US 11,884,688 B2
Borylated amino acid compositions comprising BTS and BTS(OMe) for use in boron neutron capture therapy and methods thereof
Michael Y. Torgov, Redondo Beach, CA (US); and Tioga J. Martin, Los Angeles, CA (US)
Assigned to TAE Life Sciences, LLC, Irvine, CA (US)
Filed by TAE Life Sciences, Foot Hill Ranch, CA (US)
Filed on Aug. 1, 2022, as Appl. No. 17/803,487.
Claims priority of provisional application 63/259,662, filed on Jul. 30, 2021.
Prior Publication US 2023/0271984 A1, Aug. 31, 2023
Int. Cl. C07F 5/02 (2006.01)
CPC C07F 5/025 (2013.01) 3 Claims
 
1. 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.