B. Latli et al.
radiochemical yield. The product was used as it is in the next
step.
[13C4]-4,6-Dichloro-5-nitropyrimidine ([13C4]-(3)): POCl3 (3.1 mL)
was added to the above material (0.5 g, 3.1 mmol) in one
4,6-Dihydroxy-5-nitro[5-14C]pyrimidine ([14C]-(2)): Prepared portion, followed by N,N-dimethylaniline (0.62 mL). The usual
from the above compound (1.45 g, 496 mCi) and nitric acid work up and purification by flash chromatography using
(90%, 5 mL) to obtain 646 mg of an off-white solid in 39% yield. methylene chloride as eluent gave 0.55 g of a pale yellow solid
Total activity was 193 mCi. The product was used as it is in the in 90% yield. Rf = 0.6 in 100% CH2Cl2. 1H NMR (CDCl3) d: 8.85(dt,
next step.
J
1
¼ 215:70, 13.22 Hz, 1H). 13C NMR (CDCl3) d: 152.72,
13C-- H
4,6-Dichloro-5-nitro[5-14C]pyrimidine ([14C]-(3)): Obtained as 153.02(d, J = 79.16 Hz), 143.02(t, J = 79.16 Hz). LC-MS-ES1:
described before from POCl3 (3.77 mL) and the above material Rt = 1.32, MH1 = 199.31 (100%).
(592 mg, 3.77 mmol) to give after purification by Combi-Flash
[13C4]-5-Amino-4,6-dichloropyrimidine ([13C4]-(4)): Obtained as
Companion using 40 g RediSepTM column and methylene before from the above compound (1.0 g, 5.05 mmol) and tin
chloride as eluent, 611 mg of a pale yellow solid in 86% chloride dihydrate (5.7 g, 25.0 mmol) in ethanol (20 mL). The
1
radiochemical yield (151.43 mCi). The product was used as it is in usual work up gave 880 mg of a white solid. H NMR (CDCl3) d:
the next step.
8.14(dt, J
1
¼ 213:27, 13.22 Hz, 1H), 4.45(brs, 2H). 13C NMR
13C-- H
5-Amino-4,6-dichloro[5-14C]pyrimidine ([14C]-(4)): Prepared (CDCl3) d: 146.03(m), 144.24(d, J = 70.65 Hz), 135.84(t,
from the above compound (151.43 mCi) and tin(II) chloride J = 70.65 Hz). LC-MS-ES1: Rt = 0.65, MH1 = 168.18 (100%).
dihydrate (3.48 g, 15.42 mmol) in ethanol (20 mL). The product
[13C4]-5-Amino-4,6-diiodopyrimidine ([13C4]-(5)): Prepared from
was isolated in 99% radiochemical yield, or 518 mg of a white the above compound (0.85 g, 5.05 mmol), HI in water (40%,
solid, 149.70 mCi. The product was used as it is in the next step. 15 mL) and NaI (3.7 g, 10.5 mmol). The usual work up and
5-Amino-4,6-diiodo[5-14C]pyrimidine ([14C]-(5)): The above purification of the residue by flash chromatography on
compound (500 mg, 3.04 mmol), HI in water (40%, 17 mL) and RediSepTM column (40 g) and using 1–5% MeOH/CH2Cl2 gave
1
NaI (2.3 g, 15.33 mmol) were reacted as described before. The 1.6 g of a cream-colored solid in 90% yield. H NMR (CDCl3) d:
¼ 213:47, 12.88 Hz, 1H), 4.55(brs, 2H). 13C NMR
13
1
usual work up and purification by Combi-Flash chromatography 7.29(dt, J
on RediSepTM column (40 g) and using 1–5% MeOH/CH2Cl2 gave (CDCl3) d: 147.02(dt, J = 14.02, 8.98 Hz), 144.94(td, J = 14.02,
867 mg of a cream-colored solid (121.726 mCi) in 82% radio- 63.10 Hz), 113.25(dd, J=8.98, 63.10Hz). LC-MS-ES1: Rt =1.02, MH1
C-- H
chemical yield. The product was used as it is in the next step.
5-Amino-4-iodo[5-14C]pyrimidine ([14C]-(6)): To solution of the
= 352.09 (100%).
[13C4]-5-Amino-4-iodopyrimidine ([13C4]-(6)): Prepared from the
above material (0.86 g, 2.48 mmol, 121.7 mCi) in dry THF (5 mL) above material (0.565 g, 1.61 mmol) in dry THF (5 mL) and
was added a solution of isopropyl magnesium chloride (2.0 M in isopropyl magnesium chloride (2.0 M in THF, 2 mL). The usual
THF, 2.5 mL) as described before. After the work up, the ethyl work up gave 0.4 g of an orange solid. Purification by Combi-
acetate extracts were dried over MgSO4, filtered and concen- Falsh chromatography using 40 g RediSepTM and 5–50% EtOAc/
trated in vacuo to give 0.528 g of an orange solid. Purification by CH2Cl2 to elute the product, 168 mg or 46%, Rf = 0.4 in 10%
Combi-Falsh chromatography using 40 g RediSepTM and 0–50% MeOH/CH2Cl2. The by-product 5-aminopyrimidine (7) was eluted
EtOAc/CH2Cl2 gave 435 mg of the desired product with more using 10–20% MeOH/CH2Cl2 to give 60 mg of a yellow solid in
than 95% radiopurity. A total of 95.15 mCi of material was 38% yield, Rf = 0.15 in 10% MeOH/CH2Cl2. LC-MS-ES1: MH1
obtained in 78% radiochemical yield. 5.6 mCi of 5-amino[5-14C]-
pyrimidine was also isolated as a by-product.
= 225.99 (for the desired product) and 99.10 for (7). 1H NMR
13C-- H
(CDCl3) d: 8.19(ddd, J ¼ 209:52, 12.01, 10.21 Hz, 1H),
1
13
1
7.91(ddt, J
¼ 180:10, 11.80, 6.57 Hz, 1H), 4.14(brs, 2H). 13C
C-- H
NMR (CDCl3) d: 148.63(quintet, J = 7.95 Hz), 143.50(ddd, J = 15.76,
58.26, 63.87 Hz), 139.91(dd, J = 7.27, 58.26 Hz), 118.50(dd,
Synthesis of [13C4]-5-Aminopyrimidine
[13C4]-4,6-Dihydroxypyrimidine ([13C4]-(1)): To a mixture of for- J = 8.22, 63.87 Hz). LC-MS-ES1: Rt = 4.92, MH1 = 225.99 (100%).
mamide (13C, 99 atom% 13C, 0.6 mL, 16.27 mmol) and a solution
of sodium ethoxide in ethanol (21wt%, 12 mL, 32.14 mmol) was
Synthesis of [13C4, 15N2]-5-Amino-4-Iodopyrimidine
added diethylmalonate (1,2,3-13C3, 99 atom% 13C, 1 mL,
5.81 mmol) in a 1 h period at 65–701C. After the addition was [13C4, 15N2]-4,6-Dihydroxypyrimidine ([13C4, 15N2]-(1)): Formamide
complete, the mixture was heated to 1101C and stirred for 48 h. (13C, 15N, min 99 atom% 13C, min 99 atom% 15N, 1.058 g,
After the work up and treatment with concentrated aqueous 22.51 mmol), a solution of sodium ethoxide in ethanol (21wt%,
HCl (2.5 mL) at 01C, the resulting precipitate was filtered and 12.4 mL, 33.21 mmol), and diethylmalonate ((1,2,3-13C3,
dried under reduced pressure to give 675 mg of an off-white 99 atom% 13C, 1.76 mL, 10.0 mmol) gave 842 mg of an off-white
solid. 1H NMR (d6-DMSO) d: 12.92(brs, 2H), 8.01(dt, solid in 71.35% yield. 1H NMR (d6-DMSO) d: 12.01(brs, 2H),
C-- H
C-- H
13C-- H
¼ 203:30,
13
1
13
1
8.01(dquintet,
J
J
1
9.50 Hz,
1H),
5.23(d,
J
¼ 203:45, 9.67 Hz, 1H), 5.22(d, J
¼ 165:94 Hz, 1H).
13C NMR (d6-DMSO) d: 166.17(d, J = 71.79 Hz), 149.96, 89.99
(t, J = 71.79 Hz). LC-MS-ES1: MH1 = 117.32 runs with the solvent 150.08, 90.8(m). LC-MS-ES1: Rt = 0.21 min, MH1 = 119.72 (100%)
¼ 165:89 Hz, 1H). 13C NMR (d6-DMSO) d: 166.5(m),
1
13C-- H
front.
[13C4, 15N2]-4,6-Dihydroxy-5-nitropyrimidine ([13C4, 15N2]-(2)):
[13C4]-4,6-Dihydroxy-5-nitropyrimidine ([13C4]-(2)): Nitration of The above compound (0.84 g, 7.11 mmol) and a solution of nitric
1
the above compound (0.7 g, 6.03 mmol) was accomplished with acid (90%, 3 mL) gave 550 mg of a pink solid in 47.4% yield. H
13
1
a solution of nitric acid (90%, 2.4 mL) at 01C in a 1 h period. The NMR (d6-DMSO) d: 13.28(brs, 2H), 8.76(m, J
¼ 206:47,
C-- H
product 686 mg was isolated as a pink solid in 70% yield. 1H 4.02 Hz, 1H). 13C NMR (d6-DMSO) d: 155.64(dd, J = 86.62,
9.01 Hz), 150.80(t, J = 14.06 Hz), 119.85(m). LC-MS-ES1:
13
1
NMR (d6-DMSO) d: 8.75(dt,
J
¼ 206:53, 7.99 Hz, 1H),
C-- H
4.02(brs, 2H). 13C NMR (d6-DMSO) d: 155.04(d, J = 84.73 Hz), Rt = 0.36 min, MH1 = 164.50 (100%).
150.46, 119.45(t, J = 84.73 Hz). LC-MS-ES1: Rt = 0.19, MH1
= 162.32 (100).
[13C4, 15N2]-4,6-Dichloro-5-nitropyrimidine ([13C4, 15N2]-(3)):
POCl3 (3.31 mL), the above material (0.54 g, 3.31 mmol) and
J. Label Compd. Radiopharm 2008, 51 54–58
Copyright r 2008 John Wiley & Sons, Ltd.