An efficient synthesis of enantiopure (R)-heteroarylpyrimidine Analogs

Article abstract of DOI:10.3390/molecules180911144

An efficient synthesis of enantiopure (R)-heteroarylpyrimidine analogs is described here, which involves introduction of a chiral group, formation and separation of diasteroisomers and final transformation of an amide to an ester. The absolute configuration of the enantiopure HAPs is confirmed by X-ray analysis of their intermediates.

Full text of DOI:10.3390/molecules180911144

Molecules 2013, 18, 11144-11152; doi:10.3390/molecules180911144
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molecules
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Article
An Efficient Synthesis of Enantiopure (R)-heteroarylpyrimidine
Analogs
Xiu-Yan Yang 1,2,†, Guang-Qiang Xia 2,†, Xiao-Kui Wang 2, Zhi-Bing Zheng 2, Dong-Mei Zhao 2,
Guo-Ming Zhao 2,* and Song Li 1,2,
*
1
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University,
Shenyang 110016, China
2
Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology,
Beijing 100850, China
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed; E-Mails: zhaogm@bmi.ac.cn (G.-M.Z.);
lis@bmi.ac.cn (S.L.); Tel.: +86-10-6693-0604 (G.-M.Z.); Fax: +86-10-6821-1656 (G.-M.Z.).
Received: 23 August 2013; in revised form: 3 September 2013 / Accepted: 4 September 2013 /
Published: 11 September 2013
Abstract: An efficient synthesis of enantiopure (R)-heteroarylpyrimidine analogs is
described here, which involves introduction of a chiral group, formation and separation of
diasteroisomers and final transformation of an amide to an ester. The absolute configuration
of the enantiopure HAPs is confirmed by X-ray analysis of their intermediates.
Keywords: anti-HBV; enantiopure; (R)-heteroarylpyrimidines; chiral separation; diastereomer
1. Introduction
Chronic HBV infections remain a serious public health problem worldwide. Nucleoside/nucleotide
analogs and immune modulators have been approved for the treatment of chronic hepatitis B.
Unfortunately, drug resistance and side effects have limited the utility of currently approved drugs [1,2].
Therefore new kinds of anti-hepatitis B agents are still highly desired. Heteroarylpyrimidines (HAPs) were
discovered to be a class of highly potent non-nucleoside inhibitors of HBV replication (Figure 1) [3–5].
Bay39-5493 has reached the clinical test stage as an anti-HBV candidate drug. Z060228, another novel

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HAP derivative found by our laboratory, exhibits excellent activity against HBV replication at
submicromolar concentration and is currently under preclinical study [6,7].
Figure 1. Structures of HAP analogs.
The biological activity of HAPs depends on their absolute configuration and only the (R)-enantiomers
exhibit anti-HBV activity, so the synthesis of (R)-HAPs is necessary for the further drug development.
Racemic HAPs were easily prepared from amidine, ethyl acetoacetate and benzaldehyde by a Biginelli
reaction (Scheme 1) [8]. However, enantiopure (R)-HAPs were difficult to obtain and only Goldman
et al. have reported the preparation of (R)-Bay39-5493 through a chiral-phase HPLC method [9,10].
Herein, we report on a feasible and convenient synthesis of enantiopure (R)-HAPs.
Scheme 1. Synthesis of racemic HAPs.
2. Results and Discussion
In general, the methods frequently used for the synthesis of enantiopure 1,4-dihydropyridines are
the resolution of racemic dihydropyridines, separation via diastereomeric esters, enantioselective
synthesis with chiral auxiliary groups, chemoenzymatic separation of dihydropyridines, and
chromatographic separation of enantiomers [11–13]. The synthetic strategies we first adopted for the
preparation of (R)-HAPs involved resolution of the racemic-HAPs I via diastereomeric salts using
camphorsulfonic acid as resolution reagent and direct enantioselective synthesis in the chiral
environment of quinidine or quinine, but the results were not satisfactory. Then we attempted an
indirect method with a chiral auxiliary group to synthesize (R)-HAPs as shown in Scheme 2. A chiral
group Y was introduced in starting material and a couple of diasteroisomers II were formed by the
Biginelli reaction. The enantiopure IIa and IIb could be separated by taking advantage of the
differences in their physiochemical properties and then the enantiopure IIa could be transformed into
(R)-HAPs after getting rid of the introduced chiral group Y. Apparently, the choice of chiral group Y is

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key for the whole strategy. According to their cost and practical properties, several chiral agents such
as menthol, and mandelic acid were adopted. When menthol was used, the enantiopure IIa or IIb were
not crystallized easily from common solvents. When mandelic acid was used, racemization was found
to occur under basic conditions. By comparison, (R)-1-phenylethanamine was proved to be the suitable
chiral agent, which was enantiomerically stable in the subsequent reaction steps and was removed
conveniently after enantiopure intermediate IIa was separated.
Scheme 2. Synthetic strategy analysis of enantiopure (R)-HAPs.
With this method (R)-Z060228 has been synthesized by the synthetic route shown in Scheme 3. In
the first step, acylation of (R)-1-phenylethanamine (1, >99% ee) with diketene (2) easily gave
the intermediate 3 in 95% yield [14]. Next, Knoevenagel condensation of 3 with 2-chloro-4-
fluorobenzaldehyde in the presence of acetic acid and piperidine followed by reaction with
2,4,6-trifluorobenzimidamide acetate afforded the diastereomeric 4 in 78% yield [15–17].
Scheme 3. Synthesis of (R)-Z060228.

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As we expected, the diastereomers 4a and 4b have different solubility in different solvents.
Compound 4a was easily crystallized from ethyl acetate, whose de value was >99% according to
HPLC and then 4b was easily recrystallized from ethanol.
Next we focused our attention on the transformation of amide 4a into the ester (R)-Z060228, which
was also a key step of the synthetic route. In general, esters aren’t easily obtained from the
corresponding amides. Alcoholysis of amides, especially for polyfunctional amide was problematic
because conventional methods under strongly basic and acidic conditions were only suitable for simple
amides and otherwise result in extensive substrate decomposition [18]. What’s more, the amide 4a has
lower activity because of its 1,4-dihydropyrimidine ring. In order to improve the reactivity of 4a,
introduction of an electron-withdrawing group on the amide-N atom of 4a was considered Methyl
chloroformate and glutaric anhydride were firstly selected as activation reagents, but the results were
not satisfactory because of 4a’s steric effect. Fortunately, we found that N-nitrosamide formation was
also an efficient method for activation of amides. Nitrosation of secondary amines is usually
accomplished using nitrosating agents such as nitrous acid, NaNO2/HC1, nitrogen oxides (NO, N2O3
or N2O4) and so on. To improve the yield and avoid the formation of side products, dinitrogen
tetroxide was considered as a selective and efficient reagent for N-nitrosation of the secondary
amine 4a [19–25].
However, in the course of our experiments, direct N-nitrosation of compound 4a with dinitrogen
tetroxide afforded the undesired product 8 in almost 100% yield instead of the desired compound 7.
It is noteworthy that this accidental discovery might actually be an excellent method to prepare
substituted pyrimidines. According to the analysis of the reaction and the product we concluded that
the higher activity of N1-H than the amide N-H may be the main cause (Scheme 4). To overcome this
problem, protection of the amide N1-H was required. Acylation of 4a with acetyl chloride in the
presence of triethylamine gave the intermediate 5 in good 95% yield. N-Nitrosation of 5 with
dinitrogen tetroxide easily gave the intermediate 6. Then alcoholysis of crude 6 with sodium ethoxide
in cold dry DMF afforded the desired compound (R)-Z060228 in 78% yield.
Scheme 4. Direct N-nitrosation only yielded an arylate product.

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(R)-Z060228’s optical purity (>99% ee) was checked with HPLC on a chiral stationary phase
(ULTRON ES-OVM 150 × 4.6 mm, 0.01M KH2PO4:CH3CN = 90:10, λ = 240 nm, 1.0 mL/min),
which indicated that no racemization occurred in the last two steps. (R)-Z060228’s specific rotation
was found to be [α]D20 = −92.4 (c = 1.0, CH3OH) and its absolute (R) configuration could be directly
confirmed by determination of the absolute configuration of the intermediate (4R,2'R)-5 by X-ray
crystallography (Figure 2) [26]. Using a similar reaction sequence, Bay39-5493 was prepared in 99%
ee and its specific rotation closely matched the reported value (observed: [α]2D0 = −54.6, c = 1.0,
CH3OH; lit.: [α]D20 = −52, c = 1.0, CH3OH) [27].
Figure 2. X-ray crystal structure of the intermediate 5 [28].
3. Experimental
3.1. General
1H-NMR and 13C-NMR spectra were recorded at 400 MHz and 100 MHz on a JNM-ECA-400
instrument with tetramethylsilane as an internal standard in the DMSO. ESI-MS (high resolution) mass
spectra were obtained by using a Waters Xevo G2 Qtof (ESI) mass spectrometer. Melting points were
determined using a RY-1 apparatus and are uncorrected.
3.2. Synthesis
R,R-N-(1-Phenylethyl)-4-(2-chloro-4-fluorophenyl)-2-(2,4,6-trifluorophenyl)-6-methyl-1,4-dihydro-
pyrimidine-5-carboxamide (4a) and R,S-N-(1-phenylethyl)-4-(2-chloro-4-fluorophenyl)-2-(2,4,6-
trifluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxamide
(4b).
(R)-(+)-N-(1-phenylethyl)-
3-oxobutyramide (3, 4.50 g, 22.05 mmol) and 2-chloro-4-fluorobenzaldehyde (3.50 g, 22.05 mmol) are
dissolved in anhydrous alcohol (85 mL) containing acetic acid (1 mL) and piperidine (1 mL) as
catalysts. After stirring at R.T. for 24 h, 2,4,6-trifluorobenzimidamide acetate (3.51 g, 22.05 mmol)
and sodium acetate (2.05 g, 25.00 mmol) are added. After refluxing for 20 h, the reaction mixture is
concentrated and the residue is dissolved in water (50 mL) and extracted with ethyl acetate (3 × 25 mL).
The combined organic extracts are washed with brine (20 mL × 3) and dried over anhydrous sodium
sulfate. After evaporation of the solvent in vacuo, a 1:1 mixture of diastereomeric amides 4a and 4b is
obtained and subjected to recrystallization from ethyl acetate and pentane (50:50), 4a (3.9 g, 35%) is

Molecules 2013, 18
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isolated as white particles (>99% d.e., according to HPLC). Rf = 0.34 (ethyl acetate-petroleum ether =
2:1). Mp = 208–210 °C. 1H-NMR (DMSO-d6) δ: 1.29–1.33 (3H, m); 1.97 (3H, s); 4.83–4.87 (1H, m);
5.97 (1H, s); 7.04–7.06 (2H, d, J = 6.4 Hz); 7.12–7.24 (7H, m); 7.25–7.27 (1H, m); 8.08–8.10 (1H, d,
J = 8 Hz); 9.24 (1H, s); HRMS (ESI) m/z: Calcd for C26H21ClF4N3O, 502.1304 [M+H]+; Found:
502.1299.
The mother liquor was concentrated and redissolved in anhydrous alcohol, whereby 4b is
crystallized (3.43 g, yield 31%) as white plates (>99% d.e., according to HPLC). Rf = 0.36 (ethyl
1
acetate-petroleum ether = 2:1). Mp = 197–199 °C. H-NMR (DMSO-d6) δ: 1.17–1.25 (3H, m); 2.12
(3H, s); 4.85–4.88 (1H, m); 6.01 (1H, s); 7.15–7.20 (8H, m); 7.86–7.87 (2H, d, J = 4 Hz); 7.94–7.95
(1H, m); 9.37 (1H, s); HRMS (ESI) m/z: Calcd for C26H20N3OF4Cl, 502.1304 [M+H]+; Found:
502.1299.
R,R-N-(1-phenylethyl)-N-1-acetyl-6-(2-chloro-4-fluorophenyl)-2-(2,4,6-trifluorophenyl)-4-methyl-1,6-
dihydropyrimidine-5-carboxamide (5). A solution of diastereomeric amide 4a (3.03 g, 6 mmol) and
anhydrous triethylamine (0.9 g, 9 mmol) in dry DMF (45 mL) is stirred at 0 °C, and then acetyl
chloride (0.51 mL, 7.2 mmol) is added dropwise. After stirring for 6 h, the reaction mixture is
quenched with water (60 mL), and extracted with ethyl acetate (3 × 60 mL). The combined organic
phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is
purified by column chromatography on silica gel (ethyl acetate-pentane = 1:3) to give 5 (3.11 g, 95%)
1
as a white powder. Rf = 0.4 (ethyl acetate-petroleum ether = 1:1). Mp: 183–184.2 °C. H-NMR
(DMSO-d6) δ: 1.39–1.41 (3H, d, J = 8 Hz), 2.07 (3H, s), 2.10 (3H, s), 4.95–4.99 (1H, m), 6.47 (1H, s),
7.08–7.12 (3H, m), 7.15–7.30 (5H, m); 7.45–7.51 (2H, m), 8.70–8.72 (1H, d, J = 8 Hz). HRMS (ESI)
m/z: Calcd for C28H23N3O2ClF4, 544.1409 [M+H]+; Found: 544.1398.
Ethyl
4-(R)-(2-chloro-4-fluorophenyl)-2-(2,4,6-trifluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-
carboxylate (R)-Z060228. To a solution of 5 (2.71 g, 5 mmol) in dichloromethane (50 mL) at 0 °C is
added dinitrogen tetroxide (4.60 g, 50 mmol, 10 eq.). The solution is stirred under nitrogen at 0 °C for
20h and then poured over ice, and extracted with cold dichloromethane (2 × 200 mL), the organic part
is concentrated in vacuum in an ice water bath to yield a yellow oil, which is dissolved in cold dry
DMF (150 mL, −40 °C), and sodium ethoxide (6.8 g, 100 mmol, 20 eq.) is added. The mixture is
stirred for 15 min under nitrogen atmosphere and then quenched with water (200 mL) neutralized with
4 M HCl, and extracted with ethyl acetate (150 mL × 3). The combined extracts are dried over
anhydrous sodium sulfate, and concentrated at reduced pressure. The residue is purified by column
chromatography on silica gel (ethyl acetate-dichloromethane 4:100) to give (R)-Z060228 (1.66 g,
78%) as a white powder. [α]2D0 = −92.4 (c = 1.0, CH3OH), H-NMR (DMSO-d6) δ: 1.02–1.05 (3H, t);
1
2.32 (3H, s); 3.92–3.96 (2H, m); 5.97 (1H, s); 7.21–7.45 (5H, m); 9.86 (1H, s). 13C-NMR (DMSO-d6)
δ: 14.4, 17.9, 56.0, 59.6, 96.2, 101.3, 101.5, 101.8, 115.2, 116.6, 116.8, 131.2, 131.2, 132.6, 139.8,
142.0, 147.6, 160.0, 162.4, 166.1. HRMS (ESI) m/z: Calcd for C20H15N2O2F4Cl, 427.0831 [M+H]+;
Found: 427.0827.
Ethyl 4-(R)-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
(R)-Bay39-5493. [α]2D0 = −54.6 (c = 1.0, CH3OH).1H-NMR (DMSO-d6) δ: 1.01–1.04 (3H, m); 2.50

Molecules 2013, 18
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(3H, s); 3.90–3.94 (2H, m); 5.99 (1H, s); 7.36–7.43 (3H, m); 7.90–7.91 (1H, d, J = 4 Hz); 7.97–7.98
(1H, d, J = 4 Hz); 9.96 (1H, s); HRMS (ESI) m/z: Calcd for C17H15N3O2FSCl, 380.0630 [M+H]+;
Found: 380.0628.
4. Conclusions
In summary, a novel and efficient approach to the synthesis of enantiomerically pure HAPs is
accomplished from inexpensive starting materials. Key feature of this synthesis include an introduction
of another chiral group and the alcoholysis to yield the final product. The method described herein
could be an attractive alternative for the synthesis of chiral HAPs.
Acknowledgments
We gratefully acknowledge financial support from the National Nature Science Foundation of
China (Grant No.21172263).
Conflicts of Interest
The authors declare no conflict of interest.
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