Stereocontrolled synthesis of rosuvastatin calcium via iodine chloride-induced intramolecular cyclization

Article abstract of DOI:10.1039/c5ob02245b

A novel, stereoselective approach towards rosuvastatin calcium from the known (S)-homoallylic alcohol has been developed. The synthesis is highlighted by a regio- and stereocontrolled ICl-induced intramolecular cyclization of chiral homoallylic carbonate to deliver the C₆-formyl statin side chain with a syn-1,3-diol moiety. An improved synthesis of the rosuvastatin pyrimidine core moiety is also included. Moreover, this methodology is useful in the asymmetric synthesis of structural variants of statins such as pitavastatin calcium and atorvastatin calcium and their related analogs.

Full text of DOI:10.1039/c5ob02245b

Organic &
Biomolecular Chemistry
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Stereocontrolled synthesis of rosuvastatin
calcium via iodine chloride-induced
intramolecular cyclization†
Cite this: DOI: 10.1039/c5ob02245b
Fangjun Xiong, Haifeng Wang, Lingjie Yan, Sheng Han, Yuan Tao, Yan Wu* and
Fener Chen*
A novel, stereoselective approach towards rosuvastatin calcium from the known (S)-homoallylic alcohol
has been developed. The synthesis is highlighted by a regio- and stereocontrolled ICl-induced intra-
Received 31st October 2015,
Accepted 5th December 2015
molecular cyclization of chiral homoallylic carbonate to deliver the C -formyl statin side chain with a syn-
6
1
,3-diol moiety. An improved synthesis of the rosuvastatin pyrimidine core moiety is also included. More-
DOI: 10.1039/c5ob02245b
over, this methodology is useful in the asymmetric synthesis of structural variants of statins such as pita-
vastatin calcium and atorvastatin calcium and their related analogs.
www.rsc.org/obc
4
ing from readily available (S)-epichlorohydrin (Scheme 1).
However, this process is limited by the use of hazardous tri-
Introduction
Rosuvastatin calcium (Crestor, 1, Fig. 1) is one of the most ethylborane or diethylmethoxyborane/sodium borohydride as
1
important HMG-CoA reductase inhibitors. The significant reduction systems under cryogenic conditions. Furthermore,
and sustained interest in the development of an efficient and the usage of expensive DIBAL-H for the synthesis of the pyrimi-
5
scalable synthetic route to this important statin stems from its dine core moiety 6 is also problematic in industry. As a result,
6
favorable efficiency, safe profiles, and long-term clinical an alternative approach to build a new syn-diol C -side chain
benefits in reducing the risk for cardiovascular events as an with the (4S,6S)-stereocenter and an improved synthetic
antilipidemic agent.
A key structural subunit embedded in this statin molecule
is a syn-1,3-diol, which itself presents a significant challenge to
2
synthesis. A number of procedures involving different strat-
egies for the control of the two stereocenters of the rosuvasta-
3
tin skeleton have been reported. The industrial preparation
method has mostly centered on the manipulation of the chiral
diol C -side chain 3 by well-established diastereoselective
6
Narasaka–Prasad reduction of chiral β-hydroxy-3-ketoester 2 start-
Fig. 1 Structure of rosuvastatin calcium (1).
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
People’s Republic of China. E-mail: rfchen@fudan.edu.cn, wywin8@163.com
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Industrial synthetic route of rosuvastatin calcium (1) starting
from (S)-epichlorohydrin.
c5ob02245b
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procedure for the rosuvastatin pyrimidine core are urgently
needed to improve upon the synthesis of rosuvastatin calcium
Results and discussion
(
1). Herein, we report an efficient and stereoselective synthesis We began our synthesis towards 10 upon the treatment of
of 1 by utilizing the regio- and diastereoselective ICl-induced homoallylic alcohol 13, obtained by our previously reported
6
e
intramolecular iodo-cyclization reaction, thus continuing our process from (S)-epichlorohydrin, with di-tert-butyl dicarbo-
6
work on the asymmetric synthesis of statins.
2
nate (Boc O) in petroleum ether (60–90 °C) under 4-dimethyl-
Creating new stereocenters through substrate control amino-pyridine (DMAP) catalysis (Scheme 3). The homoallylic
remains an important strategy in asymmetric synthesis. We are tert-butyl carbonate 5 was obtained in 95% yield with >99%
interested in the development of an efficient method for the purity.
construction of syn-1,3-diol moieties in statins from stereo-
The next step in the sequence utilized the intramolecular
defined homoallylic carbonate using the Bartlett–Smith intra- iodocyclization methodology to construct the chiral 1,3-syn
7
molecular iodo-cyclization reaction. Our retrosynthetic route diol motif in rosuvastatin calcium. Initially, the reaction using
for 1 is depicted in Scheme 2. The side chain double bond was 3 equiv. of IBr was conducted under the standard reaction con-
7
b
formed by the Wittig olefination of the C -formyl side chain 7 ditions (MeCN, −40 °C) reported by Smith with slight modifi-
6
and triphenylphosphonium salt 8 with a pyrimidine core. The cations (Table 1). Analysis of the crude product of this reaction
chiral side chain 7 was accessible to iodocarbonate 9 through showed that the desired product 9 (by NMR) was an unstable
routine transformations. The (4S,6S)-stereocenters in 7 were component, which underwent acetonidation with acetone in
8
established by intramolecular iodocyclization of homoallylic the presence of p-TsOH. Without purification, the acetonide
tert-butyl carbonate 10 derived from commercially available 14 was obtained in 45% yield with excellent diastereoselectivity
(
S)-epichlorohydrin. The phosphonium salt 8 was prepared via (dr > 300 : 1) (Table 1, entry 1). Our experimental results
pyrimidine acid 11 by a modification of the ketone ester 12 revealed that the diastereoselectivity of this reaction depended
5
b
using a known procedure reported by Matsushita.
upon the reaction temperature. Increasing the reaction temp-
erature from −40 °C to −20 °C and 0 °C resulted in dr > 200 : 1
and dr 98 : 2, respectively (Table 1, entries 2 and 3). It is worth
noting that 1.5 equiv. of IBr was sufficient to obtain the
desired product in excellent diastereoselectivity at the optimal
Scheme 3 Synthesis of homoallylic tert-butylcarbonate 10.
Table 1 Intramolecular iodo-cyclization of homoallylic tert-butyl car-
bonate 10
c
d
Entry Reagent
Solvent
Temp. (°C) Yield (%) dr
1
2
3
4
5
6
7
8
9
1
IBr (3 equiv.)
IBr (3 equiv.)
IBr (3 equiv.)
IBr (1.5 equiv.) MeCN
IBr (1.2 equiv.) MeCN
2 2
IBr (1.5 equiv.) CH Cl
MeCN
MeCN
MeCN
−40
−20
0
−40
−40
−40
45
37
41
47
32
60
58
47
63
22
>300 : 1
>200 : 1
98 : 2
>300 : 1
>300 : 1
>300 : 1
>300 : 1
>300 : 1
>300 : 1
>300 : 1
IBr (1.5 equiv.) t-BuOMe −40
I
2
(1.5 equiv.)
CH
CH
2
Cl
2
Cl
2
Cl
2
2
2
−40
−40
−40
ICl (1.5 equiv.)
NIS (1.5 equiv.) CH
0
a
Reaction conditions: 10 (1.1 g, 5 mmol), reagent (see table), solvent
b
(
20 mL), 1 h. Reaction conditions: 9, p-TsOH·H O (0.5 g, 2.5 mmol),
acetone (10 mL), r.t. 48 h. Isolated yield of 9 (two steps). dr of 14
2
c
d
Scheme 2 Retrosynthetic analysis of rosuvastatin calcium (1).
determined by GC-MS.
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reaction temperature (−40 °C) in MeCN (Table 1, entry 4).
However, when 1.2 equiv. of IBr was used, the yield was Koike for this pyrimidine core 6 involved the use of expensive
decreased to as low as 32% (Table 1, entry 5). Changing the DIBAL-H to perform the reduction of pyrimidine ester 5 to 6.
The original industrial synthetic approach developed by
5
b
solvent from MeCN to CH
the yield of this iodocyclization (Table 1, entries 6 and 7). In ductive process. All attempts to convert 5 into 6 using various
addition, screening of the other iodocyclization reagents (I borohydrides did not produce the desired product 6 upon
ICl, and NIS) found that ICl was the best reagent for this con- workup. The attempted two-step synthesis (alkaline hydrolysis
version, giving 63% yield of 14 (Table 1, entry 9). of the ester group in 5 followed by reduction with borohydride/
This stereoselective iodocyclization could be attributed to Lewis acid) for 6 according to the procedure of Lin and co-
2 2
Cl or t-BuOMe further improved Hence, it is strongly desirable to eliminate it from the pro-
2
,
1
0
the thermo-favoured syn-intermediate with all substitutes on workers (Scheme 5) was also unsuccessful. A difficulty of this
7
a,c
the equatorial-bond rather than the axial bond.
(Fig. 2).
method was the inability to remove the ester group of 5.
Subsequently, an improved synthesis of 6 was undertaken
The treatment of 14 with NaCN in DMSO under mild con-
ditions afforded the corresponding nitrile 15 in 91% yield. (Scheme 6). Conversion of the β-keto methyl ester 12 into
1
1
Nitrile 15 was subjected to SN2 nucleophilic displacement by β-keto benzyl ester 18 was achieved with 92% yield by simply
treatment with sodium benzoate in DMSO at 160 °C to furnish performing the reaction with benzyl alcohol at 150 °C and
benzoate 16 in 83% yield. The selective alkaline-hydrolysis of removing MeOH under distillation. The dihydropyrimidone 19
1
6 under mild conditions (K CO , MeOH, r.t. 1 h) provided was obtained in 84% yield via the Biginelli reaction of 18,
2 3
alcohol 17 in 93% yield. Oxidation of 17 with TCCA at 0 °C 4-fluorobenzaldehyde, and urea in the presence of CuCl and
9
under TEMPO catalysis afforded the C
7% yield (Scheme 4).
6
-formyl side chain 7 in conc. H
2 4 3
SO in MeOH. The exposure of 19 to 62% HNO in
8
CH Cl at 0 °C afforded pyrimidine ester 20 in 92% yield. The
2
2
treatment of 20 with tosyl chloride in BuOAc in the presence of
anhydrous K CO under mild conditions followed by reaction
2
3
with N-methylmethanesulfonamide at 120 °C resulted in the
formation of the desired sulfonamide ester 21 in 83% yield.
Palladium-promoted debenzylation of 21 in MeOH at room
temperature afforded the desired pyrimidine acid 11 in an
almost quantitative yield.
Our initial reduction of 11 was carried out using NaBH in
4
THF at reflux temperature for 24 h. Unfortunately, we were
unable to reduce this carboxyl group in 11 (Table 2, entry 1).
However, this reaction was conducted using a NaBH
reducing system that resulted in 76% conversion of 11
Table 2, entry 2). Increasing the reaction time from 24 h to
2 h did not improve the outcome of the reaction. Other addi-
tives such as ZnCl , LiCl, LiBr, I , and H SO did not generate
4 3
/AlCl
(
7
2
2
2
4
any product (Table 2, entries 3–7). Surprisingly, the use of
1
2
TMSCl as an additive was found to be very efficient for
reduction of 6 (100% conversion). The desired pyrimidine
alcohol 17 was obtained with 92% isolated yield in the pres-
Fig. 2 Proposed mechanism for iodo-cyclization reaction of 10.
1
3
ence of glass beads (Table 2, entry 8).
Scheme 4 Synthesis of C
6
-formyl side chain 7.
Scheme 5 Efforts for synthesis of 6 from 5 without DIBAL-H.
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Scheme 7 Synthesis of rosuvastatin calcium 1.
8
2 3
with K CO at 75 °C in DMSO for 2 h to form crude 22 with
E/Z > 30 : 1 (by NMR), which was purified by chromatography
to afford pure (E)-22 in 71% yield. Hydrolysis of the nitrile and
acetonide groups of 22 by HCl and NaOH and treatment with
Scheme 6 Synthesis of pyrimidine alcohol 6.
2
CaCl in a one-pot procedure gave the final product rosuvasta-
tin calcium 1 in 62% yield (Scheme 7).
a
Table 2 Reduction of acid 11 with NaBH
4
Experimental
All reagents and solvents were purchased from commercial
1
sources and used without further purification. H (400 MHz)
1
3
and C (100 MHz) NMR spectra were recorded on a Bruker
Avance 400 spectrometer using TMS or CDCl as an internal
3
standard, IR spectra were recorded on a Nicolet iS5 FT-IR
spectrometer, and optical rotations were measured by using a
JASCO P1020 digital polarimeter. EI-MS were recorded on an
Agilent 6890N/5975 spectrometer and ESI-MS were recorded
on a Waters Micromass Quattro Micro spectrometer. HRMS
were recorded on a Bruker micrOTOF spectrometer (ESI) or
Waters Micromass GCT Premier (EI).
b
c
Entry
Reagent
Conversion
Yield (%)
1
2
3
4
5
6
7
8
—
—
76%
Trace
Trace
Trace
Complex
—
—
61%
—
—
—
—
—
92%
AlCl
LiCl
3
LiBr
ZnCl
2
I
H
2
2
SO
4
TMSCl
100%
(
S)-tert-Butyl (1-chloropent-4-en-2-yl) carbonate(10)
To a stirred solution of Boc O (21.8 g, 0.1 mol) and DMAP
0.56 g, 5 mmol) in petroleum ether (200 mL, bp 60–90 °C) was
a
Reaction conditions: 11 (367 mg, 1 mmol), NaBH
4
(80 mg, 2 mmol),
2
additive (2 mmol), THF (10 mL), N
2
atmosphere, reflux, 24 h.
b
c
(
Determined by HPLC. Isolated yield.
6
e
added (S)-1-chloropent-4-en-2-ol (12 g, 0.1 mol) dropwise at r.
t. within 30 min, stirring was continued for 24 h. The reaction
mixture was filtered and washed with water, the organic phase
Triphenylphosphonium salt 8 was easily prepared by a one- was dried (Na SO ) and concentrated to dryness to afford 10
2
4
step sequence with 94% yield by refluxing 6 with triphenyl- (21.0 g, 98%) as brown oil, which was used without further
1
phosphine hydrobromide in toluene. With both 7 and 8 syn- purification. H NMR (400 MHz, CDCl3) δ = 5.77 (ddt, J = 17.2,
thesized, the Wittig reaction was carried out by treating 7 and 10.1, 7.1 Hz, 1H), 5.23–5.10 (m, 2H), 4.93–4.79 (m, 1H),
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3
2
1
1
.65 (dd, J = 11.7, 4.7 Hz, 1H), 3.60 (dd, J = 11.7, 5.6 Hz, 1H), vacuum. The residue was purified by silica gel column
1
3
.57–2.32 (m, 2H), 1.49 (s, 9H). C NMR (100 MHz, CDCl ) δ = chromatography (petroleum ether : EtOAc = 2 : 1) to afford 16
3
1
7
1
53.0, 132.2, 119.2, 82.8, 75.1, 44.94, 36.1, 27.9. MS (EI): m/z = (1.34 g, 83%) as yellow oil. [α]
64 [M-t-Bu + H] . HRMS (EI): m/z [M-t-Bu + H] calcd for (400 MHz, CDCl
D
= +5.2 (c 1.4, MeOH). H NMR
): δ = 8.04 (d, J = 7.6 Hz, 2H), 7.57 (t, J =
7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 4.38–4.14 (m, 4H),
.63–2.46 (m, 2H), 1.77 (d, J = 12.4 Hz, 1H), 1.48 (s, 3H), 1.44
+
+
3
C H ClO : 164.0240; found: 164.0243.
6
9
3
2
(
4S,6R)-4-(Chloromethyl)-6-(iodomethyl)-2,2-dimethyl-
,3-dioxane (14)
To a stirred solution of 10 (2.2 g, 10 mmol) in CH
13
(
m, 4H). C NMR (100 MHz, CDCl
3
): δ = 166.4, 133.2, 129.9,
1
1
29.7, 128.5, 116.7, 99.6, 67.0, 66.9, 64.9, 32.5, 29.7, 25.0, 19.6.
+
+
2
Cl
2
(40 mL) MS (EI): m/z = 274 [M − Me] . HRMS (ESI): m/z [M + Na] calcd
at −40 °C was added ICl (2.4 g, 15 mmol). The reaction for C16
mixture was stirred at −40 °C for 1 h and quenched with sat.
4
H19NO Na 312.1206; found: 312.1209.
aq. NaHCO
phase was dried (Na
below 20 °C. The crude 5 should be used in the next step
immediately due to its instability. Acetone (20 mL) and To a stirred solution of 16 (3.20 g, 11 mmol) in MeOH (25 mL)
p-TsOH (0.95 g, 5 mmol) were added to crude 5 and stirred at was added K CO (1.50 g, 11 mmol), the stirring was continued
3
(20 mL) and 10% aq. Na
2 3
SO (20 mL), the organic
2
-((4S,6S)-6-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)
2
SO ) and evaporated to dryness in vacuo
4
acetonitrile (17)
2
3
room temperature for 48 h to protect from light. The reaction for 1 h and then sat. aq. NH Cl (5 mL) was added, the reaction
4
mixture was concentrated under vacuum and the residue was mixture was washed with petroleum ether (50 mL × 3) to
dissolved in petroleum ether (100 mL, bp 60–90 °C), washed remove MeOBz. The methanolic phase was concentrated to
with sat. aq. NaHCO (20 mL) and 10% aq. Na SO (20 mL), remove MeOH in vacuo. The residue was dissolved in EtOAc
3
2
3
dried (Na
2 4 2 4
SO ) and evaporated to dryness in vacuo to afford 14 and washed with brine, dried (Na SO ) and evaporated to
1
7
(1.63 g, 63%) as orange oil. An analytical sample was achieved dryness in vacuo to afford 17 (1.82 g, 87%) as yellow oil. [α]
D
=
1
by silica gel column chromatography eluting with petroleum −0.5 (c 0.7, MeOH). H NMR (400 MHz, CDCl ): δ = 4.12–4.22
3
1
8
1
ether. [α]
D 3 3
= +0.3 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ): (m, 1H), 4.06–3.97 (m, 1H), 3.64 (dd, J = 11.6, 3.2 Hz, 1H), 3.53
δ = 4.05 (m, 1H), 3.90 (m, 1H), 3.53 (dd, J = 11.2, 5.6 Hz, 1H), (dd, J = 11.6, 6.0 Hz, 1H), 2.60–2.44 (m, 2H), 1.65–1.55 (m, 1H),
1
3
3
3
.42 (dd, J = 11.2, 5.6 Hz, 1H), 3.18 (dd, J = 10, 5.6 Hz, 1H), 1.47 (s, 3H), 1.46–1.38 (m, 4H). C NMR (100 MHz, CDCl3):
.12 (dd, J = 10, 6 Hz, 1H), 1.99 (dt, J = 12.8, 2.4 Hz, 1H), 1.57 δ = 116.8, 99.5, 69.1, 65.7, 64.8, 31.4, 29.7, 25.0, 19.8. MS (EI):
+
+
(
s, 1H), 1.44 (d, J = 4.4 Hz, 6H), 1.18 (dd, J = 24, 11.6 Hz, 1H). m/z = 170 [M − Me] . HRMS (ESI): m/z [M − Me] calcd for
C NMR (100 MHz, CDCl ): δ = 99.9, 69.2, 68.9, 46.9, 34.3, C H NO 170.0817; found: 170.0816.
1
3
3
8
12
3
+
2
9.7, 19.9, 8.9. MS (EI): m/z = 289 [M − Me] . HRMS (EI): m/z
+
8 2
[M] calcd for C H14ClIO 303.9727; found: 303.9733.
2
-((4S,6S)-6-Formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetonitrile (7)
To a stirred solution of 17 (1.60 g, 8.6 mmol), NaHCO (5 g,
0 mmol) and TEMPO (30 mg) in CH Cl (20 mL) and water
4 (1.52 g, 5 mmol), NaCN (228 mg, 6 mmol) and DMSO (20 mL) was added TCCA (2.10 g, 9 mmol) in portions at 0 °C,
10 mL) were stirred at room temperature for 48 h. The reac- stirring was continued for 1 h. After completion of the reac-
tion mixture was quenched with water (20 mL) and extracted tion, the mixture was extracted with CH Cl (50 mL × 3),
with CH Cl (20 mL × 4). The combination organic phase was washed with 10% aq. Na SO and NaHCO successively, dried
2
-((4S,6S)-6-(Chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)
3
acetonitrile (15)
6
2
2
1
(
2
2
2
2
2
3
3
2 4 2 4
washed with brine and dried with Na SO , the solvent was (Na SO ) and evaporated to dryness in vacuo to afford crude 7
removed under vacuum to afford 15 (0.92 g, 91%) as yellow oil. (1.29 g, 81%) as colorless oil. This unstable material should be
1
5
1
+
[
α] = +7.2 (c 1.0, MeOH). H NMR (400 MHz, CDCl ): δ = 4.15 used immediately in the next step. MS (EI): m/z = 183 [M] .
D 3
(m, 1H), 4.07 (m, 1H), 3.54 (dd, J = 11.2, 5.4 Hz, 1H), 3.41 (dd,
J = 11.2, 6.4 Hz, 1H), 2.61–2.48 (m, 2H), 1.88 (dt, J = 12.8,
Benzyl 4-methyl-3-oxopentanoate (18)
2
1
3
.4 Hz, 1H), 1.44 (d, J = 16 Hz, 6H), 1.34 (dd, J = 24, 11.6 Hz,
13
H). C NMR (100 MHz, CDCl
3
): δ = 116.7, 99.8, 68.8, 64.9, Methyl 4-methyl-3-oxopentanoate (14.4 g, 0.1 mol) and BnOH
+
3.4, 29.6, 24.9, 19.7. MS (EI): m/z = 188 [M − Me] . HRMS (EI): (21.6 g, 0.2 mol) were heated at 150 °C with continuous
+
m/z [M − H] calcd for C H ClNO 202.0635; found: 202.0631.
removal of MeOH until no MeOH was distilled out (ca. 5 h).
9
13
2
The reaction mixture was distilled under vacuum and bp
(
(4S,6S)-6-(Cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)methyl
benzoate (16)
5 (1.02 g, 5 mmol), NaOBz (1.44 g, 10 mmol) and DMSO front cut fraction containing methyl 4-methyl-3-oxopentanoate
10 mL) were stirred at 160 °C under a N atmosphere for 6 h. and BnOH resulted in a second crop of 18 (5.2 g, 24%).
The reaction mixture was then cooled to room temperature
and quenched with water (20 mL), extracted with EtOAc (s, 2H), 2.70 (hept, J = 7.2 Hz, 1H), 1.12 (d, J = 6.8 Hz, 6H).
143–144 °C per 1 kPa fraction was collected to afford 18
(
15.0 g, 68%) as colorless oil. The reaction was repeated with a
1
(
2
1
H NMR (400 MHz, CDCl ): δ = 7.36 (m, 5H), 5.17 (s, 2H), 3.55
3
1
3
(20 mL × 3). The combination organic phase was washed with
3
C NMR (100 MHz, CDCl ): δ = 206.4, 167.3, 135.4, 128.6,
+
brine and dried with Na SO , the solvent was removed under 128.4, 128.3, 67.1, 47.1, 41.3, 17.9.MS (EI): m/z = 220 [M] .
2
4
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+
Benzyl 6-(4-fluorophenyl)-4-isopropyl-2-oxo-1,2,5,6-
tetrahydropyrimidine-5-carboxylate (19)
3 4
(ESI): m/z [M + H] calcd for C23H25FN O S 458.1544; found:
458.1540.
1
8 (11.0 g, 50 mmol), 4-fluorobenzaldehyde (6.2 g, 50 mmol),
4
-(4-Fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfon-
amido)pyrimidine-5-carboxylic acide (11)
1 (2.28 g, 5 mmol) and 5%Pd/C (20 mg) were suspended in
MeOH (50 mL) and stirred under a H atmosphere at r.t. for
h. The reaction mixture was filtered and evaporated to
dryness to afford 11 (1.80 g, 98%) as a white crystalline solid.
urea (5.0 g, 83 mmol), CuCl (50 mg), conc. H SO (0.5 mL) and
2
4
MeOH (50 mL) were stirred at 50 °C for 12 h. The solvent was
removed under vacuum and the residue was allowed to stand
at 0 °C for crystallization. The crystal was filtered and washed
with water, dried in vacuo to afford 19 (15.5 g, 84%) as a color-
less crystalline solid. mp 135–137 °C. H NMR (400 MHz,
CDCl ): δ = 7.35–7.28 (m, 3H), 7.21–7.07 (m, 4H), 6.93 (t, J = 8.6
2
2
5
1
1
mp 208 °C (dec.). H NMR (400 MHz, DMSO-d
6
): δ = 13.80 (br,
3
1
3
H) 7.79 (dd, J = 8.8, 5.6 Hz, 2H) 7.38 (t, J = 8.8 Hz, 2H) 3.55 (s,
Hz, 3H), 5.65 (m, 1H), 5.37 (d, J = 2.7 Hz, 1H), 5.03 (dd, J = 27,
1
3
H) 3.47 (s, 3H) 3.23 (m, 1H) 1.25 (d, J = 6.8, 6H). C NMR
): δ = 173.5, 169.5, 165.2, 162.7, 1.61.9,
58.4, 134.1, 131.2, 131.1, 120.9, 116.4, 116.2, 42.1, 33.7, 33.2,
1
2 Hz, 2H), 4.21 (hept, J = 6.8 Hz, 1H), 1.18 (dd, J = 10.8, 7.2
1
3
(100 MHz, DMSO-d
6
1
2
Hz, 6H). C NMR (100 MHz, CDCl ): δ = 164.9, 163.6, 155.0,
1
1
3
54.9, 152.5, 147.7, 139.5, 135.8, 128.5, 128.4, 128.3, 128.2,
28.1, 115.8, 115.5, 99.6, 66.1, 55.2, 27.5, 19.9, 19.7. MS (EI):
−
+
2.0. MS (ESI): m/z = 366 [M − H] . HRMS (ESI): m/z [M + H]
S 368.1075; found: 368.1076.
+
+
calcd for C16
H
19FN
3
O
4
m/z = 368 [M] . HRMS (ESI): m/z [M + H] calcd for
369.1609; found: 369.1601.
21 2 3
C H22FN O
N-(4-(4-Fluorophenyl)-5-(hydroxymethyl)-6-isopropyl-
pyrimidin-2-yl)-N-methylmethanesulfonamide (6)
Benzyl 4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-
carboxylate (20)
To a stirred suspension of NaBH (0.38 g, 10 mmol) in anhy-
drous THF (40 mL) and glass beads (2–3 mm, 10 mL) was
4
added TMSCl (2.1 g, 20 mmol) at r.t. and heated to reflux for
To a stirred solution of NaNO
was added a solution of 19 (3.68 g, 10 mmol) in CH
10 mL) dropwise at 0 °C. After the completion of addition, the
stirring was continued for 1 h and then quenched with water
50 mL) and CH Cl (50 mL), the mixture was adjusted to pH
–8 with 50% aq. NaOH. The organic phase was separated,
dried (Na SO ) and evaporated to dryness to afford 20 (3.37 g,
2%) as an almost white solid. mp 146–147 °C. H NMR
400 MHz, CDCl ): δ = 12.82 (br, 1H) 7.53 (dd, J = 8.4, 5.2 Hz,
2
(70 mg) in 62% HNO
3
(20 ml)
3
h, then 11 (1.83 g, 5 mmol) was added and refluxed for an
additional 24 h. The reaction mixture was cooled to 0 °C and
quenched with sat. aq. NH Cl, extracted with CH Cl (20 mL ×
), washed with 10% aq. Na CO , dried (Na SO ) and evapor-
2
Cl
2
(
4
2
2
3
(
6
2
2
2
3
2
4
ated to dryness under vacuum to afford 6 (1.62 g, 92%) as a
1
4
white crystalline solid. mp 137–139 °C (Lit.
mp
2
4
1
1
1
2
(
31.5–133.6 °C). H NMR (400 MHz, CDCl ): δ = 7.79–7.82 (m,
H), 7.15 (t, J = 8.4 Hz, 2H), 4.63 (s, 2H), 3.56 (s, 3H), 3.47–3.54
m, 4H), 1.84 (br, 1H), 1.33(d, J = 6.8 Hz, 6H). C NMR
100 MHz, CDCl ): δ = 177.8, 166.3, 165.0, 162.5, 158.0, 134.0,
9
(
3
3
1
3
2
H) 7.26–7.35(m, 3H) 7.03 (d, J = 6.8 Hz, 2H) 6.97 (t, J = 8.4 Hz,
H) 5.06 (s, 2H) 3.22 (hept, J = 7.2 Hz, 1H) 1.39 (d, J = 6.8, 6H).
(
2
3
1
3
1
31.6, 131.5, 120.6, 115.5, 115.3, 57.7, 42.5, 33.1, 31.6, 22.3.
C NMR (100 MHz, CDCl ) δ = 166.4, 165.6, 163.2, 158.3,
3
+
MS (ESI): m/z = 354 [M + H] .
1
6
34.3, 130.3, 130.2, 128.83, 128.8, 128.7, 115.9, 115.7, 110.6,
+
7.9, 20.7. MS (ESI): m/z = 367 [M + H] . HRMS (ESI): m/z [M +
N-(5-((Bromotriphenylphosphoranyl)methyl)-4-(4-fluoro-phenyl)-
+
H] calcd for C H FN O 367.1452; found: 367.1467.
2
1
20
2 3
6-isopropylpyrimidin-2-yl)-N-methylmethanesulfon-amide (8)
6
(1.77 g, 5 mmol) and triphenylphosphine hydrobromide
Benzyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl-
sulfonamido)pyrimidine-5-carboxylate (21)
(
1.72 g, 5 mmol) in toluene (40 mL) were stirred under reflux
for 10 h. The reaction was cooled to r.t. with a white solid pre-
To a stirred mixture of 20 (3.66 g, 10 mmol) and K CO (1.8 g, cipitated. It was filtered and dried to afford 8 (3.18 g, 94%) as
2
3
1
4
1
1
3 mmol) in BuOAc (40 mL) was added TsCl (1.9 g, 10 mmol) a white solid. mp 232–236 °C (Lit. mp 238–242 °C). H NMR
at 40 °C, stirring was continued for 2 h and cooled to room (400 MHz, DMSO-d ): δ = 7.87(m, 3H), 7.63 (m, 6H), 7.27(m,
temperature. K CO (2.07 g, 15 mmol) and N-methyl-methane- 8H), 7.13(t, J = 8.4 Hz, 2H), 5.08 (d, J = 13.6 Hz, 2H), 3.49 (s,
6
2
3
sulfonamide (1.64 g, 15 mmol) were added and stirred at 3H), 3.40 (s, 4H), 2.86(m, 1H), 0.79(d, J = 4.4 Hz, 6H). MS (ESI):
+
1
20 °C for 12 h. Then the reaction mixture was cooled to room m/z = 598 [M − Br] .
temperature, washed with water, dried with Na SO , the
solvent was removed under vacuum and the residue was recrys-
2
4
N-(5-((E)-2-((4S,6S)-6-(Cyanomethyl)-2,2-dimethyl-1,3-dioxan-
-yl)vinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-
N-methylmethanesulfonamide (22)
4
tallized from MeOH to afford 21 (3.79 g, 83%) as a colorless
1
crystalline solid. mp 113–114 °C. H NMR (400 MHz, CDCl ): δ
3
=
7.58 (dd J = 8.8, 5.6 Hz, 2H), 7.27–7.35 (m, 3H), 7.10 (d J = 6.4 7 (0.92 g, 5 mmol), 8 (3.39 g, 5 mmol), K
2 3
CO (1.38 g,
Hz, 2H), 6.98 (t J = 8.4 Hz, 2H), 5.16 (s, 2H), 3.58 (s, 3H), 3.50 10 mmol) and DMSO (25 mL) were stirred at 75 °C under a N
2
1
3
(s, 3H), 3.20 (hept J = 6.8 Hz, 1H), 1.28 (d J = 6.8 Hz, 6H).
C
atmosphere for 3 h. The reaction mixture was quenched with
3 2 2
NMR (100 MHz, CDCl ): δ = 174.8, 167.9, 163.3, 158.5, 134.4, water (100 mL) and extracted with CH Cl (50 mL × 3). The
1
6
33.6, 130.5, 130.4, 128.8, 128.7, 128.6, 118.8, 115.8, 115.6, combined organic phase was washed with brine and dried
+
7.8, 42.5, 33.3, 33.1, 21.8. MS (ESI): m/z = 458 [M + H] . HRMS (Na SO ). The solvent was removed in vacuo and the residue
2
4
Org. Biomol. Chem.
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Organic & Biomolecular Chemistry
Paper
was purified by silica gel column chromatography (petroleum
2 S. E. Bode, M. Wolberg and M. Muller, Synthesis, 2006,
577–588.
3 (a) Z. Časar, Curr. Org. Chem., 2010, 14, 816–845; (b) Y. Wu,
F. J. Xiong and F. E. Chen, Tetrahedron, 2015, 71, 8487–
8510.
ether : EtOAc = 5 : 1) to afford 22 (1.78 g, 71%) as foam like
1
6
1
solid. mp 46–53 °C. [α]
400 MHz, DMSO-d ): δ = 7.67 (dd, J = 8.4, 5.2 Hz, 2H), 7.12 (t,
J = 8.4 Hz, 2H), 6.57 (d, J = 16.4 Hz, 1H), 5.49 (dd, J = 16.0,
D
= +5.8 (c 0.5, MeOH). H NMR
(
6
5
3
1
.2 Hz, 1H), 4.50–4.40 (m, 1H), 4.23–4.10 (m, 1H), 3.59 (s, 3H),
.54 (s, 3H), 3.38 (hept, J = 6.8 Hz, 1H), 2.63–2.47 (m, 2H),
.68–1.60 (m, 1H), 1.48 (d, J = 19.2 Hz, 6H), 1.35–1.20 (m, 7H).
4 (a) H. I. Shin, B. S. Choi, K. K. Lee, H. Choi, J. H. Chang,
K. W. Lee, D. H. Nam and N. S. Kim, Synthesis, 2004, 2629–
2632; (b) R. Sun, F. Q. Zhang, T. J. Du, L. P. Fang,
F. M. Meng and L. Liu, CN, 102180862, 2011; Chem. Abstr.,
2011, 457681.
1
3
6
C NMR (100 MHz, DMSO-d ): δ = 174.9, 164.6, 163.6, 162.1,
1
1
2
57.4, 136.6, 134.4, 134.4, 132.3, 132.2, 123.9, 121.0, 116.7,
15.2, 114.9, 99.5, 68.7, 64.9, 42.4, 35.4, 33.1, 32.0, 29.8, 24.9,
5 (a) H. Koike, M. Kabaki, N. P. Taylor and L. J. Diorazio, WO,
+
1.8, 21.7, 19.7. MS (ESI): m/z = 503 [M + H] . HRMS (ESI): m/z
2000049014,
(b) A. Matsushita, M. Oda, Y. Kawachi and J. Chika, WO,
003006439, 2003; Chem. Abst., 2003, 122651.
2000;
Chem.
Abst.,
2000,
193161;
+
[M + H] calcd for C25
H
32FN
4
O
4
S 503.2123; found: 503.2121.
2
Rosuvastatin calcium (1)
6 (a) W. Q. Chen, F. J. Xiong, Q. Liu, L. J. Xu, Y. Wu and
F. E. Chen, Tetrahedron, 2015, 71, 4730–4737;
To a stirred saturated methanolic solution of HCl (10 mL) was
added 22 (1.01 mg, 2 mmol) at −20 °C, the stirring was contin-
ued for 2 h. The reaction mixture was adjusted to pH 6–8 by
using sat. aq. NaHCO and extracted with CH Cl (50 mL × 3).
3 2 2
The combined organic phase was concentrated under vacuum,
to the residue was added MeOH (10 mL) and 1 M aq. NaOH
(
b) F. J. Xiong, H. F. Wang, L. J. Yan, L. J. Xu, Y. Tao, Y. Wu
and F. E. Chen, Org. Biomol. Chem., 2015, 13, 9813–9819;
c) X. F. Chen, F. J. Xiong, W. X. Chen, Q. Q. He and
F. E. Chen, J. Org. Chem., 2014, 79, 2723–2728;
d) X. F. Chen, F. J. Xiong, C. Zheng, J. Li and F. E. Chen,
(
(
Tetrahedron, 2014, 70, 5794–5799; (e) F. J. Xiong, J. Li,
X. F. Chen, W. X. Chen and F. E. Chen, Tetrahedron: Asym-
metry, 2014, 25, 1205–1208; (f) L. M. Hu, F. J. Xiong,
X. F. Chen, W. X. Chen, Q. Q. He and F. E. Chen, Tetrahe-
dron: Asymmetry, 2013, 24, 207–211.
(
2.5 mL) and stirred at 0 °C for 1 h, then MeOH was removed
in vacuo, 5% aq. CaCl (10 mL) was added dropwise and stirred
for 15 min, the precipitate was filtered and dried under
vacuum to afford 1 (0.62 g, 62%) as white powder. mp
1
2
2
0
15
20
40–144 °C. [α]
D
= +15.1 (c 0.3, 50%MeOH) (Lit. [α]
D
= +14.8
1
7 (a) P. A. Bartlett, J. D. Meadows, E. G. Brown, A. Morimoto
and K. K. Jernstedt, J. Org. Chem., 1982, 47, 4013–4018;
(
(
(
(
c 1, 50% MeOH)). H NMR (400 MHz, DMSO-d ): δ = 7.82–7.59
6
m, 2H), 7.26 (t, J = 8.8 Hz, 2H), 6.49 (d, J = 16.0 Hz, 1H), 5.51
dd, J = 16.0, 5.2 Hz, 1H), 4.26–4.10 (m, 1H), 3.74 (s, 1H), 3.53
s, 3H), 3.41 (m, 4H), 2.20–2.10 (m, 1H), 2.05–1.96 (m, 1H),
(
3
b) J. J. W. Duan and A. B. Smith, J. Org. Chem., 1993, 58,
703–3711; (c) P. A. Bartlett and K. K. Jernstedt, J. Am.
Chem. Soc., 1977, 99, 4829–4830.
S. Radl, J. Stach and J. Hajicek, Tetrahedron Lett., 2002, 43,
1
.55–1.45 (m, 1H), 1.26–1.35 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).
8
9
2
087–2090.
F. L. Zhang, Y. C. Qiu and C. N. Zhang, CN, 101747313,
010; Chem. Abstr., 2010, 153, 174946.
In summary, we have developed an efficient synthesis for rosu- 10 W. Q. Lin, H. J. Zheng and P. Yang, EP, 2602250, 2011;
vastatin calcium by a stereocontrolled intramolecular iodo-
Chem. Abstr., 2012, 156, 230677.
cyclization strategy starting from commercially available 11 W. L. Meyer, M. J. Brannon, C. G. Burgos,
Conclusions
2
(
S)-epichlorohydrin in addition to an improved synthesis of
T. E. Goodwin and R. W. Howard, J. Org. Chem., 1985, 50,
the pyrimidine core intermediate. This synthesis not only pro-
438–447.
vides a practical approach to rosuvastatin calcium but is also 12 A. Giannis and K. Sandhoff, Angew. Chem., Int. Ed. Engl.,
useful for the synthesis of other statins and analogs.
1989, 101, 220–222.
13 H. C. Brown, Y. M. Choi and S. Narasimhan, Inorg. Chem.,
1
981, 20, 4454–4456.
4 D. Sterk, Z. Casar, M. Jukic and J. Kosmrlj, Tetrahedron,
012, 68, 2155–2160.
1
Notes and references
2
1
J. Quirk, M. Thornton and P. Kirkpatrick, Nat. Rev. Drug 15 M. Watanabe, H. Koike, T. Ishiba, T. Okada, S. Seo and
Discovery, 2003, 2, 769–770.
K. Hirai, Bioorg. Med. Chem., 1997, 5, 437–444.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.