An efficient asymmetric synthesis of (S)-atenolol: Using hydrolytic kinetic resolution

Article abstract of DOI:10.1016/j.bmc.2004.10.057

Enantiomerically pure (S)-atenolol was prepared by using (R,R) salen Co(III) complex for the resolution of terminal epoxide. This process was carried out at room temperature in excellent enantio selectivity. The method can be applied for large-scale preparation of (S)-atenolol without any problem.

Full text of DOI:10.1016/j.bmc.2004.10.057

Bioorganic & Medicinal Chemistry 13 (2005) 627–630
An efficient asymmetric synthesis of (S)-atenolol: using
hydrolytic kinetic resolutionq
D. Subhas Bose* and A. Venkat Narsaiah
Division of Organic Chemistry, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 August 2004; accepted 28 October 2004
Available online 18 November 2004
Abstract—Enantiomerically pure (S)-atenolol was prepared by using (R,R) salen Co(III) complex for the resolution of terminal
epoxide. This process was carried out at room temperature in excellent enantio selectivity. The method can be applied for large-scale
preparation of (S)-atenolol without any problem.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ess. Herein we wish to report a better process for the
asymmetric synthesis of (S)-atenolol by using hydrolytic
kinetic resolution (HKR) method, which was introduced
by Jacobsen and co-workers.7 This technique provides
high enantioselectivity and extremely simple compared
to other approaches. The reasons to select this route
are (1) the ready availability of the catalyst, (2) the cat-
alyst would be used in small quantities (0.5mol%) and
(3) the recyclability of the catalyst and 0.55equiv
amount of water only the solvent as well as reactant
(Fig. 1, Schemes 1 and 2).
b-Adrenoreceptor antagonists are a group of com-
pounds that competitively inhibit, the effects of catechol-
amines at b-adrenergic receptors.1 These agents are
widely used in clinical medicine for the treatment of var-
ious conditions. As the b-adrenoreceptor antagonists
(b-blockers) have such a diverse range of clinical appli-
cations, the mode of delivery of these drugs becomes
crucial. In particular there has been great interest in
the percutaneous transport of b-blockers for hyperten-
sion and ocular delivery for glaucoma.2 Since the biolog-
ical activity in a racemic drug often resides in a single
enantiomer, synthesizing such drugs in their optically
pure form is becoming important.3 For instance, race-
mic atenolol is one of the top five best-selling drugs in
the world today,3b for the treatment of hypertension,
angina and also in the treatment of post-myocardial
infarction, yet the S isomer has found to avoid the occa-
sional side effect of a lowered heart rate encountered
with racemate.4
2. Results and discussion
The synthetic approach started from the commercially
available 4-hydroxy acetophenone, which was treated
with sulfur and morpholine at 100°C for well-known
Willgerodt8 reaction to obtain the thioacetomorpholide
in 85% yield. The resulted thioacetomorpholide was
hydrolyzed with 10% ethanolic NaOH solution under
reflux condition for 10h to obtain the 4-hydroxy phenyl
acetic acid. The acid compound was dissolved in meth-
anol and added catalytic amount of thionylchloride at
ice cooling, later it was refluxed to get the methyl ester.
The phenolic hydroxy group was reacted with allylbro-
mide in acetone using K2CO3 as base to obtain the allyl-
oxy compound, the resulted compound was subjected
with meta-chloroperbenzoic acid (mCPBA) in dichloro
methane (DCM) for epoxidation at room temperature.
The methyl ester functional group was maintained unto
the final stage. Because of the ester function it was a
free-floating liquid and was convenient to apply hydro-
lytic kinetic resolution method.
There are few reports in the literature for chiral synthe-
sis of atenolol using expensive chiral epichlorohydrin5 in
presence of alkali metal hydroxide, which was an highly
basic condition and another case involves the use of bio-
logical catalyst enzyme,6 which was also a lengthy proc-
Keywords: b-Blockers; Atenolol; Jacobsen catalyst; Enantiomers;
Isopropylamine.
q IICT-Communication no: 041010.
*
Corresponding author. Fax: +91 040 7160387;
vnakkirala2001@yahoo.com
e-mail:
0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.10.057

628
D. Subhas Bose, A. Venkat Narsaiah / Bioorg. Med. Chem. 13 (2005) 627–630
H
H
H
N
OH
N
O
N
O
Co
CH3
CH3
O
O
OAc
H2N
(1)
(R,R) Salen Co(III) Catalyst - A
Figure 1.
O
O
OMe
N
b,c
a
O
S
HO
HO
O
HO
2
3
4
O
OH
O
O
e
d
O
MeO
O
MeO
MeO
4
6
5
Scheme 1. Reagents and conditions: (a) sulfur, morpholine, 100°C; (b) ethanolic-NaOH solution, reflux; (c) methanol–thionyl chloride; (d) allyl
bromide, acetone, K2CO3; (e) mCPBA–DCM.
O
OH
O
OH
O
O
O
O
a
O
O
+
MeO
6
(R)
8
MeO
7
(S)
MeO
c
b
d
O
H
N
OH
CH3
CH3
O
O
O
O
MeO
(R)
10
MeO
9
(S)
1
Scheme 2. Reagents and conditions: (a) (R,R)-salen Co(III)-A; (b) isopropylamine, water, reflux; (c) TPP–DEAD, C6H6; (d) NH4OH–methanol.
The treatment of racemic epoxide with Jacobsen catalyst
(R,R) (salen Co(III)OAc) (0.5mol%) and water
(0.55equiv) at room temperature for 8h and monitored
by HPLC (ODS-Column) UV: 225nm, 60% CH3CN in
H2O. The reaction mixture was chromatographed on sil-
ica gel to give the selective epoxide S, from the racemic
The enantiomer excess of all the chiral compounds
was determined by HPLC using chiral column. The first
separated enantioselective (s) epoxide 7 was treated an
excess amount of N-isopropylamine in presence of water
at reflux for 5h to obtain the hydroxy amine compound
9 was confirmed by its 1H NMR, IR and mass
spectroscopy. Then, the hydroxy amine compound was
treated with aqueous ammonium hydroxide solution in
methanol at low temperature (0–5°C) to afford the
target molecule (S)-atenolol 1 in excellent enantio
selectivity.
mixture in 46% yield and 94% ee. The optical rotation
21
D
tion by increasing the polarity of mobile phase gave the
of 7 shows that ½aꢀ 5.7 (c 1, CHCl3) and on further elu-
(R)-diol 8 in 48% yield and 98% of ee, the optical rota-
21
D
tion ½aꢀ ꢁ7.0 (c 1, CHCl3).
The enantiomerically rich R diol 8 was treated with
triphenyl phosphine (TPP) and diethylazo dicarboxylate
(DEAD) in benzene by Mitsunobu reaction in one step
3. Conclusion
to get optically active (R) epoxide 10 (83.7% yield, 98%
ee) the optical rotation ½aꢀ ꢁ6.00 (c 1, CHCl3).
In summary, we have described here, the total synthesis
of S-atenolol in high enantioselection fashion. The key
21
D

D. Subhas Bose, A. Venkat Narsaiah / Bioorg. Med. Chem. 13 (2005) 627–630
629
intermediate was terminal epoxide from which selec-
tively using Jacobsen catalyst for hydrolytic kinetic res-
olution protocol separated S-isomer. This method can
cater the needs of pharmaceutical demand.
4.1.3. 4-Allyloxy phenyl acetic acid methyl ester (5). A
mixture of the methyl ester compound 4 (5.0g,
0.030mol), potassium carbonate (6.5g, 0.047mol) in
acetone (50mL) was stirred for some time and added
allylbromide (5.5g, 0.045mol). The resulting mixture
was stirred at reflux condition for 7h. Then the solvent
was removed under reduced pressure. The residue was
dissolved in water and extracted with ethyl acetate.
The organic layer was dried and concentrated to obtain
the crude product, which was purified by column chro-
matography to yield 5.4g (87%). IR (Neat): m 3100–
2850, 1735, 1600, 1569, 1407, 1256, 1184, 1022, 978,
4. Experimental
4.1. Chemistry
Melting points were recorded in a Buchi capillary melt-
ing point (R-535) apparatus and are uncorrected. IR
spectra were recorded on a Perkin–Elmer FT-IR 240C
1
843cmꢁ1; H NMR (CDCl3): d 3.55 (s, 2H), 3.69 (s,
1
spectrophotometer. H NMR spectra were recorded on
3H), 4.48–4.55 (m, 2H), 5.20–5.50 (m, 2H), 5.90–
6.15(m, 1H), 6.85 (d, 2H, J = 8.0Hz), 7.15 (d, 2H,
J = 8.0Hz); 13C NMR: d 171.7, 157.8, 133.4, 130.2,
126.2, 117.3, 114.8, 68.7, 51.7, 40.2; EIMS, m/z (%):
206(M+, 38) 147(79), 107(18), 78(27), 41(100).
Gemini-200 spectrometer with TMS as the internal
standard. Mass spectra were recorded on a Finnigan
MAT 1020 mass spectrometer operating at 70ev. All
chemicals or reagents were purchased from standard
commercial suppliers.
4.1.4. 1-[4[(Methoxycarbonyl) methyl] phenoxy]-2,3-
epoxy propane (racemic) (6). To a stirred mixture of
allyloxy compound 5 (5.0g, 0.024mol) in dry dichloro-
methane (50mL) was added meta-chloroperbenzoic acid
(6.5g, 0.037mol) in portions for a period of 30min at ice
cooling. After the addition of mCPBA, cooling was re-
moved and continued stirring for 15h at room tempera-
ture. The completion of the reaction was confirmed by
TLC. Then the reaction mixture was diluted by adding
dichloromethane (50mL) and washed with dilute 5%
NaHCO3, followed by water wash. The organic layer
was dried over Na2SO4 and concentrated to get crude
product, which was purified by column chromatography
4.1.1. 4-Hydroxy phenyl thioacetomorpholide (3). A mix-
ture of 4-hydroxy acetophenone (10g, 0.0735mol), pow-
dered sulfur (3.5g, 0.109mol) and morpholine (10g)
were refluxed at 100°C for 10h. The starting material
disappearance was confirmed by thin layer chromato-
graphy (TLC). Then reaction mixture was cooled to
room temperature and poured in water, followed by
extraction with ethyl acetate. The organic layer was
dried over Na2SO4 and concentrated to yield crude
product of thioacetomorpholide, which was purified
by column chromatography to yield 15g (86%). 1H
NMR (CDCl3): d 3.35–3.48 (m, 2H), 3.60–3.65 (m,
2H), 3.70–3.78 (m, 2H), 4.20 (s, 2H), 4.30–4.40 (m,
2H), 5.85 (br s, 1H, OH), 6.78 (d, 2H, J = 7.5Hz),
7.15 (d, 2H, J = 7.5Hz).
1
to yield 4.5g (84%). H NMR (CDCl3): d 2.70–2.75 (m,
1H), 2.85–2.93 (m, 1H), 3.28–3.36 (m, 1H), 3.55 (s, 2H),
3.70 (s, 3H), 3.90 (q, 1H, J = 7.5Hz), 4.15 (dd, 1H,
J = 9.5, 2.5Hz), 6.88 (d, 2H, J = 8.0Hz), 7.20 (d, 2H,
J = 8.0Hz).
4.1.2. 4-Hydroxy phenylacetic acid methyl ester (4). The
above thioacetomorpholide compound (10g, 0.042mol)
was dissolved in 10% ethanolic-NaOH solution (40mL,
15mL, EtOH, 25mL H2O) and refluxed for 10h. The
complete hydrolysis was confirmed by TLC. The solvent
was removed completely under reduced pressure. The
residue was acidified with dil HCl and extracted with
ethyl acetate. The organic layer was dried over Na2SO4
and concentrated to get crude product (5.4g). The ob-
tained compound was dissolved in methanol (50mL)
and added thionylchloride (2mL) slowly at ice cooling.
After complete addition of thionylchloride cooling was
removed and refluxed for 6h. Starting material absence
was confirmed by TLC. The solvent from the reaction
mixture was removed under reduced pressure and the
residue was poured in ice and neutralized with triethyl-
amine followed by extraction with ethyl acetate. The or-
ganic layer was dried over Na2SO4 concentrated and the
obtained crude compound was purified by column chro-
matography by eluting with a mixture of ethyl acetate
and hexane in 2:8 ratio to yield, 5.81g (83%). Mp 55–
56°C. IR (KBr): m 3496, 3087, 2963, 2841, 1708, 1618,
1878, 1347, 1269, 1135, 1063, 957, 874, 753cmꢁ1; 1H
NMR (CDCl3): d 3.52 (s, 2H), 3.73 (s, 3H), 6.65 (d,
2H, J = 8.0Hz), 7.05 (d, 2H, J = 8.0Hz). EIMS m/z
(%): 166 (M+, 48), 151(12), 132(28), 107(100), 90(10),
78(59), 52(26).
4.1.5. (S) 1-[4[(Methoxycarbonyl) methyl] phenoxy]-2,3-
epoxy propane (7). A mixture of racemic epoxide 6 (10g,
0.045mol) and (R,R) salen Co(III)OAc complex A
(0.144g, 0.225mmol) were vigorously stirred for
15min. Then cooled to 0°C, and added water
(0.45mL, 0.025mol) over a period of 1h, through syr-
inge pump. The reaction mixture was stirred at room
temperature and monitored by HPLC (ODS-column)
UV: 225nm, 60% CH3CN in H2O. The reaction mixture
was diluted with ethyl acetate, dried over Na2SO4 and
evaporated under reduced pressure. The residue was
chromatographed on silica gel using ethyl acetate and
petroleum ether 1:9 ratio. The less polar epoxide 7 eluted
21
D
ethyl acetate and petroleum ether ratio was raised to 3:7
first as colourless liquid, ½aꢀ 5.7 (c 1, CHCl3). Later the
25
D
1
to elute the diol 8, ½aꢀ ꢁ7.0 (c 1, CHCl3). H NMR:
(CDCl3): 2.70–2.75 (m, 1H), 2.85–2.93 (m, 1H), 3.28–
3.36 (m, 1H), 3.55 (s, 2H), 3.70 (s, 3H), 3.98 (q,1H,
J = 7.5Hz), 4.15 (dd, 1H, J = 9.5, 2.5Hz), 6.88 (d, 2H,
J = 8.0Hz ), 7.20 (d, 2H, J = 8.0Hz).
4.1.6. (R) 1-[4[(Methoxycarbonyl) methyl] phenoxy]-2,3-
epoxy propane (10). A mixture of the 1,2 diol compound
8 (4g, 0.0166mol) Ph3P (6.55g, 0.025mol) and diethyl-
azo dicarboxylate (4.35g, 0.025mol) in benzene

630
D. Subhas Bose, A. Venkat Narsaiah / Bioorg. Med. Chem. 13 (2005) 627–630
(40mL) was refluxed for 18h. Then the solvent was re-
moved under reduced pressure and the residue was di-
luted with ether to precipitate Ph3PO, which was
removed by filtration. The filtrate was concentrated
and the residue was chromatographed to afford a col-
EIMS: m/z (%): 266(M+, 45), 248(21), 208(11), 190(10),
150(22), 132(100), 104(31), 78(16), 52(31).
References and notes
ourless liquid of R-epoxide, yield, 3.1g (83.7%) and
21
D
½aꢀ ꢁ6.0 (c 1, CHCl3).
1. (a) Barrett, M. A. Beta-Adrenoceptive Agonists. In Recent
Advances in Cardiology, Chruchill Living stone: Edinburgh,
London, 1973; p 289; (b) Erhardt, P. W.; Woo, C. M.;
Anderson, W. G.; Gorczynski, R. J. J. Med. Chem. 1982,
25, 1408; (c) Bodor, N.; El-Koussi, A. A.; Kano, M.;
Khalifa, M. M. J. Med. Chem. 1988, 31, 1651.
2. (a) Bundgard, H.; Buur, A.; chang, S. C.; Lee, V. H. L. Int.
J. Pharm. 1988, 46, 77; (b) Bundgard, H.; Buur, A.; Chang,
S. C.; Lee, V. H. L. Int. J. Pharm. 1986, 33, 15; (c) Sorensen,
S. J.; Abel, S. R. Ann. Pharmacother. 1996, 30, 43.
3. (a) Deutsch, D. H. CHEMTECH 1991, 21, 157; (b)
Barclaysde, Z. W. Research report. Perform. Chem. 1991,
6(2), 22; (c) Borman, S. Chem. Eng. News 1990, 28, 9; (d)
Margoli, A. L. CHEMTECH 1991, 21, 160; (e) Klibanov,
A. M. Acc. Chem. Res. 1990, 23, 114; (f) Wang, C. H.
Science 1989, 244, 1145; (g) Akiyama, A.; Bednarski, M.;
Kim, M. J.; Simon, E. S.; Waldmann, H.; Whitesides, G.
M. CHEMTECH 1988, 18, 640; (h) Yamada, H.; Shimizu,
S. Angew. Chem., Int. Ed. Engl. 1988, 27, 622.
4. (a) Pearson, A. A.; Graffney, T. E.; Walle, T.; Privitera, P.
J. J. Pharmacol. Exp. Ther. 1989, 250, 759–768; (b) Sittig,
M. Pharmaceutical Manufacturing Encyclopedia, 2nd ed.;
Noyes Publications: Park Ridge, NJ, 1988; Vol. 1, p 109.
5. Kitaori, K.; Takehira, Y.; Furukawa, Y.; Yoshimoto, H.;
Otera, J. Chem. Pharm. Bull. 1997, 45, 412.
4.1.7. (S) 1-[4[(Methoxycarbonyl) methyl] phenoxy]-3-
(isopropyl amino) propan-2-ol (9). A mixture of S-epox-
ide
7
(4g, 0.018mol), isopropyl amine (15mL,
0.180mmol) and water (0.5mL) was refluxed for 5h
and the isopropyl amine was removed under reduced
pressure. The residue was diluted with water and ex-
tracted with ethyl acetate. The organic layer was dried
over Na2SO4 and concentrated. The crude product
was purified by column chromatography to afford the
21
D
pure product amino alcohol (3.8g, 78%). ½aꢀ ꢁ4.0 (c
1, CHCl3); IR (neat): m 3406, 3196, 3064, 2947, 2859,
1600, 1563, 1508, 1412, 1357, 1263, 1122, 1069, 953,
876cmꢁ1
; d 1.10 (d, 6H,
1H NMR: (CDCl3):
J = 7.0Hz), 2.80–2.90 (m, 1H), 3.00–3.10 (m, 2H), 3.45
(s, 2H) 3.75 (s, 3H), 3.85–4.00 (m, 2H), 4.15–4.25 (m,
1H), 6.80–6.90 (m, 2H), 7.15 (t, 2H, J = 6.5Hz); EIMS
m/z (%): 281 (M+, 29), 250(19), 222(12), 164(32),
106(67), 78(100), 52(43).
4.1.8. Preparation of (S)-atenolol (1). A cold solution (0–
5°C) of optically active ester compound 9 (2.0g,
7.2mmol), methanol (20mL) and NH4OH (8mL) were
mixed, stoppered and allowed to attain room tempera-
ture and stirred for 1 day and monitored by TLC. The
solvent was removed and the crude product was recrys-
6. (a) Bevinakatti, H. S.; Banerji, A. A. J. Org. Chem. 1992,
57, 6003; (b) Damle, S. V.; Patil, P. N.; Salunkhe, M. M.
Synth. Commun. 1999, 29, 3855.
7. (a) Tokunaga, M.; Larrow, J. F.; Kakinchi, F.; Jacobsen, E.
N. Science 1997, 277, 936; (b) Furrow, M. E.; Schaus, S. E.;
Jacobsen, E. N. J. Org. Chem. 1998, 63, 6776; (c) Scott, E.
S.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Haugen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 1307; (d) Brandes, B. D.; Jacobsen, E. N.
Tetrahedron: Asymmetry 1997, 23, 3927; (e) Gurjar, M. K.;
Sadalapure, K.; Adhikari, S.; Talukdar, A.; Sharma, B. V.
N. B. S.; Chorghade, M. S. Heterocycles 1998, 48, 1471.
8. Willgerodt, C. Bert. 1887, 20, 2467.
tallized with ethyl acetate to get pure product (S)-ateno-
21
D
lol (1.4g, ꢂ72%). ½aꢀ ꢁ17.0 (c 1, 1N HCl); mp 148–
150°C; IR (KBr): m 3325, 3170, 2950, 2839, 1687,
1
1596, 1506, 1329, 1263, 1139, 1054, 968, 835cmꢁ1. H
NMR: (DMSO-d6): d 1.05 (d, 6H, J = 7.0Hz), 2.70–
2.90 (m, 1H), 3.25 (d, 2H, J = 6.0Hz), 3.42 (s, 2H)
3.90–4.10 (m, 2H), 6.18 (br s, 2H), 6.85 (d, 2H,
J = 7.2Hz), 7.15 (d, 2H, J = 7.2Hz), 7.55 (br s, 1H);