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US 11,884,688 B2Granted
Borylated amino acid compositions comprising BTS and BTS(OMe) for use in boron neutron capture therapy and methods thereof
AssigneeTAE Life Sciences, LLC
InventorsMichael Y. Torgov, Tioga J. Martin
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Abstract
Borylated Amino Acid compositions comprising tyrosine derivatives BTS and BTS(OMe) and novel methods of making BTS and BTS(OMe) are disclosed herein. Consequently, the BTS and/or BTS(OMe) can be scaled up to commercial scale and administered to patients as a Neutron Capture Agent and provide a method of treating cancer, immunological disorders, and other disease by utilizing a Neutron Capture Therapy modality.
Claims3
A composition produced by a method of conversion of L-tyrosine to a target material, comprising:
- (i) Conversion of N-Boc-Tyr(3-Br, 4-MeO)—OMe (4) to the aryl boronic acid N-Boc-Tyr(3-B(OH)2-4-MeO)—OMe (5) which comprises a palladation followed by a metal exchange to the required boronic acid comprising the following:
- a. a solvent mixture comprising methanol and dimethoxyethane;
- b. a ligand substituent comprising potassium acetate;
- c. a reagent of type aryl bromide comprising N-Boc-Tyr(3-Br, 4-MeO)—OMe (4);
- d. a boronating agent comprising tetrahydroxyborane;
- e. a palladium catalyst comprising chloro((tir-tert-butylphosphine)-2-(2-aminobiphenyl))palladium (II);
- and
- f. a purification comprising (i) quenching with water, (ii) a solvent exchange comprising ethyl acetate, and (iii) a flash chromatography on silica with approximately 25% ethyl acetate in hexanes;
- (ii) Following the introduction of boronic acid, the synthesis diverges to form the compounds BTS (7) and BTS(OMe) (9);
- (iii) Conversion N-Boc-Tyr(3-B(OH)2-4-MeO)—OH (8) to reveal the structure of BTS(OMe) (9) comprising:
- a. a solution comprising 4 M hydrochloric acid in dioxane;
- b. a reagent of type tertbutylcarbamate comprising, N-Boc-Tyr(3-B(OH)2, 4-OMe)-OH;
- and
- c. a purification comprising a reverse phase chromatography with a range of 0% to 20% acetonitrile in water;
- (iv) Conversion of N-Boc-Tyr(3-B(OH)2, 4-MeO)—OMe (5) to BTS (7) which comprises a simultaneous methyl ether cleavage and carbamate removal subsequently, followed by saponification comprising:
- a. a solution comprising dichloromethane;
- b. an added reagent comprising N-Boc-Tyr(3-B(OH)2, 4-MeO)—OMe (5);
- c. a reactant comprising boron tribromide;
- d. a solvent exchange from dichloromethane to water;
- e. a reactant comprising LiOH;
- and
- f. a purification comprising a reverse phase chromatography with a range of 0% to 20% acetonitrile in water.
19 more elements
Dependencies are inferred from the claim text.