SYNTHESIS OF CELENTERAZINE Russian patent published in 2024 - IPC C07D487/04 A61F13/42 B01J20/22 C07B51/00 

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing celenterazine, involving binding 4-(5-amino-6-benzylpyrazin-2-yl)phenol with 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1,1-diethoxypropan-2-one to obtain celenterazine. 4-(5-amino-6-benzylpyrazin-2-yl)phenol is obtained (a) by treating 3-benzylpyrazin-2-amine with N-bromosuccinimide to obtain 3-benzyl-5-bromopyrazin-2-amine and (b) by reacting 3-benzyl-5-bromopyrazin-2-amine in two successive steps to obtain 4-(5-amino-6-benzylpyrazin-2-yl)phenol; where (b) provides a first step for reacting 3-benzyl-5-bromopyrazin-2-amine with 4-methoxyphenylboronic acid in the presence of a palladium catalyst - tetrakis(triphenylphosphine)palladium (0) to obtain 3-benzyl-5-(4-methoxyphenyl)pyrazine-2-amine, where the palladium catalyst tetrakis (triphenylphosphine) palladium (0) is present in amount of 5 to 10 percent by weight with respect to 3-benzyl-5-bromopyrazine-2-amine, and the second step is deprotection of 3-benzyl-5-(4-methoxyphenyl)pyrazine-2-amine to obtain 4-(5-amino-6-benzylpyrazin-2-yl)phenol; (c) further provides for coupling 4-(5-amino-6-benzylpyrazin-2-yl)phenol with 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1,1-diethoxypropan-2-one from 16 hours to 28 hours, wherein the mixture of solvents contains dioxane, water and HCl; or for 24 hours to 36 hours, wherein the mixture of solvents contains dioxane, methanol and isopropyl alcohol, and mixing the reaction mixture with activated carbon and silicon dioxide. 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1,1-diethoxypropan-2-one is synthesized i) by reacting 4-hydroxybenzaldehyde with tert-butyldimethylsilyl chloride to obtain 4-((tert-butyldimethylsilyl)oxy)benzaldehyde; ii) by reacting 4-((tert-butyldimethylsilyl)oxy)benzaldehyde with sodium borohydride to obtain (4-((tert-butyldimethylsilyl)oxy)phenyl)methanol; iii) by reacting (4-((tert-butyldimethylsilyl)oxy)phenyl)methanol with methanesulfonyl chloride to obtain tert-butyl(4-(chloromethyl)phenoxy)dimethylsilane; iv) reacting tert-butyl(4-(chloromethyl)phenoxy)dimethylsilane with magnesium to obtain (4-((tert-butyldimethylsilyl)oxy)benzyl)magnesium chloride and v) by reacting (4-((tert-butyldimethylsilyl)oxy)benzyl)magnesium chloride with ethyl-2,2-diethoxyacetate to obtain 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1,1-diethoxypropan-2-one. Invention also relates to embodiments of the method of producing celenterazine.

EFFECT: methods of producing celenterazine with high output and purity.

11 cl, 4 tbl, 5 ex