US3808233A

US3808233A - Zearalenone reduction

Info

Publication number: US3808233A
Application number: US00292449A
Authority: US
Inventors: E Hodge
Original assignee: Commercial Solvents Corp
Current assignee: IMC Chemical Group Inc; Commercial Solvents Corp
Priority date: 1972-09-26
Filing date: 1972-09-26
Publication date: 1974-04-30
Anticipated expiration: 1991-04-30
Also published as: DK130464C; DE2328605C2; CH587839A5; ZA734356B; BE805261A; DK130464B; FR2200263B1; GB1379859A; IL42623A; IL42623A0; ES417199A1; SE383745B; NL7311613A; DE2328605A1; AT330377B; ATA511973A; AU5751273A; AU475426B2; CA980785A; PH10914A

Abstract

A METHOD FOR REDUCING ZEARALINONE TO ZERALANOL IN WHICH THE PRODUCT CONTAINS A MAJOR AMOUNT OF THE HIGHMELTING DIASTEREOISOMER AND A MINOR AMOUNT OF THE LOWMELTING DIASTEREOISOMER OF ZEARALANOL IS DISCLOSED. ZEARALENONE IS CATALYTICALLY REDUCED WITH HYDROGEN FOR A TIME SUFFICIENT TO REDUCE THE ZEARALENONE TO ZEARALANOL IN THE PRESENCE OF A PLATINUM CATALYST AND A WEAK ACID HAVING A FIRST ACID IONIZATION CONSTANT OF FROM ABOUT 1X10**4 TO 5X10**1 IN WATER AT ABOUT 25:C. AND SAID ACID NOT BEING ITSELF REDUCED UNDER THE CONDITIONS OF THE ZEARALENONE REDUCTION.

Description

United States Patent 3,808,233 ZEARALENONE REDUCTION Edward B. Hodge, Terre Haute, Ind., assignor to Commercial Solvents Corporation, Terre Haute, Ind. No Drawing. Filed Sept. 26, 1972, Ser. No. 292,449 Int. Cl. C07d 9/00 U.S. Cl. 260-343.2 F 12 Claims ABSTRACT OF THE DISCLOSURE A method for reducing zearalenone to zearalanol in which the product contains a major amount of the highmelting diastereoisomer and a minor amount of the lowmelting diastereoisomer of zearalanol is disclosed. Zearalenone is catalytically reduced with hydrogen for a time suflicient to reduce the zearalenone to zearalanol in the presence of a platinum catalyst and a weak acid having a first acid ionization constant of from about 1X10 to X in water at about 25 C. and said acid not being itself reduced under the conditions of the zearalenone reduction.

This invention relates to a method for reducing zearalenone to a mixture of the highand low-melting point diastereoisomers of zearalanol.

The terms zearalenone and zearalanol conform with the nomenclature in an article in Tetrahedron Letters, Pergamon Press, Ltd., No. 27, pp. 3109-3114 (1966). When zearalenone, having the formula is converted to zearalanol, having the formula r n)a (CHM by reduction of the olefinic bond and the ketone group in the presence of hydrogen, a mixture of diastereoisomers of zearalanol is formed. This reduction, carried out in the presence of a Raney nickel catalyst, is disclosed in U.S. Pat. No. 3,239,345. The diastereoisomers differ in melting point. The disclosed reduction provides an approximately 55:45 ratio of the high-melting point to the lowmelting point diastereoisomer.

Disclosed in U.S. Patent application Ser. No. 25,265, filed Apr. 2, 1970, now U.S. Pat. 3,697,548, and in corresponding Belgium Pat. No. 765,130, is a method of catalytically reducing zearalenone to a mixture containing a major amount of the diastereoisomer of zearalanol having the higher melting point and a minor amount of diastereoisomer of zearalanol having the lower melting point in the presence of a strong acid, that is, an acid which is essentially completely ionized in an aqueous solution. This process, while producing a good conversion of zearalenone to the diasteroisomer of zearalanol having the higher melting point with a relatively rapid rate of conversion, requires reaction vessels which are extremely resistant to strong acids or requires frequent replacement of reaction vessels due to corrosion.

It was also disclosed in United States patent application Ser. No. 25,265, now U.S. Pat. No. 3,697,548, and corresponding Belgium Pat. No. 765,130, that a weak acid, e.g., acetic acid, was found unsatisfactory for promoting the reduction of zearalenone to the high boiling diastero- 3,808,233 Patented Apr. 30, 1974 isomer of zearalanol. For example, acetic acid only provides about a 15 to 20 percent reduction of zearalenone to zearalanol after a six hour reaction period.

The product can be separated utilizing a procedure disclosed in Examples I and II of U.S. Pat. No. 3,574,235 in the name of Vernon V. Young. Both diasteroisomers of zearalanol are useful as anabolic substances for oral and parenteral administration to animals in the manner disclosed in U.S. Pat. No. 3,239,345.

It has now been found that certain weak acids may be employed in a process for the catalytic reduction of zearalenone to a mixture containing a major amount, e.g., greater than weight percent, for example, about weight percent or more, of the diastereoisomer of zearalanol having the higher melting point and a minor amount, e.g., less than 45 weight percent, for example, about 40 weight percent or less, of the diasteroisomer of zearalanol having the lower melting point.

In accordance with the present invention, the reduction of zearalenone is conducted in the presence of a solvent, a platinum catalyst, and certain weak acids for a time sufiicient to reduce the zearalenone to zearalanol and provide a high ratio of the high melting point diastereoisomer to the low melting point diastereoisomer. The product will generally contain a major amount of the high melting point diastereoisomer of zearalanol. The weak acid employed in the process of the present invention has a first acid ionization constant of from about 1X10- preferably 5X10- to 5 X 10- in an aqueous solution at 25 C., and will not itself be reduced to a weaker acid under the conditions employed for the zearalenone reduction.

The term weak acid, as used herein, refers to acids which are less than essentially completely ionized in water (except in extremely dilute solution). It conforms with standard nomenclature as found in, for example, Fundamental Concepts of Chemistry, Appleton-Century-Crofts (1969), pp. 233 and 234. Such weak acids include weak acids as well as moderately strong acids. Exemplary of the weak acids which may be employed in the present invention are citric acid, tartaric acid, phosphoric acid, and oxalic acid.

The zearalenone can be prepared and purified as described in Examples II and III of U.S. Pat. No. 3,239,345. The zearalenone is advantageously suspended or dissolved in a suitable solvent, preferably a lower alkanol, e.g., ethanol, normal propyl alcohol, isopropyl alcohol and the I like, preferably those containing from 1 to 3 carbon atoms and particularly ethanol. zearalanol-producing amounts of a weak acid, often a small amount, e.g., about 0.001 to 5 volume percent (based on the solvent), preferably from about 0.01 to 3 volume percent or equivalent weight, of weak acid is added to the solvent. The reaction may be conducted in the presence of, for instance, about 2 to 10 volume percent of water.

The zearalenone and solvent can advantageously be present in amounts of, for example, from about 1 to 25 grams of zearalenone per cc. of the solvent. A platinum catalyst supported on a suitable carrier, e.g., charcoal, is advantageously used. Generally, the catalyst contains from about 0.01 to about 10 weight percent of platinum and is employed in catalytic amounts, generally a catalyst to zearalenone weight ratio of from about 0.00l:1 to 1:1.

The zearalenone is reduced in the presence of hydrogen under reducing conditions for a time suflicient to reduce substantially all of the zearalenone. Advantageously, the reduction can be carried out at a temperature of from about 15 to 100 C., preferably about 20 to 60 C. with a hydrogen pressure generally of from about 20 to 1000 p.s.i., preferably 25 to 100 p.s.i., for at least 3, preferably about 3 to 8, hours. After the reduction, the platinum catalyst is removed from the reaction mixture, e.g., by filtration, andthe resulting'mixture can; as a-matter of convenience, be concentrated, to say, a volume of from about 0.5 to 0.1 of the reaction mixture volume, and filtered again. The filtered, concentrated solution can be diisomer of zearalanol comprising catalytically reducing luted with-water, for example, in an amount of from zearalenone with hydrogen under reducing conditions in about 2 to 4 volumes of the concentrated solution, by addthe presence of zearalanol-producing amounts of a weak ing water slowly while stirring the solution. The resulting acid and catalytic amounts of platinum catalyst, said weak solution is advantageously allowed to stand at room temacid having a first acid ionization constant of from about perature for a time suflicient to allow the zearalanol to 1 10 to 5 10- in aqueous solution and said weak precipitate from the solution which can be about 2 to 4 acid not itself being reduced to a weaker acid under the hours or more. Filtration of the mixture yields the white reducing conditions.

crystals of zearalanol containing a major amount of the 2. The method of claim 1 wherein the reducing conhigh melting diastereoisomer and a minor amount of the ditions include temperatures from about to 100 C. low melting diastereoisomer which can be separated as 15 and a hydrogen pressure from about to 1000 p.s.i. and noted above. the catalyst is employed in a catalyst to zearalenone weight The following examples are presented to further illusratio from about 0.001:1 to 1:1. trate the invention and are not in limitation thereof. 3. The method of claim 2 wherein the reduction is con- EXAMPLE I ducted in the presence of a solvent consisting essentially 20 of a lower alkanol solvent.

Three grams (g) of zearalenone and 3 milliliters of 4. The method of claim 3 wherein the lower alkanol 85% phosphoric acid are added to 200 ml. of ethanol at contains from 1 to 3 carbon atoms and the solvent conroom temperature, after flushlflg With nitrogen, tains from about 0.001 to 5 volume percent (based on g. of a 5 percent platinum on charcoal catalyst is added. the l f h weak i The solutlon charged mm an Adams reducmg P 5. The method of claim 2 wherein the catalytic reacratus and g g hydrogen for 6 hours i room tion is carried out with reducing conditions including temperature un era y rogen pressure of p.s.1. The resultperatures from about 20 to and a hydrogen Pres mg reduced mlxture 1S filtered, concentrated to ml. Sure from about 25 to Si nd filtered again. Then 400 ml of water are added to a 6. The method of claim 3 wherein the solvent conthe mixture slowly w1th stirring. After 3 hours at room 30 ak f b 1 temperature the mixture is filtered to give 2 61 g of tams we an m an amount mm a out to 3 V0- ume percent, based on the volume of the solvent. zearalanol which is analyzed to be about 76% of the hlgh 7 The method of claim 2 wherein the reduction is com melting diastereoisomer and 24% of the low melting diastereoisomer ducted 1n the presence of water in an amount of about 2 5 to 10 volume percent.

EXAMPLES H t 1X 8. The method of claim 1 wherein the weak acid has The following examples were conducted in essentially a first acid ionization constant of from about 5 1O to the same procedure as that set forth in Example 1 except 5X 10-1- ditferent solvents and weak acids are employed. The re- 9. The method of claim 2 wherein the weak acid is sults of these examples are set forth in Table I. 40 tartaric acid.

TABLE I Amount zearalanol recovered Ratio of high Amt Time iit ir ei 57 33251251? Example Solvent Weak acid hrs. charged e perceni'.

II; Ethanol Tartaric 2 7 III- d d 2 8 IV. Isopropanol ..do 2 7 V t-Bntanol Phosphoric-- 2 7 VI Ethanol Oxalic 2 7 VII nn cum- 2 7 VIIL; do Succinic"--- 2 7 IX do Maleic 2 7 1 Product obtained in mostly zearalanone the results obtained are comparable to that of Example 65 VIH.

10. The method of claim 2 wherein the weak acid is phosphoric acid.

11. The method of claim 2 wherein the weak acid is oxalic acid..

12. The method of claim 2 wherein the weak acid is citric acid.

References Cited UNITED STATES PATENTS 3,687,982 8/1972 Young 260343.2 3,697,548 10/1972 Hodge 260343.2

JOHN M. FORD, Primary Examiner