An efficient approach to the key intermediate of rosuvastatin

Article abstract of DOI:10.1515/hc-2013-0202

An efficient synthetic approach to the synthesis of the 5-pyrimidinecarbaldehyde 2, which is the key intermediate of rosuvastatin, involves the aerobic oxidation of the 5-pyrimidinemethanol 1 in the presence of Co(NO₃)₂, dimethylglyoxime (DmgH₂), and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) under mild reaction conditions. The method does not require the use of hazardous or expensive chemicals and is suitable for scale-up.

Full text of DOI:10.1515/hc-2013-0202

ꢁꢁꢁꢂ
ꢀHeterocycl. Commun. 2014; 20(1): 11–13
DOI 10.1515/hc-2013-0202ꢀ
Yueqing Guan*, Guobin Zhou* and Weiqun Yang
An efficient approach to the key intermediate of
rosuvastatin
Abstract: An efficient synthetic approach to the synthe- decade (Scheme 1). However, most of them have short-
sis of the 5-pyrimidinecarbaldehyde 2, which is the key comings, such as harsh conditions, use of expensive
intermediate of rosuvastatin, involves the aerobic oxi- catalysts, long reaction time, unsatisfactory yields, and
dation of the 5-pyrimidinemethanol 1 in the presence of tedious work-up. We now report a greatly improved syn-
Co(NO3)2, dimethylglyoxime (DmgH2), and 2,2,6,6-tetra- thesis of 2.
methylpiperidine-1-oxyl (TEMPO) under mild reaction
conditions. The method does not require the use of
hazardous or expensive chemicals and is suitable for
Results and discussion
scale-up.
Oxidation of alcohols to the corresponding aldehydes or
Keywords: aerobic oxidation; key intermediate; 5-pyrimi-
dinecarbaldehyde; rosuvastatin.
ketones is of importance in fundamental research and
industrial manufacturing. Developing new and efficient
catalytic technologies for the selective aerobic oxidation
*Corresponding authors: Yueqing Guan, Department of Biological
and Chemical Engineering, Taizhou Vocational and Technical
College, Taizhou 318000, China, e-mail: yqguan@126.com; and
Guobin Zhou, Department of Chemistry, Taizhou University, Taizhou
318000, China, e-mail: gbzhou_zju@126.com
Weiqun Yang: Department of Biological and Chemical Engineering,
Taizhou Vocational and Technical College, Taizhou 318000, China
of alcohols has attracted much attention because of the
obvious advantages of dioxygen, such as abundance, low
cost, and non-toxicity of the byproduct (H2O) [16–19]. Our
current research interest is focused on the development
of the catalytic oxidation system for pharmaceuticals and
their intermediates. In this report, we describe an efficient
approach, which is based on the work of Jing et al. [20], to
the synthesis of 2 by the aerobic oxidation of 1 (Scheme 1).
The methodology of Jing was greatly expanded by us by
using readily available and inexpensive reagents. To the
best of our knowledge, this is the first example of the
preparation of 2 by using the three-component catalytic
system, namely cobalt nitrate/dimethylglyoxime/2,2,6,6-
tetramethylpiperidine-1-oxyl, abbreviated as [Co(NO3)2/
DmgH2/TEMPO]. This methodology is amendable to scal-
ing-up (Scheme 1).
Introduction
Statins [1, 2] such as atorvastatin [3, 4] and rosuvas-
tatin (Figure 1) [5, 6] are very effective inhibitors [7] of
3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA)
reductase (HMGR) and are the most powerful lipid-low-
ering agents in use for people with or at risk of cardio-
vascular disease [8]. Rosuvastatin [9] has been called a
super statin because it appears to reduce low-density
lipoprotein (LDL) cholesterol to a greater degree than
competitors in its class without additional adverse
effects. Rosuvastatin is approved for the treatment of
elevated LDL cholesterol (dyslipidemia) [10], total cho-
lesterol (hypercholesterolemia), and/or triglycerides
(hypertriglyceridemia).
The starting alcohol 1 was derived in high yield from
4-fluorobenzaldehyde as previously described [12]. The
aerobic oxidation of 1 with 1.0 mol% of Co(NO3)2, 1.0 mol%
of TEMPO, and 4.0 mol% of DmgH2 proceeded smoothly in
F
OH OH
O
A well-known key intermediate for the synthesis
of rosuvastatin is 4-(4-fluorophenyl)-6-isopropyl-2-(N-
methyl-methanesulfonamido)-5-pyrimidinecarbaldehyde
(2 in Scheme 1). Many methodologies [11–15] for the syn-
N
OH
Me
Me
Me
N
N
SO2Me
thesis of compound 2 have been developed over the past Figure 1ꢀChemical structure of rosuvastatin.
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12ꢀ
ꢀY. Guan et al.: Key intermediate of rosuvastatin
F
γ -active-MnO2 or TPAP
yield: 80.5%, [ref.15]
1. H2, CO, Pd(OAc)2, TMEDA
50 bar, 100°C, 24 h, yield: 70%
I
F
F
N
or NaOCl, TEMPO
KBr, NaHCO3
yield: 86%, [ref.11]
Me
Me
2. MsCl, Et3N
yield: 30%, [ref.13]
N
N
SO2Me
Me
3
CH2OH
CHO
Me
Me
N
N
Ac2O, DMSO, 85°C, 17 h
F
Me
Me
Me
Me
N
N
N
N
yield: 31%, [ref.14]
SO2Me
SO2Me
1. NaHCO3, DMSO, rt, 68 h
2. Ac2O, DMSO, 70°C, 7 h
1
2
Co(NO3)2/DmgH2/TEMPO
O2, 70°C, CH2Cl2
CH2Br
Me
N
yield: 94%, [ref.14]
Me
yield: 96%
N
N
SO2Me
Me
4
Scheme 1ꢀSynthesis of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-methanesulfonamido) -5-pyrimidinecarbaldehyde (2).
dichloromethane under 0.4 MPa pressure of O2 at 70°C for Synthesis of 4-(4-fluorophenyl)-6-isopropyl-
3 h. The desired product 2 was obtained in 96% yield. The
method is suitable for scale-up.
2-(N-methyl-methanesulfonamido) -5-pyrimi-
dinecarbaldehyde (2)
A 100 mL autoclave reactor, equipped with an efficient mechanical
stirrer, was charged with 35.34 g (0.10 mol) of 1, 0.156 g of TEMPO (1.0
mol%), 0.183 g of Co(NO3)2 (1.0 mol%), 0.464 g of DmgH2 (4.0 mol%),
Experimental
and 50 mL of dichloromethane. The pressure of O2 in the sealed reactor
was kept under 0.4 MPa for 3 h. During this period of time the atmos-
General commercially available chemicals were all reagent grade.
phere inside the reactor was refilled with fresh oxygen three times and
Melting points (mp) were determined on a Buchi 535 capillary melt-
the mixture was stirred and heated to 70°C. Then the mixture was cooled
ing apparatus. The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
to room temperature and treated with dichloromethane (100 mL). Then
were recorded on a Mercury Plus Varian 400 spectrometer. ESI mass
the suspension was filtered and the clear filtrate was washed with water
spectra were acquired on a Thermo Scientific LCQ spectrometer. IR
(150 mL) and a saturated aqueous solution of sodium chloride (100
spectra were determined on a Nicolet NEXUS-470 FT-IR spectrometer
mL). Concentration under reduced pressure followed by trituration of
in KBr pellets.
the residue with cyclohexane gave the desired compound 2 (yield 33.7
g, 96%) as a white solid; purity 99% (HPLC); mp 177.5–178.9°C {ref. [14],
mp 178.2°C (DSC onset) and 179.1°C (DSC peak)}; 1H NMR (CDCl3): δ 1.33
(d, 6H, J ꢀ= ꢀ 5.2 Hz), 3.62 (s, 3H), 3.61 (s, 3H), 4.02 (m, 1H), 7.21 (m, 2H), 7.64
(m, 2H), 9.98 (s, 1H); 13C NMR (CDCl3): δ 190.5, 179.1, 169.8, 165.5, 163.5,
Synthesis of 4-(4-fluorophenyl)-6-isopropyl-
158.8, 132.7, 132.6, 119.6, 116.1, 115.90, 42.5, 33.1, 32.1, 21.7; MS (ESI): m/z
2-(N-methyl-methanesulfonamido) -5-pyrimi-
352.2 ([M+H]+, 100), 353.2 ([M+2]+, 18), 354.1 ([M+3]+, 5%); IR: ν 2976, 1685,
dinemethanol (1)
1600, 1533, 1508, 1444, 1315, 1230, 1157, 1126, 956, 902, 854, 808, 779 cm-1.
This compound was obtained as a white solid by using the known
procedure described previously [12]; yield 93%; purity 99.5% (HPLC);
white solid; mp 131.9–132.8°C {ref. [14], mp 131.5°C (DSC onset) and
133.6°C (DSC peak)}; 1H NMR (DMSO-d6): δ 1.26 (d, 6H, J ꢀ= ꢀ 5.2 Hz), 3.45
(s, 3H), 3.65 (m, 4H), 4.4 (s, 2H), 7.37 (m, 2H), 7.86 (m, 2H); 13C NMR
(DMSO-d6): δ 177.7, 165.5, 164.4, 162.5, 157.8, 134.6, 132.1, 132.0, 122.5,
115.8, 115.6, 56.3, 42.1, 33.7, 31.2, 22.5; MS (ESI): m/z 354.1 ([M+H]+,
100), 355.1 ([M+2]+, 18), 356.6 ([M+3]+, 7), 376.0 ([M+Na]+, 10%); IR:
ν 3537, 2935, 1597, 1546, 1510, 1365, 1325, 1228, 1143, 1120, 1001, 952,
854, 812 cm-1.
Acknowledgments: This work was supported by the Sci-
entific Research Fund of Zhejiang Provincial Education
Department (No. Y201329469), the Science and Technology
Project of Taizhou (No. 131KY07), and the Research Founda-
tion for Post-doctoral Scientists of Taizhou (No. 2013BSH01).
Received October 13, 2013; accepted November 11, 2013; previously
published online January 10, 2014
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