910
U. Roehn et al. / Journal of Fluorine Chemistry 130 (2009) 902–912
IR (KBr) = 2939, 1700, 1670, 1654, 1467, 1095.
MS (ESI+): m/z (%) = 524 (M+1, 15), 492 (100), 412 (10).
shaken for 4 h, filtered and the remaining resin was washed with
DMF and dichloromethane and dried under vacuum. Then the resin
was treated with 1.5 ml of a mixture containing 85% TFA, 5% water,
5% phenol and 5% triisopropyl silane for 2 h, filtered followed by
precipitation of the product in methyl tert-butyl ether (MTBE)
(20 ml). The precipitate was purified by HPLC to give 7.8 mg
(10.5%) of 11b.
HRMS: calcd for C27H46O7N3: 524.3336, found: 524.3330.
[a]
25 + 22.7 (c 1.07 g/100 ml MeOH).
D
4.4.10. N-(2-(3-(3-((2R,4S,5R)-4-(1-Methoxycyclohexyloxy)-5-(1-
methoxycyclohexyloxymethyl) tetrahydrofuran-2-yl]-5-methyl-2,6-
dioxo-2,3-dihydropyrimidine-1-(6H)-yl)propylamino-2-oxoethyl-1-
(2,4,6-triisopropylphenylsulfonyl)aziridine-2-carboxamido (10c)
60 mg (0.15 mmol) 9 was dissolved in 4 ml dichloromethane, to
HPLC-MS (ES+): m/z [M+H]+ calcd: 1473.8, found: 1473.8.
4.4.13. (RS)-3-Fluoro-N-(2-(3-(3-((2R,4S,5R)-4-(1-
this was added diisopropylcarbodiimide (DIC) (46
m
l, 0.29 mmol)
methoxycyclohexyloxy)-5-(1-methoxycyclohexyloxymethyl)
tetrahydrofuran-2-yl]-5-methyl-2,6-dioxo-2,3-dihydropyrimidine-1-
(6H)-yl)propylamino-2-oxoethyl-2-(2,4,6-
followed by the addition of compound 14 (76.5 mg, 0.15 mmol).
The reaction mixture was stirred overnight at room temperature
and concentrated. The residue was purified by flash chromato-
graphy on silica gel with dichloromethane/methanol (9:1) to give
87 mg (65%) of 10c.
triisopropylphenylsulfonamido)propanamide (11c)
30 mg (0.033 mmol) 10c was dissolved in DMSO (1.5 ml)
followed by 13.6 mg (0.036 mmol) Kryptofix (K2.2.2) and 2.1 mg
(0.036 mmol) KF. The reaction mixture was stirred at 50 8C for
30 min until complete disappearance of the starting material. The
mixture was then diluted with ethyl acetate, washed with
saturated aqueous ammonium chloride solution, brine, dried over
sodium sulfate, filtered and concentrated. The residue was purified
by preparative TLC on silica gel with dichloromethane/methanol
(9.1) to give 5 mg (16%) of 11c.
1H NMR (600.1 MHz, CDCl3):
d = 7.56 (s, 1H, 55CH), 7.21 (s, 2H,
aryl), 7.01 (t, 3J = 5.9 Hz, 1H, NH), 6.72 (br t, 1H, NH), 6.35 (m, 1H,
10CH), 4.51 (m, 1H, CH–O), 4.28 (sept, 3J = 6.6 Hz, 2H, CH(CH3)2),
4.16 (m, 1H, CH–O), 4.08 (dd, 2J = 16.8 Hz, 3J = 6.2 Hz, 1H, CH2–N),
3.97 (m, 2H, C(O)CH2–N), 3.76 (dd, 2J = 16.8 Hz, 3J = 4.4 Hz, 1H,
CH2–N), 3.67 (dd, 2J = 10.6 Hz, 3J = 2.6 Hz, 1H, CH2–O), 3.57 (dd,
2J = 10.6 Hz, 3J = 2.6 Hz, 1H, CH2–O), 3.44 (dd, 2J = 7.4 Hz,
3J = 4.0 Hz, 1H, CHNAz), 3.21 (s, 3H, CH3–O), 3.18 (s, 3H, CH3–O),
3.16 (m, 2H, CH2–N), 2.92 (sept, 3J = 7.0 Hz, 1H, CH(CH3)2), 2.86 (d,
3J = 7.4 Hz, 1H, CH2NAz), 2.66 (d, 3J = 4.0 Hz, 1H, CH2NAz), 2.36 (m,
1H, 20CH2), 2.05 (m, 1H, 2CH2), 1.91 (s, 3H, CH3–C55C), 1.82–1.76
(m, 6H, cyclohexyl, CH2), 1.54–1.37 (m, 16H, cyclohexyl), 1.30–
1.26 (m, 18H, CH3) ppm.
1H NMR (600.1 MHz, CDCl3):
d = 7.62 (s, 1H, 55CH), 7.52 (dd,
3J = 7.0, 5.1 Hz, 1H, NH), 7.30 (dd, 3J = 6.6, 5.9 Hz, 1H, NH), 7.18 (s,
2H, aryl), 6.84 (d, 3J = 9.2 Hz, 1H, NH), 6.34 (dd,3J = 7.4, 6.1 Hz, 1H,
2
2
10CH), 4.89 (ddd, JH,F = 55.8 Hz, JH,H = 9.1 Hz, 3J = 3.6 Hz, 1H,
CH2F), 4.51 (m, 1H, CH–O), 4.42 (ddd, 2JH,F = 57.3 Hz, 2JH,H = 9.1 Hz,
3J = 4.0 Hz, 1H, CH2F), 4.32 (dd, 2J = 16.8 Hz, 3J = 7.3 Hz, 1H,
C(O)CH2–N), 4.21–4.15 (m, 2H, C(O)CH2–N, CH–O), 4.11 (sept,
3J = 7.0 Hz, 2H, CH(CH3)2), 4.01–3.97 (m, 2H, CH2–N), 3.71–3.66 (m,
2H, CH–NSO2aryl, CH2–O), 3.57 (dd, 2J = 10.6 Hz, 3J = 2.9 Hz, 1H,
CH2–O), 3.30 (m, 1H, CH2–N), 3.21 (s, 3H, CH3), 3.18 (s, 3H, CH3),
3.02 (m, 1H, CH2–N), 2.91 (sept, 3J = 7.0 Hz, 1H, CH(CH3)2), 2.40
13C NMR (150.9 MHz, CDCl3):
d = 167.5 (C55O), 166.7 (C55O),
164.1 (C55O), 154.2 (Ar–C), 151.4 (Ar–C), 151.1 (C55O), 134.1
(55CH), 130.1 (Ar–C), 124.1 (Ar–CH), 109.9 (55CCH3), 101.4 (OCO),
100.4 (OCO), 85.7 (CHO), 85.2 (CHO), 69.7 (NCO), 59.5 (CH2O), 48.0
(CH3O), 47.7 (CH3O), 42.7 (CH2–N), 40.2 (cyclohexyl), 38.2 (CH2–
N), 37.5 (CH–NAz), 35.5 (CH2N), 34.3 (CH(CH3)2), 34.2, 33.8, 33.5,
33.3 (cyclohexyl), 33.3 (CH2–NAz), 29.9 (CH(CH3)2), 27.2, 25.5, 25.3
(CH2, cyclohexyl), 24.9 (CH3), 24.9 (CH3), 23.5 (CH3), 22.9, 22.9,
22.9, 22.8 (CH2, cyclohexyl), 13.2 (CH3–C55).
3
(ddd, 2J = 13.2 Hz, J = 6.1, 3.0 Hz, 1H, 20CH2), 2.07–2.03 (m, 1H,
20CH2), 1.88 (s, 3H, CH3–C55C), 1.86–1.83 (m, 2H, CH2), 1.80–1.72
(m, 4H, cyclohexyl), 1.60–1.45 (m, 16H, cyclohexyl), 1.27–1.24
(div. d, 18H, CH3) ppm.
IR (KBr) = 3347, 2952, 1702, 1671, 1643.
13C NMR (150.9 MHz, CDCl3):
d = 168.5 (C55O), 168.0 (C55O),
MS (ESI+): m/z (%) = 938 (M+Na, 15), 692 (100).
164.9 (C55O), 153.7 (Ar–C), 150.6 (Ar–C), 150.6 (C55O), 134.8 (55CH),
131.6 (Ar–C), 124.1 (Ar–CH), 109.5 (55CCH3), 101.4 (OCO), 100.5
(OCO), 85.9 (CHO), 85.2 (CHO), 82.7; 81.6 (JC,F = 173.5 Hz, CH2F),
69.6 (NCO), 59.5 (CH2O), 55.9; 55.8 (2JC,F = 21.0 Hz, CH2FCH–N),
48.0 (CH3O), 47.7 (CH3O), 43.4 (CH2–N), 40.3 (cyclohexyl), 38.3
(CH2–N), 34.9 (CH2N), 34.2 (CH(CH3)2), 34.1, 33.8, 33.3, 33.1
(cyclohexyl), 29.9 (CH(CH3)2), 26.8, 25.5, 25.3 (CH2, cyclohexyl),
25.0 (CH3), 24.8 (CH3), 23.5 (CH3), 22.9, 22.9, 22.9, 22.8 (CH2,
cyclohexyl), 13.1 (CH3–C55).
HRMS: calcd for C47H73O11N5SNa: 938.4925, found: 938.4943.
25
[
a]
ꢂ 10.3 (c 1.01 g/100 ml MeOH).
D
4.4.11. (RS)-3-Fluoro-2-(2,4,6-triisopropylphenylsulfonamido)
propanamide-N-methylcarbonyl-Val-ßAla-Phe-Gly-NH2 (11a)
0.05 mmol resin bound tetrapeptide, swollen in DMF (1 ml) was
filtered and added to a solution of [2(RS)-3-fluoro-2-(2,4,6-
triisopropylphenylsulfonylamido)propanamide]-acetic
(64.6 mg, 0.15 mmol), HBTU (56.9 mg, 0.15 mmol) and diisopro-
pylethylamine (26 l, 0.15 mmol) in 1.0 ml DMF. The mixture was
acid
IR (KBr) = 3371, 2950, 2937, 1695, 1666, 1463, 1093.
MS (ESIꢂ): m/z (%) = 935 (M-1, 30), 822 (100), 710 (60).
HRMS: calcd for C47H74O11N5SK: 974.4727, found: 974.4741.
m
shaken for 4 h, filtered and the remaining resin was washed with
DMF and dichloromethane and dried under vacuum. Then the resin
was treated with 1.5 ml of a mixture containing 85% TFA, 5% water,
5% phenol and 5% triisopropyl silane for 2 h, filtered followed by
precipitation of the product in 20 ml MTBE. The precipitate was
purified by HPLC to give 11.6 mg (29%) of 11a.
4.5. 18F-Radiolabeling of synthesized compounds
4.5.1. N-Benzyl-3-[18F]fluoro-2-(4-methylphenyl sulfonamido)-
propanamide ([18F]3a)
HPLC-MS (ES+): m/z [M+H]+ calcd: 804.4, found: 804.5.
No-carrier added [18F]fluoride was produced via the 18O(p,
n)18
[
F
nuclear reaction by irradiation of enriched
[
18O]H2O.
4.4.12. (RS)-3-Fluoro-2-(2,4,6-
18F]Fluoride was trapped on an anion-exchange resin cartridge
triisopropylphenylsulfonamido)propanamide-N-methylcarbonyl-
Ava-Gln-Trp-Ala-Val-Gly-His-Fa01010-Cpa-NH2 (11b)
0.05 mmol resin bound tetrapeptide, swollen in DMF (1 ml) was
filtered and added to a solution of ((2RS)-3-fluoro-2-(2,4,6-
(Sep-Pak QMA light, Waters). The cartridge was eluted with a
solution of Kryptofix (5 mg), potassium carbonate (1 mg) in water
(500
ml) and MeCN (1 ml). The solvent was removed by heating at
110 8C under vacuum for 10 min with a stream of nitrogen.
Anhydrous MeCN (1 ml) was added and evaporated. This step of
adding acetonitrile (1 ml) was repeated again to give the dried
K[18F]F/K2.2.2 complex.
A solution of 5a (2 mg, 30 mM) in
triisopropylphenylsulfonamido)propanamide)-acetic
(43.0 mg, 0.1 mmol), HBTU (37.9 mg, 0.1 mmol) and diisopropy-
lethylamine (35 l, 0.2 mmol) in 1.0 ml DMF. The mixture was
acid
m