Concise synthesis of two β-adrenergic blocking agents in high stereoselectivity using the readily available chiral building block (2 S,2′ S,2″ S)-tris-(2,3-epoxypropyl)-isocyanurate

Article abstract of DOI:10.1021/op2001518

A concise synthesis of (S)-propranolol and (S)-metoprolol in high stereoselectivity using the readily available chiral building block (2S,2′S,2″S)-tris-(2,3-epoxypropyl)-isocyanurate (S-TGT) as the key intermediate is described.

Full text of DOI:10.1021/op2001518

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pubs.acs.org/OPRD
Concise Synthesis of Two β-Adrenergic Blocking Agents in High
Stereoselectivity Using the Readily Available Chiral Building Block
(2S,20S,200S)-Tris-(2,3-epoxypropyl)-isocyanurate
Swapnil P. Sonawane,* Gulabrao D. Patil, and Mukund K. Gurjar
API R & D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjewadi, Pune-411057, India
S Supporting Information
b
racemic mixture of R- and S-isomers. The β1 blocking activity
(cardio selectivity) of metoprolol resides in the S-isomer, while
the R-isomer exhibits β2 blocking activity.
ABSTRACT: A concise synthesis of (S)-propranolol and (S)-
metoprolol in high stereoselectivity using the readily available
chiral building block (2S,20S,200S)-tris-(2,3-epoxypropyl)-iso-
cyanurate (S-TGT) as the key intermediate is described.
Most of the β-blockers possess a general structure ArꢀOꢀ
CH2CH(OH)CH2NHCH (CH3)2 and have been used in the
form of racemic mixtures.3 There is certainly a strong need to
replace approved racemic drugs with the single enantiomers.4
There are several methods to obtain enantiomerically pure
materials, which include classical resolution via diastereomers,
chromatographic separation of enantiomers, enzymatic resolu-
tion, chiral kinetic resolution, and asymmetric synthesis.
Methods reported for the synthesis of (S)-propranolol in-
volved the use of enzymes for resolution,5 asymmetric hydro-
genation using chiral metal complexes,6 asymmetric epoxidation,7
and synthesis from sorbitol8 and also employed a polymer-
supported reagent.9
’ INTRODUCTION
Initially, Howe et al.10 synthesized (S)-propranolol (1) by re-
solution of their racemates. Thus, 1-(dimethylamino)-3-(naphthalen-
5-yloxy)propan-2-ol was resolved using (ꢀ)-O,O-di-p-toluoyl-
tartaric acid. Later, Smith et al.11 reported the synthesis of
(R)-(+)-propranolol and confirmed its configuration by correla-
tion with (S)-(+)-lactic acid. The compound 3 was prepared
from (S)-(+)-lactic acid in three steps. The key intermediate
(R)-(+)-4 was prepared starting from epichlorohydrin in four
steps (Scheme 1). After resolution, the (()-chloroaminoalcohol
afforded the (R)-(+)-chloroaminoalcohol 4. The intermediate 4
was treated with LAH to give 3 which was also prepared from
(S)-(+)-lactic acid, thereby confirming the configuration of the
final product. This synthesis is tedious and necessarily involves
resolution, in which ∼50% of another isomer is being wasted.
Similarly, synthetic strategies developed by Tsuda et al.,12
Kojima et al.,13 Katsuki et al.,14 Kazunori et al.,15 Sharpless
et al.,16 Wang et al.,17 Cardillo et al.,18 Yoshiyasu et al.,19 Rama
Rao et al.,20 Shibasaki et al.,21 Sinisterra et al.,22 Kazuhiro et al.,23
Hou et al.,24 Salunkhe et al.,25 Baeckwall et al.,26 Kamal et al.,27
Gurjar et al.,28 and Joshi et al.29 to harvest the single enantiomers
of adrenergic blockers revolve around either the use of asym-
metric catalysis, kinetic hydrolytic resolution, enzymatic resolu-
tion using lipase, or the use of R-epichlorohydrin. On a pre-
parative scale, the enantiomers of propranolol have also been
separated by multiple recrystallizations of the di(p-toluoyl)tarta-
ric acid salts.30
β-Adrenergic blocking agents (β-blockers) are important
drugs used for the treatment of hypertension and angina
pectoris.1,2 Beta blockers are a common class of prescription
drugs that counteract the stimulatory effects of adrenaline
(epinephrine) on what are called the beta receptors. There are
three known types of beta receptor, designated β1, β2, and β3.
β1-Adrenergic receptors are located mainly in the heart and in
the kidneys. β2-Adrenergic receptors are located mainly in the
lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle,
and skeletal muscle. β3-receptors are located in fat cells.
Propranolol is a known β-adrenergic blocking agent com-
monly used for the treatment of arterial hypertension (AHT) and
some cardiovascular disorders. However, its use has been passed
over by other beta-blocking agents, and side effects have been
found, mainly in asthma patients.
Metoprolol is a widely used cardio-selective beta-blocker.
However, like the rest of the other beta-blockers, it is also a
Although a number of approaches have been described in the
literature for the asymmetric synthesis of (S)-metoprolol and
Received: May 9, 2011
Published: August 24, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/op2001518 Org. Process Res. Dev. 2011, 15, 1365–1370
|

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Scheme 1
Scheme 2
(S)-propranolol, most of the methods require lengthy reaction
sequences coupled with low yield and enantioselectivity.
Synthetic efforts now need to be directed at short, practical
routes that are amenable to scale-up for API preparation. In
this context, the use of readily available chirally pure S-TGT
provided a powerful tool for the generation of enantioen-
riched (S)-metoprolol and (S)-propranolol. The other salient
features of this method include extraordinarily high levels
of selectivity, easy availability of chirally pure glycidyl deriva-
tive S-TGT,31 use of class-3 solvents, which makes it extre-
mely simple to work with compared to other approaches, and
excellent yields.
The general synthetic route we have employed for the
synthesis of (S)-propranolol and (S)-metoprolol is presented
in Scheme 3.
S-TGT was subjected to nucleophilic displacement with
phenol nucleophiles 5 and 8, respectively, to give chirally pure
oxazolidines 6 and 9 followed by the N-alkylation of 6 and 9 with
isopropyl bromide in the presence of sodium hydride to give the
enantiomerically enriched N-alkylated oxazolidines 7 and 10 .
Finally, the alkaline hydrolysis of 7 and 10 furnishes the stereo-
selective synthesis of β-blocker (S)-propranolol and (S)-meto-
prolol in high yield. The present method differs from the prior art
methods32,33 particularly in its use of different starting materials
and different molar ratios of the reactants.
Typically, the 1H NMR spectrum of 6 and 9 showed peaks at δ
5.1 and δ 4.98, respectively, due to a characteristic proton at the
chiral center and a broad signal due to amide protons at δ5.56 and δ
’ RESULTS AND DISCUSSION
On the basis of the proposed mechanism (Scheme 2), we
envisaged that (2S,20S,200S)-tris-(2,3-epoxypropyl)-isocyanurate
(S-TGT) is a substrate of special interest, as it serves as a
common intermediate for (S)-metoprolol and (S)-propranolol
and can be easily converted to compounds 6 and 9 by a
simple reaction sequence in high enantiopurity and good yields
(Scheme 3).
1
5.67. The H NMR spectrum of 7 and 10 showed multiplicity
at δ 1.23 and δ 1.21, respectively, due to the isopropyl group.
The structure of (S)-propranolol and (S)-metoprolol was
confirmed using 1H NMR, 13C NMR, and HPLC, whereas chiral
purity was confirmed by chiral HPLC.
To optimize reaction conditions, the reaction between 5 and
S-TGT was taken as a model reaction. These optimized condi-
tions were later employed for reacting corresponding phenol (8)
with S-TGT. Different solvents were screened, and the results are
reported in Table 1.
It was found that this reaction gave encouraging results in
MIBK. As shown in Table 1 when S-TGT was reacted with the
corresponding phenol 5 in acetonitrile and diethyl carbonate,
∼20% conversion was observed (Table 1, entries 3 and 9),
whereas only 10% conversion was noticed in propylene glycol
(Table 1, entry 6).
Thus, during the course of the reaction, the phenol derivative
(5 and 8, respectively) attacks the C-3, C-30, and C-300 carbon of
S-TGT and opens the epoxide ring. Subsequently, the free
hydroxyl groups attack the carbonyl functionality to form the
oxazolidinone 6 and 9, respectively, with overall retention of
stereochemistry.
As per the process disclosed by Ikeda et al.,31 S-TGT can be
obtained by alkylation of cyanuric acid with (S)-epichlorohydrin
in the presence of a phase transfer catalyst and NaOH in
75ꢀ85% yield.
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Scheme 3
Table 1. Solvent Screeninga
Table 2. Optimization of Equivalents of Base Using MIBK
Solventa
entry
KOH (equiv)b
time (h)
yield 6 (%)c
1
2
3
4
5
6
7
3
3
2
5
3
2
2
5
30
45
50
60
75
80
55
1.5
1.25
0.6
entry
solvent
MIBK
base (equiv) temp (°C) time (h) 6 %b
0.3
0.25
0.15
1
2
3
4
5
6
7
8
9
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
65
65
65
65
65
65
65
65
65
5
7
5
7
7
5
7
5
5
<40
--c
toluene
ACN
a Reaction performed on a 10 mmol scale WRT S-TGT. b Powdered
KOH having moisture content below 10% was used. c By column
chromatography.
<20
--c
--c
DMF
DMSO
propylene glycol
NMP
<10
--c
--d
KOH showed comparatively less degradation than 3.0 equiv.
Ultimately, entry 6 of Table 2 was found to be satisfactory in
terms of yield and quality.
MTBE
After optimizing the reaction conditions for 6, we focused on
alkylation of 6 using isopropyl bromide and sodium hydride.
Indeed, sodium hydride is a commonly used base for deprotona-
tion of amides, oxazolidinones, and other functional groups for
the promotion of their nucleophilic substitution, typically in
polar aprotic solvents such as DMSO, DMF, or acetonitrile. We
decided to attempt this transformation using different bases in
DMSO, and results are summarized in Table 3.
In an initial attempt, reaction of 6 with isopropyl bromide in
the presence of potassium carbonate in DMSO showed only
25ꢀ30% conversion, hence various bases such as potassium tert-
butoxide, sodium methoxide, sodium hydride, triethyl amine, etc.
were tested.
Among the bases explored, NaH (Table 3, entry 5) was found
to be satisfactory. Although DMSO is a good solvent for such
reactions, a practical disadvantage in certain important situations
is that DMSO and DMF cannot conveniently be used in
combination with NaH due to formation of an explosive mixture
above 45 °C. Attempts to try THF, CPME, 2-methyl THF, and
sulfolane as solvent were also unsuccessful. Finally, we tested
another good polar aprotic solvent N-methylpyrrolidone (NMP)
to perform this reaction at 65 °C. To our delight, the reaction
proceeded smoothly in NMP at 65 °C with superior yield and
quality, and this reaction gave 90% yield of (S)-propranolol
diethyl carbonate KOH (1.0)
<20
a Reaction performed on a 10 mmol scale with respect to (WRT) S-
TGT. b By 1H NMR, c No reaction. d Starting material insoluble.
Among all the solvents tried, only MIBK showed some
promising result in which ∼40% formation of 6 was observed.
For a commercial process, this conversion seems to be very poor
and may not be acceptable for larger-scale production, hence we
decided to study other parameters such as molar ratios of
reagents, temperature, and dilution. Eventually we found that
∼0.3 equiv of base is sufficient for transformation. This reaction
provided greater than 75% yield with greater than 98% chiral
purity, and byproduct formation due to excessive hydrolysis of
oxazolidinones was minimized. The results are summarized in
Table 2.
Using 3 equiv of KOH we could isolate only 30% desired
product (Table 2, entry 1), whereas 0.25 equiv of KOH showed a
significant increase in yield (Table 2, entry 6). Reactions were
also attempted using 0.15, 0.3, 0.6, 1.25, and 1.5 equiv of base, but
satisfactory results were obtained only using 0.25 equiv of base
(Table 2, entry 6). An amount of 0.15 equiv of base showed
45ꢀ50% unreacted TGT (Table 2, entry 7) and after 3 h reaction
was found to be stagnant and degenerative, whereas 1.5 equiv of
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Table 3. Study of Base for Alkylationa
Beijing Tech Instrument Co Ltd. and are uncorrected. Varian 1H
NMR spectra (400 MHz) and 13CNMR spectra (100 MHz)
were recorded in CDCl3 and DMSO-d6, and mass spectra were
determined on an API-2000LCMS mass spectrometer (Applied
Biosciences).
Synthesis of (S)-5-((Naphthalen-4-yloxy)methyl)oxazoli-
din-2-one (6). (2S,20S,200S)-Tris-(2,3-epoxypropyl)-isocyanu-
rate (5 kg, 16.8 mol) was added to mixture of α-naphthol
(1.453 kg, 10.08 mol) and powdered potassium hydroxide
(250 g) containing moisture less than 6% in methyl isobutyl
ketone (25 L). The resulting reaction mass was heated to
110ꢀ115 °C for 2ꢀ3 h. After TLC (CHCl3:CH3OH; 9.5:0.5)
showed disappearance of S-TGT, it was cooled and maintained
under stirring at 5ꢀ10 °C for 2 h. The precipitated solid was
filtered and dissolved in DCM (250 L). The organic layer was
washed with 10% aqueous sodium hydroxide solution. The
DCM layer was washed with sodium chloride followed by dilute
hydrochloric acid and concentrated under vacuum, and the solid
was crystallized from MIBK (25 L) to give 9.8 kg of (S)-
5-((naphthalen-4-yloxy)methyl)oxazolidin-2-one (6) as an off-
white solid in 80% yield and greater than 97% HPLC purity and
greater than 99% chiral purity.
entry
base
temp (°C)
time (h)
yield 7 (%)b
1
2
3
4
5
6
7
KOtBu
KOtBu
K2CO3
NaH
0ꢀ10
45ꢀ55
45ꢀ55
0ꢀ10
45ꢀ55
45ꢀ55
45ꢀ55
3
3
5
3
3
5
5
10ꢀ15
10ꢀ15
10ꢀ15
50ꢀ55
80ꢀ85
no reaction
5ꢀ10
NaH
TEA
DBU
a Reaction performed on a 10 mmol scale WRT 6 in DMSO.
b Isolated yield.
Scheme 4
20
MP = 159 °C, [α]D = ꢀ25.54 (c = 0.5, CHCl3). MS(CI):
calcd for C14H13NO3 (M-H)/z, 242.26; found (M-H)/z, 242.2.
1H NMR (400 MHz, CDCl3): δ = 3.73ꢀ3.76 (m, 1H), 3.84ꢀ3.88
(m, 1H), 4.29ꢀ4.37 (m, 2H), 5.08ꢀ5.13 (m, 1H), 5.56 (br s, 1H),
6.79ꢀ6.81 (d, 1H, J = 7.55 Hz), 7.34ꢀ7.38 (t, 1H), 7.44ꢀ7.78
(m, 3H), 7.8 (d, 1H), 8.18 (d, 1H). Anal. calcd for C14H13NO3:
C, 69.12; H, 5.39; N, 5.76. Found: C, 69.21; H, 5.32; N, 5.69.
[Chiral HPLC analysis; Chiral Technologies CHIRALCEL
ADH column; eluent, n-hexane:ethanol:diethyl amine; flow rate,
1 mL/min; detector, 254 nm (tR = 10.6 min) (tS = 20.47 min).]
Synthesis of (S)-3-Isopropyl-5-((naphthalen-4-yloxy)met-
hyl)oxazolidin-2-one (7). (S)-5-((Naphthalen-4-yloxy)met-
hyl)oxazolidin-2-one (6) (3 kg, 12.33 mol) was added to a
mixture of sodium hydride 60% dispersion in mineral oil
(1.152 kg, 47.9 mol), in NMP (30 L) at 0ꢀ5 °C under an inert
atmosphere. 2-Bromopropane (4.92 kg, 40 mol) was added in
four equal lots over 20 min, and the reaction mass was gradually
heated to 60ꢀ65 °C for 4ꢀ6 h. After TLC (CHCl3:CH3OH;
9.5:0.5) showed disappearance of 6, it was cooled to 5ꢀ10 °C,
and methanol (3 L) was added and poured on ice cold water
(10 L). The product was filtered and washed with water (2 ꢁ
5 L). The solid was dried under reduced pressure to give 3.16 kg
of (S)-3-isopropyl-5-((naphthalen-4-yloxy)methyl)oxazolidin-
2-one (7) as an off-white solid in 90% yield with greater than
95% HPLC purity and greater than 99% chiral purity.
precursor 7. This reaction was also tested using 1.0 and 1.5 equiv
of NaH, respectively, but satisfactory yields were obtained with
2.3 equiv of NaH. These optimized conditions were later used for
the synthesis of (S)-metoprolol precursor 10.
Finally, alkaline hydrolysis of N-alkylated oxazolidinones 7
and 10 complete the synthesis of (S)-propranolol and (S)-
metoprolol in high overall yield and high chiral purity. These
free bases were later converted to their pharmaceutically active
salts to provide an active pharmaceutical ingredient using known
methods (Scheme 4).
MP = 95 °C, [α]D20 = 5.07 (c = 0.8, CHCl3). MS(CI): calcd
1
’ CONCLUSION
for C17H19NO3 (M+H)/z, 286.34; found (M+H)/z, 286. H
NMR (400 MHz, CDCl3): δ = 3.73ꢀ3.76 (m, 1H), 3.84ꢀ3.88
(m, 1H), 4.29ꢀ4.37 (m, 2H), 5.08ꢀ5.13 (m, 1H), 5.56 (br s, 1H),
6.79ꢀ6.81 (d, 1H, J = 7.55 Hz), 7.34ꢀ7.38 (t, 1H), 7.44ꢀ7.78 (m,
3H), 7.8 (d, 1H), 8.18 (d, 1H). Anal. calcd for C14H13NO3: C,
69.12; H, 5.39; N, 5.76. Found: C, 69.21; H, 5.32; N, 5.69.
[Chiral HPLC analysis; Chiral Technologies CHIRALCEL
ADH column; eluent, n-hexane:ethanol:diethyl amine; flow rate,
1 mL/min; detector, 254 nm (tR = 7 min) (tS = 8.14 min).]
Synthesis of (S)-Propranolol (1). 85% potassium hydroxide
flakes (9.55 kg, 170.3 mol) were added to a solution of 1:1
aqueous ethanol (54 L). The solution was stirred for 10 min,
and (S)-3-isopropyl-5-((naphthalen-4-yloxy)methyl)oxazolidin-
2-one (7) (2.7 kg, 9.46 mol) was added. The resulting reaction
In summary, a concise synthesis of (S)-propranolol and (S)-
metoprolol in high stereoselectivity has been achieved using the
readily available chiral synthon S-TGT as the key step and source
of chirality. The extension of the synthetic strategy described
here employing the versatile intermediate S-TGT is being
investigated for other chiral β-blockers.
’ EXPERIMENTAL SECTION
All materials were purchased from commercial suppliers.
Unless specified otherwise, all reagents and solvents were used
as supplied by manufacturers. Melting points were determined
by an open air capillary with an X-6 melting point apparatus
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mass was refluxed for 8ꢀ10 h. After completion of the reaction
(monitored by TLC, CHCl3:CH3OH; 9.5:0.5), the excess alkali
was neutralized by acetic acid (9 L), and product was extracted in
DCM (2 ꢁ 5 L). The organic layer was concentrated under
vacuum and flash chromatographed to give 1.44 kg of (S)-
propranolol in 73% yield and greater than 98% HPLC purity.
The compound was purified using The Reveleris Flash system
on 1.5 kg pf prepacked 40 μ silicagel cartridge supplied by Grace-
USA, and the mobile phase was ethyl acetate:cyclohexane (9:1).
7.13ꢀ7.26 (d, 2H). Anal. calcd for C13H17NO4: C, 62.14; H,
6.82; N, 5.57. Found: C, 62.1; H, 6.81; N, 5.61.
[Chiral HPLC analysis; Chiral Technologies CHIRALCEL
ADH column; eluent, n-hexane:ethanol:diethyl amine; flow rate,
0.8 mL/min; detector, 254 nm (tR = 17.09 min) (tS = 18.71
min).]
Synthesis of (S)-5-((4-(2-Methoxyethyl)phenoxy)methyl)-
3-isopropyloxazolidin-2-one (10). (S)-5-((4-(2-Methoxyeth-
yl)phenoxy)methyl)oxazolidin-2-one (9) (9 kg, 35.8 mol) was
added to a mixture of sodium hydride 60% dispersion in mineral
oil (3.15 kg, 78.76 mol), in NMP (45 L) at 0ꢀ5 °C under inert
atmosphere. 2-Bromopropane (14.94 kg, 121.45 mol) was added
in four equal lots over 20 min, and the reaction mass was
gradually heated to 60ꢀ65 °C for 5ꢀ6 h. After TLC (CHCl3:
CH3OH; 9.5:0.5) showed disappearance of 9, it was cooled to
5ꢀ10 °C, and methanol (6.5 L) was added and poured on ice
cold water (180 L). The product was filtered and washed with
water (2 ꢁ 15 L). The solid was dried under reduced pressure to
give 7.88 kg of ((S)-5-((4-(2-methoxyethyl)phenoxy)methyl)-3-
isopropyloxazolidin-2-one (10) as an off-white solid in 75% yield
and greater than 96% HPLC purity and greater than 99% chiral
purity.
MP = 92 °C,34 [α]D = ꢀ21.6 (c = 1.02, EtOH). MS(CI)
20
calcd for C16H21NO2 (M+H)/z, 260.34; found (M+H)/z,
260.1. 1H NMR (400 MHz, CDCl3): δ = 1.32 (d, 6H), 3.07ꢀ
3.25 (m, 3H), 4.09ꢀ4.23 (m, 2H), 4.49 (m, 1H), 5.52 (br s, 2H),
6.78 (d, J = 7.5 Hz, 1H), 7.25ꢀ7.50 (m, 4H), 7.77ꢀ7.81 (m,
1H), 8.20ꢀ8.26 (m, 1H). Anal. calcd for C16H21NO2: C, 74.1;
H, 8.16; N, 5.4. Found: C, 74.2; H, 8.19; N, 5.51.
[Chiral HPLC analysis; Chiral Technologies CHIRALCEL
OD-R column; eluent, 0.1 M sodium perchlorate/acetonitrile =
60/40; flow rate, 0.5 mL/min; detector, 254 nm (tS = 14.1 min)
(tR = 15.27 min), Chiral purity: 99.88%.]
Synthesis of (S)-Propranolol Hydrochloride. To a solution
of (S)-propranolol (1) (1.3 kg, 5.01 mol) in isopropanol (8 L)
was bubbled dry HCl gas at 0ꢀ5 °C for 30 min, and the resulting
solid was filtered and dried under vacuum to give 1.23 kg of (S)-
propranolol hydrochloride in 84% yield and greater than 99.7%
HPLC purity.
[α]D20 = 31.2 (c = 0.8, CHCl3) MS(CI) calcd for C16H23NO4
(M+H)/z, 294.36; found (M+H)/z, 294.1. 1H NMR (400 MHz,
CDCl3): δ = 1.19ꢀ1.21 (d, 2H), 2.80ꢀ2.84 (t, 2H), 3.34 (s,
3H), 3.46ꢀ3.49 (m, 1H), 3.54ꢀ3.58 (t, 2H), 3.62ꢀ3.66 (t, 1H),
4.04ꢀ4.17 (m, 1H), 4.77ꢀ4.83 (m, 1H), 6.81ꢀ6.83 (d, 2H),
7.13ꢀ7.26 (d, 2H). Anal. calcd for C16H23NO4: C, 65.51; H, 7.9;
N, 4.77. Found: C, 65.41; H, 7.72; N, 4.71.
[Chiral HPLC analysis; Chiral Technologies CHIRALCEL
ADH column; eluent: n-hexane:ethanol:diethyl amine; flow rate,
0.8 mL/min; detector, 254 nm (tR = 9.5 min) (tS = 10.69 min).]
Synthesis of (S)-Metoprolol (2). Potassium hydroxide flakes
(85%, 25.23 kg, 449.74 mol) were added to a solution of 1:1
aqueous ethanol (143 L). The solution was stirred for 10 min,
and (S)-5-((4-(2-methoxyethyl)phenoxy)methyl)-3-isopropyloxa-
zolidin-2-one (10) (7 kg, 23.86 mol) was added. The resulting
reaction mass was refluxed for 8ꢀ10 h. After TLC (CHCl3:
CH3OH; 9.5:0.5) showed completion of reaction, excess alkali
was neutralized by acetic acid (∼22 L), and product was
extracted in DCM (2 ꢁ 30 L). The organic layer was concen-
trated under reduced pressure to give 5.36 kg of (S)-metoprolol
in 83% yield and greater than 95% HPLC purity as a semisolid
mass and greater than 99% chiral purity.
20
MP = 194ꢀ195 °C, [α]D = ꢀ25.6 (c = 1.05, EtOH); lit.
MP6,7 194ꢀ196 °C, [α]D20 = ꢀ25.6 (c = 1.05, EtOH). MS(CI)
calcd for C16H21NO2 (M+H)/z, 260.34; found (M+H)/z,
1
260.1. H NMR (400 MHz, D2O): δ = 1.40ꢀ1.42 (d, 6H),
3.34ꢀ3.59 (m, 3H), 4.27ꢀ4.36 (m, 2H), 4.48ꢀ4.8 (m, 1H),
7.03ꢀ7.05 (d, 1H), 7.51ꢀ7.55 (t, 1H), 7.61ꢀ7.96 (m, 3H),
7.98ꢀ7.99 (d, 1H), 8.30ꢀ8.32 (m, 1H). Anal. calcd for
C16H22ClNO2: C, 64.97; H, 7.50; N, 4.74. Found: C, 64.88;
H, 7.44; N, 4.71.
[Chiral HPLC analysis; Chiral Technologies CHIRALCEL
OD-R column; eluent, 0.1 M sodium perchlorate/acetonitrile =
60/40; flow rate, 0.5 mL/min; detector, 254 nm (tS = 14.1 min)
(tR = 15.27 min); chiral purity, 99.88%.]
Synthesis of (S)-5-((4-(2-Methoxyethyl)phenoxy)methyl)-
oxazolidin-2-one (9). S-TGT (5 kg, 16.8 mol) was added to a
mixture of 4-(2-methoxyethyl) phenol (8) (7.65 kg, 50.4 mol)
and powdered potassium hydroxide (250 g) containing moisture
less than 6% in methyl isobutyl ketone (25 L). The resulting
reaction mass was heated to 110ꢀ115 °C for 2ꢀ3 h. After TLC
(CHCl3:CH3OH; 9.5:0.5) showed disappearance of S-TGT, it
was cooled and maintained under stirring at 0ꢀ10 °C for 2 h.
The precipitated solid was filtered and washed with cold MIBK
(20 L), and the wet cake was dissolved in DCM (30 L). The
organic layer was washed with 10% aqueous sodium hydroxide
solution to remove unreacted phenol. The DCM layer was
washed with sodium chloride followed by dilute hydrochloric
acid and concentrated under vacuum, and the solid was cry-
stallized from methanol (6 L) to give 9.5 kg of (S)-5-((4-
(2-methoxyethyl)phenoxy)methyl) oxazolidin-2-one (9) as an
off-white solid in 75% yield in greater than 97% HPLC purity and
greater than 99% chiral purity.
[α]D20 = ꢀ8.72 (c = 10, CHCl3).29 MS(CI) calcd for C15H25-
NO3 (M+H)/z, 268.36; found (M+H)/z, 268.1. 1H NMR (400
MHz, CDCl3): δ = 1.08ꢀ1.09 (d, 6H), 2.62 (br s, 2H),
2.69ꢀ2.85 (m, 5H), 3.34 (s, 3H), 3.54 (t, 2H), 3.92ꢀ3.99 (m,
2H), 4.01ꢀ4.03 (m, 1H), 6.83ꢀ6.85 (d, 2H), 7.11ꢀ7.26 (d,
2H). Anal. calcd for C15H25NO3: C, 67.38; H, 9.42; N, 5.24.
Found: C, 67.41; H, 9.72; N, 5.71.
[Chiral HPLC analysis; DAICEL CHIRALCEL OD (4.6 ꢁ
25 cm) column; eluent, hexane/ethylalcohol/diethylamine = 70/
30/0.1; flow rate, 0.5 mL/min; detector, 254 nm (tR = 9.7 min)
(tS = 11.77 min); chiral purity: 99.8%.]
Synthesis of (S)-Metoprolol Succinate. (S)-Metoprolol (2)
(1.45 kg, 5.423 mol) was dissolved in acetone (4.35 L) and
stirred for 10 min. Succinic acid (667 g, 6.6 mol) was added, and
the resulting reaction mass was refluxed for 1 h. The clear
reaction mass was gradually cooled to 5ꢀ10 °C and stirred
for 30ꢀ60 min. The precipitated (S)-metoprolol succinate was
filtered and washed with cold acetone (500 mL), and the resulting
MP = 107 °C, [α]D20 = 8.45 (c = 0.5, CHCl3). MS(CI) calcd
for C13H17NO4 (M+Na)/z, 274.28; found (M+Na)/z, 274.1. 1H
NMR (400 MHz, CDCl3): δ = 2.8ꢀ2.84 (t, 2H), 3.34 (s, 3H),
3.52ꢀ3.62 (m, 3H), 3.73ꢀ3.78 (t, 1H), 4.08ꢀ4.16 (m, 2H),
4.92ꢀ4.98 (m, 1H), 5.66 (br s, 1H), 6.74ꢀ6.84 (d, 2H),
1369
dx.doi.org/10.1021/op2001518 |Org. Process Res. Dev. 2011, 15, 1365–1370

Organic Process Research & Development
COMMUNICATION
solid was dried under vacuum to give 1.8 kg of (S)-metoprolol
succinate in 85% yield and greater than 99.7% HPLC purity as a
white solid.
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[α]D20 = ꢀ16.2 (c = 1, MeOH), MP = 107ꢀ108 °C. MS(CI):
calcd for C15H25NO3 (M+H)/z, 268.36; found (M+H)/z,
1
268.1. H NMR (400 MHz, DMSO-d6): δ = 1.09ꢀ1.12 (d,
6H), 2.23 (s, 2H), 2.49ꢀ2.92 (m, 4H), 3.03ꢀ3.06 (m, 1H), 3.18
(s, 3H), 3.43ꢀ3.46 (t, 2H), 3.92ꢀ3.99 (m, 2H), 4.01ꢀ4.03 (m,
1H), 6.83ꢀ6.81 (d, 2H), 7.08ꢀ7.11 (d, 2H). Anal. calcd for
C15H25NO3C4H6O4: C, 59.20.38; H, 8.11; N, 3.63. Found: C,
59.18; H, 8.32; N, 3.71.
[Chiral HPLC analysis; DAICEL CHIRALCEL OD (4.6 ꢁ
25 cm) column; eluent, hexane/ethylalcohol/diethylamine = 70/
30/0.1; flow rate, 0.5 mL/min; detector, 254 nm (tR = 9.7 min)
(tS = 11.77 min); chiral purity, 99.8%.]
’ ASSOCIATED CONTENT
S
Supporting Information. Additional characterization
b
data of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) (a) Damle, S. V.; Patil, P. N.; Salunkhe, M. M. Synth. Commun.
1999, 29, 3855. (b) Damle, S. V.; Patil, P. N.; Salunkhe, M. M. Synth.
Commun. 1999, 29, 1369.
(26) Pamies, O.; Baeckwall, J. E. J. Org. Chem. 2001, 66, 4022.
(27) Kamal, A.; Sandbhor, M.; Shaik, A. Bioorg. Med. Chem. Lett.
2004, 14, 4581.
’ AUTHOR INFORMATION
Corresponding Author
*Fax: +91-20-39821445. E-mail: swapnil.sonawane@emcure.
co.in.
(28) Gurjar et al. , U. S. Patent 6,982,349.
(29) Muthukrishnan, M.; Garud, D.; Joshi, R. R.; Joshi, R. A.
Tetrahedron 2007, 63, 1872.
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(31) Ikeda et al. , E. P. Patent 1,375,498 A1.
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(33) Lee et al. , U. S. Patent 6,562,980.
(34) Sayyed, I. A.; Thakur, V. V.; Nikalje, M. D.; Dewkar, G. K.;
Kotkar, S. P.; Sudalai, A. Tetrahedron 2005, 61, 2831.
’ ACKNOWLEDGMENT
The authors wish to thank Mr. Samit S. Mehta, Emcure
Pharmaceuticals Ltd., for generous support and constant en-
couragement. The authors also wish to thank Dr. Milind M.
Gharpure for the chemistry inputs and Mr. Satyajeet Biswas for
analytical support. Finally, it is a pleasure to acknowledge the
reviewers and Editor for valuable suggestions.
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