US3189598A - Fatty acid esters of riboflavin - Google Patents
Fatty acid esters of riboflavin Download PDFInfo
- Publication number
- US3189598A US3189598A US186327A US18632762A US3189598A US 3189598 A US3189598 A US 3189598A US 186327 A US186327 A US 186327A US 18632762 A US18632762 A US 18632762A US 3189598 A US3189598 A US 3189598A
- Authority
- US
- United States
- Prior art keywords
- riboflavin
- fatty acid
- acid esters
- mixture
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
- C07D475/14—Benz [g] pteridines, e.g. riboflavin
Definitions
- This invention relates to fatty acid esters'of riboflavin and to a process for preparing same.
- riboflavin is a slightly water-soluble vitamin and, therefore, has some inconveniences for food-enrichment or pharmaceutical fields.
- 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.
- 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.
- 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.
- those having lower alkanoyl moiety can be conveniently prepared by directly reacting riboflavin with the alkanoic anhydride in the presence of concentrated perchloric acid.
- 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.
- riboflavin esters of this invention have the following structural formula:
- 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.
- 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.
- 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.
- 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.
- 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..
- reaction mixture was concen trated to dryness under reduced pressure and the residue was treated with mlaof 90% pyridine at 70 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.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Description
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
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP109760 | 1960-01-14 | ||
JP3723261 | 1961-10-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3189598A true US3189598A (en) | 1965-06-15 |
Family
ID=31948120
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US186327A Expired - Lifetime US3189598A (en) | 1960-01-14 | 1962-04-10 | Fatty acid esters of riboflavin |
Country Status (4)
Country | Link |
---|---|
US (1) | US3189598A (en) |
CH (1) | CH414658A (en) |
DE (1) | DE1179218B (en) |
GB (1) | GB943078A (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4264601A (en) * | 1979-06-12 | 1981-04-28 | The Board Of Regents Of The University Of Oklahoma | Antihypertensive agents and their use in treatment of hypertension |
US6268120B1 (en) * | 1999-10-19 | 2001-07-31 | Gambro, Inc. | Isoalloxazine derivatives to neutralize biological contaminants |
US20050112021A1 (en) * | 2000-06-15 | 2005-05-26 | Gambro, Inc. | Reduction of Contaminants In Blood and Blood Products Using Photosensitizers and Peak Wavelengths of Light |
EP1553099A1 (en) * | 2002-08-02 | 2005-07-13 | Institute of Radiation Medicine Academy of Military Medical Sciences of the Pla | A riboflavin derivative and its manufacture and uses |
US20060094547A1 (en) * | 2002-07-16 | 2006-05-04 | Ouishou Xu | Integrated pulley-torsional damper assembly |
US7094378B1 (en) | 2000-06-15 | 2006-08-22 | Gambro, Inc. | Method and apparatus for inactivation of biological contaminants using photosensitizers |
US7220747B2 (en) | 1999-07-20 | 2007-05-22 | Gambro, Inc. | Method for preventing damage to or rejuvenating a cellular blood component using mitochondrial enhancer |
US9044523B2 (en) | 2000-06-15 | 2015-06-02 | Terumo Bct, Inc. | Reduction of contaminants in blood and blood products using photosensitizers and peak wavelengths of light |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2825729A (en) * | 1955-05-24 | 1958-03-04 | Upjohn Co | Isoalloxazines |
US2970995A (en) * | 1959-03-20 | 1961-02-07 | Gen Mills Inc | Reductive acylated products of riboflavin |
-
1962
- 1962-04-10 US US186327A patent/US3189598A/en not_active Expired - Lifetime
- 1962-07-13 DE DET22463A patent/DE1179218B/en active Pending
- 1962-08-10 CH CH963462A patent/CH414658A/en unknown
- 1962-09-18 GB GB35449/62A patent/GB943078A/en not_active Expired
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2825729A (en) * | 1955-05-24 | 1958-03-04 | Upjohn Co | Isoalloxazines |
US2970995A (en) * | 1959-03-20 | 1961-02-07 | Gen Mills Inc | Reductive acylated products of riboflavin |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4264601A (en) * | 1979-06-12 | 1981-04-28 | The Board Of Regents Of The University Of Oklahoma | Antihypertensive agents and their use in treatment of hypertension |
US7220747B2 (en) | 1999-07-20 | 2007-05-22 | Gambro, Inc. | Method for preventing damage to or rejuvenating a cellular blood component using mitochondrial enhancer |
US6268120B1 (en) * | 1999-10-19 | 2001-07-31 | Gambro, Inc. | Isoalloxazine derivatives to neutralize biological contaminants |
JP2003512340A (en) * | 1999-10-19 | 2003-04-02 | ガンブロ、 インコーポレイテッド | Isoalloxazole derivatives for neutralizing biological pollutants |
US6828323B2 (en) * | 1999-10-19 | 2004-12-07 | Gambro, Inc. | Isoalloxazine derivatives to neutralize biological contaminants |
US20050112021A1 (en) * | 2000-06-15 | 2005-05-26 | Gambro, Inc. | Reduction of Contaminants In Blood and Blood Products Using Photosensitizers and Peak Wavelengths of Light |
US7094378B1 (en) | 2000-06-15 | 2006-08-22 | Gambro, Inc. | Method and apparatus for inactivation of biological contaminants using photosensitizers |
US9044523B2 (en) | 2000-06-15 | 2015-06-02 | Terumo Bct, Inc. | Reduction of contaminants in blood and blood products using photosensitizers and peak wavelengths of light |
US20060094547A1 (en) * | 2002-07-16 | 2006-05-04 | Ouishou Xu | Integrated pulley-torsional damper assembly |
EP1553099A1 (en) * | 2002-08-02 | 2005-07-13 | Institute of Radiation Medicine Academy of Military Medical Sciences of the Pla | A riboflavin derivative and its manufacture and uses |
EP1553099A4 (en) * | 2002-08-02 | 2006-06-28 | Inst Radiation Med Amms Pla | A riboflavin derivative and its manufacture and uses |
US20060293335A1 (en) * | 2002-08-02 | 2006-12-28 | Qishou Xu | Riboflavin derivative and its manufacture and uses |
Also Published As
Publication number | Publication date |
---|---|
CH414658A (en) | 1966-06-15 |
GB943078A (en) | 1963-11-27 |
DE1179218B (en) | 1964-10-08 |
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