TOLAN ET AL.
5 of 12
1
Complex 2: benzoic anhydride (82.8 mg, 0.082 mmol),
Complex 5: yield: 26 mg (48.5%). H‐NMR (400 MHz,
DMSO‐d6): δ 7.73 (d,1H, Ar‐H), 7.69 (s, 1H, Ar‐H), 7.67
(d, 1H, Ar‐H), 7.44 (d, 1H, Ar‐H), 7.22 (d, 1H, Ar‐H),
7.11 (d, 1H, Ar‐H), 6.51 (br, 6H, NH3), 3.82 (s, 3H, ‐
OCH3), 3.81 (q, 1H, ‐CHCH3), 1.88 (s, 3H, CH3COO),
1.42 (s, 3H, CH3) ppm. 195Pt{1H}‐NMR [107.6 MHz,
DMF (D2O)]: δ 1177 ppm. IR (cm−1): 3206 br (νN‐H);
3067 m, 3007 (νC‐H), 2928 w (νC‐H); 1650 s (νC=O); 1629 s
(νC=C), 1604 s; 1505; 1361; 1263 s, 1220 s (νC‐C); 1207 s
(ν‐OR); 1017 m (δC‐H); 854 s, 812 s (γC‐H). ESI‐MS (negative
ion mode): m/z = 587.04 [M − H]−, 623.02 [M + Cl]−.
Anal. calcd for C16H22Cl2N2O5Pt: C, 32.63; H, 3.73; N,
4.75%; found: C, 32.33; H, 3.80; N, 4.60%.
50 mg (0.091 mmol) of 1 in DMF (5 mL); yellow color;
yield: 25 mg (42.22%). H‐NMR (400 MHz, DMSO‐d6): δ
1
7.90 (d, 1H, Ar‐H), 7.85 (d, 1H, Ar‐H), 7.55–7.37 (m, 4H,
Ar‐H),7.50 (d, 1H, Ar‐H), 7.26 (d, 1H, Ar‐H), 7.08 (d,
1H, Ar‐H), 6.62 (br, 6H, NH3), 3.82 (s, 3H, ‐OCH3), 3.74
(m, 1H, ‐CHCH3), 1.37 (s, 3H,CH3) ppm. 195Pt{1H}‐NMR
[107.6 MHz, DMF (D2O)]: δ 1170 ppm. IR (cm−1): 3510
br (νO‐H), 3203 br (νN‐H); 3063 m, 3011 m (νC‐H), 2924 w
(νC‐H); 1644 s (νC=O); 1603; 1577; 1389; 1316; 1295 s (νC‐
C); 1209 s (ν‐OR); 1025 m (δC‐H); 856 s, 716 s (γC‐H). ESI‐
MS (negative ion mode): m/z = 685.03 [M + Cl]−. Anal.
calcd for C21H24Cl2N2O4Pt.DMF: C, 39.83; H, 4.28; N,
5.80%; found: C, 40.01; H, 4.33; N, 5.90%.
Complex 3: succinic anhydride (36.67 mg, 0.366 mmol),
50 mg (0.091 mmol) of 1 in DMF (3 mL); white color; yield:
35 mg (59.5%). H‐NMR (400 MHz, DMSO‐d6): δ 12.05 (s,
2.11.7 | Synthesis of [(1R,2R‐DACH)
(oxalato) Pt (II)] (oxaliplatin)
1
1H, COOH), 7.72 (d,1H, Ar‐H), 7.70 (s, 1H, Ar‐H), 7.67 (d,
1H, Ar‐H), 7.43 (d, 1H, Ar‐H), 7.23 (d, 1H, Ar‐H), 7.10 (d,
1H, Ar‐H), 6.49 (br, 6H, NH3), 3.89 (s, 3H, ‐OCH3), 3.82
(q, 1H, ‐CHCH3), 2.39–2.49 (m, 4H, COCH2CH2CO), 1.38
(S, 3H, CH3) ppm. 195Pt{1H}‐NMR [107.6 MHz, DMF
(D2O)]: δ 1176. IR (cm−1): 3515 br (νO‐H); 3228, 3189 br
(νN‐H); 3083 m, 3003 m (νC‐H), 2936 w (νC‐H); 1716 s,
1648 s (νC=O); 1625 s (νC=C), 1604 s; 1581; 1373; 1266 s,
1232 s, (νC‐C); 1210 s (ν‐OR); 1028 m (δC‐H); 855 s, 816 s (γC‐
H). ESI‐MS (negative ion mode): m/z = 645.05 [M − H]−,
681.02 [M + Cl]−. Anal. calcd for C18H24Cl2N2O7Pt: C,
33.41; H, 3.71; N, 4.33%; found: C, 33.19; H, 4.01; N, 4.16%.
Complex 4: glutaric anhydride (41.7 mg, 0.366 mmol),
50 mg (0.091 mmol) of 1P in DMF (3 mL); yellow color;
yield: 32 mg (53%). 1H‐NMR (400 MHz, DMSO‐d6): δ
11.98 (s, 1H, COOH), 7.72 (d,1H, Ar‐H), 7.69 (s, 1H, Ar‐
H), 7.67 (d, 1H, Ar‐H), 7.43 (d, 1H, Ar‐H), 7.23 (d, 1H,
Ar‐H), 7.10 (d, 1H, Ar‐H), 6.5 (br, 6H, NH3), 3.82 (s, 3H,
‐OCH3), 3.81 (q, 1H, ‐CHCH3), 2.3 (m, 4H, ‐COOCH2‐),
1.68 (m, 2H, ‐CH2‐), 1.43 (S, 3H, CH3) ppm. 195Pt{1H}‐
NMR [107.6 MHz, DMF (D2O)]: δ 1180 ppm. IR (cm−1):
3513 br (νO‐H), 3197 br (νN‐H); 3075 m, (νC‐H), 2976 w
(νC‐H); 1704 s, 1640 (νC=O); 1628 s (νC=C), 1604 s; 1505;
1371; 1262 s, 1230 s (νC‐C); 1207 s (ν‐OR); 1024 m (δC‐H);
854 s, 811 s (γC‐H). ESI‐MS (negative ion mode):
m/z = 659.07 [M − H]−, 695.05 [M + Cl]−. Anal. calcd
for C19H26Cl2N2O7Pt: C, 34.52; H, 3.93; N, 4.23%; found:
C, 33.95; H, 4.03; N, 4.00%.
Oxaliplatin was synthesized as described in patent
PCT/EP2010/003753[51] with slight modifications.
K2PtCl4 (2 g, 4.8 mmol) was dissolved in 40 mL of water.
To this solution, diaminocyclohexane (DACH; 5.4 g, 4.8
mmol) in 20 mL ethanol was added, and the mixture
was allowed to react for 6 hr at rt. During the reaction,
the product (DACH)PtCl2 precipitated. It was filtered
off, washed with water, methanol and acetone, and dried
under vacuum overnight. The (DACH)PtCl2 was
suspended in 60 mL of water, and 1.43 g Ag2SO4 was
added to this solution and stirred at rt for 20 hr under
light exclusion. This caused the formation of the soluble
(DACH)Pt(H2O)2‐(II)‐sulfate complex accompanied by
the formation of poorly soluble AgCl, which was filtered
off. To the filtrate containing the (DACH)Pt(H2O)2‐(II)‐
sulfate complex, 0.46 g (3.7 mmol) of oxalic acid dehy-
drate and 0.5 M NaOH were added until the pH reached
6. The mixture was stirred at rt for a further 20 hr. The
solution was concentrated in a rotavapor, until the final
product [(1R,2R‐DACH)(oxalato) platinum (II)] precipi-
tated. This was filtered off, washed with water and ace-
tone, and dried under vacuum. Yield: 0.668 g (35%).
Purity was confirmed by IR‐spectrometry and elemental
analysis. IR (cm−1): 3211 m, 3160 m, 3081 s (νN‐H); 2960
w (νC‐H); 2929 m; 2864 m; 1696 s, 1660 s, 1653 m
(νC=O); 1609 m; 1373 s; 1226 s; 1069 s; 808 s, 742 (γC‐H).
Anal. calcd for C8H14N2O4Pt: C, 24.19; H, 3.55; N,
7.05%; found: C, 23.95; H, 3.65; N, 7.01%.
2.11.6 | Synthesis of cis,cis,trans‐[Pt
(NH3)2 Cl2(RCO2)(CH3CO2)] (5)
2.11.8 | Synthesis of dihydroxyoxaliplatin,
[(1R,2R‐DACH)(oxalato) Pt (IV)(OH)2]
The monocarboxylato complex 1 (50 mg) was stirred at rt
in acetic anhydride (5 mL) for 20 hr. The reaction mixture
was lyophilized and washed with diethyl ether (2 × 5 mL)
to yield complex 5 as a white precipitate.
Oxaliplatin (0.5 g, 1.25 mmol) was oxidized with 18 mL of
30% H2O2 and 12 mL of water, as previously reported.[52]
The reaction was stirred for 1 hr at 50°C. The clear