P2Y1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 753
6.9 Hz, -NCH2-), 4.26 (2H, t, J ) 5.1 Hz, 2×-OH) 7.64 (1H, bs,
-NH-), 8.12, 8.21 (2H, 2s, H-2, H-8). MS (CI) 294 (M + 1).
HRMS (EI) Calcd for C14H23N5O2: 293.1852; Found: 293.1863.
2-[4-(6-Meth yla m in o-p u r in -9-yl)-tr a n s-bu t-2-en yl]-p r o-
p a n e-1,3-bisoxy(d iben zylp h osp h a te) (34e). Starting from
44 mg of 33e (0.159 mmol) and 555 mg of tetrabenzyl
pyrophosphate (1.11 mmol) with the same procedure shown
in the preparation of 34a , 22 mg of 34e was obtained as a
colorless oil (17%). 1H NMR (DMSO-d6) 1.85 (1H, m, -CH-),
1.98 (2H, t, J ) 7.8 Hz, -CH2CHd), 3.20 (3H, bs, N6-CH3), 3.88
(4H, m, 2×-CH2OP-), 4.62 (2H, d, J ) 5.7 Hz, -NCH2-), 4.99
(8H, m, 4×-OCH2Ph), 5.48 (1H, dt, J ) 15.6, 6.6 Hz, -CHd),
5.60 (1H, dt, J ) 15.6, 5.7 Hz, -CHd), 5.87 (1H, bs, -NH-),
7.30 (20H, m, 4×-Ph), 7.69, 8.42 (2H, 2s, H-2, H-8). 31P NMR
(CDCl3) -22.23 (s, 1′-P, 3′-P). MS (FAB+, Cs) 930 (M+ + Cs).
HRMS (FAB+) Calcd for C41H45O8N5P2Cs: 930.1798; Found:
930.1802.
9-[6-H yd r oxy-5-(h yd r oxym e t h yl)-cis-h e x-2-e n yl]-6-
m eth yla m in o-p u r in e (33d ). Starting from 0.167 g of 32d
(0.50 mmol) with the same procedure shown in the preparation
of 26, 0.101 g of 33d was obtained as white crystals (73%).
Mp 127-129 °C; Rf 0.22 (10:1 CH Cl3:MeOH). 1H NMR
(DMSO-d6) 1.61 (1H, m, -CH-), 2.44 (2H, t, J ) 6.9 Hz,
-CH2CHd), 2.97 (3H, bs, N6-CH3), 3.20-3.43 (4H, m, 2×-
CH2OH), 4.50 (2H, t, J ) 5.1 Hz, 2×-OH), 4.89 (2H, d, J ) 5.7
Hz, -NCH2-), 5.67 (2H, m, J cis ) 10.8 Hz, -CHdCH-) 7.66 (1H,
bs, -NH-), 8.10, 8.22 (2H, 2s, H-2, H-8). MS (CI) 278 (M + 1).
HRMS (EI) Calcd for C13H19N5O2: 277.1539; Found: 277.1549.
3,5-Di(br om om eth yl)-1-n itr o-ben zen e (36). A solution of
1.89 g of 3,5-di(hydroxymethyl)-1-nitrobenzene (35, 10 mmol),
5.25 g of triphenylphosphine (20 mmol), and 6.62 g of carbon
tetrabromide (20 mmol) in 50 mL of anhydrous ether was
stirred at 25 °C for 12 h under N2 atmosphere. After evapora-
tion, the residue was purified with flash silica gel column
chromatography (hex/EtOAc ) 5/1) to give 1.6 g of 36 as a
bright yellow solid (52%). 1H NMR (CDCl3) 4.53 (4H, s, 2×-
CH2Br), 6.83 (1H, s, Ph), 7.76 (1H, s, Ph), 8.20 (1H, s, Ph). MS
(EI) (M+) 309. HRMS (EI) Calcd 306.8843; Found 306.8859.
Tetr am eth yl 1-Nitr o-ben zen e-3,5-bis(m eth ylph osph on -
a te) (37). A solution of 1.4 g of 36 (4.53 mmol) in 15 mL of
trimethyl phosphite was heated at 80 °C for 6 h. After
evaporation, the residue was purified with flash silica gel
column chromatography (CHCl3/MeOH ) 30/1) to give 1.57 g
of 37 as a white solid (94%). 1H NMR (CDCl3) 3.25 (4H, d, J )
21.5 Hz, 2×-CH2P-), 3.72 (3H, s, -CH3), 3.73 (3H, s, -CH3), 3.75
(3H, s, -CH3), 3.76 (3H, s, -CH3), 7.28 (1H, s, Ph), 7.60 (1H, s,
Ph), 8.06 (1H, s, Ph). 31P NMR (CDCl3) -27.09 (m), 33.48 (m).
MS (EI) (M+) 367. HRMS (EI) Calcd 367.0586; Found 367.0592.
9-[6-Hyd r oxy-5-(h yd r oxym et h yl)-tr a n s-h ex-2-en yl]-6-
m eth yla m in o-p u r in e (33e). Starting from 0.104 g of 32e
(0.31 mmol) with the same procedure shown in the preparation
of 26, 0.066 g of 33e was obtained as white crystals (76%).
Mp 115-117 °C; Rf 0.22 (10:1 CHCl3:MeOH). 1H NMR (DMSO-
d6) 1.51 (1H, m, -CH-), 2.00 (2H, t, J ) 6.0 Hz, -CH2CHd),
2.96 (3H, bs, N6-CH3), 3.26-3.43 (4H, m, 2×-CH2OH), 4.33
(2H, t, J ) 5.4 Hz, 2×-OH), 4.89 (2H, d, J ) 5.2 Hz, -NCH2-),
5.65 (2H, m, -CHdCH-) 7.64 (1H, bs, -NH-), 8.07, 8.22 (2H,
2s, H-2, H-8). MS (CI) 278 (M + 1). HRMS (EI) Calcd for
C
13H19N5O2: 277.1539; Found: 277.1540.
2-[3-(6-Meth yla m in o-p u r in -9-yl)-p r op yl]-p r op a n e-1,3-
bisoxy(d iben zylp h osp h a te) (34a ). Starting from 29.2 mg
of 33a (0.11 mmol) with the same procedure shown in the
preparation of 28, 19 mg of 34a was obtained as a colorless
1
oil (22%). H NMR (CDCl3) 1.26 (2H, m, -CH2-), 1.87 (3H, m,
-CH2-, -CH-), 3.19 (3H, bs, N6-CH3), 3.87 (4H, dd, J ) 5.7 Hz,
6 Hz, 2×-CH2OP-), 4.03 (2H, t, J ) 6.8 Hz, -NCH2-), 4.95 and
5.02 (8H, 2d, J ) 11.7 Hz, 4×-OCH2Ph), 5.87 (1H, s, -NH-),
7.31 (20H, m, 4×-Ph), 7.62 (1H, s, H-8), 8.39 (1H, s, H-2). 31P
NMR (CDCl3) -22.27 (s, 1′-P, 3′-P). MS (FAB+, Cs) 918 (M+
+ Cs). HRMS (FAB+) (M + Cs) Calcd for C40H45O8N5P2Cs:
918.1798; Found: 918.1798.
Tetr am eth yl 1-Am in o-ben zen e-3,5-bis(m eth ylph osph on -
a te) (38). A solution of 40 mg of 37 (4.53 mmol) and 10 mg of
10% Pd/C in 3 mL of methanol was stirred at 25 °C for 1 h
under H2 atmosphere (1 atm). The mixture was filtered
through a Celite bed and purified with preparative thin-layer
chromatography (CHCl3/MeOH ) 20/1) to give 37 mg of 38 as
2-[4-(6-Met h yla m in o-p u r in -9-yl)-b u t yl]-p r op a n e-1,3-
bisoxy(d iben zylp h osp h a te) (34b). Starting from 29 mg of
33b (0.104 mmol) with the same procedure shown in the
preparation of 28, 26 mg of 34b was obtained as a colorless
1
a white solid (100%). H NMR (CDCl3) 3.06 (4H, d, J ) 21.5
1
Hz, 2×-CH2P-), 3.66 (6H, s, 2×-CH3), 3.70 (6H, s, 2×-CH3),
6.55 (2H, s, Ph), 6.59 (1H, s, Ph). 31P NMR (CDCl3) -27.09
(m), 33.48 (m): with proton decoupling off mode. MS (EI) (M+)
337. HRMS (EI) Calcd 337.0844; Found 337.0845.
oil (31%). H NMR (CDCl3) 1.24 (4H, m, 2×-CH2-), 1.76 (3H,
m, -CH2-, -CH-), 3.20 (3H, bs, N6-CH3), 3.88 (4H, m, 2×-
CH2OP-), 4.06 (2H, t, J ) 6.9 Hz, -NCH2-), 4.90 (8H, m, 4×-
OCH2Ph), 5.86 (1H, s, -NH-), 7.31 (20H, m, 4×-Ph), 7.67 (1H,
s, H-8), 8.41 (1H, s, H-2). 31P NMR (CDCl3) -22.25 (s, 1′-P,
3′-P). MS(FAB+, Cs) 932 (M+ + Cs). HRMS (FAB+) Calcd for
Eth yl 2-Ch lor o-6-m eth ylam in o-pu r in -9-yl)-acetate (40).
To a suspension of 0.132 g of NaH (3.3 mmol), which was
prewashed with 5 mL of hexanes twice, in 2 mL of anhydrous
DMF was added 0.55 g of N6-methyl-2-chloro-purine (3 mmol)
in 3 mL of DMF at 25 °C under N2 atmosphere. After the
mixture was stirred for 30 min, 0.4 mL of ethyl bromoacetate
was added, and the stirring was continued for 12 h. After
evaporation, the residue was purified with preparative thin-
layer chromatography (CHCl3/MeOH ) 25/1) to give 0.66 g of
40 as a white solid (82%). 1H NMR (CDCl3) 1.31 (3H, t, J )
6.8 Hz, -CH3), 3.20 (3H, bs, -N6-CH3), 4.26 (2H, q, J ) 6.8 Hz,
-OCH2-), 4.93 (2H, s, -NCH2CO-), 6.01 (1H, bs, -NH-), 7.78 (1H,
s, H-8). MS (EI) (M+) 269. HRMS (EI) Calcd 269.0679; Found
269.0667.
C
41H47O8N5P2Cs: 932.1954; Found: 932.1979.
2-[5-(6-Met h yla m in o-p u r in -9-yl)-p en t yl]-p r op a n e-1,3-
bisoxy(d iben zylp h osp h a te) (34c). Starting from 30 mg of
33c (0.102 mmol) and 275 mg of tetrabenzyl pyrophosphate
(0.511 mmol) with the same procedure shown in the prepara-
tion of 28, 20 mg of 34c was obtained as a colorless oil (24%).
1H NMR (CDCl3) 1.22 (6H, m, 3×-CH2-), 1.78 (2H, m, -CH2-),
1.87 (1H, m, -CH-), 3.21 (3H, bs, N6-CH3), 3.91 (4H, m, 2×-
CH2OP -), 4.11 (2H, t, J ) 6.9 Hz, -NCH2-), 4.95, 5.02 (4H, 2d,
J ) 11.7 Hz, 2×-OCH2Ph), 4.98, 5.00 (4H, 2d, J ) 12.0 Hz,
2×-OCH2Ph), 5.86 (1H, s, -NH-), 7.30 (20H, m, 4×-Ph), 7.70
(1H, s, H-8), 8.42 (1H, s, H-2). 31P NMR (CDCl3) -22.24 (s,
1′-P, 3′-P). MS (FAB+, Cs) 946 (M + Cs). HRMS (FAB+) Calcd
for C42H49O8N5P2Cs: 946.2111; Found: 946.2139.
2-Ch lor o-6-m eth yla m in o-9-yl)-a cetic Acid (41). Com-
pound 40 (0.33 g, 1.22 mmol) was dissolved in 6 mL of 1 N
NaOH with stirring at 25 °C for 1 h. The completion of the
hydrolysis was confirmed by HPLC, and the mixture was
neutralized to pH 5∼7 with 6 N HCl at 0 °C. A white
precipitate was collected by filtration, washed with water, and
dried under high vacuum to give 0.245 g of 41 as a white solid
2-[4-(6-Meth ylam in o-pu r in -9-yl)-cis-bu t-2-en yl]-pr opan e-
1,3-bisoxy(d iben zylp h osp h a te) (34d ). Starting from 50 mg
of 33d (0.18 mmol) and 679 mg of tetrabenzyl pyrophosphate
(1.26 mmol) with the same procedure shown in the preparation
1
of 28, 23 mg of 34d was obtained as a colorless oil (16%). H
1
(83%). H NMR (DMSO-d6) 2.92 (3H, s, -N6-CH3), 4.94 (2H, s,
NMR (CDCl3) 1.94 (1H, m, -CH-), 2.16 (2H, t, J ) 7.8 Hz,
-CH2CHd), 3.21 (3H, bs, N6-CH3), 3.94 (4H, t, J ) 6 Hz, 2×-
CH2OP-), 4.66 (2H, d, J ) 6.9 Hz, -NCH2-), 5.01 (8H, m, 4×-
OCH2Ph), 5.49 (1H, dt, J ) 10.8, 7.8 Hz, -CHd), 5.63 (1H, dt,
J ) 10.8, 6.9 Hz, -CHd), 5.84 (1H, bs, -NH-), 7.30 (20H, m,
4×-Ph), 7.70, 8.40 (2H, 2s, H-2, H-8). 31P NMR (CDCl3) -22.21
(s, 1′-P, 3′-P). MS (FAB+, Cs) 930 (M + Cs). HRMS (FAB+)
Calcd for C41H45O8N5P2Cs: 930.1798; Found: 930.1802.
-NCH2CO-), 8.11 (1H, s, H-8). MS (EI) (M+) 241. HRMS (EI)
Calcd 241.0366; Found 241.0358.
2-Ch lor o-9-[(d ieth a n ola m in o)ca r boxym eth yl]-6-m eth -
yla m in o-p u r in e (42). A mixture of 47 mg of 41 (0.193 mmol),
54 mg of 4-nitrophenol (0.386 mmol), 74 mg of EDAC (0.386
mmol), and 5 mg of DMAP in 1 mL of anhydrous DMF and 1
mL of CH2Cl2 was stirred at 25 °C for 2 h. After evaporation,