1754 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Tchilibon et al.
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(2-Methylbenzylamino)-2-chlo-
ropurin-9-yl]-2′,3′-O-isopropylidenebicyclo[3.1.0]hexane-
(d, J ) 6 Hz, 1H), 2.90 (d, J ) 5.1 Hz, 3H), 2.24-2.19 (m, 1H),
1.72 (br s, 2H), 1.36-1.32 (m, 1H). HRMS (M + 1)+: calculated
507.0547, found 507.0571. HPLC (system A) 20.4 min (99%),
(system B) 12.9 min (99%).
1
1′-carboxylic Acid Ethyl Ester (49). H NMR (CDCl3, 300
MHz) δ 7.58 (s, 1H), 7.32 (d, J ) 6.9 Hz, 1H), 7.23-7.16 (m,
2H), 6.07 (br s, 1H), 5.57 (d, J ) 8.4 Hz, 1H), 4.83-4.69 (m,
4H), 4.32-4.16 (m, 2H), 2.37 (s, 3H), 2.23-2.18 (m, 1H), 1.74-
1.69 (m, 1H), 1.55-1.50 (m, 4H), 1.35 (t, J ) 7.8 Hz, 3H), 1.28
(s, 3H). MS (m/e) (positive FAB) 498.3 (M)+.
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(3-Chlorobenzylamino)-2-chlo-
ropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexane-1′-car-
boxylic Acid Methylamide (18). 1H NMR (CDCl3, 300 MHz)
δ 1.17-1.39 (m, 1H), 1.45-1.61 (m, 1H), 2.01-2.09 (m, 1H),
2.81 (d, J ) 4.5 Hz, 1H), 3.91-4.08 (m, 2H), 4.78-5.05 (m,
5H), 6.71 (br s, 1H), 7.04 (br s, 1H), 7.11-7.29 (m, 4H), 7.74
(s, 1H). HRMS (M + 1)+: calcd 463.1029, found 463.1052.
HPLC (system A) 14.8 min (99%), (system B) 12.5 min (99%).
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(3-Fluorobenzylamino)-2-chlo-
ropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexane-1′-car-
boxylic Acid Methylamide (19). 1H NMR (CDCl3, 300 MHz)
δ 7.84 (s, 1H), 7.34-7.26 (m, 1H), 7.15-6.95 (m, 3H), 6.86 (br
s, 1H), 6.56 (br s, 1H), 4.88-4.80 (m, 4H), 4.08 (d, J ) 6 Hz,
1H), 2.91 (d, J ) 5.1 Hz, 3H), 2.27-2.23 (m, 1H), 1.78 (br s,
2H), 1.36-1.32 (m, 1H). HRMS (M + 1)+: calculated 447.1348,
found 447.1343. HPLC (system A) 13.6 min (99%), (system B),
16.8 min (98%).
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(3-Methylbenzylamino)-2-chlo-
ropurin-9-yl]-2′,3′-O-isopropylidenebicyclo[3.1.0]hexane-
1
1′-carboxylic Acid Ethyl Ester (50). H NMR (CDCl3, 300
MHz) δ 7.56 (s, 1H), 7.26-7.09 (m, 4H), 6.27 (br s, 1H), 5.87
(d, J ) 8.4 Hz, 1H), 4.83-4.71 (m, 4H), 4.30-4.20 (m, 2H),
2.33 (s, 3H), 2.22-2.17 (m, 1H), 1.74-1.69 (m, 1H), 1.55-1.50
(m, 4H), 1.34 (t, J ) 7.8 Hz, 3H), 1.28 (s, 3H). MS (m/e)
(positive FAB) 498.3 (M)+.
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(3-(3-Hydroxypropynyl)benzyl-
amino)-2-chloropurin-9-yl]-2′,3′-O-isopropylidenebicyclo-
[3.1.0]hexane-1′-carboxylic Acid Ethyl Ester (51). 1H NMR
(CDCl3, 300 MHz) δ 7.56 (s, 1H), 7.38 (s, 1H), 7.34-7.26 (m,
2H), 6.73 (br s, 1H), 5.87 (d, J ) 8.4 Hz, 1H), 4.82-4.70 (m,
4H), 4.46 (d, J ) 6 Hz, 2H), 4.32-4.20 (m, 2H), 2.41 (br s,
1H), 2.23-2.18 (m, 1H), 1.75-1.70 (m, 1H), 1.55-1.50 (m, 4H),
1.35 (t, J ) 7.8 Hz, 3H), 1.28 (s, 3H). MS (m/e) (positive FAB)
538.2 (M + 1)+.
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(2,5-Dichlorobenzylamino)-2-
chloropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexane-1′-
1
carboxylic Acid Methyl Amide (20). H NMR (CDCl3, 300
MHz) δ 7.94 (s, 1H), 7.60 (s, 1H), 7.43 (d, J ) 8.4 Hz, 1H),
7.34-7.30 (m, 1H), 7.04 (br s, 1H), 6.61 (br s, 1H), 5.12-4.92
(m, 1H), 431-4.22 (m, 1H), 3.03 (d, J ) 5.1 Hz, 3H), 2.31-
2.27 (m, 1H), 1.54-1.46 (m, 1H). HRMS (M + 1)+: calculated
497.0736, found 497.0797. HPLC (system A) 17.2 min (98%),
(system B) 13.8 min (97%).
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(2-Chloro-5-(3-hydroxypropy-
nyl)benzylamino)-2-chloropurin-9-yl]-2′,3′-O-isopropyli-
denebicyclo[3.1.0]hexane-1′-carboxylic Acid Ethyl Ester
1
(52). H NMR (CDCl3, 300 MHz) δ 7.63 (s, 1H), 7.48 (s, 1H),
7.32-7.22 (m, 2H), 6.63 (br s, 1H), 5.87 (d, J ) 8.4 Hz, 1H),
4.88-4.79 (m, 3H), 4.71 (d, J ) 4.8 Hz, 1H), 4.45 (d, J ) 6 Hz,
2H), 4.32-4.19 (m, 2H), 2.35 (br s, 1H), 2.23-2.18 (m, 1H),
1.75-1.68 (m, 2H), 1.55 (s, 3H), 1.35 (t, J ) 7.8 Hz, 3H), 1.28
(s, 3H). MS (m/e) (positive FAB) 572.1 (M + 1)+.
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(2-Chloro-5-iodobenzylamino)-
2-chloropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexane-
1′-carboxylic Acid Methylamide (21). 1H NMR (CDCl3, 300
MHz) δ 7.83 (m, 2H), 7.55 (d, J ) 8.4 Hz, 1H), 7.12 (d, J ) 8.4
Hz, 1H), 6.86 (br s, 1H), 6.43 (br s, 1H), 4.96-4.80 (m, 3H),
4.13-4.08 (m, 2H), 2.91 (d, J ) 5.1 Hz, 3H), 2.24-2.19 (m,
1H), 1.72 (br s, 2H), 1.36-1.32 (m, 1H). HRMS (M + 1)+:
calculated 589.0019, found 589.0029. HPLC (system A) 16.6
min (98%), (system B) 14.6 min (97%).
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(4-Aminobenzylamino)-2-chlo-
ropurin-9-yl]-2′,3′-O-isopropylidenebicyclo[3.1.0]hexane-
1
1′-carboxylic Acid Ethyl Ester (53). H NMR (CDCl3, 300
MHz) δ 7.59 (s, 1H), 7.17 (d, J ) 8.1 Hz, 2H), 6.65 (d, J ) 8.1
Hz, 2H), 6.12 (br s, 1H), 5.87 (d, J ) 8.4 Hz, 1H), 4.84 (s, 1H),
4.73-4.58 (m, 3H), 4.33-4.20 (m, 2H), 3.17 (br s, 2H), 2.26-
2.18 (m, 1H), 1.75-1.69 (m, 1H), 1.56-1.50 (m, 4H), 1.35 (t, J
) 7.8 Hz, 3H), 1.28 (s, 3H). MS (m/e) (positive FAB) 499.2 (M
+ 1)+.
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(5-Chloro-2-methoxybenzyl-
amino)-2-chloropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]-
hexane-1′-carboxylic Acid Methylamide (22). 1H NMR
(CDCl3, 300 MHz) δ 1.12-1.42 (m, 2H), 2.21-2.27 (m, 1H),
2.91 (d, J ) 4.8 Hz, 3H), 3.86 (s, 3H), 4.01-4.22 (m, 2H), 4.65-
4.83 (m, 3H), 4.95-5.01 (m, 1H), 6.42 (br s, 1H), 6.81 (d, J )
12 Hz, 1H), 6.95 (br s, 1H), 7.21-7.43 (m, 3H), 7.81 (s, 1H).
HRMS (M + 1)+: calculated 493.1158, found 493.1138. HPLC
(system A) 15.1 min (99%), (system B) 12.9 min (98%).
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(5-Chloro-2-(aminocarbonyl-
methyloxy)benzylamino)-2-chloropurin-9-yl]-2′,3′-dihy-
droxybicyclo[3.1.0]hexane-1′-carboxylic Acid Methylam-
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(3-Pyridylmethylamino)-2-chlo-
ropurin-9-yl]-2′,3′-O-isopropylidenebicyclo[3.1.0]hexane-
1
1′-carboxylic Acid Ethyl Ester (54). H NMR (CDCl3, 300
MHz) δ 8.66 (br s, 1H), 8.54 (br s, 1H), 7.73 (d, J ) 6.6 Hz,
1H), 7.67 (s, 1H), 7.34-7.27 (m, 1H) 6.26 (br s, 1H), 5.88 (d, J
) 8.4 Hz, 1H), 4.85 (br s, 3H), 4.72 (d, J ) 4.8 Hz, 1H), 4.45
(d, J ) 6 Hz, 2H), 4.33-4.20 (m, 2H), 2.24-2.18 (m, 1H), 1.75-
1.70 (m, 2H), 1.56 (s, 3H), 1.35 (t, J ) 7.8 Hz, 3H), 1.28 (s,
3H). MS (m/e) (positive FAB) 485.2 (M + 1)+.
1
ide (23). H NMR (CD3OD, 300 MHz) δ 8.04 (s, 1H), 7.38 (s,
1H), 7.25 (d, J ) 8.4 Hz, 1H), 6.94 (d, J ) 8.4 Hz, 1H), 5.07 (d,
J ) 6.3 Hz, 1H), 4.59 (s, 2H), 4.99 (d, J ) 6.3 Hz, 1H), 2.99-
2.68 (m, 5H), 2.05-2.02 (m, 1H), 1.38-1.34 (m, 1H). HPLC
(system A) 12.3 min (97%), (system B) 9.1 min (98%).
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(3-Bromobenzylamino)-2-chlo-
ropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexane-1′-car-
boxylic Acid Methyl Amide (17). The ester 39 (45 mg, 0.08
mmol) was dissolved in methanol (3 mL) and treated with an
aqueous solution of methylamine (1 mL, 40%). This mixture
was stirred at room temperature overnight, then the solvent
was evaporated to dryness, and the white residue was purified
by PTLC (chloroform/methanol 9:1) to give the uronamide17
(19.6 mg, 40%). 1H NMR (CDCl3, 300 MHz) δ 7.68 (s, 1H), 7.51
(s, 1H), 7.31-7.19 (m, 2H), 6.83 (br s, 1H), 6.30 (br s, 1H),
5.67 (d, J ) 6.9 Hz, 1H), 4.79-4.78 (m, 4H), 2.92 (d, J ) 4.5
Hz, 3H), 2.07-2.02 (m, 1H), 1.70-1.65 (m, 2H), 1.55 (s, 3H),
1.27 (s, 3H). MS (m/e) (positive FAB) 549.1 (M + 1)+.
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(5-Chloro-2-benzyloxybenzyl-
amino)-2-chloropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]-
hexane-1′-carboxylic Acid Methylamide (24).
1H NMR
(CDCl3, 300 MHz) δ 7.80 (s, 1H), 7.41-7.31 (m, 6H), 7.18 (dd,
J ) 8.7, 2.7 Hz, 1H), 6.90-6.84 (m, 2H), 6.57 (br s, 1H), 5.09
(s, 2H), 4.87-4.77 (m, 5H), 4.07 (d, J ) 6 Hz, 1H), 2.90 (d, J
) 5.1 Hz, 3H), 2.54-2.21 (m, 1H), 1.92 (br s, 2H), 1.36-1.32
(m, 1H). HRMS (M + 1)+: calculated 569.1471, found 569.1455.
HPLC (system A) 17.2 min (98%), (system B) 16.7 min (98%).
(1′S,2′R,3′S,4′S,5′S)-4′-[6-(5-Iodo-2-methoxybenzylamino)-
2-chloropurin-9-yl]-2′,3′-dihydroxybicyclo[3.1.0]hexane-
1′-carboxylic Acid Methylamide (25). 1H NMR (CDCl3, 300
MHz) δ 7.79 (s, 1H), 7.67 (s, 1H), 7.54 (dd, J ) 8.7, 2.7 Hz,
1H), 6.94 (br s, 1H), 6.65 (d, J ) 8.7 Hz, 1H), 6.48 (br s, 1H),
4.97-4.57 (m, 5H), 4.07 (m, 1H), 3.85 (s, 3H), 2.91 (d, J ) 5.1
Hz, 3H), 2.24-2.19 (m, 1H), 1.94-1.85 (br s, 2H), 1.38-1.33
(m, 1H). HRMS (M + 1)+: calculated 585.0514, found 585.0527.
HPLC (system A) 18.7 min (98%), (system B) 13.9 min (99%).
This intermediate (18 mg, 0.03 mmol) was treated with a
solution of trifluoroacetic acid in MeOH (5 mL, 10%) and H2O
(0.5 mL), and the mixture was heated at 70 °C for 3 h. The
solution was cooled, and the solvent was removed to dryness
by coevaporation with toluene in vacuo. The white residue was
purified by PTLC (chloroform/methanol 9:1) to give the final
1
product 17 (10 mg, 70%). H NMR (CDCl3, 300 MHz) δ 7.83
(s, 1H), 7.52-7.50 (m, 1H), 7.43-7.39 (m, 1H), 7.31-7.17 (m,
2H), 6.90 (br s, 1H), 6.63 (br s, 1H), 4.95-4.78 (m, 5H), 4.07