CA1036611A - Cis-zearalene and related compounds - Google Patents
Cis-zearalene and related compoundsInfo
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- CA1036611A CA1036611A CA183,623A CA183623A CA1036611A CA 1036611 A CA1036611 A CA 1036611A CA 183623 A CA183623 A CA 183623A CA 1036611 A CA1036611 A CA 1036611A
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- cis
- irradiation
- zearalene
- solution
- hydrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
ABSTRACT
Cis isomers of compounds represented by the formula wherein I is , , or
Cis isomers of compounds represented by the formula wherein I is , , or
Description
~036611 CIS-Z~R~LENE ~ND R~LATED COMPOUND~
This invention relates to a process of making cis isomers of compounds represented by the formula ~ 8 IH3 R2 ~ H~
/ 2 ~ H
C~ I '~
wherein Z is \ C=O or ~ C or ~ C < and each of Rl and R2 can be hydrogen~substituted and unsubstituted alkyl, e.g., containing from about 1 to 15 carbon atoms including lower alkyl such as methyl, ethyl, hexyl, etc., and cycloalkyl such as cyclopentyl,cyclohexyl, etc.; alkanoyl, generally containing about 1 to 25 or more carbon a~om~ including lower alkanoyl such as acetyl, valeryl, propionyl, etc.; substituted or unsubstituted aryl, for instance, monocyclic aryl containing about 5 to 10 carbon atoms or more such as phenyl, for instance;
aryl alkyl (that is an alkyl group having an aryl substituent thereon), the aryl ~ubstituent may be monocyclic aryl contain-ing about 5 to 10 carbon atom~ or more and the alkyl group is generally lower alkyl, for example, one to about slx carbon atoms, such as benzyl, bromobenzyl, and the like, Rl and R2 being the same or different with the proviso that when both Rl and R2 are hydrogen, Z i/ C ~ . These compounds are advantageously produced from their respective trans i~omers by irradiation with electromagnetic radiation having a wavelength ~, ..
~Q36611 of about 2800 to 3500 angstroms. The cis compounds of this invention can be produced essentially pure, e.g., generally above about 90 percent, often above about 97 percent pure.
Because of the ethylenic unsaturation between the 1 and 2 position carbon atoms in the lactone ring, the compounds prepared in accordance with this invention can theoretically exist in two stereoisomeric forms: cis and trans. The compound zearalene (also known as 6-(10-hydroxy-1-undecenyl)-B-resorcylic acid-~-lactone) exhibits estrogenic activity and aids in increasing the rate of growth in meat producing animals.
Zearalene may be prepared by the reduction of the keto group of -zearalenone to replace the oxygen of the keto group with two ~;
hydrogen atoms. This reaction is described, for example, in U.S. Patent No. 3,239,341 to Hodge et al.
;. :.
One or both of the hydroxy substituents on the benzene ring of zearalene may undergo replacement of the hydrogen atom with an alkyl, alkanoyl, aryl, or aryl alkyl radical. Con-ventional processes for the hydrogen replacement reaction may be employed and are illustrated, for instance, in U.S. Patent Nos. 3,239,341; 3,239,342; 3,239,347; 3,239,348; and 3,373,039 to Hodge et al.
It is realized that, for instance, cis zearalene may be prepared by the appropriate reduction of the keto group ,~ .
in cis-zearalenone to an alcohol group of hydrogens. Similarly, -the hydrogen atoms of the hydroxy groups on the benzene ring of a cis compound may be replaced to provide the desired cis-derivative.
Identification of the cis isomers can be by nuclear magnetic resonance spectroscopy (nmr). For instance, whereas the proton on the 1 position lactone ring carbon atom in trans-zearalenone exhibits an absorption at 7.14~, in cis-zearalenone '.' '~
This invention relates to a process of making cis isomers of compounds represented by the formula ~ 8 IH3 R2 ~ H~
/ 2 ~ H
C~ I '~
wherein Z is \ C=O or ~ C or ~ C < and each of Rl and R2 can be hydrogen~substituted and unsubstituted alkyl, e.g., containing from about 1 to 15 carbon atoms including lower alkyl such as methyl, ethyl, hexyl, etc., and cycloalkyl such as cyclopentyl,cyclohexyl, etc.; alkanoyl, generally containing about 1 to 25 or more carbon a~om~ including lower alkanoyl such as acetyl, valeryl, propionyl, etc.; substituted or unsubstituted aryl, for instance, monocyclic aryl containing about 5 to 10 carbon atoms or more such as phenyl, for instance;
aryl alkyl (that is an alkyl group having an aryl substituent thereon), the aryl ~ubstituent may be monocyclic aryl contain-ing about 5 to 10 carbon atom~ or more and the alkyl group is generally lower alkyl, for example, one to about slx carbon atoms, such as benzyl, bromobenzyl, and the like, Rl and R2 being the same or different with the proviso that when both Rl and R2 are hydrogen, Z i/ C ~ . These compounds are advantageously produced from their respective trans i~omers by irradiation with electromagnetic radiation having a wavelength ~, ..
~Q36611 of about 2800 to 3500 angstroms. The cis compounds of this invention can be produced essentially pure, e.g., generally above about 90 percent, often above about 97 percent pure.
Because of the ethylenic unsaturation between the 1 and 2 position carbon atoms in the lactone ring, the compounds prepared in accordance with this invention can theoretically exist in two stereoisomeric forms: cis and trans. The compound zearalene (also known as 6-(10-hydroxy-1-undecenyl)-B-resorcylic acid-~-lactone) exhibits estrogenic activity and aids in increasing the rate of growth in meat producing animals.
Zearalene may be prepared by the reduction of the keto group of -zearalenone to replace the oxygen of the keto group with two ~;
hydrogen atoms. This reaction is described, for example, in U.S. Patent No. 3,239,341 to Hodge et al.
;. :.
One or both of the hydroxy substituents on the benzene ring of zearalene may undergo replacement of the hydrogen atom with an alkyl, alkanoyl, aryl, or aryl alkyl radical. Con-ventional processes for the hydrogen replacement reaction may be employed and are illustrated, for instance, in U.S. Patent Nos. 3,239,341; 3,239,342; 3,239,347; 3,239,348; and 3,373,039 to Hodge et al.
It is realized that, for instance, cis zearalene may be prepared by the appropriate reduction of the keto group ,~ .
in cis-zearalenone to an alcohol group of hydrogens. Similarly, -the hydrogen atoms of the hydroxy groups on the benzene ring of a cis compound may be replaced to provide the desired cis-derivative.
Identification of the cis isomers can be by nuclear magnetic resonance spectroscopy (nmr). For instance, whereas the proton on the 1 position lactone ring carbon atom in trans-zearalenone exhibits an absorption at 7.14~, in cis-zearalenone '.' '~
-2 1~36Gll ~t exhibits an absorption at only 6.72~. The coupling constant, J, between the 1 and 2 position lactone ring carbon atoms is 16 Hz in the trans isomer and only 11.5 Hz in the cis isomer. As ~r regards zearalene, similar differences in the nmr absorption of the protons on the 1 and 2 position lactone ring carbon atoms are found between the cis and trans isomers.
The irradiation of the trans isomers to produce the cis-isomers of this invention can be carried out with an ultra-violet irradiation source which can produce a wavelength 10 generally in the range of about 2800 to 3500 angstroms. The `
irradiation dosages in these wavelengths may often be at least about 10 kwh./hr./kg. of starting material, preferably about -20 to 500 kwh./hr./kg. of starting material. The length of time that the trans isomer is exposed to the irradiation can vary widely depending upon such factors as the amount of trans isomer, the irradiation wavelength, dosage, etc. Generally, the irradiation is continued for a period of about 1 to 200 or more hours and preferably for a period of about 6 to i20 hours.
Typical sources of ultraviolet irradiation which can be used in the present process include mercury vapor lamps, carbon arc lamps, and tungsten arc lamps.
The irradiation is preferably effected with the trans isomers in solution in a stable solvent, i.e., one which is non-reactive with the starting material and product under the irradiation conditions. Suitable solvents include lower mono-hydric alkanols, acetonitrile, and dichloromethane. Methanol is preferred. Preferred solution concentrations are about 0.5 to 2.5, most preferably about 1 to 2, weight percent.
It is also preferred that the trans isomer be essentially free from contact with oxygen during the irradiation, the reason being that oxygen might possibly inhibit the - . - : : ~ .
1~36~i11 stereoisomerization and/or oxidize the reactants. Where solution irradiation is employed this can be achieved, for example, by first purging the solution with an inert gas such as nitrogen, argon or helium and then maintaining the solution in an atmosphere of inert gas during the irradiation.
The maximum amount of cis isomer that can be obtained in the product of the photochemical process of this invention is generally above 90 percent, e.g., approximately 97 percent.
Suitable solvent systems for the recrystallization include lower ~ -monohydric alkanol/water mixtures such as methanol/water mixtures and isopropanol/water mixtures. Most preferred is a methanol/
water mixture containing about 20 to 50 volume percent water.
The crude cis-zearalene product may conveniently be recrystallized from benzene to upgrade purity. It is generally `-advantageous to treat product solutions of cis isomers with activated charcoal so as to enhance the purity of the product.
The irradiation is preferably continued until the ;
cis/trans isomeric mixture contains at least about 90 percent, or even at least about 95 percent, of the cis isomer.
Slightly elevated, room, or lowered temperatures (e.g., about 15-45C.) and superatmospheric, atmospheric, or sub-atmospheric pressures can be used for the stereoisomerization reaction of the present invention. For reasons of economy, however, it is preferred to operate under ambient conditions, i.e., at room temperature and atmospheric pressure.
The alternative method of producing cis-zearalenol derivatives is by reducing the ketone group of the corresponding ' cis-zearalenone derivative, reducing conditions of temperature and pressure in the presence of a suitable reducing agent and ~
30 is also preferably carried out in solution in a stable solvent, -e.g., dimethylformamide, tetrahydrofuran, or a lower monohydric alkanol, such as isopropanol, methanol or ethanol. Preferred solution concentrations are about 5 to 10 weight percent.
Any reducing agent which is selective for the ketone group and unreactive with the solvent can be employed in the reaction. Most preferred is a borohydride such as sodium borohydride and potassium borohydride. The latter should not be used, however, in conjunction with an alcohol solvent. These borohydride reducing agents are advantageously employed in an amount which is at least equimolar to the amount of cis-zearalenone.
Subatmospheric, atmospheric, or superatmosPhericpressures can be used for the reduction reaction, with atmos-pheric pressure being preferred for economic reasons. The temperature to be employed will depend upon the choice of reducing agent and solvent but will generally be about 15 to 45C.
The alternative method of producing cis-zearalene or derivative thereof is by the reduction of the ketone group of cis-zearalenone or corresponding derivative of cis-zearalenone, to replace the oxygen of the ketone group with two hydrogen atoms. The reduction of the ketone group can be effected by several procedures. One of these procedures involves the Clemmensen reaction using zinc and hydrochloric acid; another involves the Wolff-Kishner reaction using hydrazine and alkali, e.g., sodium hydroxide.
Cis-compounds wherein the substituents on the benzene ring are hydroxyl groups, may be converted to compounds in which one or both of Rl and R2 are alkyl, alkanoyl, aryl, or aryl alkyl. In producing the compounds of the present invention where R is alkyl, conventional alkylation procedures may be used to replace the hydrogen atom of one or both of the hydroxyl ~0366~
groups on the benzene ring with an alkyl group. The alkylation may be by reaction with the corresponding dialkyl sulfates, e.g., dimethyl sulfate, diethyl sulfate, etc., to produce a -;
dialkyl substituted or a monoalkyl substituted compound with the alkyl group replacing the hydrogen of the hydroxyl group ortho to the ester group. The alkylation reaction may take place in a liquid medium such as water. Furthermore, a methyl group may selectively replace the hydrogen of the hydroxyl group para to the ester group on the benzene ring using diazo-methane.
The hydrogen atom hydroxyl substituents on the ~ -benzene ring may be replaced by a carbon-containing, cyclic group by a condensation reaction in a slightly alkaline, - -organic solvent medium with the corresponding acid anhydride or chloride of the cyclic compound. Illustrative of cyclic ~ -substituents, alkyl and aryl or aryl alkyl, are benzyl, bromo- - -benzyl, benzothiazolyl, phenyltetrazolyl, benzoxazolyl, tetra-hydrofuranyl, tetrahydropyranyl, cyclopentyl, cyclohexyl, naphthyl, etc.
Where R is desired to be alkanoyl, conventional acylation procedures may be used to replace the hydrogen atom of both the hydroxyl groups on the benzene nucleus with an alkanoyl radical. For instance, acylation may be effected by reaction with the corresponding acid anhydride, e.g., acetic anhydride, propionic anhydride, etc., catalyzed with, for example, sodium acetate or pyridine. Ambient conditions may be -employed although it is preferred to keep the reaction mixture cold.
The cis isomers of the present invention can be administered to animals by any suitable method, including oral and parenteral administrations or as an implant. For example, 1036~i1i the compounds can be blended with ordinary feed which contains nutritional values in an amount sufficient to produce the desired rate of growth and thus be fed directly to the animals, or the compounds can be suspended in a suitable injection suspension medium, such as peanut oil, and injected parenter- -ally. The amount of compound fed to an animal varies, of course, upon the animal, the desired rate of growth, and the like. In general, from 2.5 to 50 grams of the compound per ton of feed is typical. When an implant is used, for example a ball or cylindrical implant inserted under the skin on the ear of an animal, e.g., a lamb or steer, the implant will generally contain from 1 mg. to 100 mg, of the compound.
When an isomer of this invention is to be administered to animals in their feed, an animal feed composition may be prepared containing the usual nutritionally-balanced quantities of carbohydrates, proteins, vitamins, and minerals together with the isomer. Some of the usual sources of these dietary elements are grains, such as ground grain and grain by-products;
animal protein substances, such as those found in fish meal and meat scraps; vegetable proteins, such as soybean oil meal or peanut oil meal; vitaminaceous materials, e.g., vitamins A and D mixtures; riboflavin supplements and other vitamin B
complex members; and bone meal and limestone to provide minerals. A type of conventional feed material for use with cattle, for example, includes alfalfa hay and ground corn cobs, together with supplementary vitaminaceous substances if desired.
EXAMPLE I
".
This example illustrates the preparation of cis-zearalene from trans-zearalene in accordance with the method of this invention. One gram of trans-zearalene is dissolved -in 500 milliliters of methanol, and the solution is placed in a 500 milliliter photochemical reactor (Ace Glass Model 6515) ~ -equipped with a borosilicate glass immersion well (Ace Glass Model 6517-05). The solution is purged with nitrogen for about 12 hours and is then irradiated under a nitrogen atmos-phere with a 450-watt, medium pressure, mercury vapor lamp --(Ace Glass Model 6515-34) for 24 hours. The resulting solution is evaporated to dryness under vacuum on a rotary evaporator and the residue is recrystallized from benzene to give 0.70 gram of cis-zearalene as white crystals having a melting point of 143 to 145C. Analysis indicates the presence of 70.67 weight percent carbon and 8.27 weight percent hydrogen, as compared with theoretical values of 71.05 weight percent carbon and 7.89 weight percent hydrogen. ~
EXAMPLE II ;-Samples of cis-zearalene are tested for uterotropic `-activity according to the well known mouse uterine test. This test consists of feeding the test compound in a sesame oil carrier to ten, adult, ovariectomized female mice for three 20 days at a ration of 50, 100, and 300 micrograms of compound per mouse per day. On day four the animals are sacrificed, and the uteri are removed and weighed. The test result~ are reported in Table I.
:
`
TABLE I ~ -Test Total Uterine ~ Body Compound Dose (~g) Weight (mg) Weight Control ---- 10.3 0.041 Trans-zearalenone 300 26.2 0.100 Trans-zearalene 300 16.2 0.066 900 18.1 0.070 Cis-zearalene 150 22.6 0.087 300 30.3 0.120 ~
900 48.6 0.188 ~ -EXAMPLES III to X
Essentially the same procedure used in Example I is followed to prepare cis isomers of compounds of the general formula R2Ol~
\~H2--CH2 wherein the values of Rl, R2 and Z are set forth below for the respective examples from the corresponding trans isomers where-in the values for Rl, R2 and Z are the same as in the product.
~ . , .
The starting compounds can be produced in accordance with the above-identified United States Patents issued to Hodge.
i .
', :, . ~
_g_ :~
,, ., . ., .. ,. ... ~ . , . ~ . .. .
~ t 1l~36611 : EXAMPLE R R Z
III -CH3 -CH3 ~ CH2 IV -CH2CH3 -CH2CH3 > CH2 : . -V -C-CH3 -CH3 >CH2 ~
. VI -CH3 -CH3 > CHOH :
` VII -H benzyl > C=O ;
- VIII -H bromobenzyl ~ C=O : `:
, ' ' ~ '~
10 IX -CH3 -C-CH3 > CH2 ;
:- o -C-C4Hg -C-C4Hg > C=O
-~ a feed mixture is prepared from each of the above compounds having 10 ounces of the cis isomer per one hundred pounds of . :~
mixture comprising alfalfa hay and ground corn cobs and is -~
used to feed in daily ration portions six head of cattle.
. . .
.
. . .
.' ' ., " ' , ' .' . 1 ,:, .
:'' '' ~ ~, .
- .
.: .. :
.:: .
~: . . . . . ... .
The irradiation of the trans isomers to produce the cis-isomers of this invention can be carried out with an ultra-violet irradiation source which can produce a wavelength 10 generally in the range of about 2800 to 3500 angstroms. The `
irradiation dosages in these wavelengths may often be at least about 10 kwh./hr./kg. of starting material, preferably about -20 to 500 kwh./hr./kg. of starting material. The length of time that the trans isomer is exposed to the irradiation can vary widely depending upon such factors as the amount of trans isomer, the irradiation wavelength, dosage, etc. Generally, the irradiation is continued for a period of about 1 to 200 or more hours and preferably for a period of about 6 to i20 hours.
Typical sources of ultraviolet irradiation which can be used in the present process include mercury vapor lamps, carbon arc lamps, and tungsten arc lamps.
The irradiation is preferably effected with the trans isomers in solution in a stable solvent, i.e., one which is non-reactive with the starting material and product under the irradiation conditions. Suitable solvents include lower mono-hydric alkanols, acetonitrile, and dichloromethane. Methanol is preferred. Preferred solution concentrations are about 0.5 to 2.5, most preferably about 1 to 2, weight percent.
It is also preferred that the trans isomer be essentially free from contact with oxygen during the irradiation, the reason being that oxygen might possibly inhibit the - . - : : ~ .
1~36~i11 stereoisomerization and/or oxidize the reactants. Where solution irradiation is employed this can be achieved, for example, by first purging the solution with an inert gas such as nitrogen, argon or helium and then maintaining the solution in an atmosphere of inert gas during the irradiation.
The maximum amount of cis isomer that can be obtained in the product of the photochemical process of this invention is generally above 90 percent, e.g., approximately 97 percent.
Suitable solvent systems for the recrystallization include lower ~ -monohydric alkanol/water mixtures such as methanol/water mixtures and isopropanol/water mixtures. Most preferred is a methanol/
water mixture containing about 20 to 50 volume percent water.
The crude cis-zearalene product may conveniently be recrystallized from benzene to upgrade purity. It is generally `-advantageous to treat product solutions of cis isomers with activated charcoal so as to enhance the purity of the product.
The irradiation is preferably continued until the ;
cis/trans isomeric mixture contains at least about 90 percent, or even at least about 95 percent, of the cis isomer.
Slightly elevated, room, or lowered temperatures (e.g., about 15-45C.) and superatmospheric, atmospheric, or sub-atmospheric pressures can be used for the stereoisomerization reaction of the present invention. For reasons of economy, however, it is preferred to operate under ambient conditions, i.e., at room temperature and atmospheric pressure.
The alternative method of producing cis-zearalenol derivatives is by reducing the ketone group of the corresponding ' cis-zearalenone derivative, reducing conditions of temperature and pressure in the presence of a suitable reducing agent and ~
30 is also preferably carried out in solution in a stable solvent, -e.g., dimethylformamide, tetrahydrofuran, or a lower monohydric alkanol, such as isopropanol, methanol or ethanol. Preferred solution concentrations are about 5 to 10 weight percent.
Any reducing agent which is selective for the ketone group and unreactive with the solvent can be employed in the reaction. Most preferred is a borohydride such as sodium borohydride and potassium borohydride. The latter should not be used, however, in conjunction with an alcohol solvent. These borohydride reducing agents are advantageously employed in an amount which is at least equimolar to the amount of cis-zearalenone.
Subatmospheric, atmospheric, or superatmosPhericpressures can be used for the reduction reaction, with atmos-pheric pressure being preferred for economic reasons. The temperature to be employed will depend upon the choice of reducing agent and solvent but will generally be about 15 to 45C.
The alternative method of producing cis-zearalene or derivative thereof is by the reduction of the ketone group of cis-zearalenone or corresponding derivative of cis-zearalenone, to replace the oxygen of the ketone group with two hydrogen atoms. The reduction of the ketone group can be effected by several procedures. One of these procedures involves the Clemmensen reaction using zinc and hydrochloric acid; another involves the Wolff-Kishner reaction using hydrazine and alkali, e.g., sodium hydroxide.
Cis-compounds wherein the substituents on the benzene ring are hydroxyl groups, may be converted to compounds in which one or both of Rl and R2 are alkyl, alkanoyl, aryl, or aryl alkyl. In producing the compounds of the present invention where R is alkyl, conventional alkylation procedures may be used to replace the hydrogen atom of one or both of the hydroxyl ~0366~
groups on the benzene ring with an alkyl group. The alkylation may be by reaction with the corresponding dialkyl sulfates, e.g., dimethyl sulfate, diethyl sulfate, etc., to produce a -;
dialkyl substituted or a monoalkyl substituted compound with the alkyl group replacing the hydrogen of the hydroxyl group ortho to the ester group. The alkylation reaction may take place in a liquid medium such as water. Furthermore, a methyl group may selectively replace the hydrogen of the hydroxyl group para to the ester group on the benzene ring using diazo-methane.
The hydrogen atom hydroxyl substituents on the ~ -benzene ring may be replaced by a carbon-containing, cyclic group by a condensation reaction in a slightly alkaline, - -organic solvent medium with the corresponding acid anhydride or chloride of the cyclic compound. Illustrative of cyclic ~ -substituents, alkyl and aryl or aryl alkyl, are benzyl, bromo- - -benzyl, benzothiazolyl, phenyltetrazolyl, benzoxazolyl, tetra-hydrofuranyl, tetrahydropyranyl, cyclopentyl, cyclohexyl, naphthyl, etc.
Where R is desired to be alkanoyl, conventional acylation procedures may be used to replace the hydrogen atom of both the hydroxyl groups on the benzene nucleus with an alkanoyl radical. For instance, acylation may be effected by reaction with the corresponding acid anhydride, e.g., acetic anhydride, propionic anhydride, etc., catalyzed with, for example, sodium acetate or pyridine. Ambient conditions may be -employed although it is preferred to keep the reaction mixture cold.
The cis isomers of the present invention can be administered to animals by any suitable method, including oral and parenteral administrations or as an implant. For example, 1036~i1i the compounds can be blended with ordinary feed which contains nutritional values in an amount sufficient to produce the desired rate of growth and thus be fed directly to the animals, or the compounds can be suspended in a suitable injection suspension medium, such as peanut oil, and injected parenter- -ally. The amount of compound fed to an animal varies, of course, upon the animal, the desired rate of growth, and the like. In general, from 2.5 to 50 grams of the compound per ton of feed is typical. When an implant is used, for example a ball or cylindrical implant inserted under the skin on the ear of an animal, e.g., a lamb or steer, the implant will generally contain from 1 mg. to 100 mg, of the compound.
When an isomer of this invention is to be administered to animals in their feed, an animal feed composition may be prepared containing the usual nutritionally-balanced quantities of carbohydrates, proteins, vitamins, and minerals together with the isomer. Some of the usual sources of these dietary elements are grains, such as ground grain and grain by-products;
animal protein substances, such as those found in fish meal and meat scraps; vegetable proteins, such as soybean oil meal or peanut oil meal; vitaminaceous materials, e.g., vitamins A and D mixtures; riboflavin supplements and other vitamin B
complex members; and bone meal and limestone to provide minerals. A type of conventional feed material for use with cattle, for example, includes alfalfa hay and ground corn cobs, together with supplementary vitaminaceous substances if desired.
EXAMPLE I
".
This example illustrates the preparation of cis-zearalene from trans-zearalene in accordance with the method of this invention. One gram of trans-zearalene is dissolved -in 500 milliliters of methanol, and the solution is placed in a 500 milliliter photochemical reactor (Ace Glass Model 6515) ~ -equipped with a borosilicate glass immersion well (Ace Glass Model 6517-05). The solution is purged with nitrogen for about 12 hours and is then irradiated under a nitrogen atmos-phere with a 450-watt, medium pressure, mercury vapor lamp --(Ace Glass Model 6515-34) for 24 hours. The resulting solution is evaporated to dryness under vacuum on a rotary evaporator and the residue is recrystallized from benzene to give 0.70 gram of cis-zearalene as white crystals having a melting point of 143 to 145C. Analysis indicates the presence of 70.67 weight percent carbon and 8.27 weight percent hydrogen, as compared with theoretical values of 71.05 weight percent carbon and 7.89 weight percent hydrogen. ~
EXAMPLE II ;-Samples of cis-zearalene are tested for uterotropic `-activity according to the well known mouse uterine test. This test consists of feeding the test compound in a sesame oil carrier to ten, adult, ovariectomized female mice for three 20 days at a ration of 50, 100, and 300 micrograms of compound per mouse per day. On day four the animals are sacrificed, and the uteri are removed and weighed. The test result~ are reported in Table I.
:
`
TABLE I ~ -Test Total Uterine ~ Body Compound Dose (~g) Weight (mg) Weight Control ---- 10.3 0.041 Trans-zearalenone 300 26.2 0.100 Trans-zearalene 300 16.2 0.066 900 18.1 0.070 Cis-zearalene 150 22.6 0.087 300 30.3 0.120 ~
900 48.6 0.188 ~ -EXAMPLES III to X
Essentially the same procedure used in Example I is followed to prepare cis isomers of compounds of the general formula R2Ol~
\~H2--CH2 wherein the values of Rl, R2 and Z are set forth below for the respective examples from the corresponding trans isomers where-in the values for Rl, R2 and Z are the same as in the product.
~ . , .
The starting compounds can be produced in accordance with the above-identified United States Patents issued to Hodge.
i .
', :, . ~
_g_ :~
,, ., . ., .. ,. ... ~ . , . ~ . .. .
~ t 1l~36611 : EXAMPLE R R Z
III -CH3 -CH3 ~ CH2 IV -CH2CH3 -CH2CH3 > CH2 : . -V -C-CH3 -CH3 >CH2 ~
. VI -CH3 -CH3 > CHOH :
` VII -H benzyl > C=O ;
- VIII -H bromobenzyl ~ C=O : `:
, ' ' ~ '~
10 IX -CH3 -C-CH3 > CH2 ;
:- o -C-C4Hg -C-C4Hg > C=O
-~ a feed mixture is prepared from each of the above compounds having 10 ounces of the cis isomer per one hundred pounds of . :~
mixture comprising alfalfa hay and ground corn cobs and is -~
used to feed in daily ration portions six head of cattle.
. . .
.
. . .
.' ' ., " ' , ' .' . 1 ,:, .
:'' '' ~ ~, .
- .
.: .. :
.:: .
~: . . . . . ... .
Claims (9)
1. A process of producing a compound of the formula wherein Z is , or and each of R1 and R2 is selected from hydrogen, lower alkyl, lower alkanoyl, monocyclic aryl of about 5 to 10 carbon atoms or aryl alkyl of monocyclic aryl containing about 5 to 10 carbon atoms and lower alkyl, R1 and R2 being the same or different, with the proviso that when both R1 and R2 are hydrogen, Z is , which comprises irradiating the corresponding trans isomer with electromagnetic radiation having a wavelength generally from about 2800 to 3500 angstroms.
2. A compound of the formula:
wherein Z is , or and each of R1 and R2 are selected from hydrogen, lower alkyl, lower alkanoyl, mono-cyclic aryl of about 5 to 10 carbon atoms or aryl alkyl of mono-cyclic aryl containing about 5 to 10 carbon atoms and lower alkyl, R1 and R2 being the same or different, with the proviso that when both R1 and R2 are hydrogen, Z is , whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.
wherein Z is , or and each of R1 and R2 are selected from hydrogen, lower alkyl, lower alkanoyl, mono-cyclic aryl of about 5 to 10 carbon atoms or aryl alkyl of mono-cyclic aryl containing about 5 to 10 carbon atoms and lower alkyl, R1 and R2 being the same or different, with the proviso that when both R1 and R2 are hydrogen, Z is , whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1, wherein trans--zearalene is irradiated with electromagnetic radiation having a wavelength generally from about 2800 to 3500 angstroms, thereby to produce cis-zearalene.
4. Cis-zearalene, whenever prepared or produced by the process of claim 3 or by an obvious chemical equivalent thereof.
5. The process of claim 1, wherein the material irradiated is in solution during the irradiation.
6. The process of claim 1, wherein the solution is essentially devoid of oxygen and is in an atmosphere of inert gas during the irradiation.
7. The process of claim 5, wherein the solution is essentially devoid of oxygen and is in an atmosphere of inert gas during the irradiation.
8. The process of any one of claims 1, 5 or 6, wherein the material irradiated is in solution in a lower monohydric alkanol during the irradiation.
9. The process of claim 7, wherein the material irradiated is in solution in a lower monohydric alkanol during the irradiation.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31711772A | 1972-12-21 | 1972-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1036611A true CA1036611A (en) | 1978-08-15 |
Family
ID=23232189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA183,623A Expired CA1036611A (en) | 1972-12-21 | 1973-10-17 | Cis-zearalene and related compounds |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5238560B2 (en) |
| AR (1) | AR198706A1 (en) |
| AT (1) | AT330379B (en) |
| BE (1) | BE808879R (en) |
| CA (1) | CA1036611A (en) |
| CH (1) | CH587840A5 (en) |
| DE (1) | DE2361061A1 (en) |
| ES (1) | ES421340A1 (en) |
| FR (1) | FR2246269B2 (en) |
| GB (1) | GB1405228A (en) |
| IE (1) | IE38756B1 (en) |
| IL (1) | IL43530A (en) |
| NL (1) | NL7316781A (en) |
| PH (1) | PH10907A (en) |
| ZA (1) | ZA738129B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0231012A (en) * | 1988-07-20 | 1990-02-01 | Kayou Kogyo Kk | Insert |
-
1973
- 1973-10-17 CA CA183,623A patent/CA1036611A/en not_active Expired
- 1973-10-19 ZA ZA738129*A patent/ZA738129B/en unknown
- 1973-10-31 IL IL43530A patent/IL43530A/en unknown
- 1973-11-13 AR AR250976A patent/AR198706A1/en active
- 1973-11-19 PH PH15234A patent/PH10907A/en unknown
- 1973-11-20 CH CH1627673A patent/CH587840A5/xx not_active IP Right Cessation
- 1973-11-29 JP JP48133116A patent/JPS5238560B2/ja not_active Expired
- 1973-11-30 FR FR7342719A patent/FR2246269B2/fr not_active Expired
- 1973-12-03 ES ES421340A patent/ES421340A1/en not_active Expired
- 1973-12-07 DE DE2361061A patent/DE2361061A1/en active Pending
- 1973-12-07 NL NL7316781A patent/NL7316781A/xx not_active Application Discontinuation
- 1973-12-11 GB GB5739073A patent/GB1405228A/en not_active Expired
- 1973-12-12 IE IE2252/73A patent/IE38756B1/en unknown
- 1973-12-18 AT AT1060773A patent/AT330379B/en not_active IP Right Cessation
- 1973-12-20 BE BE139077A patent/BE808879R/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH587840A5 (en) | 1977-05-13 |
| IL43530A (en) | 1977-06-30 |
| ES421340A1 (en) | 1976-07-01 |
| IE38756L (en) | 1974-06-12 |
| NL7316781A (en) | 1974-06-25 |
| JPS5238560B2 (en) | 1977-09-29 |
| IE38756B1 (en) | 1978-05-24 |
| AT330379B (en) | 1976-06-25 |
| ATA1060773A (en) | 1975-09-15 |
| DE2361061A1 (en) | 1974-07-11 |
| PH10907A (en) | 1977-10-04 |
| GB1405228A (en) | 1975-09-10 |
| BE808879R (en) | 1974-04-16 |
| FR2246269A2 (en) | 1975-05-02 |
| AR198706A1 (en) | 1974-07-15 |
| JPS4988891A (en) | 1974-08-24 |
| ZA738129B (en) | 1974-08-28 |
| FR2246269B2 (en) | 1977-10-28 |
| AU6180873A (en) | 1975-05-01 |
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