Conclusiones parciales

N1,N3-Bis(2,3-diacetoxy)propylcarbamonyl)-5-(N-(2,3-

diacetoxy)propylacetamido)-2,4,6-triiodoisophthalamide (110) [py])

Iohexol 55 (10.0 g, 12.0 mmol) and acetic anhydride (9.00 mL, 96.0 mmol) were combined in pyridine (150 mL), warmed to 50 oC and left stirred for 48 h. Once the reaction had cooled water (100 mL) was added, the product was extracted with EtOAc (4 x 100 mL), washed with water (2 x 100 mL), 2M aq. HCl (2 x 100 mL) and sat. aq. NaHCO3 (100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude acetate 110 [py] (10.3 g) as an off-white solid. The crude product was purified by column chromatography (EtOAc) to furnish the title compound 110 [py] (7.90 g, 7.32 mmol, 61%) as a white solid. Rf (EtOAc)

154 0.57; m.p. 92 – 93 oC; vmax/cm-12996 (NH), 1731 (C=O), 1650 (N-C=O), 1543 (NH- C=O); δH (400 MHz, CDCl3) 6.85 (1H, m, NH), 6.51 (1H, m, NH), 5.40 – 5.19 (3H, m, CH2-CH-CH2), 4.49 – 4.33 (4H, m, OCH2-CH and NHCH2-CH), 4.33 – 4.16 (4H, m, OCH2-CH and NHCH2-CH), 3.98 - 3.87 (2H, m, NCH2-CH), 3.77 - 3.60 (2H, m, OCH2-CH), 2.10 (12H, s, CO2-CH3), 2.09 (3H, s, N-CO-CH3), 1.91 (6H, s, CO2- CH3); δC (100 MHz, CDCl3) 170.7, 170.6, 170.5, 170.4, 170.3, 170.2, 169.6, 169.3, 169.1 (C=O), 151.3, 151.1, 150.8 (ArC), 99.1 (CO-C-CI), 89.7, 89.6 (CN-CI), 70.2, 70.0, 69.9 (CH2-CH-CH2), 63.3, 63.0 (O-CH2-CH), 46.2 (N-CH2-CH), 40.1, 39.9 (NH-CH2-CH), 22.8 (N-CO-CH3), 21.4, 21.2, 21.1, 21.0, 20.8, 20.6 (CO2-CH3); m/z (ES+) 1095.9 [M+Na]+, found: 1095.9341 [M+Na]+ (C31H38I3N3NaO15 requires 1095.9335); found C: 34.3, H: 3.5, N: 3.9, C31H38I3N3O15 requires C: 34.7, H: 3.6, N: 3.9.

N1,N3-Bis(2,3-diacetoxy)propylcarbamonyl)-5-(N-(2,3-

diacetoxy)propylacetamido)-2,4,6-triiodoisophthalamide (110 [I2])

Iohexol 55 (7.50 g, 9.13 mmol) and iodine (0.23 g, 0.91 mmol) were combined in acetic anhydride (6.90 mL, 73.0 mmol) and left to stir at r.t. for 5 days. Water (10.0 mL) and sat. aq. Na2SO3 (20.0 mL) were then added and the product subsequently extracted with EtOAc (3 x 50.0 mL). The combined organic layers were washed with sat. aq. Na2S2O3 (100 mL) and then sat. aq. NaHCO3 (100 mL), dried (MgSO4) and

155 concentrated in vacuo to yield crude acetate 110 [I2] (9.57 g) as a yellow solid. This was purified by column chromatography (EtOAc) to furnish the title compound 110 [I2] (3.90 g, 3.65 mmol, 40%) as a white solid. Rf (EtOAc) 0.39; m.p. 87-88 oC;

vmax/cm-1 3280 (NH), 2910 (CH), 1729 and 1655 (C=O), 1541 (NH-C=O); δH (400 MHz, CDCl3) 6.86 – 6.76 (1H, m, NH), 6.51 – 6.36 (1H, m, NH), 5.33 - 5.16 (3H, m, CH2-CH-CH2), 4.38 – 4.26 (3H, m, OCH2-CH), 4.23 – 3.91 (3H, m, OCH2-CH), 3.87 – 3.68 (2H, m, NHCH2-CH), 3.64 – 3.44 (4H, m, NHCH2-CH and NCH2CH), 2.02 – 2.00 (12H, m, CO2-CH3), 1.97 (3H, s, N-CO-CH3), 1.89 – 1.80 (6H, m, CO2- CH3); δC (100 MHz, CDCl3) 170.8, 170.7, 170.6, 170.5, 170.3, 170.2, 169.7, 169.4, 169.2 (C=O), 151.1, 150.8, 150.7 (Ar-C), 99.1 (CO-C-CI), 89.8, 89.6 (CN-CI), 70.1, 69.9, 68.4 (CH2-CH-CH2), 63.7, 63.0 (OCH2-CH), 46.2, 46.1 (OCH2-CH and N- CH2-CH), 40.1, 39.9 (NH-CH2-CH), 22.9 (NCO-CH3), 21.2, 21.1, 21.0, 20.8, 20.6, 20.5 (CO2-CH3); m/z (ES+) 1095.7 [M+Na]+, found: 1095.9336 [M+Na]+ (C31H38I3N3NaO15 requires 1095.9335); found C: 34.3, H: 3.5, N: 3.9, C31H38I3N3O15 requires C: 34.7, H: 3.6, N: 3.9.

N1,N3-Bis(2,3-dipentanoyloxy)propyl)-5-(N-(2,3-

dipentanoyloxy)propylacetamido)-2,4,6-triiodoisophthalamide (111)

Iohexol 55 (10.0 g, 12.2 mmol) and iodine (0.31 g, 1.22 mmol) were combined in valeric anhydride (19.2 mL, 97.4 mmol) and left to stir at r.t. for 6 days. Water (20.0

156 mL) was added and the product subsequently extracted with EtOAc (3 x 30.0 mL). The combined organic phase was washed with sat. aq. Na2S2O3 (50.0 mL), dried (MgSO4) and concentrated in vacuo to yield crude product 111 (23.5 g). This was purified by column chromatography (1:1 petrol/ EtOAc) to give the title compound

111 (2.20 g, 1.71 mmol, 14%) as a yellow oil. Rf (1:1 petrol/ EtOAc) 0.73; vmax/cm-1: 3283 (N-H), 2957 (CH), 1736 (C=O), 1542 (NH-C=O); δH (400 MHz, CDCl3) 7.35 – 7.12 (1H, m, NH), 6.93 – 6.83 (1H, m, NH), 5.22 – 5.05 (3H, m, 3 x CH2-CH-CH2), 4.34 – 4.28 (2H, m, OCH2-CH), 4.25 – 4.18 (1H, m, NCH2-CH), 4.17 – 4.04 (4H, m, OCH2-CH), 3.88 – 3.76 (1H, m, NCH2-CH), 3.76 – 3.32 (4H, m, NH-CH2-CH), 2.25 – 1.93 (12H, m, CO2-CH2), 1.73 – 1.66 (3H, m, N-CO-CH3), 1.51 – 1.37 (12H, m, 6 x CH2-CH2-CH2), 1.29 – 1.11 (12H, m, 6 x CH2-CH3), 0.77 (18H, tt, J 10.0, 5.0, 6 x CH2-CH3); δC (100 MHz, CDCl3) 174.2, 174.1, 173.3, 173.1, 173.0, 172.7, 169.7, 169.5, 169.1 (9 x C=O), 151.0, 150.5, 146.1 (3 x ArC), 99.3 (CCO-CI-CCO), 89.9, 89.6 (CN-CI-CCO), 69.8, 69.7, 68.0 (3 x CH2-CH-CH2), 63.6, 63.0, 62.8 (OCH2-CH), 46.3, 46.2 (NH-CH2-CH), 39.9 (N-CH2-CH), 33.9, 33.8, 33.7, 33.5, 33.2, 33.1 (6 x CO2-CH2), 26.9, 26.8, 26.7, 26.5, 26.4, 26.2 (6 x CH2-CH2-CH2), 22.8 (N-CO-CH3), 22.4, 22.3, 22.1, 22.0, 21.9, 21.8 (6 x CH2-CH3), 13.8, 13.7, 13.6, 13.5, 13.4, 13.3 (6 x CH2-CH3); m/z (ES+) 1348.0 [M+Na]+, found: 1348.2160 [M+Na]+ (C49H74I3N3NaO15 requires 1348.2152).

157

N1,N3-Bis((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(N-((2,2-dimethyl-1,3-

dioxolan-4-yl)methyl)acetamido)-2,4,6-triiodoisophthalamide (116 [CuSO4])

Iohexol 55 (7.50 g, 9.13 mmol), anhydrous CuSO4 (2.91 g, 18.3 mmol) and TsOH (0.35 g, 1.83 mmol) were combined in acetone (100 mL) and heated to 50 oC for 3 days. The solution was dried (MgSO4) and concentrated in vacuo to give the crude product 116 [CuSO4] (8.20 g) as a brown solid. This was purified by column chromatography (EtOAc) to give the title compound 116 [CuSO4] (5.50 g, 5.84 mmol, 64%) as a white solid. Rf (EtOAc) 0.66; m.p. 264-265 oC; vmax/cm-1 3268 (NH), 2983 (CH), 1686 (C=O), 1550 (NH-C=O); δH (400 MHz, CDCl3) 6.63 – 5.99 (2H, m, NH), 4.47 – 4.26 (3H, m, CH), 4.20 – 4.01 (4H, m, NCH2-CH, OCH2-CH), 3.80 – 3.60 (5H, m, NHCH2-CH, OCH2-CH), 3.46 – 3.30 (2H, m, NHCH2-CH), 3.22 – 3.06 (1H, m, NCH2-CH), 1.82 (3H, s, NCO-CH3), 1.38 (6H, s, CO2(CH3)2), 1.28 (9H, s, CO2(CH3)2), 1.22 (3H, s, CO2(CH3)2); δC (100 MHz, CDCl3) 170.3 (N-C=O), 169.5, 169.4 (NH-C=O), 151.5, 151.2 (Ar-C-C=O), 148.9 (Ar-C-N), 109.7, 109.4, 109.3 (CO2(CH3)2), 98.5 (CCO-CI), 89.8, 89.5 (CN-CI), 74.3, 73.8 (CH2-CH-CH2), 68.9, 67.1 (OCH2-CH), 52.7 (NCH2-CH), 42.4, 42.2 (NH-CH2-CH), 27.1, 26.9, 25.5, 25.3 (CO2(CH3)2), 22.9 (N-CO-CH3); m/z (ES+) 963.8 [M+Na]+, found 963.9641 [M+Na]+ (C28H38I3N3NaO9 requires 963.9640); found C: 35.5, H: 4.0, N: 4.2, C28H38I3N3O9 requires C: 35.7, H: 4.1, N: 4.5.

158

N1,N3-Bis((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(N-((2,2-dimethyl-1,3- dioxolan-4-yl)methyl)acetamido)-2,4,6-triiodoisophthalamide (116 [TsOH])

Iohexol 55 (7.50 g, 9.13 mmol) and TsOH (0.17 g, 0.91 mmol) were combined in DMF (75.0 mL), 2,2-dimethoxypropane (4.50 mL, 36.5 mmol) was added and the reaction left to stir at r.t. for 24 h. Water (50.0 mL) was added and the product extracted in EtOAc (3 x 100 mL). The combined organic layers were washed 2M aq. HCl (100 mL) and NaHCO3 (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude product 116 [TsOH] (10.1 g) as a yellow solid. This was purified by column chromatography (EtOAc) to yield the title compound 116 [TsOH] (7.31 g, 7.76 mmol, 85%) as a white solid. Rf (EtOAc) 0.58; m.p. 271-273 oC; vmax/cm-1 3265 (NH), 2983 (CH), 1638 (C=O), 1546 (NH-C); δH (400 MHz, CDCl3) 6.71 – 6.34 (2H, m, NH), 4.39 – 4.18 (3H, m, CH2-CH-CH2), 4.09 – 4.02 (1H, m, NCH2-CH), 4.01 - 3.93 (2H, m, O-CH2-CH), 3.76 – 3.49 (6H, m, NHCH2-CH, OCH2-CH), 3.39 – 3.21 (2H, m, NHCH2-CH), 3.16 - 2.98 (1H, m, NCH2-CH), 1.74 (3H, s, N-CO- CH3), 1.30 (6H, s, CO2(CH3)2), 1.21 (9H, s, CO2(CH3)2), 1.13 (3H, s, CO2(CH3)2); δC (100 MHz, CDCl3) 170.3 (N-C=O), 169.4 (NH-C=O), 151.5, 151.2 (Ar-C-C=O), 148.8 (Ar-C-N), 109.7, 109.3 (CO2(CH3)2), 98.4 (CO-CI), 89.9, 89.5 (CN-CI), 74.2, 73.8 (CH2-CH-CH2), 69.0, 67.2 (OCH2-CH), 52.7 (NCH2-CH), 42.4 (NHCH2-CH), 27.1, 26.9, 25.5, 25.3 (CO2(CH3)2), 23.0 (N-CO-CH3); m/z (ES+) 963.6 [M+Na]+,

159 found: 963.9644 [M+Na]+ (C28H38I3N3NaO9 requires 963.9640); found C: 35.3, H: 4.0, N: 4.3, C28H38I3N3O9 requires C: 35.7, H: 4.1, N: 4.5.

1,1-Dimethoxycyclopentane (123)

Cyclopentanone (15.0 g, 0.18 mol), trimethyl orthoformate (39.1 mL, 0.36 mol) and zinc chloride (2.40 g, 0.02 mol) were combined in anhydrous methanol (75.0 mL) and heated to reflux for 4 days. The resulting crude mixture was distilled under vacuum to yield the title compound 123 (29-32 oC, 9.45g, 0.07 mol, 41%) as a colourless liquid. Rf (9:1 petrol/ EtOAc) 0.45; b.p. 29-32 oC (8 mbar), lit.255 b.p. 50

o

C (27 mbar); vmax/cm-1 2950 (CH), 1450 (OCH3); δH (400 MHz, CDCl3) 3.13 (6H, s, OCH3), 1.72 – 1.65 (4H, m, C(OCH3)-CH2), 1.62 – 1.55 (4H, m, CH2-CH2); δC (100 MHz, CDCl3) 111.3 (C(OCH3)2), 49.2 (2 x OCH3), 34.3 (C(OCH3)-CH2), 23.3 (CH2-CH2); m/z (ES+) 153.1 [M+Na]+, found: 153.088 [M+Na]+ (C7H14NaO2 requires 153.0888).

N1,N3-Bis(1,4-dioxaspiro[4.4]nonan-2-ylmethyl)-5-(N-(1,4-dioxaspiro[4.4]nonan- 2-ylmethyl)acetamido)-2,4,6-triiodoisophthalamide (124)

160 Iohexol 55 (7.50 g, 9.13 mmol), dimethyl cyclopentanone ketal (4.75 g, 36.5 mmol) and TsOH (0.35 g, 1.83 mmol) were combined in DMF (30.0 mL) and stirred at r.t. for 30 h. Water (50.0 mL) was added and the product extracted with EtOAc (3 x 50.0 mL). The combined organic layers were washed with 2M aq. HCl (100 mL) and sat. aq. NaHCO3 (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude product 124 (6.22 g) as an off-white solid. This was purified by flash column chromatography (1:2 petrol/ EtOAc) to yield the title compound 124 (3.50 g, 3.47 mmol, 38%) as a white solid. Rf (1:2 petrol / EtOAc) 0.36; m.p. 266-267 oC;

vmax/cm-1 3250 (NH), 2934 (CH), 1638 (C=O), 1553 (NH-C=O); δH (400 MHz, CDCl3) 6.67 – 6.03 (2H, m, 2 x NH), 4.43 – 4.20 (3H, m, 3 x CH2-CH-CH2), 4.17 – 4.06 (1H, m, NCH2-CH), 4.05 - 3.93 (3H, m, OCH2-CH), 3.84 – 3.55 (5H, m, NHCH2-CH, OCH2-CH), 3.34 – 3.30 (2H, m, NHCH2-CH), 3.24 – 3.08 (1H, m, NCH2-CH), 1.82 (3H, s, N-CO-CH3), 1.78 – 1.66 (12H, m, O2C-CH2-CH2), 1.62 – 1.50 (12H, m, CH2-CH2); δC (100 MHz, CDCl3) 170.3 (N-C=O), 169.5, 169.3 (NH- C=O) 151.5, 151.2 (Ar-C-C=O), 148.8 (Ar-C-N), 119.6 (O2C-(CH2)2), 119.2 (O2C- (CH2)2), 100.6 (CO-CI-CO), 98.5, 98.4 (CN-CI), 73.8, 73.4 (CH2-CH-CH2), 68.8, 67.1 (OCH2-CH), 52.6 (NCH2-CH), 42.5, 42.4 (NH-CH2-CH), 36.7, 36.6, 36.2, 36.0 (O2C-CH2), 23.7, 23.6, 23.3, 23.3 (CH2-CH2), 23.0 (N-CO-CH3); m/z (ES+) 1041.8 [M+Na]+, found: 1042.0104 [M+Na]+ (C34H44I3N3NaO9 requires 1042.0109); found C: 40.1, H: 4.4, N: 4.3, C34H44I3N3O9 requires C: 40.1, H: 4.4, N: 4.1.

161

N1,N3-Bis(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-5-(N-(1,4-dioxaspiro[4.5]decan- 2-ylmethyl)acetamido)-2,4,6-triiodoisophthalamide (119)

Iohexol 55 (7.00 g, 8.52 mmol), anhydrous CuSO4 (2.72 g, 17.05 mmol) and TsOH (0.32 g, 1.70 mmol) were combined in cyclohexanone (30.0 mL), stirred and heated to 85 oC for 6 days. The solution was diluted with EtOAc (30.0 mL), filtered, dried (MgSO4) and concentrated in vacuo to give crude product 119 (12.3 g) as brown oil. This was purified by column chromatography (19:1 petrol/ EtOAc) to furnish the title compound 119 (1.03 g, 1.02 mmol, 12%) as an off-white solid. Rf (19:1 petrol/

EtOAc) 0.52; m.p. 157 – 158 oC; vmax/cm-1 3274 (NH), 2930 (CH), 1648 (C=O), 1541 (NH-C=O); δH (400 MHz, CDCl3) 6.50 – 6.30 (2H, m, NH), 4.52 – 4.32 (3H, m, CH2-CH-CH2), 4.25 – 3.99 (3H, m, OCH2-CH and NCH2-CH), 3.84 – 3.71 (6H, m, OCH2-CH and NHCH2-CH), 3.51 – 3.37 (2H, m, NHCH2-CH), 3.21 (1H, t, J 12.0, NCH2-CH), 1.93 – 1.74 (3H, m, N-CO-CH3), 1.67 – 1.46 (24H, m, CH2 of cyclohexane ring), 1.38 (6H, s, CH2 of cyclohexane ring); δC (100 MHz, CDCl3) 173.5 (N-C=O), 169.4, 169.2 (NH-C=O), 151.5, 151.2 (Ar-C-C=O), 148.9 (Ar-C-N), 110.4, 110.1, 109.1 (O2C-(CH2)2), 100.9 (CO-CI-CO), 98.5, 98.4 (CO-CI-CN), 73.6, 73.4 (CH2-CH-CH2), 68.4, 66.7 (OCH2-CH), 52.7 (NCH2-CH), 42.7, 42.5 (NHCH2- CH), 36.7, 36.6, 35.0, 34.9, 34.7, 34.4, 25.1, 24.0, 23.8 (CH2 of cyclohexane ring), 23.0 (N-CO-CH3); m/z (ES+) 1084.1 [M+Na]+, found 1084.0573 [M+Na]+ (C37H50I3N3NaO9 requires 1084.0579).

162

1,1-Dimethoxycyclohexane (121)

Cyclohexanone (10.0 g, 102 mmol), trimethyl orthoformate (22.3 mL, 204 mmol) and zinc chloride (1.39 g, 10.2 mmol) were combined in anhydrous methanol (50.0 mL) and heated to reflux for 4 days. The resulting crude mixture was distilled under vacuum to give the title compound 121 (44-46 oC, 10.7 g, 74.5 mmol, 73%) as a colourless liquid. Rf (4:1 Petrol/ EtOAc) 0.63, b.p. 44-46 oC (8 mbar), Lit.256 b.p. 66

o

C (26 mbar); vmax/cm-1: 2936 (CH), 1445 (COCH3); δH (400 MHz, CDCl3) 3.10 (6H, s, 2 x C-O-CH3), 1.60 – 1.52 (4H, m, C(OCH3)2-CH2), 1.43 (4H, dt, J 11.5, 6.0, C(OCH3)2-CH2-CH2), 1.35 – 1.30 (2H, m, C-CH2-CH2-CH2); δC (100 MHz, CDCl3) 99.6 (C(OCH3)2), 47.3 (2 x C-O-CH3), 32.7 (C(OCH3)2-CH2), 25.6 (C-CH2-CH2- CH2), 22.8 (C(OCH3)2-CH2-CH2); m/z (ES+) 167.1 [M+Na]+, found: 167.1043 [M+Na]+ (requires C8H16NaO2 167.1048).

N1,N3-Bis(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-5-(N-(1,4-dioxaspiro[4.5]decan- 2-ylmethyl)acetamido)-2,4,6-triiodoisophthalamide (119)

Iohexol 55 (7.50 g, 9.13 mmol) and TsOH (1.74 g, 1.83 mmol) and cyclohexanone dimethyl ketal (5.60 mL, 36.5 mmol) were combined in DMF (30.0 mL) and stirred at r.t. for 24 h. Water (50.0 mL) was added and the product extracted in EtOAc (3 x

163 100 mL). The combined organic layers were washed with 2M aq. HCl (100 mL) and sat. aq. NaHCO3 (100 mL), dried (MgSO4) and concentrated in vacuo to give crude product 119 (9.29 g) as a white solid. This was purified by column chromatography (EtOAc) to yield the title compound 119 (6.71g, 6.30 mmol, 69%) as a white solid. Rf (EtOAc) 0.72; m.p. 154-156 oC; vmax/cm-1 3283 (NH), 2931 (CH), 1743 (C=O), 1542 (NH-C=O); δH (400 MHz, CDCl3) 6.46 - 5.76 (2H, m, NH), 4.45 – 4.37 (1H, m, CH2-CH-CH2), 4.37 – 4.29 (2H, m, CH2-CH-CH2), 4.20 – 4.09 (1H, m, NCH2- CH), 4.08 – 3.92 (3H, m, OCH2-CH), 3.80 – 3.63 (5H, m, OCH2-CH and NH-CH2- CH), 3.45 – 3.30 (2H, m, NHCH2-CH), 3.22 – 3.09 (1H, m, NCH2-CH), 1.85 – 1.81 (3H, m, N-CO-CH3), 1.61 – 1.40 (24H, m, CH2 of cyclohexane ring), 1.33 (6H, bs, CH2 of cyclohexane ring); δC (100 MHz, CDCl3) 171.4 (N-C=O), 169.3, 169.1 (NH- C=O), 151.4, 151.2 (Ar-C-C=O), 148.9 (Ar-C-N), 110.4, 110.2, 109.8 (O2C-(CH2)2), 100.4 (CO-CI-CO), 98.5, 98.4 (CO-CI-CN), 73.7, 73.6 (CH2-CH-CH2), 68.4, 66.9, 66.7 (OCH2-CH), 52.7 (NCH2-CH), 42.7, 42.0 (NHCH2-CH), 36.9, 36.8, 36.7, 36.6, 36.2, 35.4, 35.0, 34.9, 34.7, 27.0, 25.0, 24.0, 23.9, 23.8, 23.0 (CH2 of cyclohexane ring), 23.0 (N-CO-CH3); m/z (ES+) 1083.8 [M+Na]+, found: 1084.0583 [M+Na]+ (C37H50I3N3NaO9 requires 1084.0579); found C: 42.1, H: 4.8, N: 3.8, C37H50I3N3O9 requires C: 41.9, H: 4.8, N: 4.0.

164