January 2013
New Efficient and Flexible Synthetic Route to Emivirine and Its Analogs
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129–130°C. ESI‐MS: m/z = 275.2 [M+H]+. H NMR (300 MHz,
CDCl3)δ: 9.48 (1H, s, NH), 7.37–7.14 (5H, m, ArH), 5.17
(2H, s, NCH2O), 4.19 (2H, s, CH2Ph), 3.70–3.61 (2H, q,
OCH2CH3), 2.06 (3H, s, CH3-C5), 1.22–1.18 (3H, t, CH2CH3);
13C NMR (75 MHz, CDCl3)δ: 163.75 (C‐4), 151.84 (C‐2),
149.72 (C‐6), 134.76, 129.29, 128.82, 127.35 (C‐aryl),
111.01 (C‐5), 72.82 (NCH2O), 64.99(OCH2Me), 34.01
(CH2Ph‐C6), 15.05 (OCH2CH3) 10.97 (CH3-C5).
compound 4 was desulfurized by suspension in 10% aq
chloroacetic acid (200 mL) and subsequent reflux for 24 h.
After cooling to room temperature the precipitate was filtered
off, washed with cold EtOH and Et2O and finally dried to give
compound 5 as white solid (5.48 g, 66.1%). mp 224–226°C.
ESI‐MS: m/z = 244.2 [M+H]+.
6‐Benzyl‐5‐methyluracil (5b). This compound was prepared as
white solid following the procedure described for the preparation of
5. Yield: 63.6%; mp 257–258°C. ESI‐MS: m/z = 217.2 [M+H]+.
6‐Benzyl‐5‐ethyluracil (5c) [6]. This compound was
prepared as white solid following the procedure described for
the preparation of 5. Yield: 68.2%; mp 236–237°C. ESI‐MS:
m/z = 231.2 [M+H]+.
6‐Benzyl‐1‐ethoxymethyl‐5‐ethyluracil (7c). This compound
was prepared as white solid following the procedure described
for the preparation of MKC‐442. Yield: 90.6%; mp 103–104°
C. ESI‐MS: m/z = 289.2 [M+H]+. 1H NMR (300 MHz,
CDCl3)δ: 9.46 (1H, s, NH), 7.36–7.01 (5H, m, ArH), 5.15 (2H,
s, NCH2O), 4.12 (2H, s, CH2Ph), 3.68–3.58 (2H, q, OCH2Me),
2.52–2.43 (2H, q, CH2Me), 1.21–1.13 (3H, t, OCH2CH3),
1.09–1.02 (3H, t, CH2CH3). 13C NMR (75 MHz, CDCl3)δ:
163.74 (C‐4), 152.90 (C‐2), 148.53 (C‐6), 135.23, 129.29,
127.89, 127.36 (C‐aryl), 116.01 (C‐5), 72.59 (NCH2O), 64.67
(OCH2Me), 33.02 (CH2Ph‐C6), 18.92 (CH2CH3), 14.86
(OCH2CH3), 13.97 (CH2CH3).
6‐Benzyl‐1‐benzyloxymethyl‐5‐methyluracil (8b). This
compound was prepared as white solid following the
procedure described for the preparation of TNK‐651. Yield:
73.6%; mp 94–95°C. ESI‐MS: m/z = 337.2 [M+H]+. 1H
NMR (300 MHz, CDCl3)δ: 9.44 (1H, s, NH), 7.39–7.07
(10H, m, ArH), 5.25 (2H, s, NCH2O), 4.67 (2H, s, OCH2Ph),
4.17 (2H, s, CH2Ph), 2.03 (CH3-C5); 13C NMR (75 MHz,
CDCl3)δ: 163.74 (C‐4), 151.90 (C‐2), 149.53 (C‐6), 137.23,
134.66, 129.29, 128.48, 128.03, 127.89, 127.36 (C‐aryl),
111.01 (C‐5), 72.19 (NCH2O), 71.67 (OCH2Ph), 34.02
(CH2Ph‐C6), 10.97 (CH3-C5).
6‐Benzyl‐1‐ethoxymethyl‐5‐isopropyluracil (MKC‐442). To a
suspension of the compound 5 (1.2 g, 5.0 mmol) in anhydrous
CH2Cl2 (30 mL) was added N,O‐bis‐(trimethylsilyl)‐acetamid
(BSA) (3.2 mL, 11.0 mmol) and stirring was continued until all
the starting material had dissolved. Then chloromethyl phenyl
ether (0.57 g, 6.0 mmol) and LiI (0.07 g, 0.5 mmol) was added
and stirred at r.t for 3 h. Saturated aq NaHCO3 (10 mL) was
added to quench the reaction. The organic phase was separated
and the aqueous layer extracted with CH2Cl2. The combined
organic phase was dried with Na2SO4. After evaporation of the
solvent under reduced pressure, the product was purified by
column chromatography with EtOAc‐PE (1:5) to obtain the
pure product as white solid (1.38 g, 91.5%). mp.105–108°C.
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(Lit [1]. mp. 109–110°C); H NMR (300 MHz, CDCl3)δ: 8.97
(1H,br s,NH), 7.36–7.11 (5H,m,ArH), 5.13 (2H,s,NCH2O), 4.18
(2H,s,CH2Ph), 3.65–3.60 (2H,q,OCH2Me), 2.90–2.82 (1H,m,
CHMe2), 1.29–1.27 (6H,d, CHMe2), 1.20–1.17 (3H,t, OCH2Me);
13C NMR (75 MHz, CDCl3)δ: 162.23 (C‐4), 151.82 (C‐2), 148.46
(C‐6), 135.44, 129.19, 127.26, 127.22 (C‐aryl), 119.71 (C‐5), 72.91
(NCH2O), 65.00 (OCH2CH3), 33.50 (CH2Ph), 28.34 (CHMe2),
20.39 (CHMe2), 15.03 (OCH2CH3); HRESI‐MS m/z: calcd for
C17H22N2O3, 303.17090[M+H]+; found 303.17032.
6‐Benzyl‐1‐benzyloxymethyl‐5‐ethyluracil (8c). This
compound was prepared as white solid following the procedure
described for the preparation of TNK‐651. Yield: 78.5%. mp
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92–93°C. ESI‐MS: m/z = 351.2 [M+H]+. H NMR (300 MHz,
CDCl3)δ: 9.96 (1H, s, NH), 7.43–7.07 (10H, m, ArH), 5.39
(2H, s, NCH2O), 4.67 (2H, s, OCH2Ph), 4.15 (2H, s, CH2Ph),
2.48–2.41 (2H, q, CH2CH3), 1.12–1.06 (3H, t, CH2CH3); 13C
NMR (75 MHz, CDCl3)δ: 162.24 (C‐4), 151.90 (C‐2), 148.53
(C‐6), 137.33, 135.36, 129.19, 128.58, 128.03, 127.89, 127.26
(C‐aryl), 119.01 (C‐5), 73.09 (NCH2O), 71.87 (OCH2Ph),
33.52 (CH2Ph‐C6), 28.24 (CH2CH3), 20.97 (CH2CH3).
6‐Benzyl‐1‐benzyloxymethyl‐5‐isopropyluracil (TNK‐651). To
a suspension of the compound 5 (1.2 g, 5.0 mmol) in anhydrous
CH2Cl2 (30 mL) was added N,O‐bis‐(trimethylsilyl)‐acetamid
(BSA) (3.2 mL, 11.0 mmol) and stirring was continued until all
the starting material had dissolved. Then chloromethyl phenyl
ether (0.94 g, 6.0 mmol) and LiI (0.07 g, 0.5mmol) was added
and stirred at r.t for 3h. Saturated aq NaHCO3 (10mL) was
added to quench the reaction. The organic phase was separated
and the aqueous layer extracted with CH2Cl2. The combined
organic phase was dried with Na2SO4. After evaporation of the
solvent under reduce pressure, the product was purified by
column chromatography with EtOAc‐PE (1:5) to obtain the
pure product as white solid (1.57 g, 86.5%). mp.112–115°C.
Acknowledgments. The authors thank the National Science
Foundation of China (20672008, 20972011) and grants from the
Ministry of Science and Technology of China (2005CB523103)
for the financial support.
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(Lit [2]. mp. 112–113°C); H NMR (300 MHz, CDCl3)δ: 8.87
(1H, s, NH), 7.33–7.25 (8H, m, ArH), 7.06–7.04 (2H, d, ArH),
5.21(2H, s, NCH2O), 4.65 (2H, s, OCH2Ph), 4.16 (2H, s,
CH2Ph), 2.88–2.81 (1H, m, CHMe2), 1.27–1.25 (6H, d,
CHMe2); 13C NMR (75 MHz, CDCl3)δ: 162.09 (C‐4), 151.79
(C‐2), 148.37 (C‐6), 137.33, 135.29, 129.21, 128.48, 128.00,
127.78, 127.27 (C‐aryl), 119.79 (C‐5), 72.96 (NCH2O), 71.81
(OCH2Ph), 33.48 (CH2Ph), 28.32 (CHMe2), 20.40 (CHMe2);
HRESI‐MS m/z: calcd for C22H24N2O3, 365.18536[M+H]+;
found 365.18597.
6‐Benzyl‐1‐ethoxymethyl‐5‐methyluracil (7b). This
compound was prepared as white solid following the procedure
described for the preparation of MKC‐442. Yield: 83.9%; mp
REFERENCES AND NOTES
[1] Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Inouye,
N.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T. J
Med Chem 1995, 38, 2860.
[2] Hopkins, A. L.; Ren, J.; Esnouf, R. M.; Willcox, B. E.; Jones,
E. Y.; Ross, C.; Miyasaka, T.; Walker, R. T.; Tanaka, H.; Stammers,
D. K.; Stuart, D. I. J Med Chem 1996, 39, 1589.
[3] (a) Andrew, L. P.; Jingshan, R.; Hiromichi, T.; Masanori,
B.; Mika, O.; David, I. S.; David, K. S. J Med Chem 1999, 42, 4500;
(b) Nasser, R. E.; Per, T. J.; Dahan, B.; Anne, M. B.; Erik, B. P.; Nielsen,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet