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Publication numberUS3189598 A
Publication typeGrant
Publication dateJun 15, 1965
Filing dateApr 10, 1962
Priority dateJan 14, 1960
Also published asDE1179218B
Publication numberUS 3189598 A, US 3189598A, US-A-3189598, US3189598 A, US3189598A
InventorsYagi Kunio
Original AssigneeYagi Kunio
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Fatty acid esters of riboflavin
US 3189598 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent FATTY ACH) ESTERS OF RIBOFLAVIN Kunio Yagi, 30 l-chome, Meigetsu-cho, Shower-kn, Nagoya-shi, Japan No Drawing. Filed Apr. 10, 1962, Ser. No. 186,327 Claims priority, application Japan, Jan. 14, 1960,

1 Claim. (Cl. 260211.3)

The present application is a continuation-in-part of ap-. I

plication Serial No. 78,668, filed December 27, 1960, now abandoned.

This invention relates to fatty acid esters'of riboflavin and to a process for preparing same.

It has been well known that riboflavin is a slightly water-soluble vitamin and, therefore, has some inconveniences for food-enrichment or pharmaceutical fields.

According to this invention 1 have found that riboflavin may be rendered fat-soluble by esterification with fatty acids. A fatty acid ester of riboflavin can be prepared by reacting riboflavin with an alkanoyl halide having 4 to 20 carbon atoms. The reaction may be carried out in an inert solvent, such as benzene, chloroform or other halogenated hydrocarbons, in the presence of an acid acceptor such as pyridine. Since riboflavin has four free hydroxy groups in the molecule, it is preferable to use more than four moles of the alkanoyl halide per mole of riboflavin. As an alkanoyl halide, I prefer to use those having 4 to 20 carbon atoms such as butyryl, hexanoyl, octanoyl, capryl, lauroyl, myristoyl, palmitoyl and stearoyl chloride or bromide.

The process of the present invention also includes the use of corresponding acid anhydride instead of said acid halide. After the reactants have been heated for the desired length of time, the riboflavin ester is recovered by evaporation of the solvent under reduced pressure or by pouring the reaction mixture into inert solvents in which the riboflavin ester is insoluble.

Among the fatty acid esters, those having lower alkanoyl moiety can be conveniently prepared by directly reacting riboflavin with the alkanoic anhydride in the presence of concentrated perchloric acid. For example, the butyric ester of riboflavin can be obtained in high yield by adding a small amount of 60% perchloric acid into a mixture of riboflavin and butyric anhydride with stirring at room temperature and then pouring the reaction mixture into water.

The fatty acid esters of riboflavin thus prepared may be recovered and purified by recrystallization from ether, benzene or ethanol. The riboflavin esters of this inven tion are substantially tasteless and odorless, and are quite soluble in many conventional solvents, such as ethanol, pyridine, benzene, chloroform, or neutral fats, in each of which riboflavin itself is almost insoluble.

The riboflavin esters of this invention have the following structural formula:

3,189,598 Patented 'June 15, 1965 wherein RCO stands for a straight chain alkanoyl grou containing from 4 to 20 carbon atoms.-

It has been found that the compounds of this invention possess vitamin B activity. When administered orally, the compounds are easily hydrolyzed with human digestive juices into riboflavin and corresponding fatty acids, and effect vitamin B activity. It has been found that the compounds are'hydrolyzed with neither saliva nor gastric juices, but with duodenal juice. Among many of the compounds riboflavin tetrabutyrate is most easily hydrolyzed. This can be illustrated by the test described below.

Each of the substrates was suspended in a mixture'of 0.3 ml. of 0.1 M phosphoric acid-buffered solution (pH 8.5) and 0.2 ml. of human duodenal juice at a concentration of 1x10- M. The substrate solutions were incu-' bated for 30 minutes at 37 C. and the degradation rate of each of the substrates was assayed by the lumiflavin fluorescence method (Yagi, J. Biochem., vol. 43, page It has also been found that the compounds of the invention show vitamin B activity on dietary scurvy using male albino rats. Among the compounds, riboflavin tetrabutyrate increases the body weight of rats as much as free riboflavin and it prevents ariboflavinosis remarkably. However, others were found to have little growth-promoting activity.

It has also been found that when the compounds of this invention are administered to the living body by intramusclar injection, the blood level of total riboflavin rises more slowly, and remains at an effective level for a longer period than with free riboflavimj- Furthermore, the administered riboflavin is substantially excreted in urine for a longer period of time than is free riboflavin. For example, when 5 mg. of free riboflavin is administered to a rabbit, weighting about 3 kg., by intramuscular injection, the blood level of total riboflavin reaches a peak within 30 to 60 minutes and a substantial quantity of the given riboflavin is excreted in urine within a few hours. However, in the case of riboflavin tetrabutyrate, the blood level of total riboflavin reaches a peak on more than 12 hours after the injection, and 30 to 40% of the given riboflavin is excreted in urine within 24 hours.

From the foregoing, it is apparent that the compounds of this invention are useful in nutritional and medical fields, and sometimes more advantageously than free riboflavin. The invention is further illustrated by the following examples.

Example 1 1 g. of riboflavin was suspended in 300 ml. of a 1:1 mixture of pyridine-chloroform. Into this suspension, 15 g. of palmitoyl chloride in 50 ml. of chloroform was dripped at 0 C. with vigorous stirring within about 1 hour. The mixture was stirred for an additional 14- r H, 10.61 N, 4.21..

. yellow oil.

i The solution was allowed to stand overnight .in' a refrigerator, whereby riboflavin tetrapalmitate crystallized out.

7 Example) L1 4;; er riboflavin was s'uspended in '300 m1. of 11-1 mixture of pyridine-chloroform. Into this suspension;

10 gr of capryl chloride in 50 ml; of chloroform was dripped at C. withvigorous stirring within about 1 Yield, 2 g yellow crystals melting at 78. C.. Y after recrystallizationfrom absolute ethanol;

.:iAnalysiS. Calcu1ated C81H146016N4 C; .Found: C, 72.93; H, -10.73,; N, 4.41;

: lized out.

hour.= QThe mixture was stirred; for an additional "14 hours at 33 ,C; The reaction mixture was'coneentrated to dryness under reduced pressure and the-residue was treated with 100 ml. of 9 0% pyridine at70 C. for I minutes in order :to decornpose'the remaining capryl chloride into capric acid. After-the solution was con-' centrated to dryness, the residue was dissolved in a small amount of ether.

The elua'te was condensed to remove pyridine whereby riboflavin tetracaprate .was obtained. Yield, 1.5 i g.

f 1 offribofiavin was suspended in 300 nila'of 1:1 I rnixtureof pyridine-chloroform. Into this suspension,

5.6 goof butyryl chloride in ml. of chloroform: was

, dripped. at..03 .C. 1 with vigorous stirring within about 1 hour. The mixture was stirred for an-additional '14: hours. at "38 C. i The "reaction mixture was concen trated to dryness under reduced pressure and the residue was treated with mlaof 90% pyridine at 70 C.

fo'r'QOminutes in ordertoidecomposelthe remaining hutyryl chloride into butyrici acid. 7 After the solution was concentrated to dryness, a small amount of saturated. solution of sodium bicarbonate in water was added to the residue and the mixture was. extracted with V The solution was poured into a column of Florisil (an activated mangesium silicate): The column was washed with a small amount of ether and ethanol successively, and then eluted with pyridine;

" dride. 25

ether. 7

ether. The extract was dried with sodiumisulfate and then ether was removed; The'residue was dissolved in ether and insoluble matter was filtered off. The filtrate was condensed, to dryness and the residue was treated with petroleum ether on a water-bath, and then filtered. The filter cake was dissolved in' ether and a major part of the ether wa'siremoved b'yevapora tiona The residue 1 'was cooled, whereby" riboflavin tetrabuty'rate crystal- Yield, 1' -g., yellowish orange crystals meltafter recrystallization irom j ing at 145 to 147 C.

, Example 4.

' 1 g. of riboflavin was added to elO'mlliof butyricfan hydride; The mixture was heated 5011 an oilbath at C. to C. 'for '6hoi1rs. 'The'resultantsolution was concentrated under reduced pressure .Ribofla'vin f tetrabutyrate was crystallized from theresidue" using;

Yield, 1 g., yellowish crystals meltether as a solvent. ing at C. to 147 C.

Example' 5 1 of riboflavin was added to 10 inl. of butyric anhy- To the mixture was added 05ml. of 60% aque-' ous solution of perchloric acid at. room temperature with .vigorous stirringi The reaction mixture was V poured into 50 nil. of water. After the orangefyellowr.

ifsh layer was concentrated under reduced pressure, ribo flavin tetrabutyrate was crystallized from ether. g. of riboflavintetrabutyrate melting at 145 C. to 147' V Cewas obtained. 7

'Iclaimy "V Riboflavin 21314? ,5-tetrabutyrate.

I f 'Refe rences Qitedbythe Enaminer V V 'UNITED SVTATES'PA'VTENTS. 52,825,729

LEWIs GOTT S Prir nmyExaminer;

3/58;Peterin"g et al. 260 2113 2,970,995" 2/61 .Wheeler. "26O-'- 21V1.37

Patent Citations
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US2825729 *May 24, 1955Mar 4, 1958Upjohn CoIsoalloxazines
US2970995 *Mar 20, 1959Feb 7, 1961Gen Mills IncReductive acylated products of riboflavin
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US4264601 *Jun 12, 1979Apr 28, 1981The Board Of Regents Of The University Of OklahomaAntihypertensive agents and their use in treatment of hypertension
US6268120 *Oct 19, 1999Jul 31, 2001Gambro, Inc.Isoalloxazine derivatives to neutralize biological contaminants
US6828323 *Feb 5, 2001Dec 7, 2004Gambro, Inc.Isoalloxazine derivatives to neutralize biological contaminants
US7094378Jun 15, 2000Aug 22, 2006Gambro, Inc.Method and apparatus for inactivation of biological contaminants using photosensitizers
US7220747May 6, 2003May 22, 2007Gambro, Inc.Method for preventing damage to or rejuvenating a cellular blood component using mitochondrial enhancer
US9044523Aug 17, 2007Jun 2, 2015Terumo Bct, Inc.Reduction of contaminants in blood and blood products using photosensitizers and peak wavelengths of light
US20050112021 *Nov 5, 2004May 26, 2005Gambro, Inc.Reduction of Contaminants In Blood and Blood Products Using Photosensitizers and Peak Wavelengths of Light
US20060094547 *Jul 10, 2003May 4, 2006Ouishou XuIntegrated pulley-torsional damper assembly
US20060293335 *Jul 29, 2003Dec 28, 2006Qishou XuRiboflavin derivative and its manufacture and uses
EP1553099A1 *Jul 29, 2003Jul 13, 2005Institute of Radiation Medicine Academy of Military Medical Sciences of the PlaA riboflavin derivative and its manufacture and uses
U.S. Classification544/251
International ClassificationC07D475/14
Cooperative ClassificationC07D475/14
European ClassificationC07D475/14