Efficient method of synthesizing combretastatin A-4 prodrugs
AssigneeOXiGENE, Inc.
InventorsFaye Seyedi, Jonathan Gale, Reem Haider, John Hoare, Amy Baldwin
Life of this patent
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Abstract
Methods of synthesizing a phosphate ester of combretastat-in A-4 and trans-isomers thereof in which combretastatin A-4 is reacted with dibenzylphosphite in the presence of carbon tetrabromide, or with 2,2,2-trichloroethyl phosphorodichloridate, to form a phosphate ester of combretastatin A-4 with protecting groups thereon.
Claims35
A method of synthesizing a phosphate ester of combretastatin A-4 and trans-isomers thereof in which:
- combretastatin A-4 having the following chemical structure
- 14
- is reacted with dibenzylphosphite in the presence of carbon tetrabromide to form said phosphate ester of combretastatin A-4 with protecting groups thereon.
A method of synthesizing a phosphate ester of combretastatin A-4 and trans-isomers thereof in which:
- combretastatin A-4 having the following chemical structure
- 15
- is reacted with 2,2,2-trichloroethyl phosphorodichloridate forming said phosphate ester of combretastatin A-4 with protecting groups thereon.
A method of synthesizing a phosphoric acid of combretastatin A-4 and trans-isomers thereof in which:
- a phosphate ester of combretastatin A-4 with protecting groups thereon having the following chemical structure
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- is reacted with bromotrimethylsilane to form said phosphoric acid of combretastatin A-4.
A method of synthesizing combretastatin A-4 prodrugs and trans-isomers thereof as phosphate salts comprising:
- reacting combretastatin A-4 having the following chemical structure
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- with an activated phosphorylating agent having hydroxyl-protecting groups thereon wherein said phosphorylating agent is either dibenzylphosphite/carbon tetrabromide or 2,2,2-trichloroethyl phosphorodichloridate, to form a phosphate ester of combretastatin with protecting groups thereon;
- deprotecting said hydroxyl-protecting groups with a deprotecting agent to yield a phosphoric acid of combretastatin A-4;
- and
- reacting said phosphoric acid with reactive agent to form a phosphate salt of combretastatin A-4.
The method of synthesizing combretastatin A-4 prodrugs and trans-isomers thereof comprising:
- dissolving combretastatin A-4 in acetonitrile to form a first solution;
- admixing triethylamine and carbon tetrabromide in said first solution to form a second solution;
- dissolving dibenzylphosphite in acetonitrile to said second solution to form a third solution;
- admixing said third solution to said second solution to form a fourth solution;
- and
- admixing bromotrimethylsilane to said fourth solution and treating with sodium methoxide in methanol to form a fifth solution of phosphate salt of combretastatin A-4.
In a method of preparing combretastatin A-4 prodrugs and trans-isomers thereof by forming a reaction mixture of combretastatin A-4 with a phosphorylating agent to form a phosphate ester with protecting groups thereon, cleaving said protective groups with a deprotecting agent to form a phosphoric acid derivative of combretastatin A-4 and treating said phosphoric acid with a reactive agent to form a phosphate salt of combretastatin A-4, the improvement of said method wherein:
- said phosphorylating agent is either dibenzylphosphite/carbon tetrabromide or 2,2,2-trichloroethyl phosphorodichloridate;
- the deprotecting agent is bromotrimethylsilane when said phosphorylating agent is dibenzylphosphite/carbon tetrabromide and Zn/Cu amalgam when said phosphorylating agent is said 2,2,2-trichloroethyl phosphorodichloridate;
- and
- said reactive agent forms X-phosphate salt of combretastatin A-4, wherein X is selected from the group consisting of sodium, cesium, calcium, lithium, magnesium, manganese, potassium, zinc, imidazole, morpholine, piperazine, piperidine, pyrazole, pyridine, adenosine, cinchonine, glucosamine, quinine, quinidine, tetracycline and verapamil.
In a method of preparing combretastatin A-4 prodrugs and trans-isomers thereof by treating combretastatin A-4 with a phosphorylating agent to form a phosphate ester of combretastatin A-4 with protecting groups thereon, cleaving said protective groups with a deprotecting agent to form phosphoric acid derivative of combretastatin A-4 and treating said phosphoric acid with an agent to form a salt of combretastatin A-4 phosphate, the improvement of said method wherein:
- said combretastatin A-4 is dissolved in acetonitrile, triethylamine and carbon tetrabromide to form a first solution;
- adding to said first solution the phosphorylating agent dibenzylphosphite to form a second solution comprising said phosphate ester;
- said second solution is treated with the deprotecting agent bromotrimethylsilane to form a phosphoric acid solution;
- and
- said phosphoric acid solution is treated with a reactive agent to form X-phosphate salt of combretastatin A-4, wherein X is selected from the group consisting of sodium, cesium, calcium, lithium, magnesium, manganese, potassium, zinc, imidazole, morpholine, piperazine, piperidine, pyrazole, pyridine, adenosine, cinchonine, glucosamine, quinine, quinidine, tetracycline and verapamil.
A method of synthesizing a combretastatin A-4 prodrug, comprising:
- (a) obtaining a phosphonium salt of 3,4,5-trimethoxybenzyl bromide by mixing a brominating reagent and 3,4,5-trimethoxybenzyl alcohol in toluene to obtain said bromide, and adding triphenylphosphine thereto;
- (b) obtaining tritylated isovanillin by mixing an amine base, isovanillin, and trityl chloride in an ether solvent, and after quenching, adding heptane and ethyl acetate;
- (c) mixing a suspension of said phosphonium salt in tetrahydrofuran, an alkyl lithium reagent, and a slurry of said tritylated isovanillin, to obtain a cis/trans stilbene;
- (d) reacting said cis/trans stilbene with an acid to obtain a product consisting essentially of cis combretastatin A-4;
- and
- (e) synthesizing a combretastatin A-4 prodrug by reacting said cis combretastatin A-4 with an activated phosphorylating agent having hydroxyl-protecting groups thereon wherein said phosphorylating agent is either dibenzylphosphite/carbon tetrabromide or 2,2,2-trichloroethyl phosphorodichloridate, to form a phosphate ester of combretastatin with protecting groups thereon;
- deprotecting said hydroxyl-protecting groups with a deprotecting agent to yield a phosphoric acid of combretastatin A-4;
- and reacting said phosphoric acid with reactive agent to form a phosphate salt of combretastatin A-4.
A method of synthesizing combretastatin A-4 prodrugs as phosphate salts comprising reacting combretastatin A-4 with a phosphite having the formula HPOY2 where Y is benzyl, tert butyl, butyl, ethyl, isopropyl, methyl, phenyl or propyl, in the presence of carbon tetrabromide, to form a phosphate ester of combretastatin with protecting groups thereon;
- deprotecting said hydroxyl-protecting groups with a deprotecting agent to yield a phosphoric acid of combretastatin A-4;
- and reacting said phosphoric acid with reactive agent to form a phosphate salt of combretastatin A-4.
Dependencies are inferred from the claim text.