Oxaliplatin

Oxaliplatin is a DNA synthesis inhibitor. It causes DNA crosslinking damage, prevents DNA replication and transcription and causes cell death.

A mixture of 50 g of potassium tetrachloroplatinate (0.12 mol), trans-l-1, 2-diamino cyclohexane, 13.74 g (0.12 mol), 25.15 g of silver oxide (0.10 mol) and 13.66 g of oxalic acid dihydrate (0.10 mol) were heated together in 3 liters of DM water at 90-100° C. for 10-12 h. The reaction mixture was cooled to 50° C. filtered through celite. The filtrate was treated with 0.5 g of potassium iodide at 30° C. for 10-12 h in dark. Then again filtered through celite. The filtrate was treated with activated carbon to remove colour. Removal of 2.8 liters of water at 60° C. under vacuum produces oxaliplatin as a white crystalline solid (10 g, 20percent).A mixture of 3, 88 g of fine powdered DACHPtCISilver nitrate (80.6 g) is added to a suspension of 88.9 g of (SP-4-2)-dichloro-[(1R, 2R)-1, 2-cyclohexanediamine-N, N']platinum(II) in 900 ml of water, and the obtained mixture is stirred for 70 hours at room temperature, in the dark. The insoluble portion is filtered off of the reaction mixture, and this portion is washed with 100 ml of water. Tetraethylammonium (2, 5 g) iodide is added to the filtrate mixed with the washing liquid, and the obtained mixture is stirred for 16 hours. Activated charcoal (0, 6 g) is added to the reaction mixture, and the mixture is filtered. Oxalic acid dihydrate (29, 5 g) is added to the obtained filtrate under stirring, and 4 hours later the precipitated oxaliplatin is filtered off. The filter cake is washed with 30 ml of water and 500 ml of ethanol divided into five portions, and the raw product is dried in a vacuum drier. After recrystallisation from water, the separated oxaliplatin is washed with 30 ml of water and 400 ml of ethanol divided into five portions, and dried in a vacuum drier at 70 °C up to a constant weight. Oxaliplatin is obtained in a yield of 50, 2 g (54 percent of the theoretical yield based on the starting (SP-4- 2)-dichloro-[(1R, 2R)-1, 2-cyclohexanediamine-N, N']platinum(II). The obtained oxaliplatin contains less than 0.001 percent by weight of alkali metals, less than 0.0002 percent by weight of silver, and less than 0.001 percent of nitrates (NO3). The content of oxalic acid is lower than 0.01 percent by weight.A mixture 3.88 g of fine powdered DACHPtCICis-diiodo-trans-l-1, 2-diaminocyclohexane (50 g, 0.09 mol) prepared as per example-1 was heated with stirring in 2.5 liters of DM water at 80-90° C. with acetic acid (10.66 g) and silver oxide, 20.88 g (0.09 mol). The reaction was complete in 4 h (by HPLC). The reaction mixture was filtered through celite and the clear filtrate was treated with dipotassium oxalate monohydrate, 14.9 g (0.08 mmol) at 60° C. under stirring.The reaction was continued at this temperature for 5 h and then subsequent work up produced 21.44 g of oxaliplatin (60percent).A mixture of silver oxide (27.14g, 0.1 lmol) and oxalic acid dihydrate (14.75g, 0.1 lmol) and cis-dichloro-trans-l-1, 2-diaminocyclohexane platinum(II), 50g (0. 13mol) prepared as per example-2 in 2.5liters of DM water was heated at 90-100 C. for 1-2 hours. Temperature of the reaction mixture was brought down to 60 C. The reaction was continued for 12h at this temperature. Completion of the reaction was checked by HPLC. The reaction mixture was filtered through celite and the filtrate treated with 0.5g of potassium iodide as in example-3. Carbon treatment followed by water removal produces oxaliplatin (20g, 38percent).A mixture of silver oxide (27.14 g, 0.11 mol) and oxalic acid dihydrate (14.75 g, 0.11 mol) and cis-dichloro-trans-l-1, 2-diaminocyclohexane platinum(II), 50 g (0.13 mol) prepared as per example-2 in 2.5 liters of DM water was heated at 90-100° C. for 1-2 hours. Temperature of the reaction mixture was brought down to 60° C. The reaction was continued for 12 h at this temperature. Completion of the reaction was checked by HPLC. The reaction mixture was filtered through celite and the filtrate treated with 0.5 g of potassium iodide as in example-3. Carbon treatment followed by water removal produces oxaliplatin (20 g, 38percent).Cis-diiodo-trans-l-1, 2-diaminocyclohexane (40g, 0.07 mol) prepared as per example-1 was heated at 90-100° C. in 2 liters of DM water with 16.48g of silver oxide (0.07 mol) and oxalic acid dihydrate, 8.06 g (0.06 mol) for 10-12h. The reaction mixture was filtered through celite and worked up as usual to give 8.3g of oxaliplatin (30percent).Cis-diiodo-trans-l-1, 2-diaminocyclohexane (40 g, 0.07 mol) prepared as per example-1 was heated at 90-100° C. in 2 liters of DM water with 16.48 g of silver oxide (0.07 mol) and oxalic acid dihydrate, 8.06 g (0.06 mol) for 10-12 h. The reaction mixture was filtered through celite and worked up as usual to give 8.3 g of oxaliplatin (30percent).A mixture of 25g of cis-dichloro-trans-l-1, 2-diaminocyclohexane platinum(II) (0.065 mol), 15.25g of silver oxide (0.065 mol) and acetic acid (7.9g, 0.13 mol) was heated at 60-70 C. in 1.25 liters of DM water and progress of the reaction monitored by HPLC. Cis-dichloro compound was consumed in 4-5 h and the cis-diacetato compound was formed in 85-90percent (by HPLC). To the reaction was added dipotassium oxalate mono- hydrate (10.76g, 0.058mol) and heating continued with reaction monitoring. The reaction was complete in 6h. The reaction mixture was cooled to RT and filtered through celite 2-3 times to get a clear filtrate which was treated with potassium iodide to remove dissolved silver ions. Carbon treatment and water recovery produces 17.5g of oxaliplatin (67percent).; EXAMPLE-6 Cis-oxalato-trans-l-1, 2-diaminocyclohexane platinum(II) (Oxaliplatin); A mixture of 25g of cis-dichloro-trans-l-1, 2-diaminocyclohexane platinum(II) (0.065 mol), 15.25g of silver oxide (0.065 mol) and acetic acid (7.9g, 0.13 mol) was heated at 60-70 C. in 1.25 liters of DM water and progress of the reaction monitored by HPLC. Cis-dichloro compound was consumed in 4-5 h and the cis-diacetato compound was formed in 85-95percent (by HPLC). The reaction mixture was filtered through celite 2-3 times to get a clear filtrate. Water was recovered at 50 C under reduced pressure to give cis-diacetato-trans-l-diaminocyclohexane platinum(II) as a white solid (21g, 83percent). The above solid (21g, 0.049 mol) was again dissolved in water 2.1 liters and heated with dipotassium oxalate monohydrate, 8.11 g (0.044 mol) at 60-70 C for 5-6h. Workup of the reaction as in example-5 produced 17. 5g of oxaliplatin (67percent).; EXAMPLE-8 Cis-oxalato-trans-l-1, 2-diaminocyclohexane platinum(II) (Oxaliplatin); Cis-diiodo-trans-l-1, 2-diaminocyclohexane (50g, 0.09 mol) prepared as per example-1 was heated with stirring in 2.5 liters of DM water at 80-90 C. with acetic acid (10.66g) and silver oxide, 20.88g (0.09 mol). The reaction was complete in 4h (by HPLC). The reaction mixture was filtered through celite and the clear filtrate was treated with dipotassium oxalate monohydrate, 14.9g (0.08 mol) at 60 C. under stirring. The reaction was continued at this temperature for 5h and then subsequent work up produced 21.44g of oxaliplatin (60percent).Example 4 (comparative); All procedures were made at room temperature in the absence of light.A mixture 3, 80 g of fine powdered 97percent DACHPtCIA mixture of 50g of potassium tetrachloroplatinate (0.12 mol), trans-l-1, 2-diamino cyclohexane, 13.74g (0.12 mol), 25.15g of silver oxide (0.10 mol) and 13.66g of oxalic acid dihydrate (0.10 mol) were heated together in 3 liters of DM water at 90-100 C for 10-12 h. The reaction mixture was cooled to 50 C. filtered through celite. The filtrate was treated with 0.5g of potassim iodide at 30 C for 10-12h in dark. Then again filtered through celite. The filtrate was treated with activated carbon to remove colour. Removal of ~2.8 liters of water at 60 C. under vacuum produces oxaliplatin as a white crystalline solid (10g, 20 percent).An aqueous solution of tetrabutylammonium oxalate, prepared by dissolving oxalic acid (8.29 g, 0.0658 mol) in a 40percent solution of tetrabutylammonium hydroxide (approx. 88 mL, 0.131 mol) and adjusting the pH to 7, was added to solid dichloro((frans-E-1 , 2- diaminocyclohexane)platinum(ll)) (1Og, 0.0263 mol) followed by 1.1 L of isoamyl alcohol (3-methyl-1-butanol). In this mixture, the molar ratio of platinum(ll) compound:oxalate was 1 :2.5, the ratio of alcohohwater (v/v) 95:5, and the amount of dichloro((fra/7s~.-1 , 2- diaminocyclohexane)platinum(ll) in the solvent reaction mixture was 8.3 g/L.The mixture was stirred for 8h whilst its internal temperature was thermostatically maintained at 85°C. During this time the relatively insoluble dichloro(frans-t-1 , 2-diaminocyclohexane)platinum(ll) was replaced by white oxaliplatin which precipitated out of solution.Thereafter, the mixture was cooled at 4°C, the solids collected by suction filtration and washed with several volumes of dry acetone. The relatively A mixture of 25 g of cis-dichloro-trans-l-1, 2-diaminocyclohexane platinum(II) (0.065 mol), 15.25 g of silver oxide (0.065 mol) and acetic acid (7.9 g, 0.13 mol) was heated at 60-70° C. in 1.25 liters of DM water and progress of the reaction monitored by HPLC.Cis-dichloro compound was consumed in 4-5 h and the cis-diacetato compound was formed in 85-90percent (by HPLC). To the reaction was added dipotassium oxalate mono-hydrate (10.76 g, 0.058 mol) and heating continued with reaction monitoring. The reaction was complete in 6 h. The reaction mixture was cooled to RT and filtered through celite 2-3 times to get a clear filtrate which was treated with potassium iodide to remove dissolved silver ions. Carbon treatment and water recovery produces 17.5 g of oxaliplatin (67percent).; Example-6; Cis-oxalato-trans-l-1, 2-diaminocyclohexane platinum(II) (Oxaliplatin); A mixture of 25 g of cis-dichloro-trans-l-1, 2-diaminocyclohexane platinum(II) (0.065 mol), 15.25 g of silver oxide (0.065 mol) and acetic acid (7.9 g, 0.13 mol) was heated at 60-70° C. in 1.25 liters of DM water and progress of the reaction monitored by HPLC.Cis-dichloro compound was consumed in 4-5 h and the cis-diacetato compound was formed in 85-95percent (by HPLC). The reaction mixture was filtered through celite 2-3 times to get a clear filtrate. Water was recovered at 50° C. under reduced pressure to give cis-diacetato-trans-l-diaminocyclohexane platinum(II) as a white solid (21 g, 83percent). The above solid (21 g, 0.049 mol) was again dissolved in water 2.1 liters and heated with dipotassium oxalate monohydrate, 8.11 g (0.044 mol) at 60-70° C. for 5-6 h. Workup of the reaction as in example-5 produced 17.5 g of oxaliplatin (67percent).

A antitumor agent with activity against colorectal cancer. Cytotoxicity follows the formation of adducts with DNA Used to treat colorectal cancer. Anti-tumor drugs for the treatment of rectal cancer