An Asymmetric Synthesis of Rosuvastatin Calcium

Article abstract of DOI:10.1055/s-0035-1562787

A novel asymmetric synthesis of a (3R,5S)-dihydroxyhexanoic ester is described. The ester, which serves as the precursor for generating the side chain of rosuvastatin, is synthesized from d-glucose and subsequently coupled, under Wittig olefination condit

Full text of DOI:10.1055/s-0035-1562787

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
N. Vempala et al.
Paper
Synthesis
An Asymmetric Synthesis of Rosuvastatin Calcium
Naresh Vempalaa,b
OH
OH
OH
OH
O
O
O
Settipalli Venkateswara Raoa
Anireddy Jaya Shreeb
Braja S. Pradhan*a
6 steps
5 steps
HO
Ph3CO
CN
HO
O
O
OH
D-glucose
OH
Wittig reaction
a Primodia Chemicals and Pharmaceuticals Pvt. Ltd., R & D
Centre, 4th Floor, S-9, T.I.E, Phase-II, Gate-1, Balanagar,
Hyderabad, 500 037, India
Ca2+
OH OH
O
O
O
–
CO2
2 steps
brajasundar@yahoo.com
N
O
N
O
O
1 step
O
O
b Centre for Chemical Sciences and Technology, Institute of
Science and Technology, Jawaharlal Nehru Technological
University Hyderabad, Kukatpally, Hyderabad, 500 085,
India
S
S
Me
N
Me
N
Me
N
Me
N
F
F
2
rosuvastatin calcium
overall yield: 3.5% in 14 steps
Received: 15.04.2016
Accepted after revision: 20.06.2016
Published online: 16.08.2016
Ca2+
OH OH
–
DOI: 10.1055/s-0035-1562787; Art ID: ss-2016-n0254-op
CO2
N
O
O
Abstract A novel asymmetric synthesis of a (3R,5S)-dihydroxyhexano-
ic ester is described. The ester, which serves as the precursor for gener-
ating the side chain of rosuvastatin, is synthesized from D-glucose and
subsequently coupled, under Wittig olefination conditions, with a
phosphonium ylide derived from an appropriately substituted pyrimi-
dine moiety. The coupling results in the formation of a precursor con-
taining all the structural features of rosuvastatin. This precursor is con-
verted into rosuvastatin calcium following a well-established procedure.
S
Me
N
Me
N
F
2
1
Figure 1 Structure of rosuvastatin calcium
with a 4-fluorophenyl ring, a methane sulfonamide group
and an isopropyl group.
Key words total synthesis, rosuvastatin calcium, Wittig olefination,
lactone reduction, diastereoselective reduction, sugar chemistry, D-
glucose
The retrosynthetic analysis of rosuvastatin calcium (1)1
is illustrated in Scheme 1. The ester 2 serves as the key in-
termediate from which rosuvastatin calcium is synthesized.
Disconnecting the ester 2 at the double bond provides two
obvious fragments, a pyrimidine moiety and a hexanoic es-
ter moiety. The phosphonium salt 3, based on the substitut-
ed pyrimidine fragment, can be coupled with the aldehyde
4 under Wittig olefination conditions to provide the desired
ester 2. The aldehyde 4 can be obtained from D-glucose.
Rosuvastatin has evoked much interest as a synthetic
target by many research groups.2 Watanabe and co-work-
ers3 were the first to report a synthesis of rosuvastatin cal-
cium (Scheme 2). Their synthesis involved coupling the
substituted pyrimidine3 6 with the resonance-stabilized
phosphonium ylide4 7 under Wittig olefination conditions.
The coupling resulted in the formation of key rosuvastatin
precursor 8. The precursor was converted into rosuvastatin
calcium in four synthetic operations, including a step that
involved diastereoselective reduction5 of a carbonyl group
using diethylmethoxyborane and sodium borohydride at
–78 °C. The ylide 7 was synthesized from diethyl 3-hydroxy-
Rosuvastatin1 belongs to a class of drugs called HMG-
CoA reductase inhibitors. These inhibitors are widely
known as statins and have been found to be effective in
combating hypercholesterolemia (elevated cholesterol lev-
els). Rosuvastatin is the most recent entrant into this class
(Figure 1). It is widely prescribed for the treatment of hy-
percholesterolemia.
Rosuvastatin, like all the other drugs in this class, has a
heptanoic acid side chain possessing two chiral centers at
positions C-3 and C-5 on its backbone. Each center bears a
hydroxy group and the absolute configurations of the
groups are R and S, respectively. However, the structural
similarity of rosuvastatin with other statins ends here. The
structural feature that distinguishes it from the others in
the group is the presence of a substituted pyrimidine ring
attached to the aliphatic side chain through a carbon–car-
bon double bond having E stereochemistry. The remaining
three available positions on the pyrimidine are substituted
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
N. Vempala et al.
Paper
Synthesis
cium following well-established synthetic operations.7 The
hexanoic ester 4 was prepared8 from L-malic acid in nine
steps, including a step that involved diastereoselective re-
duction using triethylborane and sodium borohydride.
Ca2+
OH OH
–
CO2
N
O
O
S
Me
N
N
Me
Br–
F
1
2
O
O
+
N
PPh3
O
O
O
CO2t-Bu
S
+
Me
N
N
Me
3
4
O
O
O
F
N
O
O
O
S
O
O
Me
N
N
Me
CO2t-Bu
N
F
O
O
2
rosuvastatin
calcium
S
Me
N
N
Me
2
Br–
PPh3
F
O
O
O
+
Scheme 3 An alternative synthetic strategy for the synthesis of rosu-
N
+
O
O
O
vastatin calcium6
O
S
Me
N
N
H
Me
4
3
The notable difference between both synthetic strate-
gies lies in the way the 1,3-dihydroxyheptanoic acid side
chain is installed in the molecule. The second strategy of-
fers an additional advantage because the aldehyde 4 has the
potential to be used for generating the side chain of other
statins. For this reason, we embarked upon an investigation
of the second synthetic strategy to synthesize rosuvastatin
calcium.
F
H
O
O
OH
D-glucose
OH
HO
5
Scheme 1 Retrosynthetic analysis of rosuvastatin calcium
From the point of view of industrial operations, the sec-
ond synthetic strategy demands the development of a prac-
tical synthesis of the aldehyde 4. Many synthetic strategies
for the synthesis of this aldehyde8,9 have been reported. We
have developed an alternative, practical route for the manu-
facture of this aldehyde. The notable features of this route
are that it uses a cheap starting material, avoids the Narasaka
reduction5 and the use of reagents such as n-butyllithium
and sodium bis(trimethylsilyl)amide. D-Glucose, which is
cheap and readily available in 100% optical purity, was used
as the starting material in our route. It was carried through
reliable synthetic operations using readily available re-
agents to furnish the required aldehyde 4.
glutarate in nine steps. The synthesis required stereoselec-
tive desymmetrization of a prochiral anhydride intermedi-
ate with the lithium salt of benzyl (R)-mandelate at –78 °C.
O
OTBS
CHO
N
Ph3P
CO2Me
O
O
+
S
Me
N
N
7
Me
6
F
O
OTBS
Our synthesis10 commenced with the preparation of a
tritylated lactone (Scheme 4). D-Arabino lactone 5, which
was prepared11,12 on a commercial scale in excellent yield
from D-glucose, was treated with trityl chloride and pyri-
dine to furnish the tritylated lactone 9 in 96% yield.
CO2Me
N
O
O
rosuvastatin
calcium
S
Me
N
N
Me
8
F
The lactone 9 was treated with methanesulfonyl chlo-
ride and pyridine triggering β-elimination13 of the hydroxy
group and generated a double bond in the molecule. The
α,β-unsaturated lactone 10 thus formed was subsequently
reduced by catalytic hydrogenation in ethyl acetate at 110
psi using 5% palladium over charcoal (10% w/w, Pd/C) as the
catalyst. The saturated lactone 11 was obtained in 90%
yield. The reduction, as predicted, was highly diastereose-
Scheme 2 The first reported synthesis of rosuvastatin calcium3
An alternative synthetic strategy6 (Scheme 3) involved
Wittig olefination between the phosphonium ylide 36b and
the fully functionalized aliphatic hexanoic ester 4. The reac-
tion resulted in the formation of the rosuvastatin precursor
2, which was subsequently converted into rosuvastatin cal-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
N. Vempala et al.
Paper
Synthesis
The cyano compound 14 precipitated out from the reac-
tion mixture on cooling. It was filtered off and carried over
to the following step as a wet mass. The wet mass was re-
fluxed in methanol with an aq solution of sodium hydrox-
ide at 70 °C for 15 hours to give the acid 15 as its sodium
salt. The salt 15 precipitated out from the reaction mixture
during concentration. The precipitate was filtered off, dried
and carried over to the following step without further puri-
fication. The overall yield of the salt 15 over four steps was
68%.
H
H
O
O
O
refs. 11, 12
O
a
D-glucose
RO
H
HO
OH
HO
OH
HO
9
5
H
O
O
O
O
c
b
RO
RO
OSO2Me
OSO2Me
10
11
R = Ph3C
In the next step, the sodium salt 15 was treated with 2-
bromopropane in dimethylformamide to provide the iso-
propyl ester 16 in 78% yield. With the ester 16 in hand, our
research was then directed toward finding appropriate re-
agents and conditions to deprotect the trityl group. The re-
moval of the trityl group, which had served so well not only
in controlling the facial selectivity of the hydrogenation but
also facilitating the isolation of the intermediates, proved
challenging. A host of reagents known for removing trityl
groups were utilized. Amongst all these reagents, ferric
chloride15 was the best, cleanly removing the trityl group in
dichloromethane at –10 °C to provide the desired triol. The
triol was not isolated from the reaction mixture, but was
instead treated in situ with acetyl chloride and pyridine at –
78 °C. The reaction resulted in selective acetylation of the
primary hydroxy group to furnish the acetate 17 in 67%
yield. The acetate 17 was then treated with 2,2-dimethoxy-
propane, acetone and a catalytic amount of pyridinium p-
toluenesulfonate (PPTS)16 to protect both the hydroxy
groups. The isopropylidene derivative 18 thus obtained was
subjected to Zemplén saponification17 with methanol and a
catalytic amount of sodium methoxide to furnish alcohol
19. The alcohol 19 was oxidized using sodium hypochlorite,
potassium bromide and a catalytic amount of TEMPO18 in a
biphasic reaction medium of water and dichloromethane.
The oxidation provided the aldehyde 4 in 81% yield (Scheme
6).
Scheme 4 Reagents and conditions: (a) trityl chloride, pyridine, –10 °C
to r.t., 22 h, 96%; (b) MsCl, pyridine, N2, –14 °C to –8 °C, 8 h, 60%; (c) 5%
Pd/C, EtOAc, H2, 110 psi, 15 °C, 24 h, 90%.
lective; the undesired diastereoisomer could not be detect-
ed. The steric hindrance stemming from the bulk of the tri-
tyl protecting group dictated effectively the facial selectivi-
ty of the hydrogenation, forcing hydrogen to approach
preferentially the surface of the double bond from the less
hindered side. The relative stereochemistry of the chiral
center bearing the methanesulfonyl group was determined
unequivocally by NOESY NMR spectroscopy.
The lactone 11 was reduced using one equivalent of so-
dium borohydride in a mixture of methanol and dichloro-
methane (2:3 v/v) (Scheme 5). Under the mildly basic con-
ditions of reduction, the primary hydroxy group acted as a
nucleophile and displaced the neighboring mesyl group in
an SN2 fashion, providing the epoxide 13. The epoxide was
not isolated but was treated in situ with sodium cyanide.
The reaction opened up the epoxide ring14 to provide an
elongated carbon skeleton, attaching a nitrile functional
group at the site of opening. The ring-opening seemed to
occur exclusively from the primary carbon side of the epox-
ide, as evidenced from the fact that the other regioisomer
could not be detected.
OH OSO2Me
OH OH
O
Ph3CO
OH
H
a
b
O
Ph3CO
O
15
b
a
O
12
Ph3CO
16
OSO2Me
11
O
O
O
OH OH
O
OH
c
O
AcO
AcO
Ph3CO
O
O
18
O
4
17
13
OH OH
OH OH
O
O
O
O
O
O
c
d
CO2– Na+
e
Ph3CO
CN
Ph3CO
O
HO
O
15
14
19
Scheme 5 Reagents and conditions: (a) NaBH4, CH2Cl2/MeOH, r.t., 20 h;
(b) NaCN, H2O, 0 °C to r.t., 48 h; (c) NaOH, H2O, MeOH, 70 °C, 15 h; 68%
overall yield in 4 steps.
Scheme 6 Reagents and conditions: (a) 2-bromopropane, DMF, 65 °C,
78%; (b) (i) FeCl3·6H2O, CH2Cl2, –10 °C, 3 h, MgSO4; (ii) AcCl, pyridine,
–78 °C, N2, 4 h, 67% (2 steps); (c) acetone, 2,2-dimethoxypropane,
PPTS, 15 h, 80%; (d) NaOMe, MeOH, –10 °C, 2 h, 98%; (e) TEMPO, NaOCl,
KBr, H2O, CH2Cl2, –5 °C, 81%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
N. Vempala et al.
Paper
Synthesis
The aldehyde 4 was then coupled with the triphenyl-
phosphonium salt of the pyrimidine moiety 3 under Wittig
olefination conditions (Scheme 7) in dimethyl sulfoxide at
70 °C under the influence of potassium carbonate. The cou-
pling provided the ester 2 in 62% yield. The ester was con-
verted into rosuvastatin calcium following a well-estab-
lished procedure.7 The diastereomeric excess of rosuvasta-
tin calcium was found to be >99% de. The melting point of
rosuvastatin calcium salt was found to be 147–154 °C (Lit.7f
145–150 °C).
using Merck aluminum coated silica gel 60 F254 plates. Yields refer to
crude compounds unless otherwise noted. Specific optical rotations
were recorded on a Rodolph Autopol V Polarimeter. Melting points
were obtained using an SRS Optimelt MPA 100 melting point appara-
tus. Infrared spectra were recorded on an FT IR Bruker Alpha T spec-
trometer using OPUS software. 1H NMR (300 or 400 MHz) and 13C
NMR (75 or 100 MHz) spectra were recorded using Bruker and Varian
spectrometers and CDCl3 or DMSO-d6 as the solvent. Chemical shifts
are reported in parts per million relative to CDCl3 (1H, δ 7.24; 13C, δ
77.0) or DMSO-d6 [1H, δ 2.50 (quin, JH–D = 1.9 Hz); 13C, δ 39.5]. Data are
reported as follows: chemical shift, multiplicity (s = singlet, d = dou-
blet, dd = doublet of doublets, t = triplet, sept = septet, m = multiplet,
br = broad), coupling constant, integration. Mass spectra were ob-
tained using an Agilent 6400 Series Triple Quad LC/MS system version
B.06.00. HRMS (ESI)+ spectra were obtained with an Agilent 6250 Q-
TOF instrument. The diastereomeric ratio of the final product was de-
termined by HPLC.
Br–
O
O
O
+
N
PPh3
O
O
O
+
S
O
Me
N
Me
N
4
a
3
F
5-O-(Triphenylmethyl)-3-deoxy-2-O-(methanesulfonyl)-D-glycero-
pent-2-enono-1,4-lactone (10)
O
O
O
Methanesulfonyl chloride (4.6 kg, 40.15 mol) was added dropwise to
a cold solution of the tritylated lactone 9 (6.85 kg, 17.56 mol) in pyri-
dine (9.71 kg, 122.76 mol) over a period of 8 h under nitrogen. During
the addition, the temperature of the mixture was maintained be-
tween –14 °C and –8 °C. After completion of the addition, the mixture
was stirred at this temperature for 5 h. The mixture was poured onto
crushed ice (15 kg) and stirred for 0.5 h. The precipitated solid was
filtered off and washed thoroughly with H2O. To purify further, the
solid was slurried with i-PrOH and filtered. This process was repeated
one more time. The solid thus obtained was air dried to furnish the
crude α,β-unsaturated lactone 10 (6 kg). The crude material (6 kg)
was dissolved in EtOAc (60 L) and the solution was heated to reflux.
Activated charcoal (2.4 kg) was then added to the solution at this tem-
perature. After 1 h at reflux, the hot solution was filtered through a
pad of Celite and the pad washed with hot EtOAc (3 L). The washings
were combined with the filtrate, concentrated to a volume of approx-
imately 40 L and cooled to r.t. The precipitated solid was filtered and
dried to give the desired α,β-unsaturated lactone 10 (4.74 kg, 60%) as
a white solid.
N
O
O
O
S
Me
N
Me
N
F
2
b
Ca2+
OH OH
–
CO2
N
O
O
S
Me
N
Me
N
F
2
1
Scheme 7 Reagents and conditions: (a) K2CO3, DMSO, N2, 70 °C, 4 h,
62%; (b) (i) HCl, MeCN, r.t., 5 h, tert-butylamine, –5 °C to r.t., 1 h, 70%;
(ii) NaOH, 40 °C, 1 h, Ca(OAc)2, H2O, r.t., 1 h, 85%.
25
[α]D –42.3 (c 0.5, CHCl3); mp 182.5–184.7 °C; Rf = 0.33 (hexane/
EtOAc, 7:3).
In conclusion, we have reported the synthesis of rosu-
vastatin calcium (1) in 3.5% overall yield and a total of 14
steps. A novel asymmetric synthesis of (3R,5S)-dihydroxy-
hexanoic ester 4 starting from D-glucose, and subsequent
coupling with the phosphonium ylide 36b under Wittig ole-
fination conditions gave appropriately functionalized pre-
cursor 2. This precursor was converted into rosuvastatin
calcium following the literature procedure.7 The synthesis
has the potential to be scaled up and adopted for the indus-
trial production of rosuvastatin.
IR (KBr): 3134, 2930, 1783, 1594, 1400, 1334, 1257, 1212, 1181, 1114,
1073, 1028 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.40 (m, 6 H), 7.39–7.30 (m, 6 H),
7.30–7.25 (m, 3 H), 7.10 (d, J = 2.0 Hz, 1 H), 5.12–5.04 (m, 1 H), 3.54
(dd, J = 4.4, 10.4 Hz, 1 H), 3.43 (dd, J = 4.8, 10.4 Hz, 1 H), 3.34 (s, 3 H).
13C NMR (100 MHz, CDC13): δ = 165.9, 143.0, 137.7, 135.2, 128.5,
128.0, 127.4, 87.2, 78.0, 63.0, 39.5.
MS: m/z = 449 [M – H]–.
HRMS: m/z (M – H)– calcd for C25H21O6S: 449.1054; found: 449.3904.
5-O-(Triphenylmethyl)-3-deoxy-2-O-(methanesulfonyl)-D-threo-
pentono-1,4-lactone (11)
All reactions were carried out in oven- or flame-dried glassware un-
der a moisture-free atmosphere. Pyridine was distilled prior to use.
All other reagents were used as supplied. CH2Cl2, EtOAc, MeOH, ace-
tone, hexane, DMF, toluene, DMSO and i-PrOH were obtained from
commercial sources and used as supplied without distillation. LR
grade MeCN was used. Unless otherwise noted, reactions were me-
chanically stirred and monitored by thin-layer chromatography (TLC)
The α,β-unsaturated lactone 10 (120 g, 266.4 mmol) was dissolved in
EtOAc (1200 mL) at 70 °C. After complete dissolution, the mixture was
allowed to cool to 35 °C and charged into an autoclave. 5% Pd/C (12 g)
was added to the solution under nitrogen. The mixture was cooled to
15 °C and stirred at this temperature under a hydrogen pressure of
110 psi until the reaction was complete as indicated by TLC. The mix-
ture was filtered through a pad of Celite. The Celite pad was washed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
N. Vempala et al.
Paper
Synthesis
with EtOAc (100 mL). The washings were combined with the filtrate
and concentrated under reduced pressure at 40 °C. The saturated lac-
tone 11 (109 g, 90%) was obtained as a white solid.
[α]D25 –7.9 (c 0.5, CHCl3); mp 129.5–130.8 °C; Rf = 0.25 (hexane/EtOAc,
(3 × 400 mL). The aq layer was concentrated under reduced pressure
at 70 °C to furnish a gummy solid. Toluene (300 mL) was added to the
gummy compound and the mixture was concentrated under vacuum
at 70 °C. This process was repeated to furnish the sodium salt of the
tritylated acid 15 (196 g, 68% in 4 steps) as a white solid.
7:3).
The salt 15 (196 g, 457.4 mmol) was suspended in DMF (588 mL) and
2-bromopropane (128 mL, 1.37 mol) was added to the stirred suspen-
sion at r.t. The mixture was heated to 65 °C and maintained at this
temperature for 15 h after which time another batch of 2-bromopro-
pane (85.66 mL, 914.8 mmol) was added. After 7 h at this tempera-
ture, a third batch of 2-bromopropane (85.66 mL, 914.8 mmol) was
added and the mixture was maintained at this temperature until the
reaction was complete (approximately 15 h) as indicated by TLC. The
reaction mixture was concentrated, first at atmospheric pressure at
60 °C to recover unreacted 2-bromopropane, and then under reduced
pressure at 60 °C to remove DMF. The resulting oil was dissolved in
EtOAc (588 mL), and the organic layer was washed with H2O (500 mL),
10% aq NaHCO3 solution (2 × 200 mL), H2O (2 × 250 mL) and brine
(500 mL), then dried over Na2SO4 and concentrated under reduced
pressure at 40 °C. The isopropyl ester 16 (160 g, 78%) was obtained as
a colorless syrup.
IR (KBr): 3135, 2933, 1782, 1594, 1489, 1400, 1257, 1215, 1172 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.40 (m, 6 H), 7.37–7.28 (m, 6 H),
7.28–7.22 (m, 3 H), 5.40–5.35 (dd, J = 9.2, 10.0 Hz, 1 H), 4.60–4.50 (m,
1 H), 3.44 (dd, J = 3.6, 10.8 Hz, 1 H), 3.28 (s, 3 H), 3.26 (dd, J = 5.2, 10.8
Hz, 1 H), 2.80–2.60 (m, 1 H), 2.50–2.30 (m, 1 H).
13C NMR (100 MHz, CDC13): δ = 170.9, 143.0, 128.5, 128.0, 127.0, 86.9,
76.0, 73.8, 64.0, 39.6, 31.0.
MS: m/z = 451 [M – H]–.
HRMS: m/z (M – H)– calcd for C25H23O6S: 451.1212; found: 451.3105.
(3S,5S)-3,5-Dihydroxy-6-(trityloxy)hexanenitrile (14)
NaBH4 (25.5 g, 674.0 mmol) was added to a solution of the saturated
lactone 11 (305 g, 674.0 mmol) in a mixture of CH2Cl2 (915 mL) and
MeOH (610 mL) at –10 °C over a period of 0.5 h. After completion of
the addition, the mixture was stirred for 1 h at –5 °C, allowed to
warm to r.t. and stirred at this temperature for 20 h. The mixture was
filtered and the residue washed with MeOH (200 mL). The washing
was combined with the filtrate and the combined organic layer con-
centrated under reduced pressure at 35 °C to recover CH2Cl2. To the
concentrated mixture thus obtained, MeOH (915 mL) was added and
the mixture was cooled to 0 °C. An aq solution of NaCN (82.66 g, 1.68
mol dissolved in 610 mL of H2O) was added and the mixture was al-
lowed to warm to r.t. and stirred for 48 h at this temperature. The
mixture was cooled to 0 °C, H2O (610 mL) was added and the mixture
was stirred for 0.5 h. The precipitated material was filtered off and
washed with cold H2O (100 mL) to furnish the cyano compound 14
(260 g) as a white gummy solid. The material was carried over to the
next step without drying or further purification.
[α]D25 –1.2 (c 0.5, CHCl3); Rf = 0.55 (hexane/EtOAc, 7:3).
IR (KBr): 3137, 1723, 1594, 1400, 1327, 1109, 1071, 991 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.20 (m, 15 H), 5.10 (sept, J = 6.3
Hz, 1 H), 4.30–4.20 (m, 1 H), 4.10–4.00 (m, 1 H), 3.90–3.70 (m, 1 H),
3.40–3.20 (m, 1 H), 3.20–3.10 (m, 2 H), 2.60–2.40 (m, 2 H), 1.80–1.50
(m, 2 H), 1.25 (d, J = 6.3 Hz, 6 H).
13C NMR (100 MHz, CDC13): δ = 171.0, 143.0, 128.0, 127.9, 127.8,
127.2, 127.1, 86.0, 71.0, 68.3, 68.2, 67.0, 41.0, 39.0, 21.0.
MS: m/z = 449 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C28H32O5Na: 471.2142; found:
471.2153.
[α]D25 +15.9 (c 0.5, CHCl3); Rf = 0.16 (hexane/EtOAc, 6:4).
Isopropyl (3R,5S)-6-Acetoxy-3,5-dihydroxyhexanoate (17)
Ferric chloride hexahydrate (FeCl3·6H2O) (250 g, 928.0 mmol) was
added to a solution of the isopropyl ester 16 (320 g, 713.4 mmol) in
CH2Cl2 (3.84 L) at –10 °C under nitrogen. The mixture was stirred at
this temperature for 3 h when the reaction was complete as indicated
by TLC. MgSO4 (640 g) was added and the mixture was stirred for 10
min at this temperature. Pyridine (172.6 mL, 2.14 mol) was then add-
ed and the mixture was stirred at this temperature for a further 10
min. The mixture was cooled to –78 °C and CH3COCl (76.9 mL, 1.07
mol) was added at this temperature under nitrogen over a period of 1
h. The mixture was stirred under these conditions until the reaction
was complete (approximately 4 h), as indicated by TLC. The mixture
was allowed to warm to 10 °C after which H2O (4 L) was added. The
mixture was allowed to warm to r.t. and stirred for 20 min at this
temperature. The separated organic layer was washed with 5% dilute
HCl (750 mL), sat. NaHCO3 solution (2 × 1 L), H2O (1 L) and brine (2 L),
dried over Na2SO4 and filtered. The filtrate was concentrated under
reduced pressure at 40 °C to furnish a thick oil. MeOH (320 mL) was
added to the oil. The mixture was cooled to –20 °C and stirred for 0.5
h at this temperature. The precipitated solid was filtered off and
washed with MeOH (320 mL). The filtrate was concentrated under re-
duced pressure at 40 °C to furnish the acetate 17 (118 g, 67%) as a
light yellow oil.
IR (KBr): 3136, 2932, 1593, 1487, 1400, 1321, 1219, 1111, 1070 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 7.60–7.40 (m, 6 H), 7.40–7.20 (m, 9
H), 5.30 (d, J = 3.9 Hz, 1 H), 5.00 (d, J = 4.5 Hz, 1 H), 4.00–3.80 (m, 2 H),
3.20–3.00 (m, 1 H), 3.00–2.80 (m, 1 H), 2.70–2.50 (m, 2 H), 1.90–1.70
(m, 1 H), 1.70–1.60 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 143.9, 128.0, 127.8, 126.9, 119.0,
85.7, 67.6, 66.7, 64.0, 40.4, 25.1.
MS: m/z = 388 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C25H25NO3Na: 410.1724; found:
410.1746.
Isopropyl (3R,5S)-3,5-Dihydroxy-6-(trityloxy)hexanoate (16)
An aq solution of NaOH (53.74 g, 1.34 mol, in 1.3 L of H2O) was added
to a stirred solution of the cyano compound 14 (260 g, 671.0 mmol)
in MeOH (1.3 L) at r.t. The mixture was heated to 70 °C and main-
tained at this temperature for 15 h when the reaction was complete
as indicated by TLC. The mixture was allowed to cool to r.t., concen-
trated under reduced pressure at 40 °C and cooled to 0 °C when a
gummy solid precipitated out of the reaction mixture. The aq layer
was decanted off and H2O (930 mL) and EtOAc (930 mL) were added
to the gummy residue in succession at r.t. The mixture was stirred for
0.5 h at this temperature during which time the layers separated. The
organic layer was separated and the aq layer extracted with EtOAc
[α]D25 –14 (c 0.5, CHCl3); Rf = 0.33 (CHCl3/MeOH, 9:1).
IR (KBr): 3137, 2984, 1728, 1594, 1399, 1259, 1108, 1071 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
N. Vempala et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 5.10 (sept, J = 6.4 Hz, 1 H), 4.30–4.20
(m, 1 H), 4.15–4.09 (m, 1 H), 4.10–4.05 (m, 1 H), 4.01 (dd, J = 6.2, 11.0
Hz, 1 H), 3.50–3.20 (br, 2 H), 2.46 (d, J = 6.0 Hz, 2 H), 2.00 (s, 3 H),
1.70–1.55 (m, 2 H), 1.23 (d, J = 6.4 Hz, 6 H).
13C NMR (100 MHz, CDC13): δ = 172.0, 171.0, 69.7, 68.4, 68.3, 68.1,
41.7, 38.5, 21.77, 21.76, 20.89.
Isopropyl 2-[(4R,6S)-6-Formyl-2,2-dimethyl-1,3-dioxan-4-yl)ace-
tate (4)
A solution of the alcohol 19 (80 g, 324.8 mmol) in CH2Cl2 (400 mL)
was added to a mixture of KBr (3.86 g, 32.48 mmol) and TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy radical) (507 mg, 3.248 mmol)
in CH2Cl2 (400 mL) at –5 °C. An aq solution of 15% NaOCl (177 mL,
357.2 mmol; pH adjusted to 9.0–9.5 with a sat. solution of NaHCO3)
was added dropwise to the mixture over a period of 1 h at this tem-
perature. On completion of the reaction as indicated by TLC, a 10% aq
solution of Na2S2O3 (300 mL) was added at this temperature. The aq
phase was extracted with CH2Cl2 (150 mL) and the extract combined
with the organic layer. The combined organic layer was washed with
brine (200 mL), dried over Na2SO4 and concentrated under vacuum at
40 °C to give the aldehyde 4 (64 g, 81%) as a light yellow oil. The crude
material was carried over to the next step.
MS: m/z = 249 [M + H]+, 271 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C11H20O6Na: 271.1152; found:
271.1164.
Isopropyl 2-[(4R,6S)-6-(Acetoxymethyl)-2,2-dimethyl-1,3-dioxan-
4-yl]acetate (18)
2,2-Dimethoxypropane (232 mL) was added to a solution of the ace-
tate 17 (116 g, 467 mmol) in acetone (232 mL) at r.t. Next, PPTS (23.48
g, 93 mmol) was added to the mixture under nitrogen, and the mix-
ture was stirred for 15 h at this temperature. After completion of re-
action as indicated by TLC, the mixture was concentrated under re-
duced pressure at 38 °C, diluted with hexane (600 mL) and stirred for
0.5 h at r.t. The precipitated solid was filtered off and washed with
hexane. The filtrate was washed with H2O (2 × 500 mL) and brine
(500 mL), dried over Na2SO4 and concentrated under reduced pres-
sure at 35 °C to give the acetonide 18 (108 g, 80%) as a light yellow oil.
Rf = 0.30 (hexane/EtOAc, 7:3).
Isopropyl 2-[(4R,6S)-6-{(E)-2-[4-(4-Fluorophenyl)-6-isopropyl-2-
(N-methylmethylsulfonamido)pyrimidin-5-yl]vinyl}-2,2-dimeth-
yl-1,3-dioxan-4-yl]acetate (2)
A solution of the aldehyde 4 (64 g, 262.0 mmol) in DMSO (184 mL)
was added to a solution of the triphenylphosphonium salt of the pyr-
idinium moiety 3 (142.2 g, 209.6 mmol) in DMSO (200 mL) at r.t. un-
der nitrogen. The mixture was heated to 70 °C and K2CO3 (27.15 g,
196.45 mmol) was added to the mixture. After 0.5 h at this tempera-
ture, another batch of K2CO3 (27.15 g, 196.45 mmol) was added under
nitrogen and the mixture was maintained at this temperature for 3 h
when the reaction was complete as indicated by TLC. The mixture
was allowed to cool to r.t. and toluene (500 mL) was added. After 0.5 h
at this temperature, H2O (1 L) was added and the mixture was stirred
for a further 0.5 h when the layers separated. The aq layer was ex-
tracted with toluene (200 mL) and the extract was combined with the
organic layer. The combined organic layer was washed with H2O
(2 × 500 mL) and brine (200 mL), dried over Na2SO4 and concentrated
under vacuum at 50 °C to furnish crude ester 2. i-PrOH (320 mL) was
added to the crude residue and the mixture was stirred at r.t. for 1 h.
The mixture was cooled to 0 °C to –5 °C and stirred for a further 1 h at
this temperature to initiate precipitation of the solid. The precipitated
solid was filtered, washed with i-PrOH (50 mL) and dried to furnish
the ester 2 (92 g, 62%) as an off white solid.
[α]D25= +16.4 (c 0.5 CHCl3); Rf = 0.46 (hexane/EtOAc, 6:4).
IR (KBr): 3134, 2992, 2360, 1737, 1594, 1399, 1239, 1204, 1172 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.04 (sept, J = 6.2 Hz, 1 H), 4.40–4.28
(m, 1 H), 4.20–4.08 (m, 1 H), 4.10–4.04 (m, 1 H), 4.02 (dd, J = 6.0, 11.2
Hz, 1 H), 2.50 (dd, J = 7.2, 15.2 Hz, 1 H), 2.35 (dd, J = 5.6, 15.2 Hz, 1 H),
2.08 (s, 3 H), 1.62–1.55 (m, 1 H), 1.46 (s, 3 H), 1.39 (s, 3 H), 1.40–1.25
(m, 1 H), 1.23 (d, J = 6.2 Hz, 6 H).
13C NMR (100 MHz, CDC13): δ = 170.9, 170.2, 99.0, 67.9, 67.1, 67.0,
65.6, 41.6, 32.5, 29.8, 21.7, 20.9, 19.5.
MS: m/z = 289 [M + H]+.
HRMS: m/z [M + H]+ calcd for C14H25O6: 289.1646; found: 289.1656.
Isopropyl 2-[(4R,6S)-6-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxan-
4-yl]acetate (19)
NaOMe (3.18 g, 58.9 mmol) was added to a solution of the acetonide
18 (85 g, 294.8 mmol) in MeOH (425 mL) at –10 °C under nitrogen,
and the mixture was stirred for 2 h at this temperature. After comple-
tion of reaction as indicated by TLC, the mixture was neutralized with
aq 10% citric acid solution (17 mL) and concentrated under reduced
pressure at 35 °C to furnish a gummy residue. The residue was dis-
solved in EtOAc (400 mL). The organic layer was washed with H2O
(2 × 250 mL) and brine (250 mL), dried over Na2SO4 and concentrated
under reduced pressure at 40 °C. The alcohol 19 (71.0 g, 98%) was ob-
tained as a light yellow oil.
[α]D25 +10.2 (c 0.5, CHCl3); mp 132.5–133.8 °C; Rf = 0.4 (hexane/EtOAc,
8:2).
IR (KBr): 3134, 2987, 1723, 1596, 1551, 1512, 1398, 1335, 1154, 1111
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 5.4 Hz, 1 H), 7.64 (d, J = 5.4
Hz, 1 H), 7.10 (d, J = 5.4 Hz, 1 H), 7.08 (d, J = 5.4 Hz, 1 H), 6.50 (d, J =
16.4 Hz, 1 H), 5.47 (dd, J = 5.6, 16.4 Hz, 1 H), 5.10 (sept, J = 6.4 Hz, 1 H),
4.50–4.40 (m, 1 H), 4.40–4.20 (m, 1 H), 3.57 (s, 3 H), 3.52 (s, 3 H), 3.38
(sept, J = 6.6 Hz, 1 H), 2.50 (dd, J = 6.8, 15.2 Hz, 1 H), 2.36 (dd, J = 5.6,
15.2 Hz, 1 H), 1.60–1.50 (m, 1 H), 1.49 (s, 3 H), 1.41 (s, 3 H), 1.25 (d, J =
6.6 Hz, 6 H), 1.23 (d, J = 6.4 Hz, 6 H), 1.20–1.10 (m, 1 H).
13C NMR (100 MHz, CDC13): δ = 174.0, 170.0, 163.4, 162.0 (d, JC–F
248 Hz), 157.0, 137.0, 134.0 (d, JC–F = 3 Hz), 132.2 (d, JC–F = 8.4 Hz),
123.0, 121.0, 115.0 (d, JC–F = 22 Hz), 114.0, 99.0, 69.0, 67.9, 65.0, 42.0,
41.0, 35.9, 33.0, 31.9, 29.9, 21.80, 21.79, 21.7, 19.7.
[α]D25 +16.2 (c 0.5, CHCl3); Rf = 0.27 (hexane/EtOAc, 7:3).
IR (KBr): 3134, 2989, 2940, 1730, 1594, 1399, 1204, 1171, 1109 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.03 (sept, J = 6.3 Hz, 1 H), 4.40–4.20
(m, 1 H), 4.10–3.90 (m, 1 H), 3.66–3.55 (m, 1 H), 3.55–3.45 (m, 1 H),
2.5.0 (dd, J = 7.0, 15.3 Hz, 1 H), 2.40 (dd, J = 6.0, 15.3 Hz, 1 H), 2.00 (t,
J = 6.0 Hz, 1 H), 1.55–1.47 (m, 1 H), 1.47 (s, 3 H), 1.39 (s, 3 H), 1.40–
1.30 (m, 1 H), 1.24 (d, J = 6.3 Hz, 6 H).
13C NMR (75 MHz, CDC13): δ = 170.0, 99.0, 69.0, 67.0, 65.8, 65.6, 41.0,
31.0, 30.0, 21.8, 19.7.
=
MS: m/z = 564 [M + H]+.
HRMS: m/z [M + H]+ calcd for C28H39FN3O6S: 564.2538; found:
564.2559.
MS: m/z = 247 [M + H]+.
HRMS: m/z [M + H]+ calcd for C12H23O5: 247.1539; found: 247.1553.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
N. Vempala et al.
Paper
Synthesis
Rosuvastatin Calcium (1)
surements, melting points and optical rotations for all the com-
pounds described herein. The authors also thank Dr. J. S. Yadav,
Former Director, CSIR-IICT, Tarnaka, Hyderabad, 500007 and Dr. Md.
Ataur Rahman for going through this manuscript and for providing
useful suggestions.
Dilute HCl (25 mL, 0.02 M) was added to a stirred solution of the ester
2 (13 g, 460 mmol) in MeCN (90 mL) at r.t. under nitrogen. The mix-
ture was heated to 30 °C and maintained at this temperature for 5 h
when the reaction was complete as indicated by TLC. The mixture
was cooled to 25 °C and an aq solution of NaOH (25 mL, 1 M) was
added. After 0.5 h at this temperature, NaCl (15 g) was added, the
mixture was cooled to –5 °C and dilute HCl (1 M) was added until the
pH attained 3.5. Another batch of NaCl (15 g) was added to the reac-
tion mixture at which point the layers separated. The organic layer
was diluted with MeCN (300 mL) and filtered through a pad of Celite.
The Celite pad was washed with MeCN (16 mL). The washings were
combined with the filtrate, cooled to –5 °C, and tert-butylamine (2.7
mL) was added at this temperature. The mixture was warmed to r.t.,
stirred for 1 h and again cooled to 0 °C. The mixture was maintained
at this temperature for 0.5 h. The precipitated solid was filtered off,
washed with cold MeCN and dried under vacuum at 27 °C to give the
tert-butylamine salt of rosuvastatin (9.0 g, 70%).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562787.
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References
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A solution of NaOH (648 mg, 17.1 mmol) in demineralized H2O (9 mL)
was added to a solution of the tert-butylamine salt of rosuvastatin (9
g, 17.1 mmol) in demineralized H2O (45 mL) at 27 °C and the mixture
was heated to 40 °C. After 1 h at this temperature, the mixture was
cooled to 30 °C and tert-butyl acetate (27 mL) was added. The mixture
was stirred for 0.5 h to remove tert-butylamine and non-polar organ-
ic impurities. The process was repeated twice to ensure complete re-
moval of non-polar impurities. Dilute HCl (1 M) was added to the
mixture under nitrogen until the pH attained 9–9.5. The mixture was
filtered through a filter paper (40 microns), and a solution of Ca(OAc)2
(1.6 g, 10.2 mmol) in demineralized H2O (9 mL) was added to the fil-
trate. The mixture was stirred for 1 h at 27 °C. The precipitated solid
was filtered off, washed with deionized H2O (2 × 18 mL) and dried
under high vacuum at 27 °C for 24 h to furnish rosuvastatin calcium
(1) (6.9 g, 85%) as a white powder.
[α]D25 –2.3 (c 0.5, CHCl3); mp 147–154 °C (Lit7f 145–150 °C).
IR (KBr): 3148, 1596, 1547, 1398, 1332, 1228, 1153, 1113, 1070, 965,
776 cm–1
.
1H NMR (400 MHz, D2O): δ = 7.57 (t, J = 5.2, 7.6 Hz, 2 H), 6.96 (t, J = 8.4
Hz, 2 H), 6.49 (d, J = 15.2 Hz, 1 H), 5.39 (d, J = 15.2 Hz, 1 H), 4.30 (br, 1
H), 4.10 (br, 1 H), 3.60–3.40 (br, 1 H), 3.51 (s, 3 H), 3.46 (s, 3 H), 3.24
(m, 1 H), 2.33 (br, 2 H), 1.65–1.45 (br, 1 H), 1.53 (br, 1 H), 1.39 (br, 1 H),
1.15 (d, J = 5.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 174.0, 164.0, 163.0, 161.0, 157.0,
139.0, 134.0, 132.0, 123.0, 120.0, 114.9, 114.7, 76.0, 71.0, 42.0, 33.0,
32.0, 21.0.
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MS: m/z = 482 [acid, M + H]+, 504 [acid, M + Na]+.
HRMS: m/z [acid, M + H]+ calcd for C22H29FN3O6S: 482.1753; found:
482.1767.
Diastereomeric excess: >99% [column: ID CHIRALPAK IB-3 (4.6 × 250
mm) 3 μ; mobile phase: n-hexane/EtOH/IPA/TFA = 90:5:5:0.3; flow
rate = 1 mL/min; T = 25 °C].
Acknowledgment
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RR District, Hyderabad-78 for extending extensive analytical support
in profiling rosuvastatin calcium. The authors also thank Laxai-Avan-
ti, IKP Knowledge Park, RR District, Hyderabad-78, Dr. Reddy’s Labo-
ratories, University of Hyderabad, Hyderabad, India and Vishnu
Chemicals Limited, Hyderabad for recording NMR spectra, NOE mea-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H