RU2148581C1 - Method of synthesis of 2',3',4',5'-tetrabenzoyl-5-acetyl-1,5-dihydroriboflavin - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention describes method of synthesis of 2',3',4',5'-tetrabenzoyl-5-acetyl-1,5-dihydroriboflavin by debenzoylation of 3,2',3',4',5'-pentabenzoylriboflavin that results to formation of 2',3',4',5-tetrabenzoylriboflavin. The latter is subjected for reductive acetylation in the presence of 3-5% of palladium on aluminium oxide being without isolation from reaction mixture. EFFECT: increased yield of end product (by 25%), simplified technology of synthesis.

Description

 The invention relates to organic chemistry, and in particular to a method for producing 2 ', 3', 4 ', 5'-tetrabenzoyl-5-acetyl-1,5-dihydroriboflavin (benzaflavin), and can be used in the pharmaceutical industry and medicine.

 A known method of producing benzaflavin by reducing 2 ', 3', 4 ', 5'-tetrabenzoylriboflavin (I) with zinc dust in an environment of acetic acid and acetic anhydride at a boil with a yield of 85.7% [1]. (Copyright certificate 413148, 1974).

 The disadvantage of this method is the difficulty of its reproduction on an industrial scale, since the isolation of the target product involves washing with hot acetic acid, distillation of acetic acid and acetic anhydride in vacuum, as well as a large consumption of solvents (hexane and chloroform) at the final stage of product isolation.

A known method of producing benzaflavin by reducing 3.2 ', 3', 4 ', 5'-pentabenzoylriboflavin (II) with hydrogen in the presence of 3 - 5% Pd / C at 25-30 atm. and 125 - 130 ^o C for 3.5 hours with a yield of 80%. (Chemistry, Biochemistry and Pharmacology of Vitamin B ₂ and its derivatives. // Collected Works. - M., 1988, p. 9. - [2]).

 The disadvantage of this method is the relatively low yield of benzaflavin and the complexity of the technology for its production, due to the high process temperature and high pressure, in addition, the resulting product contains impurities of isoalloxazine structure.

There is also a method for producing benzaflavin by debenzoylation of II by boiling in an acetic acid medium with the formation of I (86% yield) and subsequent hydrogenation of the latter with hydrogen in the presence of Pd / C in an acetic acid and acetic anhydride medium in an autoclave at 25-30 ^° C for 10 hours. The yield of benzaflavin is 80% [2]. (Chemistry, Biochemistry and Pharmacology of Vitamin B ₂ and its derivatives. // Collected Works. - M., 1988, p. 8).

 The disadvantage of this method is the need for the allocation of 2 ', 3', 4 ', 5'-tetrabenzoylriboflavin, which complicates the process technology, as well as a low yield. The total yield of benzaflavin after two stages of the process is 68.8%.

 An object of the present invention is to increase the yield and simplify the technology for producing benzaflavin.

 This is achieved by the method of producing benzaflavin by debenzene II with the formation of 2 ', 3', 4 ', 5'-tetrabenzoylriboflavin followed by reductive acetylation of the latter in the presence of a catalyst, the hallmark of which is the use of 3 - 5% palladium on alumina as a catalyst and conducting a reductive acetylation reaction without isolation of intermediate I.

The reductive acetylation reaction without isolation of intermediate 2 ', 3', 4 ', 5'-tetrabenzoylriboflavin simplifies the process technology, and the use of 3 - 5% Pd / Al ₂ O ₃ as a catalyst allows to increase the yield of benzaflavin to 95%, and also reduce the time of reductive acetylation to 2 hours, which also simplifies the process.

The essence of the method is as follows: 3.2 ', 3', 4 ', 5'-pentabenzoylriboflavin is heated in a mixture of acetic acid and acetic anhydride, taken in a ratio of 1: 1-1: 2 at 100 - 120 ^o C for 1 - 4 hours, cooled to 20 - 25 ^o C, a catalytic amount of 3 - 5% Pd / Al ₂ O _{3 was} added, and with vigorous stirring, hydrogen was passed at 50 - 80 ^o C for 1 - 8 hours, the catalyst was separated by filtration, obtained the solution was poured into a 4-times volume of distilled water, and the precipitate was filtered off, washed until neutral washing water, dried at 50 - 55 ^o C b s access light. The yield of benzaflavin 93.78 - 95.5%.

Example:
A mixture of 16 g of 3.2 ', 3', 4 ', 5'-pentabenzoylriboflavin, 160 ml of acetic acid and 160 ml of acetic anhydride is heated with stirring at 110 ^o C for 2 hours, then the mixture is cooled to 20 ^o C, add 0 32 g of 5% Pd / Al ₂ O ₃ and hydrogen gas is passed under vigorous stirring. The reaction mixture is heated with stirring at 70 ^o C for 2 hours. At the end of the hydrogenation, the catalyst is separated, the reaction solution is poured into 2 l of distilled water with stirring. The precipitate formed is washed to pH of the washings (pH 5-6), then dried. Yield 14 g (93.78%).

 The quality of the preparation obtained corresponds to VFS N 42-2002-95.

Moisture Content 1.97%; the preparation contains 98.4% C ₄₇ H ₄₀ N ₄ O ₁₁ in terms of an anhydrous substance, is practically insoluble in water, readily soluble in chloroform and acetone, sparingly soluble in 95% alcohol; The UV spectrum has a maximum absorption at 306 ± 2 nm, a minimum at 290 ± 2 nm; sulfate ash from 1 g of the drug - 0.11%.

 Using the present invention allows to increase the yield of benzaflavin by more than 25%, and also to simplify the technology of its production by reducing the number of process steps, as well as reducing the hydrogenation time from 10 to 2 hours.

Used Books
1. Copyright certificate N 413148, 1974, BI N 4.

2. Chemistry, Biochemistry and Pharmacology of Vitamin B ₂ and its derivatives. // Collection of works. - M., 1988.

Claims (1)

 The method of obtaining 2 ', 3', 4 ', 5' - tetrabenzoyl-5-acetyl-1,5-dihydroriboflavin by debenzoylation of 3, 2 ', 3', 4 ', 5' - pentabenzoylriboflavin followed by reductive acetylation of the obtained 2 ', 3 ', 4', 5 '- tetrabenzoylriboflavin in the presence of a catalyst, characterized in that 3 to 5% palladium on alumina is used as a catalyst, and the reductive acetylation reaction is carried out without isolation of the intermediate 2', 3 ', 4', 5 '- tetrabenzoylriboflavin.