its tartrate
salt is marketed under brand name Exelon. Rivastigmine was
first synthesized by resolution of the racemic rivastigmine
using (þ)-di-O,O0-p-toluoyl tartaric acid monohydrate in
Edin, M.; Bogar, K.; Kaynak, F. B.; Backvall, J.-E. J. Am. Chem. Soc. 2005,
127, 8817–8825. (f ) Hilker, I.; Rabani, G.; Verzijl, G. K. M.; Palmans,
A. R. A.; Heise, A. Angew. Chem., Int. Ed. 2006, 45, 2130–2132. (g) Akai, S.;
Tanimoto, K.; Kanao, Y.; Egi, M.; Yanamoto, T.; Kita, Y. Angew. Chem.,
Int. Ed. 2006, 45, 2592–2595. (h) Eckert, M.; Brethon, A.; Li, Y. X.; Sheldon,
R. A.; Arends, I. W. C. E. Adv. Synth. Catal. 2007, 349, 2603–2609. (i) Ko
S.-B.; Baburaj, B.; Kim, M.-J.; Park, J. J. Org. Chem. 2007, 72, 6860–6864.
( j) Kim, M.-J.; Lee, H. K.; Park, J. Bull. Korean Chem. Soc. 2007, 28, 2096–
ꢀ
ꢀ
€
2098. (k) Bogar, K.; Vidal, P. H.; Leon, A. R. A.; Backvall, J.-E. Org. Lett.
2007, 9, 3401–3404. (l) Kim, M.-J.; Choi, Y. K.; Kim, S.; Kim, D.; Han, K.;
Ko, S.-B.; Park, J. Org. Lett. 2008, 10, 1295–1298. (m) Haak, R. M.; Berthiol,
F.; Jerphagnon, T.; Gayet, A. J. A.; Tarabiono, C.; Postema, C. P; Ritleng,
V.; Pfeffer, M.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G.
J. Am. Chem. Soc. 2008, 130, 13508–13509.
(9) Kim, N.; Ko, S.-B.; Kwon, M. S.; Kim, M.-J.; Park, J. Org. Lett. 2005,
7, 4523–4526.
(1) Polinsky, R. J. Clin. Ther. 1998, 20, 634–647.
(2) Rosler, M.; Anand, R.; Cicin-Sain, A.; Gauthier, S.; Agid, Y.;
Dal-Bianco, P.; Stahelin, H. B.; Hartman, R.; Gharabawi, M. Brit. Med. J.
1999, 318, 633–638.
(3) Reading, P. J.; Luce, A. K.; McKeith, I. G. Movement Disord. 2001,
16, 1171–1174.
(4) McKeith, I.; Del Ser, T.; Spano, P.; Emre, M.; Wesnes, K.; Anand, R.;
Cicin-Sain, A.; Ferrara, R.; Spiegel, R. Lancet 2000, 356, 2031–2036.
(5) Enz, A. GB 2203040A, 1987.
(10) For the DKRs of secondary alcohols using other heterogeneous
racemization catalysts, see: (a) Wuyts, S.; De Temmerman, K.; De Vos,
D. E.; Jacobs, P. A. Chem.;Eur. J. 2005, 11, 386–397. (b) Wuyts,S.;Wahlen, J.;
Jacobs, P. A.; De Vos, D. E. Green Chem. 2007, 9, 1104–1108. (c) Zhu,
Y. Z.; Fow, K. L.; Chuah, G. K.; Jaenicke, S. Chem.;Eur. J. 2007, 13, 541–547.
(11) The synthesis of 2 required a long reaction time (5 days), while the
synthesis of 3 was complete within 1 day because the polymer-attached
benzoyl chloride (4) was more reactive than its benzyl chloride counterpart.
DOI: 10.1021/jo9027374
r
Published on Web 03/26/2010
J. Org. Chem. 2010, 75, 3105–3108 3105
2010 American Chemical Society

Han et al.
JOCNote
TABLE 2. Recycling of Catalysts in the DKR of 6a
run
conv (%)b
eepc (%)
1
2
3
>97
>97
96
61
>97
>99
>99
>99
>99
>99
4
5d
aReaction conditions: 6 (0.50 mmol), 3 (4 mol % Ru), Novozym-435
(10 mg/mmol), isopropenyl acetate (1.5 equiv), K2CO3 (1 equiv), toluene
(0.5 mL), rt, 1 d. bMeasured by 1H NMR. cMeasured by HPLC with a
chiral column. d1 equiv of fresh K2CO3 was added.
FIGURE 1. Polymer-supported ruthenium catalysts.
TABLE 1. Recycling of 3 in the Racemization of (S)-6a
SCHEME 3. Asymmetric Synthesis of Rivastigminea
run
reaction time (h)
% ee of 6b
1
2
3
4
5
8
8
8
8
8
2
5
1
0
2
aReaction condition: (S)-6 (0.15 mmol), 3 (4 mol % Ru), K2CO3
(1 equiv), toluene (0.5 mL), rt. bDetermined by HPLC.
SCHEME 1. Preparation of Polymer-Bound Ruthenium
Complex 3
SCHEME 2. DKR of 6
aReaction conditions: (i) Et(Me)NCOCl (2 equiv), NaH (2 equiv), CH2-
Cl2 (0.3 M), rt, 4 h, 85%; (ii) NaBH4 (1 equiv), MeOH (1 M), 0 °C,
10 min, 99%; (iii) 3 (4 mol % Ru), Novozym-435 (30 mg/mmol),
isopropenyl acetate (1.5 equiv), K2CO3 (1 equiv), toluene (0.3 M), rt, 1 d,
96%, 99% ee; (iv) K2CO3 (2equiv), MeOH/H2O (v/v = 4/1, 0.3 M), rt, 2 h,
92%, 99% ee; (v) MeSO2Cl (1.3 equiv), Et3N (3 equiv), CH2Cl2 (0.2
M), 0 °C, 30 min, and then Me2NH in THF (4 equiv), rt, 2 d, 77%.
of 4 mol % of 3 and 1 equiv of K2CO3 at room temperature was
complete within 8 h. The racemization activity remains unal-
tered even after five repeated use of 3 and K2CO3.
clearly indicate that the catalysts (3 and lipase) are recyclable
several times without losing their activities.12
The application of DKR using 3 in the synthesis of
rivastigmine is described in Scheme 3. Alcohol intermediate
10 for DKR was prepared in two steps from commercially
available starting material 8. The reaction of 8 with N-ethyl-
N-methylcarbamoyl chloride afforded 9 (85% yield) which
in turn was reduced with NaBH4 to give 10 quantitatively.13
Before the DKR of 10, its enzymatic kinetic resolution
(EKR) was examined to see if it is resolved with a satisfactory
enantioselectivity. The EKR of 10 (0.3 mmol) was carried
out in the presence of isopropenyl acetate as acyl donor with
Novozym-435 (30 mg/mmol of substrate) in toluene at room
temperature. The reaction proceeded to 50% completion in
We then explored the DKR of racemic 6 with recycling 3
and a commercial lipase (Candida antarctica lipase B im-
mobilized on polyacrylic resin; trade name, Novozym-435).
The first run for the DKR of 6 was carried out with a solution
containing isopropenyl acetate (1.5 equiv) as acyl donor,
3 (4 mol %), Novozym-435 (10 mg/mmol of substrate), and
potassium carbonate (1 equiv) in toluene at room tempera-
ture for 1 day (Scheme 2). The first DKR reaction proceeded
smoothly to afford the acetate 7 in good isolated yield (96%)
and high optical purity (99% ee). Then, the DKR reaction
was repeated four times with the recycling of both 3 and
lipase. After each run, the solid mixture containing catalysts
and K2CO3 was separated from the reaction mixture, washed
3 times with dry toluene, and then reused. In the fourth run,
the conversion was only 61% after 1 day, but the catalytic
activity was resumed by the addition of 1 equiv of fresh
potassium carbonate in the fifth run (Table 2). These results
(12) The removal of potassium carbonate from the polymer-attached
catalysts and the separation between the latter were not tried because they
were not readily separable.
(13) N-Ethyl-N-methylcarbamoyl chloride was prepared from triphos-
gene and ethylmethylamine in the presence of sodium bicarbonate in
methylene chloride.
3106 J. Org. Chem. Vol. 75, No. 9, 2010

Han et al.
JOCNote
12 h to give enantiomerically enriched substrate and product
((S)-10, >99% ee; 11, 99% ee), indicating that the enzymatic
enantioselectivity for the resolution is excellent (E = >400).
The DKR of 10 (1 mmol) was then carried out with 3
(4 mol %), Novozym-435 (30 mg/mmol), isopropenyl acetate
(1.5 equiv), and K2CO3 (1 equiv) in toluene at room tem-
perature for 1 day. The acylated product 11 was obtained in
96% isolated yield and 99% ee. The DKR reaction was
repeated with 3, lipase, and K2CO3, all of which were
recovered from the first reaction, under identical conditions
to give 11 with similarly good results (94% isolated yield,
99% ee). Ester 11 was hydrolyzed under alkaline conditions
(K2CO3/MeOH/H2O) at room temperature for 2 h to give
(R)-10 (92% isolated yield, 99% ee) without loss in optical
purity. Finally, (R)-10 was transformed into target com-
pound 1 (77% isolated yield and 97% ee)14 via a mesylated
intermediate according to the known procedure.15 The over-
all yield was 57% from 8.
(10 mL) and dried under vacuum to give 3 of orange solid
(466 mg, 49% yield). The solid with 4.25 wt % of ruthenium was
identified by ICP mass. The product’s molecular weight was
2381 g/mol in accordance with the result of ICP mass. FT-IR
(cm-1): 2043, 1990, 1715.
General Procedure for Recycling of 3 in the Racemization of
Optically Active 1-Phenylethanol ((S)-6). A suspension contain-
ing K2CO3 (21 mg, 0.15 mmol), 3 (14 mg, 6 μmol), and (S)-6
(17 μL, 0.15 mmol) in dry and degassed toluene (500 μL) was
stirred at room temperature under argon atmosphere in a 50 mL
Schlenk flask. After 8 h, the solution was removed, and the solid
catalysts were washed with dry and degassed toluene (3 ꢀ 500 μL).
Immediately, 1-phenylethanol (17 μL, 0.15 mmol) and toluene
(500 μL) were added, and the mixture was stirred for 8 h. These
procedures were repeated four times.
DKR of 6. A suspension containing K2CO3 (69 mg, 0.5 mmol), 3
(48 mg, 20 μmol), Novozym-435 (5 mg, 10 mg/mmol), isopropenyl
acetate (83 μL, 0.75 mmol), and 6 (55 μL, 0.5 mmol) in dry and
degassed toluene (1.7 mL) was stirred at room temperature under
argon atmosphere in a 50 mL Schlenk flask. After 24 h, the reaction
mixture was filtered. The filtrate was concentrated, and the residue
was purified by column chromatography on silica gel to give
(R)-ester (7) (96% yield, 99% ee).
Recycling of the Catalytic System in DKR of 6. A suspension
containing K2CO3 (21 mg, 0.15 mmol), 3 (14 mg, 6 μmol),
Novozym-435 (1.5 mg, 10 mg/mmol), isopropenyl acetate (25 μL,
0.23 mmol), and 6 (17 μL, 0.5 mmol) in dry and degassed toluene
(500 μL) was stirred at room temperature under argon in a 25 mL
Schlenk flask. After 24 h, the solution was removed, and the
solid residue was washed with dry and degassed toluene (3 ꢀ
500 μL). Immediately, 6 (17 μL, 0.15 mmol), isopropenyl acetate
(25 μL, 0.23 mmol), and toluene (500 μL) were added, and
the solution was stirred for 24 h. These procedures were repeated
5 times. In the fifth recycling reaction, 1 equiv of fresh K2CO3
was added before 6, isopropenyl acetate, and toluene were
added.
Synthesis of 3-Acetylphenyl Ethyl(methyl)carbamates (9). To
a suspension containing 30-hydroxyacetophenone (8, 1.12 g,
8.3 mmol) in dry CH2Cl2 (15 mL) were added NaH (60%,
dispersion in mineral oil, 660 mg, 16.6 mmol) and N-ethyl-
N-methylcarbamoyl chloride (2 g, 16.5 mmol) at 0 °C under argon
atmosphere, and the resultant mixture was stirred for 4 h. The
reaction was quenched by addition of H2O (5 mL). The reaction
mixture was extracted with CH2Cl2/H2O, and the organic layer
was combined, dried over Na2SO4, and evaporated to obtain crude
product. The residue was purified with column chromatography
(silica gel, MeOH/CH2Cl2 = 1/10) to provide oily 9 (1.55 g, 85%
yield): 1H NMR (CDCl3, 300 MHz, ppm) δ 7.81-7.77 (m, 1H),
7.70 (s, 1H), 7.48-7.43 (m, 1H), 7.36-7.33 (m, 1H), 3.53-3.39 (m,
2H), 3.05 (d, J = 25.12 Hz, 3H), 2.60 (s, 3H), 1.29-1.18 (m, 3H);
13C NMR (CDCl3, 75 MHz, ppm) δ 197.3, 154.3, 151.8, 138.4,
129.4, 126.7, 125.1, 121.7, 44.2, 34.3, 33.9, 26.7, 13.3, 12.4; HRMS
(EI) C12H15NO3 calcd 221.1052 (Mþ), found 221.1050.
In summary, we have demonstrated a highly efficient
synthesis of rivastigmine via chemoenzymatic DKR using
a recyclable enzyme and a polymer-bound racemization catalyst.
This synthesis presents an illustrative application of enzyme-
metal cocatalysis for asymmetric synthesis of chiral drugs.
Experimental Section
Preparation of Polystyrene Containing Benzoyl Chloride (4). A
solution of methyl 4-hydroxybenzoate (685 mg, 4.5 mmol) in N,
N-dimethylformamide (20 mL) was added dropwise to a sus-
pension of chloromethyl polystyrene (882 mg, 3.0 mmol; sus-
bstitution: 3.4 mmol/g), cesium carbonate (1.47 g, 4.5 mmol),
and sodium iodide (135 mg, 0.9 mmol) in N,N-dimethylforma-
mide (10 mL) at room temperature. The mixture was stirred at
room temperature. After 1 day, the result solid was filtered,
washed with water (20 mL), acetone (20 mL) and CH2Cl2
(20 mL), and dried under vacuum to give polystyrene containing
methyl benzoate (12) of yellow solid (1.23 g, 100% yield; FT-IR,
1718 cm-1). A mixture of tetrahydrofuran and water (v/v = 2: 1,
30 mL) was added to solid mixture of 12 (1.23 g, 3.0 mmol) and
sodium hydroxide (240 mg, 6.0 mmol) at room temperature. The
mixture was stirred at room temperature. After 1 day, the result
solid was filtered, washed with water (20 mL), acetone (20 mL),
and CH2Cl2 (20 mL), and dried under vacuum to give polystyr-
ene containing benzoic acid (13) of pale yellow solid (1.15 g,
97% yield; FT-IR, 1723 cm-1). A solution of thionyl chloride
(436 μL, 6.0 mmol) in dry toluene (10 mL) was added dropwise
to a suspension of 13 (1.15 g, 2.9 mmol) in dry toluene (20 mL) at
120 °C and refluxed for 1 day. The reaction mixture was cooled
to room temperature and filtered. The result solid was washed
with CH2Cl2 (20 mL) twice, and dried under vacuum to give 4 of
brown solid (1.09 g, overall 88% yield; FT-IR, 1717 cm-1).
Synthesis of Polymer-Supported Ruthenium Catalyst (3). In a
50-mL flask equipped with a grease-free high-vacuum stopcock
were placed 4 (414 mg, 1.0 mmol), η4-(C4Ph4CO)(CO)3Ru (5)
(570 mg, 1.0 mmol), and dry toluene (20 mL) under argon
atmosphere. The mixture was stirred at 130 °C for 1 day. The
reaction mixture was cooled to room temperature and filtered.
The result solid was washed with acetone (10 mL) and CH2Cl2
Synthesis of 3-(1-Hydroxyethyl)phenyl Ethyl(methyl)carba-
mates (10). To a solution of 9 (1 g, 4.52 mmol) in dry methanol
(3.5 mL) was added added sodium borohydride (171 mg, 4.52 mmol)
at 0 °C under argon atmosphere. The reaction mixture was
stirred at 0 °C for 10 min. After completion of the reaction was
confirmed by TLC, the reaction was quenched by careful
addition of H2O (1 mL), and methanol was evaporated. The
residue was extracted with CH2Cl2/H2O, and the organic layers
were combined and dried over MgSO4. The solvent was evapo-
rated under reduced pressure to provide 10 as a colorless oil (1 g,
(14) [R]25D = -32.8 (c = 1.3, EtOH) (lit.5 [R]20D = -32.1 (c = 5, EtOH)).
The ee value was determined by modifying the HPLC method reported in the
literature: Srinivasu, M. K.; Rao, B. M.; Reddy, B. S.; Kumar, P. R.;
Chandrasekhar, K. B.; Mohakhud, P. K. J. Pharm. Biom. Anal. 2005, 38,
320–325.
(15) Fieldhouse, R. PCT WO 2005/058804 A1, 2005. In this reference,
mesyl anhydride was used as mesylating agent. In our case, we employed
mesyl chloride instead of mesyl anhydride.
1
99% yield): H NMR (CDCl3, 300 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); 13C NMR
(CDCl3, 75 MHz, ppm) δ 154.7, 151.7, 147.6, 129.2, 122.2,
J. Org. Chem. Vol. 75, No. 9, 2010 3107

Han et al.
JOCNote
120.6, 118.8, 69.9, 44.1, 34.2, 33.8, 25.0, 13.2, 12.5; HPLC
(Chiracel-OD, n-hexane/2-propanol =95/5, flow rate =1.0 mL/
min, UV 217 nm) (S)-10 = 17.27 min, (R)-10 = 20.13 min;
HRMS (EI) C12H17NO3 calcd 223.1208 (Mþ), found 223.1206.
Typical Procedure for Enzymatic KR of 10. To a solution of 10
(22 mg, 0.1 mmol) and isopropenyl acetate (15 μL, 0.15 mmol) in
anhydrous toluene (300 μL, 0.3 M) was added Novozym-435
(3 mg, 30 mg/mmol) under an argon atmosphere. The mixture was
stirred at room temperature for 12 h. The enzyme was removed
from the reaction mixture by filtration through a Celite. The sol-
vent was evaporated under reduced pressure to give an oily mix-
ture. For determination of optical purities (eep and ees), the mixture
was dissolved in 2-propanol without further purification and then
subjected to the analysis by HPLC with a chiral column (condition:
Chiracel-OD, n-hexane/2-propanol=95/5, flow rate=1.0 mL/min,
UV 217 nm (R)-11 = 10.70 min, (S)-11 = 12.64 min, (S)-10 =
17.27 min, (R)-10 = 20.13 min.).
DKR of 10. A suspension containing K2CO3 (140 mg, 1 mmol),
3 (95 mg, 40 μmol Ru), Novozym-435 (30 mg, 30 mg/mmol of sub-
strate), isopropenyl acetate (150 μL, 1.5 mmol), and 10 (223 mg,
1 mmol) in dry and degassed toluene (2.5 mL) was stirred at room
temperature under argon atmosphere in a 50 mL Schlenk flask.
After 24 h, the reaction mixture was filtered. The filtrate was
concentrated, and the residue was purified by column chromatog-
raphy (silica gel, n-hexane/EtOAc = 1/1) to give (R)-ester (11) as a
colorless liquid (254 mg; 96% yield, 99% ee): 1H NMR (CDCl3,
300 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), 4.92-4.86 (m, 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); 13C NMR (CDCl3, 75 MHz, ppm) δ 170.3, 154.5, 151.6,
143.0, 129.3, 122.9, 121.3, 119.5, 71.8, 44.1, 34.3, 33.8, 22.1, 21.3,
13.2, 12.5; HPLC (Chiracel-OD, n-hexane/2-propanol =95/5,
flow rate =1.0 mL/min, UV 217 nm) (R)-11 = 10.70 min,
(S)-11 = 12.64 min; [R]25D = þ68.2 (c = 1.1, CHCl3, 99% ee);
HRMS (EI) C14H19NO4 calcd 265.1314 (Mþ), found 265.1310.
Hydrolysis of 11. To a solution of 11 (133 mg, 0.5 mmol) in
methanol (1.6 mL) were added potassium carbonate (138 mg,
1 mmol) and H2O (0.4 mL). The reaction mixture was stirred at
room temperature for 2 h. Methanol was removed by evapora-
tion, and the aqueous solution was extracted with CH2Cl2.
The organic layers were combined, dried over Na2SO4, and
evaporated under reduced pressure. The residue was purified by
a column chromatography (silica gel, n-hexane/EtOAc = 1/1)
1
to give oily (R)-10 (101 mg; 92% yield, 99% ee). H and 13C
=
NMR and HRMS were that same as the data of 10: [R]24
þ25.3 (c = 1.1, CHCl3, 99% ee).
D
Synthesis of Rivastigmine (1). To a solution of (R)-10 (100 mg,
0.45 mmol) in dry CH2Cl2 (1.6 mL) was added distilled triethy-
lamine (200 μL, 1.35 mmol) at 0 °C under argon atmosphere in a
25 mL Schlenk flask, and the reaction solution was stirred for
10 min. Methanesulfonyl chloride dissolved in dry CH2Cl2 (v/v
10%, 500 μL, 0.59 mmol) was added to the cold reaction mixture
dropwise over 30 min at 0 °C. The reaction solution was stirred
at 0 °C for 1 h, dimethylamine (2 M solution in THF, 1 mL) was
added, and the reaction mixture was stirred at room tempera-
ture for 2 d. After completion of the reaction was confirmed by
TLC, the reaction mixture was poured in 1 M HCl and extracted
with CH2Cl2 and the organic layer was extracted again with 1 M
HCl. Both aqueous layers were combined and neutralized with
2 M NaOH until the pH was above 10 and then extracted with
CH2Cl2. The organic layers were combined, dried over Na2SO4,
and evaporated under reduced pressure to provide oily 1 (96 mg,
77% yield): [R]25 = -32.8 (c = 1.3, EtOH) (lit.5 [R]20
=
D
D
-32.1 (c = 5, EtOH)); HRMS (EI) C14H22N2O2 calcd 250.1681
(Mþ), found 250.1683. 1H and 13C NMR data are in good
agreement with those reported in the literature.6 For determin-
ing the enantiopurity of 1, a small amount of 1 was mixed with
one equivalent of (R,R)-tartaric acid in ethanol and the resulting
mixture was then analyzed by HPLC14(Chiracel-OD, n-hexane/
2-propanol/trifluoroacetic acid =80/20/0.3, flow rate =1.5 mL/
min, UV 220 nm): (R)-1= 10.91 min, (S)-1= 14.00 min; 97% ee.
Acknowledgment. This work was supported by National
Research Foundation of Korea (2009-0087801). We thank
the Korean Goverment for supporting our graduate pro-
gram (BK21 Program).
1
Supporting Information Available: Copies for H and 13C
NMR spectra and HPLC chromatographs of products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3108 J. Org. Chem. Vol. 75, No. 9, 2010