US2929713A - Preparation of coumestrol esters and use thereof - Google Patents
Preparation of coumestrol esters and use thereof Download PDFInfo
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- US2929713A US2929713A US713514A US71351458A US2929713A US 2929713 A US2929713 A US 2929713A US 713514 A US713514 A US 713514A US 71351458 A US71351458 A US 71351458A US 2929713 A US2929713 A US 2929713A
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- coumestrol
- esters
- ester
- acid
- estrogenic
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
Definitions
- esterification-promoter such as for example the alkali metal salt of the acid in question (e.g., sodium acetate when coumestrol acetate is being prepared), pyridine, quinoline, potassium carbonate, or the like.
- the coumestrol esters are readily isolatable from the reaction mixture on addition of water since they are'relatively insoluble in this solvent.
- mice were fed with the ration ad libitum, supplying a definite amount of ration to each animal so that at the end of the test the amount of ration consumed by each animal can be calculated whereby to determine the amount of test material ingested by each animal.
- the feed may contain on the order of 0.001 to 1 1b. of estrogenic factor per ton of feed.
- the estrogenic factor may be applied for example to chickens, turkeys, geese, ducks, swine, sheep, cattle, horses, and so forth.
- important practical effects are gained including increased rate of gain and increased efiiciency of feed utilization.
- the invention is of particularly practical value as applied to animals, such as steers, which are grown primarily for meat.
- the animals are caused to gain Weight more rapidly and produce more flesh per unit weight of feed with resulting economic benefits.
- Coumestrol may also be prepared by organic synthesis as described in the copending application of O. H. Emerson and E. M. Bickoff, Serial No. 710,586, filed Jan. 22, 1958, now Patent No. 2,884,427, granted April 28, 1959.
- omega (2,4-dimethoxyphenyl) resacetophenone is reacted with methyl chloroformate and the product reacted with alkali to produce 3(2,4-dimethoxyphenyl)-4,7-dihydroxy coumarin.
- the latter compound is then heated with aniline hydrochloride to effectuate a de-methylation and cyclization to produce coumestrol.
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Polymers & Plastics (AREA)
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- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
PREPARATIQN F COUMESTROL ESTERS AND USE THEREGF No Drawing. Application February 5, 1958 Serial No. 713,514
18 Claims. (Cl. 99-2) (Granted under Title 35, U.S. Code (1952), see. 266) A non-exclusive, irrevocable, royalty-free license in the invention herein described, throughout the world for all purposes of the United States Government, with the power to grant sublicenses for such purposes, is hereby granted to the United States of America. v
This invention relates in general to new coumarin derivatives, processes of synthesizing them, and methods and compositions for practical utilization of these compounds. The objects of the invention include the provision of novel methods for synthesizing coumestrol esters, the provision of coumestrol esters as new compounds, the provision of animal feeds and other compositions containing these esters, and the provision of methods for producing and utilizing such compositions. Further objects and advantages of the invention will be evident from the description herein.
In our copending patent application Serial No. 693,785, filed Oct. 31, 1957, now Patent No. 2,890,116, granted June 9, 1959, there is disclosed a previously unknown compound and methods for isolating it from forage crops such as ladino clover, alfalfa, etc. It is also disclosed that the compound exhibits estrogenic activity and may be employed in animal raising to obtain increased weight gain and increased efiiciency of feed utilization. The compound in question has been named coumestrol and structurally it is 7',6-dihydroxycoumarino (3,4-3,2)-coumarone having the formula This compound will be referred to herein as coumestrol for the sake of brevity without loss of accuracy.
It has now been found that the esters of coumestrol constitute valuable estrogenic agents. Moreover, these esters possess significant advantages over coumestrol in that they are more stable and are more readily produced in pure, crystalline form than coumestrol. The esters exhibit essentially the same estrogenic activity as coumestrol and may be employed in analogous manner in animal raising as further explained below.
In accordance with the invention, coumestrol esters may be readily prepared by acylating coumestrol. A preferred embodiment of the process is set forth below by way of illustration but not limitation:
Example 1 Three parts by weight of coumestrol was suspended in 90 parts by weight of acetic anhydride and 10 parts by weight of sodium acetate. The mixture was brought to .a boil then poured into ice water. The separated crystals of coum strol diacetate were removed by filtration. The product, obtained in essentially the theoretical yield, was
2,929,713 i atented Mar. 22, 196i.)
recrystallized from acetone-ethanol. was 234-235 C.
Analysis-Calculated for C H O C, 64.75%; H, 3.44%. Found:'C, 64.7%; H, 3.51%. The compound may also be termed 7 ',G-diacetyloxycoumarino-( 3',4'-3,2) coumarone.
It will be found in a practice of the method exemplified above that many variations may be followed within the scope of the invention. For example, the acetic anhydride may be replaced by other acylating agents to obtain esters of acids other than acetic acid. Thus the acylating agent may be, for example, the anhydride, chloride, bromide, or iodide of any aliphatic acid such as acetic, propionic, butyric, isobutyric, valeric, isovaleric, caproic, caprylic, capric, lauric, myristic, palmi tic, stearic, olei c, palmitoleic, arachidic, and so forth. It is obvious that by selection of the acylating agent, any desired coumestrol ester can be prepared. The acylating agent is employed in a. proportion to furnish at least 2 moles of the acyl radical per mole of coumestrol thusto ensure esterifying both hydroxyl groups. To enhance contact between the reactants an inert solvent may be added, or, in the alternative, such an excess of acylating agent may be used as to function both as reactant and solvent. Suitable inert .solvents are, for example, benzene, toluene, xylene, dioxane, acetone, ether, methylethyl kctone, diethyl "ketone, di-isopropyl ether, the diethyl ether of ethylene glycol, etc. The temperature of reaction is not critical and may be varied, for example, about from 0 to '175" C. The reaction is, of course, complete when the desired di-ester is formed. To expedite the esterification it is preferred to add to the re action system a conventional esterification-promoter such as for example the alkali metal salt of the acid in question (e.g., sodium acetate when coumestrol acetate is being prepared), pyridine, quinoline, potassium carbonate, or the like. The coumestrol esters are readily isolatable from the reaction mixture on addition of water since they are'relatively insoluble in this solvent.
The coumestrol esters of the invention are new compounds not hitherto described or prepared, nor are they present in any natural plant or animal materials. These compounds may be represented by the formula Its melting point represent the same or dilferent aliphatic acyl radicals derived for example, from acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, arachidic acid, or the like.
The esters of coumestrol have many advantages over coumestrol itself. Primarily, the esters are more stable and can be stored for long periods without change; coumestrol tends to oxidize on storage. Moreover, the esters are easier to isolate because they crystallize readily producing pure products characterized by sharp melting points. Moreovenit has been ascertained that coumestrol esters exhibit essentially the same estrogenic properties, qualitatively and quantitatively, as coumestrol. That such would be the case could not have been foretold in view of the substantial difference in compositionfthat is, the
free hydroxyl groups in coumestrol and the ester groups in the new compounds. in a matter so complex as a physiological effect on animals, it would have been expected that conversion of the hydroxy to ester groups would fundamentally alter the physiological response.
The estrogenic activity of coumestrol diacetate is illustrated by the following example.
Example II Estrogenic assays were conducted by feeding female mice with a basal ration containing coumestrol diacetate. Another batch of the mice were fed the basal ration containing coumestrol. A control batch of mice were fed the basal ration as such. Each batch of mice contained animals. After a period of 7 days, the mice were sacrificed and their uteri were excised and weighed. An increase in uterine weight denotes estrogenic activity in the material under test, the greater the uterine weight over the control, the more potent the material tested. The basal ration had the following composition:
Ingredient: Proportion, percent Corn meal 75 Linseed oil cake meal Crude casein l0 Codliver oil 3 Bone ash 1.5 Sod. chloride 0.5
In these tests, the mice were fed with the ration ad libitum, supplying a definite amount of ration to each animal so that at the end of the test the amount of ration consumed by each animal can be calculated whereby to determine the amount of test material ingested by each animal.
The results of the assays are set forth below:
Amount Average Materiel tested led. mg. uterine per weight,
mouse mg.
Control (basalration) 8.7 Qoumes 0. 375 30. 6 D0 0. 75 $0. 8 Coumestrol diaeetate 0. 5 31. 7 Do l. 0 90. 0
It is well known in the field of animal husbandry that it is often desirable to provide animals with estrogenic preparations particularly weight gain and increasing efiiciency of feed utilization. Such effects can be obtained by adding to the regular diet a minor proportion of diethylstilbestrol. Also, estrogenic agents such as diethylstilbestrol can be implanted subcutaneously in animals to obtain the desired effects. such procedure is commonly employed with fowls. The coumestrol esters of the invention display estrogenic properties and can be employed in place of known estrogenic compounds, as in feeds or in subcutaneous implantation, to accomplish like results of accelerating weight gain and increasing the proportion of flesh produced per lb. of feed. The cournestrol esters constitute a source of high and uniform estrogenic potency. As a consequence they can be administered to animals in controlled dosages to obtain predetermined physiological responses. Problems of low estrogenic concentration and variable estrogenic activity as encountered in direct feeding of forage containing natural estrogenic principles are completely obviated. Moreover, administration of the cournestrol esters does not involve any physical difiiculty of feeding because the esters can be administered in feeds or other compositions the ingredients of which can be selected to be compatible with the digestive systems or other characteristics of the animals in question. Also, the coumestrol esters can be administer by subcutaneous implantation or other techniques which require an active materialfree from extraneous components. Anotherpoint for the purpose of increasing $3;
is that the cournestrol esters are free from growth-inhibiting factors, saponins, or other detrimental agents naturally present in forage materials. Consequently, administration of the coumestrol esters to animals yields the useful results of attaining desired physiological response without any undesired side effects such as growth inhibition, bloating, etc.
The coumestrol esters of the invention may be employed in animal husbandry in the same manner as conventional with diethylstilbestrol and other known estrogenic agents. Thus the esters may be administered by incorporating them in conventional feeds; by addition to water or other fluid; by addition to grit fed to birds; by administration in capsules, pellets or by injection; by implantation of pellets, and so forth. The amount of the eser to be administered will of course vary depending on the type of animal, the body weight thereof, the physiological response desired, and the mode of administration. For example where the estrogenic factor is administered in admixture with a feed, dosage of the estrogenic factor may be that physiologically equivalent to about from 0.01 to 8 milligrams of diethylstilbestrol per 100 lbs. of body weight per day. Generally it is preferred to administer the estrogenic factor by incorporating it in a con entional feed. Thus the feed may consist mainly of vegetable material such as corn, wheat, barley, milo, hay, dehydrated alfalfa or other forage material, soybean meal, cottonseed meal, distillers grains, peanut meal, oat hulls, bran, corn stalks, corn cobs, sorghum, beet pulp, or the like. For a high-energy diet, a major proportion of grain or oil-seed meal is preferred. In addition to the main vegetable portion, the feed may contain the usual supplements such as mineral salts, vitamin preparations, fish meal, fish oil, linseed oil, antibiotic supplements, and so forth. In general the feed may contain on the order of 0.001 to 1 1b. of estrogenic factor per ton of feed. The estrogenic factor may be applied for example to chickens, turkeys, geese, ducks, swine, sheep, cattle, horses, and so forth. Thereby, important practical effects are gained including increased rate of gain and increased efiiciency of feed utilization. As noted above, the invention is of particularly practical value as applied to animals, such as steers, which are grown primarily for meat. Thus by application of the teachings of the invention the animals are caused to gain Weight more rapidly and produce more flesh per unit weight of feed with resulting economic benefits.
Coumestrol required as a starting material in the synthesis of the invention may be isolated from ladino clover, alfalfa, or strawberry clover by the procedures disclosed and claimed in our above-mentioned Patent 2,890,116. An illustrative example of isolating comics trol from ladino clover is set forth below.
Example III I A. Dehydrated ladino clover (430 lbs.) was covered with enough water to make 400 gallons and the mass was stirred overnight. The next day the mixture was filtered, the filtrate being discarded. The filter cakes were dried yielding 222 lbs. of dried solid material.
B. The dried material from step A was extracted with Skellysolve C (a petroleum distillate consisting mostly of normal heptane and having a boiling range of -208" F.) until the extract was no longer colored. A total of about 2000 gallons of solvent was used.
C. The solid residue from step B was repeatedly extracted with ether until the extract was no longer colored. A total of about 2000 gallons of ether was employed. The ether-insoluble solid residue was discarded. The ether extract was evaporated leaving a solid residue weighing 5 kilos and being a concentrate of coumestrol.
D. The coumestrol concentrate of step C was dissolved in warm chloroform employing 1 liter of the latter per 300 grams of concentrate. This solution was extracted with an aqueous solution of sodium carbonate having a pH of 12 employing 2 liters of carbonate solution per liter of chloroform solution. The resulting aqueous extract was separated, acidified to pH 6-6.5 with hydrochloric acid, then extracted with 5 liters of ether. The ether extract was separated and evaporated leaving 150 grams of further refined coumestrol.
E. The product of step D was then subjected to countercurrent distribution in the IOU-tube Craig apparatus, employing the solvent system described below. After distribution in solvent at, coumestrol was found to be concentrated in tubes 69 to 90. The material in these tubes was then distributed in solvent b whereby coumestrol was found to be concentrated in tubes 56-80. The materail in these tubes was distributed in solvent c whereby coumestrol was found to be concentrated in tubes 30 to 60. The material in these tubes was distributed in solvent d and coumestrol was found to be concentrated in tubes 25-58. The material in these tubes was distributed in solvent e and coumestrol was found to be concentrated in tubes 40-76. The material in these tubes was finally distributed by a 280-tube transfer in solvent 1 whereby it was found that coumestrol was concentrated in tubes 30 to 60. The liquid in these tubes was evaporated leaving a solid residue which was recrystallized from methanol-chloroform to yield 2 grams of pure, crystalline coumestrol.
The solvents used in the countercurrent distributions were as follows, the figures referring to parts by volume:
l A petroleum distillate consisting essentially of normal hexane and having a boiling range of 146-158" F.
Coumestrol may also be prepared by organic synthesis as described in the copending application of O. H. Emerson and E. M. Bickoff, Serial No. 710,586, filed Jan. 22, 1958, now Patent No. 2,884,427, granted April 28, 1959. In this synthesis omega (2,4-dimethoxyphenyl) resacetophenone is reacted with methyl chloroformate and the product reacted with alkali to produce 3(2,4-dimethoxyphenyl)-4,7-dihydroxy coumarin. The latter compound is then heated with aniline hydrochloride to effectuate a de-methylation and cyclization to produce coumestrol.
Having thus described the invention, what is claimed is:
1. An ester of coumestrol with an aliphatic carboxylic acid, of the formula wherein each of the radicals 0 ll RC- represents an aliphatic acyl radical.
2. Coumestrol acetate having the formula of claim 1 wherein each of the radicals i e o is the acetyl radical.
3. The method for preparing a coumestrol ester which comprises reacting coumestrol with an aliphatic acylating agent to produce an ester of coumestrol.
4. The method for preparing coumestrol diacetate which comprises reacting coumestrol with acetic anhydride to produce coumestrol diacetate.
5. A method of stimulating the growth of animals which comprises administering to the animals a physiologically adequate amount of an ester of coumestrol with an aliphatic carboxylic acid.
6. A method of stimulating the growth of animals which comprises supplying the animals with a diet containing a physiologically adequate amount of an ester of coumestrol with an aliphatic carboxylic acid.
7. The method of stimulating the growth of animals which comprises supplying the animals with a diet containing a major proportion of edible vegetable material and a minor proportion of an ester of coumestrol with an aliphatic carboxylic acid, the proportion of the latter being sufiicient to cause the animals to gain weight more rapidly and with consumption of less feed than would be the case were the animals supplied the vegetable material alone.
8. The method of claim 5 wherein the coumestrol ester is coumestrol diacetate.
9. The method of claim 6 wherein the coumestrol ester is coumestrol diacetate.
10. The method of claim 7 wherein the coumestrol ester is coumestrol diacetate.
11. An animal feeding composition comprising a major proportion of a non-toxic, ingestible carrier material and a minor but physiologically adequate proportion of an ester of coumestrol and an aliphatic carboxylic acid.
12. An animal feed comprising a major proportion of edible vegetable material and a minor but physiologically adequate proportion of an ester of coumestrol and an aliphatic carboxylic acid.
13. The composition of claim 11 wherein the coumestrol ester is coumestrol diacetate.
14. The composition of claim 12 wherein the coumestrol ester is coumestrol diacetate.
15. A method of increasing the dietary value of an animal feeding preparation containing mainly non-toxic, ingestible carrier material which comprises adding to the preparation a minor but physiologically adequate proportion of an ester of coumestrol and an aliphatic carboxylic acid.
16. A method of increasing the dietary value of an animal feed containing mainly edible vegetable material which comprises added to said feed a minor but physiologically adequate amount of an ester of coumestrol and an aliphatic carboxylic acid.
17. The method of claim 15 wherein the coumestrol ester is coumestrol diacetate.
18. The method of claim 16 wherein the coumestrol ester is coumestrol diacetate.
No references cited.
Claims (1)
1. AN ESTER OF COUMESTROL WITH AN ALIPHATIC CARBOXYLIC ACID, OF THE FORMULA
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US713514A US2929713A (en) | 1958-02-05 | 1958-02-05 | Preparation of coumestrol esters and use thereof |
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US713514A US2929713A (en) | 1958-02-05 | 1958-02-05 | Preparation of coumestrol esters and use thereof |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4831086A (en) * | 1987-10-05 | 1989-05-16 | Allied-Signal Inc. | Cyanato group containing phenolic resins, phenolic triazines derived therefrom |
US20110198082A1 (en) * | 2010-02-18 | 2011-08-18 | Ncs Oilfield Services Canada Inc. | Downhole tool assembly with debris relief, and method for using same |
US8931559B2 (en) | 2012-03-23 | 2015-01-13 | Ncs Oilfield Services Canada, Inc. | Downhole isolation and depressurization tool |
-
1958
- 1958-02-05 US US713514A patent/US2929713A/en not_active Expired - Lifetime
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4831086A (en) * | 1987-10-05 | 1989-05-16 | Allied-Signal Inc. | Cyanato group containing phenolic resins, phenolic triazines derived therefrom |
US20110198082A1 (en) * | 2010-02-18 | 2011-08-18 | Ncs Oilfield Services Canada Inc. | Downhole tool assembly with debris relief, and method for using same |
US8490702B2 (en) | 2010-02-18 | 2013-07-23 | Ncs Oilfield Services Canada Inc. | Downhole tool assembly with debris relief, and method for using same |
US8931559B2 (en) | 2012-03-23 | 2015-01-13 | Ncs Oilfield Services Canada, Inc. | Downhole isolation and depressurization tool |
US9140098B2 (en) | 2012-03-23 | 2015-09-22 | NCS Multistage, LLC | Downhole isolation and depressurization tool |
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