The use of a lactonized statin side-chain precursor in a concise and efficient assembly of pitavastatin

Article abstract of DOI:10.1055/s-0031-1290916

A concise and simple synthetic route to pitavastatin is described. The approach involves a highly stereoselective Wittig olefination reaction between a lactonized statin side-chain precursor and the triphenylphosphonium bromide salt of the corresponding quinoline heterocyclic core. The necessary O-tert-butyl(dimethyl)silyl-protected pitavastatin lactone was obtained in 75% yield and high purity by simple crystallization from aqueous methanol. Subsequent deprotection, hydrolysis, and cation exchange in a one-pot operation provided pitavastatin calcium in 93% yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290916

1700▌
PAPER
paper
The Use of a Lactonized Statin Side-Chain Precursor in a Concise and
Efficient Assembly of Pitavastatin
Pitavastatin through a Lactonized Side-Chain Precursor
Jan Fabris,a,b Zdenko Časar,*b,c Ivana Gazić Smilovićb
a
Cadonic Consultancy Services, LL.C., Cesta na postajo 74, 1351 Brezovica pri Ljubljani, Slovenia
b
Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27,
1234 Mengeš, Slovenia
c
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
Fax +386(1)7237382; E-mail: zdenko.casar@sandoz.com
Received: 16.02.2012; Accepted after revision: 09.03.2012
hypercholesterolemia and combined dyslipidemia;11 other
indications are also under investigation.12 The initial syn-
thesis of the drug and its refinements (Scheme 1) were
performed well in advance of its entry into the market and
Abstract: A concise and simple synthetic route to pitavastatin is
described. The approach involves a highly stereoselective Wittig
olefination reaction between a lactonized statin side-chain precursor
and the triphenylphosphonium bromide salt of the corresponding
quinoline heterocyclic core. The necessary O-tert-butyl(dimeth- they involved a Horner–Wadsworth–Emmons (HWE)
yl)silyl-protected pitavastatin lactone was obtained in 75% yield
and high purity by simple crystallization from aqueous methanol.
Subsequent deprotection, hydrolysis, and cation exchange in a one-
rivatives B.13,14 Subsequent early synthetic approaches
pot operation provided pitavastatin calcium in 93% yield.
olefination of the phosphine oxide derivative A (derived
from alcohol 1) with the O-protected linear side-chain de-
were based on complex multistep syntheses from epichlo-
rohydrin,15 as well as on various strategies involving hy-
Key words: Wittig reactions, heterocycles, quinolines, lactones,
drugs
droboration–cross coupling or hydrosilylation–cross
coupling reactions between the heterocyclic iodide C and
the O-protected acetylenic linear side-chain precursor
D.16 Later, a method based on an aldol condensation was
developed, starting from the vinylogous heterocyclic al-
dehyde E17 and the acetoacetate F. Aldehyde E can be
prepared from aldehyde G. By applying Scettri’s titani-
um-BINOL complex-catalyzed aldol condensation,18 re-
searchers at Novartis19 succeeded in refining the method
to an asymmetric version. The latest synthetic approach,
reported by Acemoglu et al.,20 is based on HWE coupling
of the heterocyclic aldehyde G with the phosphonate-type
side-chain precursor H.
Statins, which are inhibitors of 3-hydroxy-3-methylgluta-
ryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.88), a
crucial enzyme in the biosynthesis of cholesterol,1 were
discovered as natural compounds in the late 1970s.2 Since
then, researchers have refined the structures of this group
of drugs with the aim of increasing their potency and effi-
ciency. Indeed, several semisynthetic derivatives (for ex-
ample, simvastatin3 and pravastatin4) and, ultimately,
fully synthetic derivatives have been produced. These
compounds, which are frequently known as super statins,
consist of a heterocyclic core attached to a chiral 3,5-dihy-
droxyhept-6-enoic or -heptanoic acid side-chain residue.5
Currently, four compounds from this group are actively
used in improving the lives of patients worldwide: fluva-
statin,6 atorvastatin,7 rosuvastatin,8 and the recently intro-
duced pitavastatin.9 Pitavastatin has several unique
structural features; for example, it is the only super statin
that has a cyclopropyl moiety instead of an isopropyl
group attached to the heterocyclic quinoline core (Scheme
1). These structural features are associated with some
unique properties of pitavastatin; for example, pitava-
statin, unlike many other medicines, is resistant to metabo-
lization through the cytochrome P450 pathway in the
liver.10 This suggests that pitavastatin might fulfill an un-
met medical need by minimizing possible interactions
with other drugs that a patient might be taking. Pitava-
statin has already been approved for primary treatment of
The synthetic approaches discussed above21 have several
drawbacks. These include lengthy synthetic routes;12,15,21c
the use of dangerous or odorous chemicals, such as disul-
fides,15 dimethyl sulfide,12,15 diazomethane,12 phosphorus
pentachloride,21c phosphorus tribromide,21c or diisobutyl-
aluminum hydride;12,14,21c the need to perform multiple
steps under cryogenic conditions;14,15,17,19,20,21c the use of
transition-metal catalysts at high loads;16,19 the production
of stereochemically impure mixtures of product;17 or the
involvement of chiral auxiliaries that necessitate addition-
al protection and deprotection steps.12,20 Recently, we re-
ported the first approach to a lactonized statin side chain
precursor22 and we demonstrated its use in the assembly of
rosuvastatin.23 In light of the drawbacks of known syn-
thetic routes to pitavastatin discussed above, we were
prompted to consider pitavastatin as an interesting syn-
thetic target. Here, we present a detailed study of the
synthesis of pitavastatin (2) via the O-tert-butyl(dimeth-
yl)silyl-protected pitavastatin lactone (3) by coupling of
the lactonized statin side-chain derivative 4 with a phos-
phorus-containing heterocyclic precursor 5 (Scheme 2).
SYNTHESIS 2012, 44, 1700–1710
Advanced online publication: 26.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290916; Art ID: SS-2012-T0161-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pitavastatin through a Lactonized Side-Chain Precursor
1701
O
O
OPG OPG
O
Het:
O
F
OH
OH
CHO
O
OR
OR
CO2Ca1/2
OH
PR2
B
F
Het
Ph
Het
Het
E
1
A
OPG OPG
O
O
RO
O
OTBS O
P
OR
RO
N
Het
I
D
H
H
N
Het CHO
C
G
pitavastatin
Scheme 1 The main synthetic approaches to pitavastatin
We began our study by preparing various phosphorus- because of the presence of the less-polar organic anion. As
containing quinoline heterocyclic derivatives 5 (Scheme a first step, we prepared the alcohol 126 in 88% isolated
3) in which the phosphorus atom was substituted with yield from the alkyl bromide 6 by simple hydrolysis with
groups with various degrees of steric hindrance and a sodium bicarbonate in refluxing aqueous acetonitrile for
range of electronic properties that might affect the out- 64 hours. In contrast to the procedure that we recently de-
come of the olefination step. Phosphonium bromide salts veloped for synthesizing heterocyclic precursors of rosu-
5a,24 5c, 5d, and 5f14c,21c were prepared by reaction of the vastatin,27 the direct one-pot formation of trifluoroacetate
alkyl bromide 6 with various phosphines in toluene or tet- salts 5 from alcohol 1 did not give satisfactory yields or
rahydrofuran at 50 °C. In general, high yields (85–93%) product purities.28 We therefore decided to adopt a two-
were obtained for phosphine precursors substituted with step approach. In the first step, alcohol 1 was treated with
butyl, cyclohexyl, or phenyl groups, whereas the more- trifluoroacetic anhydride in the presence of triethylamine
hindered tert-butyl derivative gave only a 66% isolated in tetrahydrofuran at room temperature for two hours.
yield of 5c. Because counterions can play an important This gave the trifluoroacetate ester 7 in 93% yield. Treat-
role in the course of a Wittig reaction,25 we also prepared ment of 7 with various phosphines in refluxing toluene for
the phosphonium trifluoroacetate salts 5b, 5e, and 5g, six hours gave the desired salts 5b, 5e, and 5g in high
which should have been more soluble in apolar solvents yields (78–90%).
Z = phosphorus moiety
R = 4-FC6H4
R
OTBS
O
OTBS
R
OH
OH
R
N
CO2Ca1/2
Z
+
O
O
O
O
N
N
3
4
5
2
Scheme 2 Retrosynthetic analysis of pitavastatin synthesis
O
R2
PR1
3 Br
R2
N
OH
R2
O
R2
N
PR1
3 CF3CO2
CF3
d
c
N
N
5a, R1 = Bu (85%)
5c, R1 = t-Bu (66%)
5d, R1 = Cy (93%)
5f, R1 = Ph (90%)
a
7 (93%)
5b, R1 = Bu (82%)
5e, R1 = Cy (78%)
5g, R1 = Ph (90%)
1 (88%)
b
O
O
e (R1 = Et)
R2
Br
R2
N
P(OEt)2
R2
PR1
2
g
R2 = 4-FC6H4
ref. 14
f (R1 = Ph)
ref. 14
N
N
5i, R1 = Et (67%)
5j, R1 = Ph (91%)
6
5h (82%)
Scheme 3 Syntheses of various phosphorus-derivatized quinoline precursors 5. Reagents and conditions: (a) R1 P (1.1 to 1.65 equiv), toluene
3
or THF, 50 °C, 0.5 h; (b) NaHCO3 (2.0 equiv), aq MeCN, reflux, 64 h; (c) (F3CCO)2O (1.5 equiv), Et3N (2.0 equiv), THF, r.t., 2 h; (d) R1 P
3
(2.0 equiv), toluene, reflux, 6 h; (e) NaOEt (1.1 equiv), Et2PCl (1.0 equiv), THF, 0 °C, 1 h then reflux 18 h; (f) Ph2POEt (2.0 equiv), toluene,
reflux, 64 h; (g) P(OEt)3 (2.0 equiv), toluene, reflux, 18 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1700–1710

1702
J. Fabris et al.
PAPER
The reaction of chloro(diethyl)phosphine with the sodium wanted to ascertain whether the base was sufficiently
ethoxide gave ethyl diethylphosphinite in situ; this subse- strong to form the corresponding ylide through proton ab-
quently reacted with 6 under refluxing conditions for 18 straction from salt 5d. To clarify this point, we used butyl-
hours to give the phosphine oxide 5i in 67% yield. Phos- lithium as the base in a similar reaction (entry 5). This
phine oxide 5j and phosphonate ester 5h were prepared gave product (E)-3 in higher but nevertheless disappoint-
according to a protocol described by Hiyama et al.14b in ing yield (22%), mainly as a result of a decrease in the
similar yields to those previously reported (Scheme 3).
yield of 9 to 3%, while 67% of the initial salt 5d was re-
covered. This suggests that the cyclohexyl moieties on
phosphorus provide sufficient steric hindrance to direct
the ylide formed from 5d to react by a similar pathways to
that adopted by 5c. Additional evidence for this was pro-
vided by testing the trifluoroacetate salt 5e (entry 6); this
gave 22% of (E)-3, together with 19% of 9 and 39% of the
initial salt 5e.
Having prepared a range of quinoline derivatives 5, we
continued our investigation by studying the olefination
step. We chose to use quinoline 5 (1.0 mmol) in toluene
(30 mL) with sodium hexamethyldisilazide (NaHMDS)
or butyllithium (1.05 mmol) and 4 (1.1 mmol) in toluene
(20 mL) at 60 °C as our standard reaction conditions
(Scheme 4 and Table 1). Initially, we were eager to ex-
plore the tributylphosphonium bromide salt 5a and its tri- Reactions on phosphorus substituted with phenyl groups,
fluoroacetate analogue 5b, which had performed well in a however, gave considerably better yields. The triphe-
synthesis of rosuvastatin.23 Interestingly, the bromide salt nylphosphonium bromide 5f gave the cleanest reaction,
5a provided a higher conversion to (E)-3 (77%) than did providing an 83% yield of (E)-3, along with 11% of (Z)-3
the corresponding trifluoroacetate 5b (63%); this was be- and small amounts of other side products (Table 1, entry
cause the latter gave a greater level of impurity 9, which 7). When the trifluoroacetate analogue 5g was used (entry
rose to 20% in the case of 5b as opposed to 6% in the case 8), poorer results were obtained, in accordance with the
of 5a, whereas levels of other impurities, such as (Z)-3 and observations for the tributyl derivatives 5a and 5b. To ex-
8 were similar (Table 1, entries 1 and 2). As demonstrated plore the scope and limitation of the olefination reaction,
previously, 8 is formed by reaction between the ylide from we also tested the phosphonate ester 5h and the phosphine
5 and residual water or a source of protons, such as a oxides 5i and 5j. Disappointingly, when sodium hexa-
protic solvent or the acidic α-carbonyl protons on the lac- methyldisilazide was used as a base, 5h–j gave negligible
tone 4 skeleton, whereas 9 is the product of a base- amount of the desired (E)-3 (entries 9–11). Interestingly,
mediated elimination of the silyl protecting group after however, no (Z)-3, 8, or 9 were detected in the crude mix-
abstraction of the α-carbonyl protons on the skeleton of tures. The starting compounds 5h–j in variable amounts
lactone 4.23 Surprisingly, the tri-tert-butylphosphonium (66–91%), together with some unidentified decomposi-
bromide 5c did not give any (E)-3 in the crude mixture tion products, were the only compounds remaining in the
(entry 3). Instead, the starting material 5c (43%) and un- reaction mixture after isolation of the product. To confirm
identified decomposition products were found in the mix- that these results were not the result of an insufficiently
ture, showing that steric hindrance blocked the addition of strong base used for proton abstraction from 5h–j during
the ylide species of 5c to the carbonyl group of aldehyde carbanion formation, we also tested butyllithium (entries
4 before other decomposition reactions could occur.29 The 12–14). In these cases, the results were similar to those
effect of the substitution pattern of the phosphorus moiety observed with sodium hexamethyldisilazide; low levels of
was further probed with the tricyclohexylphosphonium (E)-3, (Z)-3, 8, and 9 were formed and the product mix-
bromide salt 5d and its trifluoroacetate analogue 5e. Un- tures contained variable amounts of the starting materials
expectedly, 5d gave a low (5%) conversion into (E)-3 (en- 5h–j (39–72%), together with larger amounts of decom-
try 4) when sodium hexamethyldisilazide was used as the position products.
base, and large amounts of the initial salt 5d (47%) and 9
(22%) were present in the crude product. We therefore
These results are in sharp contrast with observations of
Hiyama et al.,14b where phosphonate esters (e.g., 5h) and
OTBS
R1 = 4-FC6H4
Z = PR2 +X–
HO
O
4'
O
3
CH2Cl2
OH
P(=O)(OR2)2
O
OTBS
1. base
2.
P(=O)R2
r.t.
2
OTBS
O
TBSO
R1
N
R1
R1
N
R1
R1
Z
O
O
O
O
O
(E)
(E)
(Z)
O
4
O
+
+
+
temp, solvent
N
N
N
8
5a–j
(E)-3
(Z)-3
9
Scheme 4 Study of the olefination reaction of aldehyde 4 with various phosphorus-derivatized quinoline heterocyclic precursors 5
Synthesis 2012, 44, 1700–1710
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pitavastatin through a Lactonized Side-Chain Precursor
1703
Table 1 Screening of the Olefination Step with Aldehyde 4 and Various Phosphorus-Derivatized Quinoline Heterocyclic Precursors 5
Entrya
(E)-3 (%)b (Z)-3 (%)b 8 (%)b
9 (%)b
5 (%)b
5 (HetCH2Z)
Base
5a [Z = P+(Bu3)Br–]
1
2
NaHMDS
NaHMDS
NaHMDS
NaHMDS
BuLi
77
63
–
12
12
–
5
3
3
1
–
1
3
2
–
–
–
–
–
2
6
20
–
–
–
–
5b [Z = P+(Bu3)CF3CO2 ]
5c [Z = P+(t-Bu3)Br–]
5d [Z = P+(Cy3)Br–]
5d [Z = P+(Cy3)Br–]
3
43
47
67
39
1
4
5
4
22
3
5
24
22
83
69
1
4
5e [Z = P+(Cy3)CF3CO2 ]
–
6
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
BuLi
6
19
2
5f [Z = P+(Ph3)Br–]
7
11
10
–
5g [Z = P+(Ph3)CF3CO2 ]
–
8
8
9
9
5h [Z = P(=O)(OEt)2]
5i [Z = P(=O)Et2]
5j [Z = P(=O)Et2]
5h [Z = P(=O)(OEt)2]
5i [Z = P(=O)Et2]
5j [Z = P(=O)Et2]
–
66
87
91
39
72
67
10
11
12
13
14
1
–
–
4
–
–
9
1
6
BuLi
–
–
1
BuLi
5
–
3
a All reactions were performed in toluene at 1.0-mmol scale. The olefination step between aldehyde 4 and the corresponding ylide after depro-
tonation of 5 was performed at 60 °C.
b Yields as ratios determined by HPLC analyses of crude products. Average data from two consecutive runs are given. The sum of the products
is below 100% owing to the presence of unidentified byproducts. Standards for 8 and 9 were prepared by an independent procedure.
the phosphine oxide derivative 5j provided the desired disilazides. The most pronounced difference was ob-
olefination coupling product with an O-protected linear served with potassium tert-butoxide which provided the
side chain D in moderate-to-high yields, although the lowest conversion into (E)-3 (41%), produced more impu-
phosphine oxide gave higher yields and greater E-selec- rity 9, and left a significant amount of the starting salt 5f
tivity. This behavior can probably be explained in terms of (entry 4). Magnesium bis(diisopropylamide) (MgBDA)
the basicity of the ylides and phosphorus carbanions in- and butyllithium performed similarly (entries 5 and 6) and
volved in the olefination step. Indeed, the pKa values for gave a lower 65–67% conversion into (E)-3 compared
benzylic-type phosphonium salts range from 16 to 19, with sodium hexamethyldisilazide (entry 2), accompanied
whereas those of benzylic-type phosphine oxides are in by an 18–21% recovery of starting salt 5f. The solvent
the range 28–29 and those of benzylic-type phosphonates screen showed that acetonitrile (entry 7) was significantly
are about 28.30 Therefore, carbanions formed by deprot- inferior to toluene and that tetrahydrofuran was slightly
onation of phosphine oxides or phosphonates are signifi- inferior to toluene (entry 8). The temperature screen re-
cantly stronger bases than those formed from vealed that a higher temperature has a beneficial effect;
phosphonium salts. This suggests that the lactonized side the conversion into (E)-3 at 25 °C was lower than that at
chain precursor 4 is too sensitive to strongly basic phos- 60 °C or 90 °C (entries 9–11).
phine oxide or phosphonate carbanions and that it under-
Having identified the optimal reaction conditions, we per-
formed a preparative experiment on a 3-mmol scale by us-
ing sodium hexamethyldisilazide at 60 °C in toluene, and
we tested the possibility of purifying the crude mixture by
goes elimination at the relatively acidic α-carbonyl
proton,23,31 as well as other side-reactions, ahead of olefi-
nation.
Next, we explored the lead coupling system 5f and 4 in crystallization. To our delight, the desired (E)-3 was iso-
more details by investigating the effects of the type of lated in 75% yield after crystallization of the crude Wittig
base, the solvent, and the temperature on the outcome of mixture from aqueous methanol. HPLC analysis showed
the reaction (Table 2). The difference between lithium, so- that the purity of the isolated product was better than 99%.
dium, and potassium hexamethyldisilazides (Table 2, en-
tries 1–3) was negligible and all gave a high (81–83%)
With the desired protected pitavastatin lactone (E)-3 in
hand, we continued to explore its further transformation
conversion into (E)-3 together with 11–12% of (Z)-3 and
into pitavastatin calcium (2). Initially, we examined the
0–5% of 8 or 9. Various other bases were also screened,
deprotection step with the well-established reagent tetra-
but all performed less well than alkali metal hexamethyl-
butylammonium fluoride (TBAF).23 To our delight lac-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1700–1710

1704
J. Fabris et al.
PAPER
99% overall yield. This stimulated us to consider the in-
corporation of cation exchange as the final step of a one-
pot procedure to achieve a one-pot three-step conversion
of (E)-3 into 2. When (E)-3 was deprotected then hydro-
lyzed under the established conditions and the resulting
aqueous solution of pitavastatin sodium (11) was treated
with 1.2 equivalents of calcium chloride in water at room
temperature, the desired pitavastatin calcium (2) was iso-
lated in 93% yield over the three steps (Scheme 5).
Table 2 Investigation of the Optimal Reaction Conditions for the
Olefination Step of Aldehyde 4 with Triphenylphosphonium Bromide
5f
Entrya
(E)-3c (Z)-3c 8c
(°C)b (%) (%) (%) (%) (%)
9c 5c
Base
Solvent Temp
1
2
LiHMDS toluene 60
NaHMDS toluene 60
81
83
81
41
65
67
7
11
11
12
7
–
3
1
2
1
1
1
2
5
6
1
–
3
KHMDS
t-BuOK
MgBDAd
BuLi
toluene 60
toluene 60
toluene 60
toluene 60
In conclusion, we have performed a detailed study of the
olefination reactions of various phosphorus-derivatized
quinoline heterocyclic core precursors with a lactonized
statin side chain bearing an exocyclic formyl moiety. The
best coupling results were obtained with the triphe-
nylphosphonium bromide salt of the heterocyclic precur-
sor. Under the optimal reaction conditions, the prime
coupling partners gave the desired protected pitavastatin
lactone in a high isolated yield (75%) and a high purity af-
ter a simple crystallization of the crude olefination mix-
ture from aqueous methanol. Subsequent transformation
into the desired pitavastatin calcium was efficiently and
concisely performed in an excellent yield (93%) as a one-
pot procedure. We believe that because our route to
pitavastatin uses favorable process conditions and is sim-
ple, concise, and efficient, it is suitable for adaptation to
industrial use.
4
13 35
5
9
1
1
21
18
6
8
7
NaHMDS MeCN
NaHMDS THF
60
60
5
20 17 39
8
75
77
83
83
12
12
11
11
3
2
1
2
9
7
2
3
–
1
2
1
9
NaHMDS toluene 25
NaHMDS toluene 90
NaHMDS toluene 60
10
11e
a Reactions were generally performed on 1.0-mmol scale.
b Temperature of the olefination step between the aldehyde 4 and the
ylide formed by deprotonation of 5f.
c Yields determined as a ratio by HPLC analysis of the crude products.
Average data from two consecutive runs are given. The sum of the
product is less than 100% owing to the presence of unidentified by-
products. Standards for 8 and 9 were prepared by an independent pro-
cedure.
Reagents and solvents were acquired from commercial sources and
used without further purification. Reactions were monitored by us-
ing analytical TLC plates (Merck; silica gel 60 F254, 0.25 mm), and
compounds were visualized with UV radiation. Silica gel grade 60
(70–230 mesh, Merck) was used for column chromatography.
HPLC analysis were performed with MeCN–H2O as the mobile
phase (MeCN gradient 50–100%) on a Waters 2487 instrument with
dual λ-absorbance detector and a Waters X Terra RP-18 (250
× 4.6 mm, 3.5 μm) column. All the NMR spectra were recorded
with a Bruker Avance III 500-MHz spectrometer at 25 °C. 1H NMR
spectra were obtained at 500 MHz, 13C NMR spectra were obtained
d Magnesium bis(diisopropylamide).
e Reaction was performed on 3.0-mmol scale.
tone 10 could be isolated in 92% yield by treatment of (E)-
3 with 1.75 equivalents of TBAF in tetrahydrofuran at
room temperature for 19 hours. Hydrolysis of 10 with
1.075 equivalents of sodium hydroxide in 4:1 tetrahydro-
furan–water at 30 °C for one hour, followed by freeze-
drying, gave pitavastatin sodium 11 in 99% yield. To
shorten the reaction sequence to the final product 2, we
next tested a one-pot procedure for conversion of (E)-3
into 11. Deprotection of (E)-3 followed by hydrolysis and
freeze-drying under similar reaction conditions to those
established for the single-step processes provided 11 in
at 125 MHz, 19F NMR spectra were obtained at 470 MHz, and 31
P
NMR spectra were obtained at 202 MHz. Chemical shifts are re-
ported in ppm downfield from TMS as the internal standard or to the
peak of the residual nondeuterated solvent, CDCl3 (7.24 ppm in the
1H spectrum or 77.23 ppm in the 13C spectrum) or CD3OD (4.87
ppm in the 1H spectrum or 49.15 ppm in the 13C spectrum). The cou-
pling constants (J) are given in hertz. Melting points were deter-
CO2Ca1/2
CO2Na
OH
R = 4-FC6H4
OTBS
O
OH
O
HO
HO
OH
R
R
N
R
N
R
N
O
O
a
b
c
N
one-pot
93% over 3 steps
(E)-3
10
11
2
Scheme 5 Concise and efficient three-step one-pot conversion of the protected pitavastatin lactone (E)-3 into pitavastatin 2. Reagents and con-
ditions: (a) TBAF (2.3 equiv), AcOH–THF, 0 °C to r.t., 18 h; (b) 8.0 M aq NaOH (1.075 equiv), THF–H2O, 30 °C, 1 h; (c) aq CaCl2 (1.2 equiv),
H2O, 30 °C, 18 h.
Synthesis 2012, 44, 1700–1710
© Georg Thieme Verlag Stuttgart · New York

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Pitavastatin through a Lactonized Side-Chain Precursor
1705
mined with a Mettler Toledo DSC822e apparatus (heating rate
10 °C/min) and are referred to as onset values and peak values. Op-
tical rotations were measured on a Perkin Elmer 341-series polarim-
eter. IR spectra were recorded on a Thermo Nicolet Nexus FTIR
spectrometer; only noteworthy absorptions are listed. High-resolu-
tion mass spectra were obtained with a VG-Analytical AutospecQ
instrument and a Q-TOF Premier instrument. All reactions involv-
ing air or moisture-sensitive reagents were performed under N2 in
oven-dried glassware by using syringe/septum cap techniques.
and then cooled to 0 °C. Et2O was added and stirring was continued
for another 0.5 h before the precipitate was filtered off and washed
with Et2O. The product was dried under reduced pressure to give the
pure pitavastatin phosphonium bromide salt.
Tributyl{[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-
yl}phosphonium Bromide (5a)32
In accordance with the general procedure, a soln of quinoline 6
(17.8 g, 50.0 mmol) in toluene (500 mL) was treated with PBu3
(20.6 mL, 82.5 mmol, 1.65 equiv). The product was precipitated
with Et2O (75 mL), filtered off, and washed with Et2O (3 × 75 mL)
to give a white crystalline solid; yield: 23.8 g (85%); mp 182.6 °C
(onset), 183.9 °C (peak); Rf = 0.11 (MeOH).
[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methanol (1)
H2O (100 mL) was added slowly to a soln of quinoline 6 (17.8 g,
50.0 mmol) in MeCN (350 mL) until precipitation occurred. An ad-
ditional portion of MeCN (150 mL) was added to dissolve the pre-
cipitate then NaHCO3 (8.40 g, 100.0 mmol, 2.0 equiv) was added
and the suspension was stirred under reflux for 64 h. The MeCN
was then evaporated under reduced pressure and the residue was
dissolved in EtOAc (500 mL), washed with H2O (3 × 500 mL), and
dried (MgSO4). The solvent was removed under reduced pressure to
give an oily residue from which the desired product was precipitat-
ed by addition of hexane (200 mL). The precipitate was filtered off
and washed with hexane (3 × 150 mL) to give a white crystalline
solid; yield: 12.9 g (88%); mp 133.3 °C (onset), 134.7 °C (peak);
Rf = 0.24 (hexane–EtOAc, 3:1).
IR (KBr): 3463, 3067, 3036, 2961, 2932, 2871, 1603, 1513, 1490,
1230, 1157, 1055, 915, 833, 769, 599, 559 cm–1.
1H NMR (500 MHz, CD3OD): δ = 0.89 (t, J = 7.3 Hz, 9 H), 1.23 (m,
6 H), 1.30–1.45 (m, 8 H), 1.50 (m, 2 H), 2.23 (m, 6 H), 2.51 (m, 1
H), 4.25 (d, J = 14.0 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.46 (m, 1
H), 7.53 (m, 2 H), 7.60 (m, 2 H), 7.74 (m, 1 H), 7.99 (d, J = 8.4 Hz,
1 H).
13C NMR (125 MHz, CD3OD): δ = 13.8 (d, J = 12.5 Hz), 16.7, 20.7,
21.1, 22.0, 22.3, 24.3 (d, J = 4.6 Hz), 25.0 (d, J = 16.0 Hz), 118.0
(d, J = 21.8 Hz), 121.2 (d, J = 8.6 Hz), 127.1, 127.5 (d, J = 58.4
Hz), 129.9, 131.4, 133.4, 133.9 (d, J = 4.4 Hz), 148.7, 148.8 (d,
J = 6.3 Hz), 162.6 (d, J = 2.1 Hz), 164.5 (d, J = 248.8 Hz).
IR (KBr): 3429, 3069, 3008, 2898, 2848, 2739, 1605, 1579, 1560,
1513, 1495, 1414, 1390, 1331, 1312, 1225, 1163, 1159, 1068, 1034,
1018, 982, 931, 842, 772, 746, 687, 612 cm–1.
31P NMR (202 MHz, CD3OD): δ = 33.5.
1H NMR (500 MHz, CDCl3): δ = 1.02–1.13 (m, 2 H), 1.30–1.41 (m,
2 H), 1.72 (t, J = 5.5 Hz, 1 H), 2.57 (m, 1 H), 4.73 (d, J = 5.5 Hz, 2
H), 7.17–7.23 (m, 2 H), 7.25–7.33 (m, 4 H), 7.59 (ddd, J = 2.2 Hz,
J = 6.2 Hz, J = 8.4 Hz, 1 H), 7.95 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 10.0, 14.7, 59.6, 115.6 (d,
J = 21.5 Hz), 125.6, 126.3, 126.5, 128.9, 129.3, 129.5, 131.5 (d,
J = 8.0 Hz), 132.5 (d, J = 3.1 Hz), 146.6, 147.4, 162.5, 162.7 (d,
J = 247.6 Hz).
HRMS–ESI: m/z [M + H]+ calcd for C31H42FNP: 478.3033; found:
478.3032.
Tri-tert-butyl{[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-
yl]methyl}phosphonium Bromide Toluene Solvate (5c)
In accordance with the general procedure, a soln of quinoline 6
(14.2 g, 40.0 mmol) in toluene (150 mL) was treated with t-Bu3P
(8.90 g, 44.0 mmol, 1.1 equiv) in toluene (50 mL). The product was
precipitated with Et2O (100 mL), filtered off, and washed with Et2O
(2 × 100 mL) to give a white crystalline solid; yield: 14.8 g (66%);
mp >250 °C (onset), >250 °C (peak); Rf = 0.07 (MeOH).
HRMS–ESI: m/z [M + H]+ calcd for C19H17FNO: 294.1289; found:
294.1290.
IR (KBr): 3424, 2982, 1600, 1509, 1488, 1399, 1379, 1298, 1225,
1159, 1054, 910, 842, 832, 768 cm–1.
1H NMR (500 MHz, CD3OD): δ = 1.38 (m, 3 H), 1.51 (d, J = 14.3
Hz, 29 H), 2.35 (s, 0.9 H, PhMe), 2.61 (m, 1 H), 4.61 (br s, 2 H),
7.17 (m, 0.9 H, PhMe), 7.25 (m, 0.6 H, PhMe), 7.46 (m, 1 H), 7.52
(m, 3 H), 7.73 (m, 3 H), 7.94 (m, 1 H).
13C NMR (125 MHz, CD3OD): δ = 15.5 (br s), 18.2, 21.8 (d,
J = 29.9 Hz), 31.0, 42.5 (d, J = 24.2 Hz), 118.0 (br s), 122.2 (d,
J = 8.7 Hz), 126.5 (PhMe), 126.8, 127.2, 127.6, 129.3 (PhMe),
129.8, 130.1 (PhMe), 131.5, 133.3, 135.6 (br s), 148.4, 149.2 (d,
J = 5.1 Hz), 163.5, 164.8 (d, J = 249.7 Hz).
[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methyl Tri-
fluoroacetate (7)
Et3N (4.85 mL, 35.0 mmol, 2.0 equiv) and (F3CCO)2O (3.70 mL,
26.3 mmol, 1.5 equiv) were added to a soln of alcohol 1 (5.13 g,
17.5 mmol) in anhyd THF (25 mL) and the soln was stirred at r.t.
for 2 h. THF was removed under reduced pressure and the residue
was cooled on an ice bath. Anhyd MeOH was added to precipitate
a yellow–white solid that was filtered off and washed with cold an-
hyd MeOH (2 × 50 mL) to give a white crystalline solid; yield: 6.32
g (93%); mp 126.1 °C (onset), 127.5 °C (peak); Rf = 0.53 (hexane–
EtOAc, 3:1).
IR (KBr): 3439, 3073, 3005, 1788, 1604, 1582, 1514, 1494, 1399,
1343, 1227, 1161, 1155, 1095, 1068, 1055, 929, 903, 860, 845, 775,
743, 728, 683, 610, 561, 517 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.00–1.30 (m, 2 H), 1.30–1.60 (m,
2 H), 2.31 (m, 1 H), 5.52 (s, 2 H), 7.15–7.55 (m, 6 H), 7.73 (m, 1 H),
8.06 (d, J = 8.3 Hz, 1 H).
31P NMR (202 MHz, CD3OD): δ = 57.7.
HRMS–ESI: m/z [M + H]+ calcd for C31H42FNP: 478.3033; found:
478.3033.
Tricyclohexyl{[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-
yl]methyl}phosphonium Bromide (5d)
13C NMR (125 MHz, CDCl3): δ = 9.7, 15.1, 65.1, 114.7 (q,
J = 285.8 Hz), 116.0 (d, J = 21.6 Hz), 123.1, 126.1, 126.3, 126.8,
129.3, 130.4, 131.4 (d, J = 8.1 Hz), 131.6 (d, J = 3.2 Hz), 148.2,
149.4, 157.3 (q, J = 42.5 Hz), 161.8, 163.1 (d, J = 248.7 Hz).
19F NMR (470 MHz, CDCl3): δ = –113.6, –75.9.
HRMS–ESI: m/z [M + H]+ calcd for C21H16F4NO2: 390.1112;
In accordance with the general procedure, a soln of quinoline 6
(17.8 g, 50.0 mmol) in THF (100 mL) was treated with PCy3 (15.4
g, 55.0 mmol, 1.1 equiv). The product was precipitated with Et2O
(75 mL), filtered off, and washed with Et2O (4 × 75 mL) to give a
white crystalline solid; yield: 29.7 g (93%); mp 146.8 °C (onset),
153.0 °C (peak); Rf = 0.13 (MeOH).
IR (KBr): 3426, 3053, 2930, 2858, 1601, 1511, 1489, 1448, 1224,
1062, 1054, 785 cm–1.
found: 390.1112.
1H NMR (500 MHz, CD3OD): δ = 1.15–1.30 (m, 9 H), 1.34 (m, 2
H), 1.40–1.55 (m, 8 H), 1.55–1.65 (m, 6 H), 1.65–1.85 (m, 9 H),
2.40–2.53 (m, 4 H), 4.19 (d, J = 13.0 Hz, 2 H), 7.34 (d, J = 8.4 Hz,
Pitavastatin Phosphonium Bromide Salts; General Procedure
The appropriate phosphine was added to a stirred soln of quinoline
6 in anhyd toluene or THF. The soln was stirred at 50 °C for 0.5 h
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1700–1710

1706
J. Fabris et al.
PAPER
1 H), 7.44 (m, 1 H), 7.52 (m, 2 H), 7.57 (m, 2 H), 7.72 (m, 1 H), 7.95
(d, J = 8.4 Hz, 1 H).
HRMS–ESI: m/z [M + H]+ calcd for C31H42FNP: 478.3033; found:
478.3031.
13C NMR (125 MHz, CD3OD): δ = 14.3, 17.0, 18.3 (d, J = 40.3 Hz),
26.4, 27.7 (d, J = 11.9 Hz), 28.0 (d, J = 3.1 Hz), 33.1 (d, J = 37.1
Hz), 118.3 (d, J = 21.9 Hz), 121.4 (d, J = 8.2 Hz), 127.0, 127.2,
127.8, 129.9, 131.5, 133.5, 134.1 (d, J = 7.8 Hz), 148.6, 149.1 (d,
J = 5.5 Hz), 162.5, 164.6 (d, J = 249.0 Hz).
31P NMR (202 MHz, CD3OD): δ = 32.4.
HRMS–ESI: m/z [M + H]+ calcd for C37H48FNP: 556.3503; found:
Tricyclohexyl{[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-
yl]methyl}phosphonium Trifluoroacetate (5e)
White crystalline solid; yield: 1.31 g (78%); mp 182.7 °C (onset),
187.7 °C (peak); Rf = 0.09 (MeOH).
IR (KBr): 3426, 3065, 2936, 2854, 1692, 1511, 1489, 1447, 1220,
1198, 1159, 1108, 913, 854, 811, 797, 766, 714, 599, 560 cm–1.
1H NMR (500 MHz, CD3OD): δ = 1.15–1.30 (m, 9 H), 1.34 (m, 2
H), 1.40–1.55 (m, 8 H), 1.55–1.65 (m, 6 H), 1.65–1.85 (m, 9 H),
2.35–2.52 (m, 4 H), 4.17 (d, J = 13.0 Hz, 2 H), 7.34 (d, J = 8.4 Hz,
1 H), 7.42 (m, 1 H), 7.45–7.60 (m, 4 H), 7.70 (m, 1 H), 7.94 (d,
J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CD3OD): δ = 14.3, 17.0, 18.1 (d, J = 40.5 Hz),
26.4, 27.7 (d, J = 11.9 Hz), 28.0 (d, J = 4.3 Hz), 33.1 (d, J = 37.1
Hz), 118.3 (d, J = 21.9 Hz), 118.5 (q, J = 294.0 Hz), 121.3 (d,
J = 8.3 Hz), 127.0 (d, J = 2.5 Hz), 127.2, 127.8, 129.9, 131.5, 133.5
(d, J = 2.3 Hz), 134.0 (d, J = 8.1 Hz), 148.6 (d, J = 2.1 Hz), 149.1
(d, J = 5.7 Hz), 162.4 (d, J = 2.6 Hz), 162.8 (q, J = 34.0 Hz), 164.6
(d, J = 249.3 Hz).
556.3509.
{[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methyl}(tri-
phenyl)phosphonium Bromide (5f)32
In accordance with the general procedure, a soln of quinoline 6
(10.0 g, 28.1 mmol) in THF (50 mL) was treated with PPh3 (8.10 g,
30.9 mmol, 1.1 equiv). The product was precipitated with Et2O (50
mL), filtered off, and washed with Et2O (4 × 50 mL) to give a white
crystalline solid; yield: 15.6 g (90%); mp >250 °C (onset), >250 °C
(peak) {Lit.14c 245 °C (dec.)}; Rf = 0.14 (MeOH).
IR (KBr): 3424, 3049, 3000, 1513, 1491, 1438, 1221, 1108, 780,
747, 721, 688, 565 cm–1.
1H NMR (500 MHz, CD3OD): δ = 0.64 (br s, 2 H), 1.05 (br s, 2 H),
2.04 (m, 1 H), 5.25 (d, J = 11.5 Hz, 2 H), 6.83 (br s, 2 H), 7.15 (d,
J = 8.4 Hz, 1 H), 7.18–7.33 (m, 8 H), 7.38 (m, 1 H), 7.64 (m, 6 H),
7.71 (m, 1 H), 7.89 (m, 3 H), 7.94 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CD3OD): δ = 12.1, 17.4, 28.4 (d, J = 48.0 Hz),
117.7 (d, J = 21.8 Hz), 118.6, 119.3, 121.2 (d, J = 8.8 Hz), 127.2,
127.7, 129.9, 131.6, 131.7, 132.9, 133.0 (d, J = 7.6 Hz), 135.4 (d,
J = 9.8 Hz), 136.7, 148.7, 150.1 (d, J = 6.8 Hz), 162.6 (d, J = 2.3
Hz), 164.4 (d, J = 248.5 Hz).
19F NMR (470 MHz, CD3OD): δ = –114.2, –77.4.
31P NMR (202 MHz, CD3OD): δ = 32.2.
HRMS–ESI: m/z [M + H]+ calcd for C37H48FNP: 556.3503; found:
556.3499.
{[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methyl}(tri-
phenyl)phosphonium Trifluoroacetate (5g)
White crystalline solid; yield: 1.47 g (90%); mp 203.8 °C (onset),
208.2 °C (peak); Rf = 0.07 (MeOH).
IR (KBr): 3432, 3059, 2996, 2926, 1686, 1513, 1491, 1438, 1226,
1198, 1158, 1109, 913, 722, 690 cm–1.
1H NMR (500 MHz, CD3OD): δ = 0.60 (br s, 2 H), 1.04 (br s, 2 H),
1.97 (m, 1 H), 5.17 (d, J = 11.7 Hz, 2 H), 6.75 (br s, 2 H), 7.12 (d,
J = 8.4 Hz, 1 H), 7.24 (m, 8 H), 7.35 (m, 1 H), 7.61 (m, 6 H), 7.68
(m, 1 H), 7.86 (m, 3 H), 7.92 (d, J = 8.4 Hz, 1 H).
31P NMR (202 MHz, CD3OD): δ = 20.5.
HRMS–ESI: m/z [M + H]+ calcd for C37H30FNP: 538.2094; found:
538.2091.
Pitavastatin Phosphonium Trifluoroacetate Salts; General Pro-
cedure
The appropriate phosphine (5.0 mmol, 2.0 equiv) was added to a
soln of trifluoroacetate 7 (0.973 g, 2.5 mmol) in anhyd toluene (10
mL) and the mixture was stirred under reflux for 6 h. The solvent
was then removed under reduced pressure, anhyd Et2O (10 mL) was
added, and the suspension was stirred at r.t. overnight. The precipi-
tate was filtered off and washed with anhyd Et2O (4 × 15 mL) to
give the pure pitavastatin phosphonium trifluoroacetate salt.
13C NMR (125 MHz, CD3OD): δ = 12.0, 17.3, 27.4, 28.3 (d,
J = 48.2 Hz), 117.7 (d, J = 21.9 Hz), 118.4 (q, J = 293.4 Hz), 118.6,
119.3, 121.1 (d, J = 8.9 Hz), 127.2 (d, J = 1.6 Hz), 127.7 (d, J = 1.2
Hz), 129.9 (d, J = 1.5 Hz), 131.6 (d, J = 12.6 Hz), 131.6, 132.9,
133.0, 135.4 (d, J = 9.9 Hz), 136.7 (d, J = 3.0 Hz), 148.7 (d, J = 2.6
Hz), 150.1 (d, J = 7.0 Hz), 162.6 (d, J = 3.4 Hz), 162.9 (q, J = 34.0
Hz), 164.4 (d, J = 248.6 Hz).
Tributyl{[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-
yl}phosphonium Trifluoroacetate (5b)
White crystalline solid; yield: 1.24 g (82% yield); mp 113.6 °C (on-
set), 115.3 °C (peak); Rf = 0.09 (MeOH).
19F NMR (470 MHz, CD3OD): δ = –114.9, –77.7.
31P NMR (202 MHz, CD3OD): δ = 20.5.
HRMS–ESI: m/z [M + H]+ calcd for C37H30FNP: 538.2094; found:
538.2089.
IR (KBr): 3433, 3078, 2960, 2930, 2872, 1687, 1226, 1197, 1139,
1118, 921, 782, 715 cm–1.
Diethyl {[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]meth-
yl}phosphonate (5h)32
1H NMR (500 MHz, CD3OD): δ = 0.85 (t, J = 7.3 Hz, 9 H), 1.17 (m,
6 H), 1.25–1.40 (m, 8 H), 1.46 (m, 2 H), 2.12 (m, 6 H), 2.39 (m, 1
H), 4.14 (d, J = 14.6 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.42 (m, 1
H), 7.47 (m, 2 H), 7.54 (m, 2 H), 7.70 (m, 1 H), 7.95 (d, J = 8.4 Hz,
1 H).
13C NMR (125 MHz, CD3OD): δ = 13.6, 13.7, 16.6, 20.8 (d,
J = 45.9 Hz), 21.9 (d, J = 44.9 Hz), 24.3 (d, J = 5.0 Hz), 25.0 (d,
J = 16.0 Hz), 118.0 (d, J = 21.9 Hz), 118.5 (q, J = 293.4 Hz), 121.0
(d, J = 8.7 Hz), 127.1 (d, J = 2.9 Hz), 127.3, 127.7, 130.0 (d, J = 0.9
Hz), 131.4 (d, J = 0.9 Hz), 133.4, 133.9 (d, J = 6.5 Hz), 148.8 (d,
J = 2.4 Hz), 148.9 (d, J = 6.2 Hz), 162.5 (d, J = 3.1 Hz), 162.9 (q,
J = 34.1 Hz), 164.6 (d, J = 248.9 Hz).
This compound was prepared by slight modification of the proce-
dure described in the literature.14
A soln of quinoline 6 (1.07 g, 3.0 mmol) and P(OEt)3 (1.03 mL, 6.0
mmol, 2.0 equiv) in toluene (10 mL) was refluxed for 18 h. The sol-
vent was then evaporated under reduced pressure and the residue
was purified by column chromatography [silica gel, hexane–EtOAc
(1:1)] to give a white crystalline solid; yield: 1.02 g (82%); mp
88.6 °C (onset), 90.6 °C (peak) (Lit.14c 89 °C); Rf = 0.21 (hexane–
EtOAc, 1:1).
IR (KBr): 3443, 3075, 2983, 2919, 1600, 1580, 1559, 1512, 1493,
1319, 1252, 1217, 1158, 1150, 1092, 1062, 1050, 1016, 960, 944,
837, 764, 567, 550, 542, 502 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.06 (m, 2 H), 1.16 (m, 6 H), 1.29
(br s, 2 H), 2.62 (m, 1 H), 3.40 (d, J = 22.5 Hz, 2 H), 3.8–4.0 (m, 4
19F NMR (470 MHz, CD3OD): δ = –114.3, –77.6.
31P NMR (202 MHz, CD3OD): δ = 33.4.
Synthesis 2012, 44, 1700–1710
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pitavastatin through a Lactonized Side-Chain Precursor
1707
H), 7.15 (d, J = 8.4 Hz, 1 H), 7.19 (m, 2 H), 7.25 (m, 1 H), 7.32 (m,
2 H), 7.55 (m, 1 H), 7.92 (d, J = 8.4 Hz, 1 H).
31P NMR (202 MHz, CDCl3): δ = 27.7.
HRMS–ESI: m/z [M + H]+ calcd for C31H26FNOP: 478.1731;
13C NMR (125 MHz, CDCl3): δ = 10.3, 15.5, 16.5 (d, J = 5.8 Hz),
28.9 (d, J = 139.2 Hz), 62.1 (d, J = 6.8 Hz), 115.5 (d, J = 21.4 Hz),
123.0 (d, J = 9.8 Hz), 125.6, 126.3, 126.8 (d, J = 2.9 Hz), 128.9,
129.0, 132.0 (d, J = 7.4 Hz), 133.0, 146.7 (d, J = 8.3 Hz), 146.8 (d,
J = 2.2 Hz), 161.9 (d, J = 3.4 Hz), 162.7 (d, J = 247.3 Hz).
31P NMR (202 MHz, CDCl3): δ = 25.6.
HRMS–ESI: m/z [M + H]+ calcd for C23H26FNO3P: 414.1629;
found: 478.1729.
Olefination Reactions of Aldehyde 4 with Phosphorus-Deriva-
tized Quinoline Heterocyclic Precursors 5; General Procedure
A soln of hydrate 4′22 (304 mg, 1.1 mmol, 1.1 equiv) in anhyd
CH2Cl2 (25 mL) was stirred at r.t. for 2 h. The resulting soln was
warmed to 45 °C and purged with N2 to remove the mixture of
CH2Cl2 and H2O. The appropriate solvent (20 mL) was then added
to the resulting white solid residue to form an anhyd soln of pure al-
dehyde 4.
found: 414.1629.
2-Cyclopropyl-3-[(diethylphosphoryl)methyl]-4-(4-fluorophe-
nyl)quinoline (5i)
A three-necked reaction flask was dried at 85 °C under vacuum for
2 h then charged under N2 with quinoline derivative 5 (1.0 mmol,
1.0 equiv) followed by anhyd solvent (30 mL). A soln of base (1.05
mmol, 1.05 equiv) was then added to the mixture to form a colored
soln or suspension. The mixture was heated to 25, 60, or 90 °C and
stirred for 10 min, during which time the color of the soln or suspen-
sion remained unchanged. The prepared soln of aldehyde 4 was then
added with vigorous stirring. The reaction was normally complete
within 1 min (except in the case of phosphonate derivative, where it
was complete within 10 min). The solvent was evaporated under re-
duced pressure and the crude product was analyzed by NMR spec-
troscopy and by HPLC. The results of these reactions are listed in
Tables 1 and 2.
A suspension of NaOEt (3.01 g, 44.2 mmol, 1.1 equiv) in anhyd
THF (120 mL) was cooled to 0 °C on an ice bath under N2. A soln
of Et2PCl (5.01 g, 40.2 mmol, 1.0 equiv) in anhyd THF (5 mL) was
then added with intense stirring. The resulting mixture was stirred
at 0 °C while the progress of the reaction was monitored by 31P
NMR. When the reaction was complete (1 h), the mixture was
warmed to r.t. and the resulting Et2POEt soln was added to a soln of
quinoline 6 (16.0 g, 44.2 mmol, 1.1 equiv) in anhyd THF (25 mL).
The mixture was refluxed with stirring for 18 h under N2 then
cooled to r.t. The precipitated NaCl was filtered off and THF was
removed under reduced pressure. The oily residue was purified by
column chromatography [silica gel, CH2Cl2–MeOH (20:1)] to give
a white crystalline solid; yield: 10.2 g (67%); mp 142.8 °C (onset),
144.2 °C (peak); Rf = 0.28 (CH2Cl2–MeOH, 20:1).
(4R,6S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-{(E/Z)-2-[2-cyclo-
propyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}tetrahydro-2H-
pyran-2-one [(E/Z)-3]
IR (KBr): 3441, 3067, 3046, 3026, 2969, 2941, 2908, 2882, 1598,
1575, 1559, 1511, 1492, 1403, 1319, 1216, 1147, 1137, 1093, 1027,
1015, 912, 864, 854, 767, 602, 561 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.82–0.95 (m, 6 H), 1.10 (m, 2 H),
1.32 (m, 2 H), 1.40–1.60 (m, 4 H), 2.26 (m, 1 H), 3.45 (d, J = 13.8
Hz, 2 H), 7.17 (d, J = 8.3 Hz, 1 H), 7.19–7.32 (m, 5 H), 7.55 (m, 1
H), 7.92 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 5.7 (d, J = 4.7 Hz), 10.9, 16.0,
21.7 (d, J = 65.9 Hz), 30.1 (d, J = 58.0 Hz), 116.0 (d, J = 21.4 Hz),
123.7 (d, J = 7.9 Hz), 125.7, 126.0, 126.5, 129.0, 129.1, 132.1 (d,
J = 7.5 Hz), 133.1, 145.9 (d, J = 5.7 Hz), 146.8, 162.0, 162.7 (d,
J = 248.4 Hz).
A three-necked flask was dried at 85 °C under vacuum for 2 h then
charged, under N2, with quinoline 5f (1.86 g, 3.0 mmol) and anhyd
toluene (90 mL) added sequentially. A 0.6 M soln of NaHMDS in
toluene (5.25 mL, 3.15 mmol, 1.05 equiv) was added to form an
orange-red suspension of the corresponding ylide. The mixture was
heated to 60 °C and stirred for 10 min while the color of suspension
remained unchanged. A soln of aldehyde 4 (3.3 mmol, 1.1 equiv) in
toluene (30 mL) was then added to the ylide suspension with vigor-
ous stirring. The reaction was complete within 1 min. The solvent
was removed under reduced pressure and the crude residue from the
Wittig reaction was dissolved in EtOAc (100 mL), washed with
H2O (100 mL), and dried (Na2SO4). The solvent was removed com-
pletely by evaporation and the residue was crystallized from 20:3
MeOH–H2O (23 mL) to give a white crystalline solid; yield: 1.16 g
(75%). An analytically pure sample of (Z)-3 as a yellowish oil was
obtained by column chromatography [silica gel, hexane–t-BuOMe
(2:1)].
31P NMR (202 MHz, CDCl3): δ = 49.1.
HRMS–ESI: m/z [M + H]+ calcd for C23H26FNOP: 382.1731;
found: 382.1730.
2-Cyclopropyl-3-[(diphenylphosphoryl)methyl]-4-(4-fluoro-
phenyl)quinoline (5j)32
(4R,6S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-{(E)-2-[2-cyclopro-
pyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}tetrahydro-2H-py-
ran-2-one [(E)-3]
This compound was prepared by a slight modification of the proce-
dure described in the literature.14
25
Mp 157.2 °C (onset), 159.2 °C (peak); [α]D +22.5 (c 1.12,
A soln of quinoline 6 (3.56 g, 10.0 mmol) and EtOPPh2 (4.65 g, 20.2
mmol, 2.0 equiv) in toluene (70 mL) was refluxed for 64 h. The sol-
vent was then removed under reduced pressure and the solid residue
was washed with hexane (3 × 50 mL) to give a white crystalline sol-
id; yield: 4.35 g (91%); mp 172.9 °C (onset), 175.1 °C (peak)
(Lit.14c 170 °C); Rf = 0.08 (hexane–EtOAc, 3:1).
CH2Cl2); Rf = 0.18 (hexane–t-BuOMe, 2:1).
IR (KBr): 3440, 3065, 3003, 2950, 2926, 2895, 2855, 1741, 1606,
1516, 1492, 1344, 1252, 1241, 1222, 1163, 1074, 1046, 930, 847,
837, 775, 767 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.04 (s, 3 H), 0.06 (s, 3 H), 0.86
(s, 9 H), 1.02 (m, 2 H), 1.33 (m, 2 H), 1.48 (ddd, J = 2.6 Hz, J = 11.2
Hz, J = 13.9 Hz, 1 H), 1.60 (m, 1 H), 2.39 (m, 1 H), 2.55 (m, 2 H),
4.23 (m, 1 H), 5.11 (m, 1 H), 5.63 (dd, J = 6.6 Hz, J = 16.2 Hz, 1 H),
6.65 (dd, J = 1.2 Hz, J = 16.2 Hz, 1 H), 7.11–7.22 (m, 4 H), 7.29
(ddd, J = 1.2 Hz, J = 6.7 Hz, J = 8.2 Hz, 1 H), 7.32–7.36 (dd,
J = 1.1 Hz, J = 8.4 Hz, 1 H), 7.57 (ddd, J = 1.5 Hz, J = 6.7 Hz,
J = 8.3 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = –4.7 (d, J = 10.7 Hz), 10.6 (d,
J = 5.4 Hz), 16.0, 18.1, 25.8, 36.8, 39.4, 63.5, 76.1, 115.5 (dd,
J = 11.4 Hz, J = 21.4 Hz), 125.7, 126.0, 126.2, 128.4, 128.8, 129.1,
129.1, 132.0 (dd, J = 7.8 Hz, J = 43.5 Hz), 133.4 (d, J = 3.2 Hz),
135.1, 144.7, 147.2, 160.7, 162.4 (d, J = 247.4 Hz), 170.0.
IR (KBr): 3433, 3052, 3007, 2926, 1514, 1491, 1437, 1421, 1398,
1314, 1224, 1192, 1162, 911, 837, 768, 715, 565, 510 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.87 (m, 2 H), 1.21 (m, 2 H), 2.56
(m, 1 H), 4.03 (d, J = 13.9 Hz, 2 H), 6.77 (m, 2 H), 6.95 (m, 2 H),
7.04 (d, J = 8.3 Hz, 1 H), 7.19 (m, 1 H), 7.28–7.34 (m, 4 H), 7.35–
7.46 (m, 6 H), 7.52 (m, 1 H), 7.92 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 10.2, 16.3, 33.5 (d, J = 65.1 Hz),
115.5 (d, J = 21.4 Hz), 123.4 (d, J = 8.8 Hz), 125.5, 126.0, 126.5,
128.6 (d, J = 11.7 Hz), 128.8, 129.0, 131.1 (d, J = 9.1 Hz), 131.5 (d,
J = 7.6 Hz), 131.9, 132.7, 133.5, 146.6, 146.8, 162.3, 162.3 (d,
J = 247.6 Hz).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1700–1710

1708
J. Fabris et al.
PAPER
HRMS–ESI: m/z [M + H]+ calcd for C31H37FNO3Si: 518.2521;
found: 518.2519.
H), 7.13–7.22 (m, 4 H), 7.26–7.35 (m, 2 H), 7.58 (ddd, J = 1.7 Hz,
J = 6.5 Hz, J = 8.3 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 1.2, 10.6 (d, J = 4.2 Hz), 16.1,
29.6, 77.7, 115.6 (d, J = 21.4 Hz), 121.7, 125.8, 126.1, 126.2, 128.6,
129.1, 129.2 (d, J = 12.8 Hz), 132.0 (dd, J = 7.9 Hz, J = 33.8 Hz),
133.4 (d, J = 3.2 Hz), 134.1, 144.5, 144.7, 147.2, 160.7, 162.5 (d,
J = 247.4 Hz), 163.8.
HRMS–ESI: m/z [M + H]+ calcd for C25H21FNO2: 386.1551; found:
386.1545.
(4R,6S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-{(Z)-2-[2-cyclopro-
pyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}tetrahydro-2H-py-
ran-2-one [(Z)-3]
[α]D25 +102.7 (c 0.98, CH2Cl2); Rf = 0.11 (hexane–t-BuOMe, 2:1).
IR (NaCl): 3460, 3064, 3005, 2954, 2928, 2896, 2856, 1742, 1608,
1560, 1514, 1489, 1417, 1388, 1348, 1233, 1158, 1076, 1043, 1015,
928, 907, 837, 777, 737, 703, 558 cm–1.
1H NMR (500 MHz, CDCl3): δ = –0.26 (s, 3 H), –0.11 (s, 3 H), 0.46
(s, 9 H), 0.9–1.9 (m, 6 H), 2.1–2.8 (m, 3 H), 4.16 (m, 1 H), 5.14 (m,
1 H), 5.73 (m, 1 H), 6.52 (br s, 1 H), 7.0–7.5 (m, 6 H), 7.58 (m, 1
H), 7.91 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = –5.2, –4.8, 11.1 (d, J = 26.5 Hz),
12.3, 15.4, 17.6, 25.3, 36.0, 39.3, 63.5, 73.3, 115.6 (d, J = 21.5 Hz),
115.9 (d, J = 20.5 Hz), 125.6, 126.1 (m), 129.2 (d, J = 7.3 Hz),
129.7, 131.2, 132.0, 144.9, 147.7, 160.4, 161.7, 163.6, 169.8.
(4R,6S)-6-{(E)-2-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-
yl]vinyl}-4-hydroxytetrahydro-2H-pyran-2-one (10)
A soln of TBAF·3H2O (551 mg, 1.75 mmol, 1.75 equiv) and AcOH
(286 μL, 5.0 mmol, 5.0 equiv) in THF (3 mL) was cooled on an ice
bath and a soln of (E)-3 (517 mg, 1.0 mmol) in THF (2 mL) was
added. The mixture was stirred for 19 h at r.t. then concentrated un-
der reduced pressure to give a residue that was dissolved in EtOAc
(25 mL). The soln was washed successively with H2O (25 mL), sat.
aq NaHCO3 (25 mL), brine (25 mL), and H2O (25 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced pressure
to give a white crystalline solid; yield: 370 mg (92%); mp 141.0 °C
HRMS–ESI: m/z [M + H]+ calcd for C31H37FNO3Si: 518.2521;
found: 518.2514.
25
(onset), 143.6 °C (peak) (Lit.20 137–139 °C); [α]D +12.5 (c 0.98,
2-Cyclopropyl-4-(4-fluorophenyl)-3-methylquinoline (8)
20
CH2Cl2) {Lit.20 [α]D +9.8 (c 1, CHCl3)}; Rf = 0.13 (hexane–
The soln in toluene of the ylide formed from 5f (1.0 mmol) was pre-
pared in the same way as described above. The ylide suspension was
heated to 45 °C and excess H2O was added with vigorous stirring.
The solvent was removed under reduced pressure and the residue
was purified by column chromatography [silica gel, EtOAc–hexane
(1:3)] to give a white crystalline solid; yield: 239 mg (86%); mp
143.2 °C (onset), 144.3 °C (peak); Rf = 0.55 (hexane–EtOAc, 2:1).
EtOAc, 1:1).
IR (KBr): 3433, 3065, 3005, 2924, 1736, 1604, 1513, 1489, 1412,
1375, 1223, 1159, 1094, 1064, 1039, 971, 921, 845, 764, 725, 557
cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.96–1.06 (m, 2 H), 1.24–1.36 (m,
2 H), 1.53 (ddd, J = 3.0 Hz, J = 10.6 Hz, J = 13.9 Hz, 1 H), 1.76 (m,
1 H), 2.35 (m, 1 H), 2.45 (br s, 1 H), 2.56 (ddd, J = 1.4 Hz, J = 3.9
Hz, J = 17.8 Hz, 1 H), 2.66 (dd, J = 4.8 Hz, J = 17.8 Hz, 1 H), 4.21
(m, 1 H), 5.16 (m, 1 H), 5.58 (dd, J = 6.4 Hz, J = 16.2 Hz, 1 H), 6.67
(dd, J = 1.3 Hz, J = 16.2 Hz, 1 H), 7.10–7.21 (m, 4 H), 7.26–7.34
(m, 2 H), 7.57 (ddd, J = 1.7 Hz, J = 6.5 Hz, J = 8.4 Hz, 1 H), 7.93
(d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 10.5 (d, J = 25.5 Hz), 16.1, 35.7,
38.6, 62.0, 76.3, 115.4 (dd, J = 11.7 Hz, J = 21.3 Hz), 125.7, 126.0,
126.1, 128.2, 128.6, 128.7, 129.1, 131.8 (dd, J = 7.7 Hz, J = 25.1
Hz), 133.1 (d, J = 2.5 Hz), 135.0, 144.7, 146.8, 160.5, 162.3 (d,
J = 247.3 Hz), 170.7.
IR (KBr): 3442, 3057, 3004, 1599, 1582, 1513, 1493, 1413, 1313,
1215, 1157, 1093, 1060, 931, 900, 862, 839, 769, 605, 556, 516
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.06 (m, 2 H), 1.30 (m, 2 H), 2.27–
2.35 (m, 4 H), 7.17–7.23 (m, 4 H), 7.23–7.31 (m, 2 H), 7.54 (ddd,
J = 1.8 Hz, J = 6.4 Hz, J = 8.3 Hz, 1 H), 7.96 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 9.2, 15.5, 16.7, 115.7 (d, J = 21.4
Hz), 125.4, 125.9, 126.7, 128.0, 128.2, 129.1, 131.4 (d, J = 7.9 Hz),
134.0 (d, J = 3.2 Hz), 144.9, 146.4, 162.1, 162.5 (d, J = 246.7 Hz).
HRMS–ESI: m/z [M + H]+ calcd for C19H17FN: 278.1340; found:
278.1340.
HRMS–ESI: m/z [M + H]+ calcd for C25H23FNO3: 404.1654; found:
404.1653.
(6S)-6-{(E)-2-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-
yl]vinyl}-5,6-dihydro-2H-pyran-2-one (9)
Sodium (3R,5S,6E)-7-[2-Cyclopropyl-4-(4-fluorophenyl)quino-
lin-3-yl]-3,5-dihydroxyhept-6-enoate (Pitavastatin Sodium; 11)
Synthesis from lactone 10: 8.0 M aq NaOH (67 μL, 0.54 mmol,
1.075 equiv) was added to a soln of 10 (202 mg, 0.5 mmol) in 4:1
THF–H2O (2.5 mL) at 30 °C, and the mixture was stirred for 1 h.
The THF was removed under the reduced pressure and the remain-
ing aqueous soln was lyophilized to give a white amorphous solid;
yield: 220 mg (99%).
Et3N (4.16 mL, 30.0 mmol, 3.0 equiv) was added to a soln of lactone
10 (4.03 g, 10.0 mmol) in CH2Cl2 (40 mL), previously cooled on an
ice bath, and the mixture was stirred for 15 min. MeSO2Cl (1.16
mL, 15.0 mmol, 1.5 equiv) was added dropwise and, after another
30 min, the mixture was warmed to r.t. The reaction was completed
within 18 h. The organic layer was washed with sat. aq NaHCO3 (50
mL), dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified by column chromatography [silica gel,
EtOAc–hexane (1:3)] to give a white crystalline solid; yield: 3.30 g
(86%); mp 152.1 °C (onset), 156.3 °C (peak) (Lit.15 168–168.5 °C);
[α]D25 –51.4 (c 1.22, CH2Cl2) {Lit.15 [α]D29 –57.84 (c 1.49, CHCl3)};
Rf = 0.09 (hexane–EtOAc, 3:1).
One-pot synthesis from lactone (E)-3: A soln of TBAF·H2O (0.73 g,
2.3 mmol, 2.3 equiv) and AcOH (377 μL, 6.6 mmol, 6.6 equiv) in
THF (6 mL) was cooled on an ice bath. A soln of (E)-3 (0.52 g, 1.0
mmol) in THF (2 mL) was added and the mixture was stirred for 32
h at r.t. The solvent was removed under reduced pressure and the
residue was dissolved in EtOAc (20 mL). The organic layer was
washed successively with H2O (20 mL) and brine (20 mL) then con-
centrated under reduced pressure. A 4:1 mixture of THF–H2O (5.0
mL) was added, the soln was warmed to 30 °C, and 8.0 M aq NaOH
(134 μL, 1.08 mmol, 1.075 equiv) was added. The mixture was
stirred at 30 °C for 1 h before the THF was removed under reduced
pressure. The aqueous phase was washed with hexane (20 mL) then
evaporated to remove residual dissolved hexane. The resulting pure
aqueous soln of pitavastatin sodium was lyophilized to give a white
amorphous solid; yield: 0.44 g (99%); [α]D25 +21.4 (c 0.61, MeOH);
Rf = 0.13 (CH2Cl2–MeOH, 5:1).
IR (KBr): 3441, 3064, 3015, 2963, 2928, 1724, 1512, 1490, 1415,
1388, 1261, 1244, 1217, 1161, 1093, 1070, 1055, 1018, 974, 914,
831, 815, 807, 774 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.98–1.07 (m, 2 H), 1.28–1.38 (m,
2 H), 2.11 (dddd, J = 2.6 Hz, J = 2.8 Hz, J = 10.5 Hz, J = 18.3 Hz,
1 H), 2.23 (dddd, J = 1.2 Hz, J = 4.5 Hz, J = 5.5 Hz, J = 18.3 Hz, 1
H), 2.36 (m, 1 H), 4.90 (dddd, J = 1.3 Hz, J = 4.5 Hz, J = 6.1 Hz,
J = 10.5 Hz, 1 H), 5.67 (dd, J = 6.1 Hz, J = 16.2 Hz, 1 H), 5.98 (ddd,
J = 1.2 Hz, J = 2.6 Hz, J = 9.8 Hz, 1 H), 6.71 (dd, J = 1.3 Hz,
J = 16.2 Hz, 1 H), 6.78 (ddd, J = 2.8 Hz, J = 5.5 Hz, J = 9.8 Hz, 1
Synthesis 2012, 44, 1700–1710
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pitavastatin through a Lactonized Side-Chain Precursor
1709
IR (KBr): 3427, 3067, 3006, 2931, 1604, 1576, 1513, 1489, 1411,
1313, 1221, 1158, 1118, 1094, 1066, 1026, 972, 919, 843, 762, 619,
559 cm–1.
1H NMR (500 MHz, CD3OD): δ = 1.13 (m, 2 H), 1.25 (m, 2 H), 1.38
(m, 1 H), 1.65 (m, 1 H), 2.25 (dd, J = 8.1 Hz, J = 15.3 Hz, 1 H), 2.33
(dd, J = 4.4 Hz, J = 15.3 Hz, 1 H), 2.54 (m, 1 H), 3.80 (m, 1 H), 4.33
(m, 1 H), 5.65 (dd, J = 6.6 Hz, J = 16.2 Hz, 1 H), 6.67 (dd, J = 1.0
Hz, J = 16.2 Hz, 1 H), 7.21–7.41 (m, 6 H), 7.66 (ddd, J = 1.6 Hz,
J = 6.7 Hz, J = 8.3 Hz, 1 H), 7.97 (d, J = 8.2 Hz, 1 H).
13C NMR (125 MHz, CD3OD): δ = 10.6 (d, J = 12.9 Hz), 17.2, 44.7,
45.2, 68.0, 71.5, 116.6 (t, J = 20.5 Hz), 126.7, 127.0, 127.2, 127.6,
128.9, 130.4, 131.4, 133.2 (dd, J = 7.9 Hz, J = 48.4 Hz), 134.5 (d,
J = 2.4 Hz), 141.8, 146.4, 147.6, 162.8, 164.7, 180.6.
Curr. Med. Chem. 2007, 14, 243. (g) Endo, A. Nat. Med. (N.
Y., NY, U. S.) 2008, 14, 1050.
(3) Also known as velostatin, with the brand name Zocor®
(Merck & Co). For selected literature, see: Hoffman, W. F.;
Alberts, A. W.; Anderson, P. S.; Chen, J. S.; Smith, R. L.;
Willard, A. K. J. Med. Chem. 1986, 29, 849.
(4) FDA-approved in 1996; also known as eptastatin, with the
brand name of Pravachol® (Bristol-Myers Squibb); see:
Tsujita, Y.; Kuroda, M.; Shimada, Y.; Tanzawa, K.; Arai,
M.; Kaneko, I.; Tanaka, M.; Masuda, H.; Tarumi, C.;
Watanabe, Y. Biochim. Biophys. Acta 1986, 877, 50.
(5) Časar, Z. Curr. Org. Chem. 2010, 14, 816.
(6) FDA-approved in 1993 with the brand name Lescol®
(Novartis Pharma AG); for selected literature, see:
Fuenfschilling, P. C.; Pascale, H.; Mutz, J.-P. Org. Process
Res. Dev. 2007, 11, 13; and references cited therein.
(7) FDA-approved in 1996 with the brand name Lipitor®
[Pfizer (Parke–Davis)]; for selected literature, see: Roth, B.
D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.;
Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.;
Sliskovic, D. R.; Stratton, C. D.; Wilson, M. J. Med. Chem.
1991, 34, 357.
(8) FDA-approved in 2003 with the brand name Crestor®
(AstraZeneca); for selected literature, see: Watanabe, M.;
Koike, H.; Ishiba, T.; Okada, T.; Sea, S.; Hirai, K. Bioorg.
Med. Chem. 1997, 5, 437.
(9) The last super-statin group member, pitavstatin, with the
brand name Livalo® (Kowa Co., Ltd.), was launched in
Japan in 2003, approved by the FDA in 2009, and entered the
US market in 2010; for selected literature, see: Watson, K.
E. Rev. Cardiovasc. Med. 2010, 11, 26.
(10) (a) Kajinami, K.; Mabuchi, H.; Saito, Y. Expert Opin. Invest.
Drugs 2000, 9, 2653. (b) Mukhtar, R. Y. A.; Reid, J.;
Reckless, J. P. D. Int. J. Clin. Pract. 2005, 59, 239. (c) Yee,
L. L.; Wright, E. A. Clin. Ther. 2011, 33, 1023. (d) Baker,
W. L.; Datta, R. Adv. Ther. 2011, 28, 13. (e) Corsini, A.;
Ceska, R. Curr. Med. Res. Opin. 2011, 27, 1551.
(11) (a) Iglestas, P.; Díez, J. J. Expert Opin. Invest. Drugs 2003,
12, 1777. (b) Scharnagl, H.; März, W. Curr. Top. Med.
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(c) Hayashi, T.; Yokote, K.; Saito, Y.; Iguchi, A. Expert
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Waldrop, B. A.; Wensel, B. Ann. Pharmacother. 2010, 44,
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HRMS–ESI: m/z [M + H]+ calcd for C25H25FNO4: 422.1762; found:
422.1760.
Calcium (3R,5S,E)-7-(2-Cyclopropyl-4-(4-fluorophenyl)quino-
lin-3-yl)-3,5-dihydroxyhept-6-enoate (Pitavastatin Calcium; 2)
One-Pot Synthesis: A soln of TBAF·3H2O (7.24 g, 23.0 mmol, 2.3
equiv) and AcOH (3.78 mL, 66.0 mmol, 6.6 equiv) in THF (30 mL)
was cooled on an ice bath and a soln of (E)-3 (5.17 g, 10.0 mmol)
in THF (20 mL) was added. The mixture was stirred at r.t. for 18 h
then the solvent was removed under reduced pressure and the resi-
due was dissolved in EtOAc (200 mL). The organic layer was
washed successively with H2O (200 mL) and brine (200 mL) then
concentrated under reduced pressure. The residue was dissolved in
4:1 THF–H2O (50 mL) and the soln was warmed to 30 °C and treat-
ed with 8.0 M aq NaOH (1.34 mL, 10.8 mmol, 1.075 equiv). After
1 h, conversion was complete and the THF was removed under re-
duced pressure. The residual aqueous phase was washed with hex-
ane (200 mL) and any residual dissolved hexane was distilled off.
The resulting aqueous soln of pitavastatin sodium (50 mL) was
treated with a soln of CaCl2 (1.33 g, 12.0 mmol, 1.2 equiv) in H2O
(3 mL). A white precipitate immediately formed and the resulting
suspension was stirred at r.t. for 18 h. The precipitate was collected
by filtration, washed with H2O (3 × 100 mL), and dried at 40 °C un-
der vacuum to give a white solid; yield: 4.11 g (93%); [α]D25 +20.5
[c 1.00, MeCN–H2O (1:1)]; the spectroscopic properties were in
agreement with the literature data.20
Acknowledgment
We acknowledge the assistance of L. Kolenc, S. Borišek, M.
Borišek, R. Burja, and M. Uštar with some analytical work. We are
also grateful to Dr. M. Črnugelj for acquiring NMR spectra, to Dr.
D. Urankar (University of Ljubljana) for HRMS analysis, and to
Professor J. Košmrlj (University of Ljubljana) for valuable discus-
sions. The authors thank Lek Pharmaceuticals d.d. and EN-FIST
Centre of Excellence for supporting this project. J.F. thanks the Pu-
blic Agency for Technology of the Republic of Slovenia (TIA) for
a young researcher fellowship (MR-10/75).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinIfatgnonmSorti
i
npfurotIangSiuptor
(15) Takano, S.; Kamikubo, T.; Sugihara, T.; Suzuki, M.;
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© Georg Thieme Verlag Stuttgart · New York