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With 2,4,6-trimethyl-pyridine; silver trifluoromethanesulfonate In dichloromethane for 96h; Under dry N2;
24 A Preparation of a Mitoxantrone Di-Galactoside Conjugate
Method A: Under anhydrous conditions and a dry nitrogen gas atmosphere, mitoxantrone, di-hydrochloride salt (40 mg, 77 mmole) was suspended in dry dichloromethane (20 mL) containing sym-collidine (40 mL) and 3 A molecular sieves (0.3 g). Acetobromogalactose (196 mg, 0.0.48 mmole), silver triflate (123 mg, 0.48 mmole) and additional sym-collidine (120 mL, 0.91 mmole) were added, and the reaction flask stirred in the dark for 4 days. The reaction mixture was applied directly to a column of silicagel G (70-230 mesh, 25 g) slurry-packed in chloroform, and eluted with 9:1 chloroform:methanol (250 mL) and 1:1:0.1:0.1 ethylacetate:methanol:triethylamine:water (300 mL). Fractions containing the first bluish product to elute from the column were combined and evaporated to give the crude peracetylated galactoside (142 mg). [00177] This sample was dried in vacuo overnight, over P2O5. It was dissolved in anhydrous methanol (20 mL)-cooled to 0° C., and 25% (w/v) sodium methoxide/methanol (500 mL, 2.19 mmole) added and allowed to stir at 0° C. for 2 hours and at 25° C. for 14 hours. The reaction mixture was neutralized with washed, dry IRC50 (H+) resin (1 gram) and the resin filtered and washed with fresh methanol (20 mL) chloroform (20mL) and water (20 mL). The combined filtrates were evaporated and dried in vacuo to a blue glass (75 mg) that was to a preparative t.l.c. plate (Silicagel GF: 20×20 cm, 1 mm thickness) and eluted with 1:1 acetone:methanol. The product band (Rf=0.75-0.85) was removed and the product eluted from the silica using 1:1 acetone:methanol. The eluted product fraction was filtered, evaporated and recrystallized from methanol:diethylether (1:10) to give a blue-white powder (9 mg, 20%). 1H-n.m.r. analysis was consistent with the structure as shown.
24 B Preparation of a Mitoxantrone Di-Galactoside Conjugate
Method B: p-Nitrophenyl β-D-galactopyranoside (150 mg, 0.50 mmole) was dissolved in 0.1 M Na2HPO4/0.01 M MgCl2 buffer, pH 7.0 (4.0 mL) and Tris buffer (pH 7.3, 1.0 mL) was added. Mitoxantrone, dihydrochloride salt (50 mg, 0.11 mmole) was added, and the mixture vortex mixed for 3 min. E. coli β-Galactosidase (172 μL of a 500 U/mL solution in water, 86 U total) was added and the solution rotated slowly at 25° C. for 24 hours. T.l.c. analysis (SiO2 plate, irrigant=8:2:1:0.1 isopropanol:water:triethylamine:acetic acid) indicated product formation. Purification is carried out by preparative t.l.c using the similar systems to those employed in Method A above, to give the title compound
54 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone, tetrachloride, bis(dicyclopentadienyl zirconium chelate)
EXAMPLE 54 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone, tetrachloride, bis(dicyclopentadienyl zirconium chelate) A 1.0 g. portion of 1,4-bis[2-(2-hydroxyethylamino)-ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride and 220 mg. of potassium hydroxide are dissolved in 25 ml. of ethanol. A 1.1 g. portion of zirconocene dichloride is added and the mixture is refluxed for 6 hours, cooled and filtered, giving 1.5 g. of the desired product as a blue powder, m.p. >350° C.
58 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone, dichloride, bis(cuprous chloride chelate)
EXAMPLE 58 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone, dichloride, bis(cuprous chloride chelate) A mixture of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride, potassium hydroxide and cuprous chloride in methanol is reacted as described in Example 54, giving 500 mg. of the desired product as a black solid.
With potassium hydroxide; iron(III) chloride In methanol
59 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone, dichloride, bis(ferric chloride chelate)
EXAMPLE 59 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone, dichloride, bis(ferric chloride chelate) A mixture of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride, potassium hydroxide and ferric chloride in methanol is reacted as described in Example 54, giving 500 mg. of the desired product as a blue solid.
With hydrogenchloride; In water; at 52 - 60℃; for 0.5h;pH Ca. 2.8 - 3;Inert atmosphere;
In a 500 ml three-necked flask, add 10 g of mitoxantrone, 80 ml of water, protect with nitrogen, stir, and add about 5.8 ml of 8 M hydrochloric acid dropwise at room temperature. If the pH of the solution exceeds 3 during the reaction,Then use 8M hydrochloric acid solution to adjust the solution pH to about 2.8, and then stir at 52-60 C.Add an appropriate amount of water, stir until completely dissolved, continue stirring for 0.5 hours, then add 50ml of methanol,120ml of absolute ethanol, stored below 0 C, after the precipitation is fully analyzed, suction filtration,Wash twice with a small amount of methanol, suction filter, and place the obtained solid in a flask.Add an appropriate amount of water to heat and stir to dissolve, and then use about 50ml of ethanol,Approximately 160 ml of isopropyl alcohol is used as a crystallization solvent for recrystallization.After the crystals were fully analyzed, the solution was filtered with suction. The solid was washed with a small amount of methanol and filtered with suction.The obtained solid was thinned and dried in an oven at 35 C. for about 5 hours to obtain 6.4 g of a blue-black crystalline solid.
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