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Synthesis of Penciclovir
3903
(10.0 g, 37.7 mmol) in portions over a period of 10 min with vigorous
stirring. Stirring was continued in an ice-bath for 1.5 h, the reaction
mixture was diluted with CH2Cl2 (200 mL) and washed with saturated
aq NaHCO3 (2 ꢂ 200 mL). The organic layer was dried over anhydrous
MgSO4 and evaporated to yield a light yellow oil. The crude product was
purified by silica-gel column chromatography with hexane–acetone (3:1,
1
v/v) to give 13 (5.3 g, 81%) as a pale yellow oil. The H NMR spectrum
indicated that this was a mixture of cis and trans isomers in an approxi-
mately 1:1.5 ratio. For the cis isomer: 1H NMR (CDCl3) ꢀ 1.80 (br s, 1H,
H-5), 2.40 (pseudo q, 2H, J ¼ 7 Hz, CH2CH2Br), 3.60 (pseudo t, 2H,
J ¼ 7 Hz, CH2CH2Br), 4.07 (br d, 2H, J ¼ 11 Hz), and 4.15 (br d, 2H,
J ¼ 11 Hz) (H-4 and H-6), 5.51 (s, 1H, H-2), 7.3–7.5 (m, 5H, Ar H); for
the trans isomer: 1H NMR (CDCl3) ꢀ 1.71 (pseudo q, 2H, J ¼ 7 Hz,
CH2CH2Br), 2.37 (m, 1H, H-5), 3.39 (pseudo t, 2H, J ¼ 7 Hz,
CH2CH2Br), 3.59 (pseudo t, 2H, J ¼ 11 Hz, H-4ax and H-6ax), 4.27
(dd, 2H, J ¼ 11 and 5 Hz, H-4eq and H-6eq), 5.42 (s, 1H, H-2), 7.3–7.5
(m, 5H, Ar H). Without further characterization the product 13 was used
in the next step the same day (see below).
2-Amino-6-chloro-9-[2-(2-phenyl-1,3-dioxane-5-yl)-
ethyl]guanine (14)
A mixture of 13 (4.0 g, 14.8 mmol), 2-amino-6-chloropurine (9) (2.8 g,
16.3 mmol) and K2CO3 (3.4 g, 24.6 mmol) in anhydrous DMF (50 mL)
was stirred at room temperature for 3 d. The brown colored reaction
mixture was then filtered and the filtrate was evaporated to give a dark
orange oil. The crude product was placed on a silica-gel column and
eluted first with CHCl3–MeOH (80:1, v/v) to remove less polar impurities
and then with CHCl3–MeOH (60:1, v/v) to give 14 (5.0 g, 94% based on
1
13). The H NMR spectrum indicated that this was a mixture of cis and
trans isomers in an approximately 1:1.5 ratio. For the cis isomer:
1H NMR (CDCl3) ꢀ 1.43 (br s, 1H, H-50), 2.42 (pseudo q, 2H, J ¼ 7 Hz,
CH2CH2N), 4.12 (t, 2H, J ¼ 7 Hz, CH2CH2N), 4.15 (br s, 4H, H-40 and
H-60), 5.13 (br s, 2H, NH2), 5.53 (s, 1H, H-20), 7.3–7.5 (m, 5H, Ar H),
1
7.80 (s, 1H, H-8); for the trans isomer: H NMR (CDCl3) ꢀ 1.71 (pseudo
q, 2H, J ¼ 7 Hz, CH2CH2N), 2.18 (m, 1H, H-50), 3.63 (pseudo t,
2H, J ¼ 11 Hz, H-40ax and H-60ax), 4.12 (t, 2H, J ¼ 7 Hz, CH2CH2N),
4.30 (dd, 2H, J ¼ 11 and 5 Hz, H-40eq and H-60eq), 5.13 (br s, 2H,
NH2), 5.44 (s, 1H, H-20), 7.3–7.5 (m, 5H, Ar H), 7.77 (s, 1H, H-8).
HRFABMS: calcd. for C17H19ClN5O2 (M þ H) 360.1227. Found:
360.1216.