US2400034A - Racemic estrogenic compounds - Google Patents
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- US2400034A US2400034A US538090A US53809044A US2400034A US 2400034 A US2400034 A US 2400034A US 538090 A US538090 A US 538090A US 53809044 A US53809044 A US 53809044A US 2400034 A US2400034 A US 2400034A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/20—Preparation of ethers by reactions not forming ether-oxygen bonds by hydrogenation of carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
Definitions
- the ovarian follicular hormone obtained from I natural sources e. g. from theurine of pregnant female mammals
- I natural sources e. g. from theurine of pregnant female mammals
- this invention is directedis the chemical synthesis of substances having a potency approaching or-equal to-that of the natural hormone so that such substances may be widely dispensed and the. benefits flowing therefromgrendered available to a much larger group of patients than is possible in the case of the hormone obtained from natural sources.
- racemic mixtures may be isolated from this conglomerate having a potency higher than thatpossessed by the conglomerate of isomers.
- A is an inorganic .acid radica1 of the type represented by -SO4H, --PO4H:.
- the ter- 4 after contains a methoxy group: 02 will be alkoxy when the appropriate starting compound has an alkoxy group.
- any alkoxy group may be obtained in the final product, or by converting the OH groups in the final phenolic compound.
- the synthetic compound having this formula has two asymmetric carbon atoms and therefore four stereoisomers. It has been discovered that these may be separated into two racemic mixtures. Each of these mixtures ma then be converted into a compound havingthe general formula set forth above and there will then be obtained, from each racemic mixture, four. stereo isomers in the form of two racemic mixtures which may be separated. 'Ihus instead of attempting to separate a conglomerate of four racemic mixtures (eight stereoisomers) the probtures.
- any suitable condensing agent may be used, e. g., hydrochloric acid.
- the intermediate compound produced as shown in Step II is in the form of two racemic mixtures, one liquid and one solid. These mixtures are separated preferably by dissolving the two mixtures in a solvent, e. g., alcohol, and separating the solid racemic mixture by crystallization. The melting point of the said solid is 82 C. Evaporation of the solvent from the mother liquid leaves the liquid racemic mixture as a residue.
- Step IV hydrogenation is carried out by known methods, as by means of catalysts as described in the co-pending case referred to above, and these methods need not be elaborated. The same is true of the demethylation of Step V, which may be accomplished, for example, in the presence of inorganic mineral, acids as described in the co-pending case, or by means of inorganic bases as set forth below.
- Steps III to v to the solid racemic mixture produced as per Step II results in a compound havingthe formula shown a produced in Step V in the form of two solid racemic mixtures, both of which are crystalline, one having a melting point of C.-and the other a melting point of 144' 0.
- w mav be separatc o cn-cn-cn ocn n m m lstio a O O i e a n ed by fractional crystallization. Ithas been discovered that the product having the highest melting point of 160 C. has a higher potency than that having the lower melting point of 144 C.
- either or both of the 0H radicals may be converted into any desired other species of the general radical X by employing etherification, esterification, Or other appropriate methods.
- the solid racemic mixture of compounds hav ing the formula of the intermediate compound obtained as shown in Step II is preferred to the late dissolved in 800 'cc. of warm ethanol. From this solution, on standing over night in the refrigerator, the solid isomer (A) of 1,3--di-(pmethoxy-phenyl) -2-ethyl pentanone-l separates. After filtration and recrystallization from etha n01, this fraction weighs72 grams and melts at 82 C.
- a second isomer (B) may be obtained by liquid racemic mixture obtained in that step,
- This invention includes a further improvement residing in reducing or eliminating this loss in yield, by effecting appropriate changes in configuration in the liquid mixture in respect to one or morev of the carbon atoms in the 3-ca'rbon chain connecting the aromatic nuclei.
- One method is to enolize the liquid racemic mixture produced in Step II to change the configuration of the middle carbon atom in the 3-carbon chain.
- Step II --A solution of 178 grams (0.6 mole) of the above chalconein 500 cc. of dry ether is added evaporation of the ethanol from the above filtrate and distillation of the residue under reduced pressure. Itisapale yellow oil.
- Step HI grams of the solid form (A) of 1,3-di-(p-methoxy-phenyl) -2-ethyl pentanone as prepared in Step II is dissolved in 300 cc. of dry etherand added slowly to a stirred solution of 55 rams of methyl magnesium iodide in- 350 cc. of dry ether.
- the reaction ,mixture is refluxed on the steam bath for five hours and then-poured into 2 liters of ice water containing 200 cc. of concentrated hydrochloric acid.
- the ether layer is separated, the aqueous solution extracted once with ether, the combined solutions dried and the ether distilled therefrom.
- the primary reaction product which remains is heated at 150 C., whereupon water is evolved.
- the resulting final product is 2,4-di-(p-methoxy phenyl)-3-ethyl equivalent of hydrogen has been absorbed.
- Step V --A mixture of 7 grams or 2,4-di-(pmethoxy phenyl) -3-ethyl hexane (as prepared in StepIV) with 14 grams of potassium hydroxide and 25 cc. of ethanol is heated. at 200 C.'for 18 hours in a rocking autoclave. The resulting thick, clear liquid is diluted with water and filtered with charcoal to remove a slight turbidity, and the filtrate is acidified. The precipitate is extracted into ether, the solution dried and. the ether distilled oil. The residue may be sublimed in a high vacuum. From this sublimate two isomeric compounds can be obtained by fractional crystallization from benzene.
- Both are white solids and have the structure 2,4-di-(p-hydroxy phenyl) -3-ethyl-hexane.
- One of the isomers has a melting point of 160 C. and theother a melting aration of the racemic mixtures is eifected by slowly to a well-stirred solution of grams (1.8 65
- the radicals R in the formulas may be any alkyl radicals.
- the following specific examples of compounds having estrogenie is then distilled at mm. pressure and the distil- 1
- These compounds and their corresponding ethers can be prepared by the methods above disclosed.
- the ethers and esters can be prepared by applying standard etherification or esteriflcationtechnique CH: 51H: 11 2:
- the number of carbon atoms in each of the alkyl substituents on the propane bridge be'not greater than five, although the activity of compounds having substituents higher in the series is demonstratedby numerous examples, some of which are included herein.
- Process for preparing estrogenic compounds which comprises treating with wherein R is allryl and R1 is selected from the class consisting of H and alkyl, in the presence of an agent selected from the class consisting of inorganic mineral acids and inorganic bases, thereby forming a compound of the formula no OR treating the latter in the cold with RzMgX, wherein R: is alkyl and X is any halide except fluoride, thereby forming solid and liquid isomers of a diphenyl propanone represented by the formula 5 Hr -WU separating the solid from the liquid isomers thereof, treating the solid isomers under refiux ing conditions with RaMgX, where R: is an alkyl group and X is the same as before, thereby producing a compound of the formula ititif hydrogenating the latter in presence of a hydrogenation catalyst to a compound of the formula with wherein R is alkyl and R1 is selected from the class consisting of H and alkyl, in the presence of an agent selected from the class consisting of in
- Process for preparing estrogenic compounds which comprises treating BOGCHO wherein R is alkyl and Bi is selected from the class consisting of H and alkyl, in the presence of an. agent selected from the class consisting of inorganic mineral acids and inorganic bases,
- Process for preparing estrogenic compounds wnien comprises treating anisaldehyde with pride, thereby forming solid and liquid isomers of methoxy butyrophenone in the presence of hydrogen halide, thereby forming iA-dimethoxyalpha-ethvlchalcone; treating the latter in the cold with ethyl magnesium halide except the fluol,3-di(p-methoxyphenyl) 2 ethyl pentanone- 1; the solid from the liquid isomers thereof, treating the solid isomers under refluxing conditions with methyl magnesium halide except I the fluoride, whereby there is produced 2,4-di(pmethoxyphenyl) -3-ethyl hexene; hydrogenating the latter compound in the presence of a hydrogenation catalyst to 2,4-diip-meth'onphenyl) -3- ethyl hexan
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Description
Patented May 7,
UNITED STATES PATENT OFFICE Ralph C. Tallman, Westfleld, Stuart, New York, N. 1.,
.1 N.J.,sndAlfred mto felin a 00., New York, N. Y, a corporation of New York so mam. Application May :0, 1944;
Seth! No. 53am Claims. (01. sac-'41s) of .the female menstrual cycle and the "absence.
be accompanied by various pathothereof may logical symptoms.
The ovarian follicular hormone obtained from I natural sources, e. g. from theurine of pregnant female mammals, is too expensive to render it available for wide-spread use and the problem to the solution of which this invention is directedis the chemical synthesis of substances having a potency approaching or-equal to-that of the natural hormone so that such substances may be widely dispensed and the. benefits flowing therefromgrendered available to a much larger group of patients than is possible in the case of the hormone obtained from natural sources.
In our copending application Serial No. 363,669, there is a disclosure of compounds having the general formula x0 it 15: 15 --0x C i i i 2 and the use thereof as substitutes for the female follicular hormone. In that application those compounds are called Type V and it is pointed out that x may be selected from the group consisting of; H, alkyl, acyl; and ester radicals of phosphoric or sulfonic acid, and that each R is alkyl. 1
Various species of this X radical are listed asfollows ;for the purpose of illustration:
C:H1 etc.
' CHICO- canoe- OlHiCO This term is derived from pounds havingthe above general formula, com- The radical OX may be in the para position. v
A study of this formula reveals that, considering the chain of three carbon atoms connecting the aromatic nuclei, the terminal carbon atoms must always be asymmetric while the middle carbon atom may or may not 'be. Therefore the number of possible stereoisomers will either be four or eight. It has been discovered that it is possible to iso late from the conglomerate of isomers obtained by synthesis a single racemic mixture having a potency greater than that-of the mixture or conglomerate of isomers.
It is therefore an object of this invention to isolate from the conglomerate of stereoisomers obtained by synthesizing compounds having theabOV general formula, 8 racemic mixture having a potency (expressed in terms of its action as a substitute for the natural fem'aleovarian follicular hormone) greater than that of the mixture or conglomerate from which said racemic'mixture is'isolated. a
c Having defined the substances generically, it may be said that the various specie'sare distinguished by the positionand specific nature of the ox radical and the specific nature of thealkyl radicals R. I
It has been discovered that, among the compounds having the formula xo n lg 1g ox t. c. r29
are particularly desirable. When compounds having this formula are synthesized a conglomerate or mixture of eight stereoisomers is obtained because each of the three carbon atoms in 40 the chain connectinir the aromatic nuclei is asymmetric;
It has been discovered that individual racemic mixtures may be isolated from this conglomerate having a potency higher than thatpossessed by the conglomerate of isomers.
Objects of the following:
1. To synthesize compounds eral formula e iii v a xo it it iz ox I and to isolatefrom the conglomerate of stereoinvention therefore include the having the gen- I isomers thereby obtained. an individual racemic mixture having a potency greater than that of the conglomerate, in other words to obtain an individual racemic mixture of two compounds each having the above formula and to use it as a substitute for the ovarian follicular hormone obtainedfrom natural sources,
ortho, meta or 2. To obtain a racemic mixture of two compounds each having the formula .4. To obtain a racemic mixture of two compounds each having the formula 1 D Q Oalkyl o m1 5. To obtain a racemic mixture of two compounds each having the formula 6. To obtain a racemic mixture of two compounds having the formula t ta. ta
where A is an inorganic .acid radica1 of the type represented by -SO4H, --PO4H:.
It has been further discovered that the isolation of individual racemic mixtures from the conglomerate of isomers may be facilitated by the following general method:
First prepare an intermediate compound which we call a diphenyl propanone having the formula H n t t x0 7 it his the. ox where X has the definition given above. The
processes set forth in the said application flied of even date herewith may be used for this purpose.
Thus, as set forth in that application, the ter- 4 after, contains a methoxy group: 02 will be alkoxy when the appropriate starting compound has an alkoxy group. In this way any alkoxy group may be obtained in the final product, or by converting the OH groups in the final phenolic compound.
- The synthetic compound having this formula has two asymmetric carbon atoms and therefore four stereoisomers. It has been discovered that these may be separated into two racemic mixtures. Each of these mixtures ma then be converted into a compound havingthe general formula set forth above and there will then be obtained, from each racemic mixture, four. stereo isomers in the form of two racemic mixtures which may be separated. 'Ihus instead of attempting to separate a conglomerate of four racemic mixtures (eight stereoisomers) the probtures.
There are several ways of producing various species of the above mentioned intermediate compound and converting it into a compound having the general formula above set forth. One method will be shown as follows for purposes of illustration: .This will be done by first showing the reactions and then ing them.
giving detail for effect- H n Qv- In Step I any suitable condensing agent may be used, e. g., hydrochloric acid. The intermediate compound produced as shown in Step II is in the form of two racemic mixtures, one liquid and one solid. These mixtures are separated preferably by dissolving the two mixtures in a solvent, e. g., alcohol, and separating the solid racemic mixture by crystallization. The melting point of the said solid is 82 C. Evaporation of the solvent from the mother liquid leaves the liquid racemic mixture as a residue.
Either the solid or liquid racemie mixture may then be submitted to the following series of reactions:
omoOfi-gm-gnoo cm OHz-Mg-I i I 1H5 H omoO-cd-cn C -ocm EH: sHl lHl O 1 41 H onto 0cm mt HI El :35
. omoO-on-on-on-O-ocm JJH: IHI sHI Hi dis i I am In Step IV hydrogenation is carried out by known methods, as by means of catalysts as described in the co-pending case referred to above, and these methods need not be elaborated. The same is true of the demethylation of Step V, which may be accomplished, for example, in the presence of inorganic mineral, acids as described in the co-pending case, or by means of inorganic bases as set forth below. Y
Application of Steps III to v to the solid racemic mixture produced as per Step II results in a compound havingthe formula shown a produced in Step V in the form of two solid racemic mixtures, both of which are crystalline, one having a melting point of C.-and the other a melting point of 144' 0., w mav be separatc o cn-cn-cn ocn n m m lstio a O O i e a n ed by fractional crystallization. Ithas been discovered that the product having the highest melting point of 160 C. has a higher potency than that having the lower melting point of 144 C. These melting points relate to the specific substance shown as produced in Step V and will be different when the H radical is inthe ortho or meta position and also when it is substituted by other species of the radical X shown in the general formula. The position of the OH group is determined bythe corresponding position of the CHaO group.
Having obtained a phenolic compound as shown in Step V, either or both of the 0H radicals may be converted into any desired other species of the general radical X by employing etherification, esterification, Or other appropriate methods.
The solid racemic mixture of compounds hav ing the formula of the intermediate compound obtained as shown in Step II is preferred to the late dissolved in 800 'cc. of warm ethanol. From this solution, on standing over night in the refrigerator, the solid isomer (A) of 1,3--di-(pmethoxy-phenyl) -2-ethyl pentanone-l separates. After filtration and recrystallization from etha n01, this fraction weighs72 grams and melts at 82 C. A second isomer (B) may be obtained by liquid racemic mixture obtained in that step,
because the conversion of said solid mixture as shown in Steps III to V produces two solid racemic mixtures possessing the action of the follicular hormone in a potency of especially high value. The formula of the compounds in these two solid racemic mixtures is' that produced as shown in Step V. To use the solid, but not the liquid mixture would represent a considerable loss in yield of the mixtures produced as shown in Step V because the liquid and solid mixtures are about equal in weight.
This invention includes a further improvement residing in reducing or eliminating this loss in yield, by effecting appropriate changes in configuration in the liquid mixture in respect to one or morev of the carbon atoms in the 3-ca'rbon chain connecting the aromatic nuclei. One method is to enolize the liquid racemic mixture produced in Step II to change the configuration of the middle carbon atom in the 3-carbon chain.
' For example, by enolizing the liquid racemic mixstep I.Into a mixture of 100 grams of 9-,
methoxy butyrophenone and 74 grams anisaldehyde, maintained at -20 C.,'dry hydrogen chloride gas is bubbled until the total weight is increased by grams. The thick mass resultin is allowed to stand over night, is then heated to 130-150 C. until all water and hydrogen chloride has been driven off, and is finally distilled under reduced pressure. Following a small amount of lower-boiling forerun, the desired 4,4-di-methoxy-e-ethylchalcone distills at'190-200" C. under 1 mm. pressure. It is a bright yellow oil.
Step II.--A solution of 178 grams (0.6 mole) of the above chalconein 500 cc. of dry ether is added evaporation of the ethanol from the above filtrate and distillation of the residue under reduced pressure. Itisapale yellow oil.
Step HI. grams of the solid form (A) of 1,3-di-(p-methoxy-phenyl) -2-ethyl pentanone as prepared in Step II is dissolved in 300 cc. of dry etherand added slowly to a stirred solution of 55 rams of methyl magnesium iodide in- 350 cc. of dry ether. The reaction ,mixture is refluxed on the steam bath for five hours and then-poured into 2 liters of ice water containing 200 cc. of concentrated hydrochloric acid. The ether layer is separated, the aqueous solution extracted once with ether, the combined solutions dried and the ether distilled therefrom. The primary reaction product which remains is heated at 150 C., whereupon water is evolved. The resulting final product is 2,4-di-(p-methoxy phenyl)-3-ethyl equivalent of hydrogen has been absorbed. The
solution is then filtered free Of the catalyst, diluted with water and neutralized with sodium hydroxide; The product is extracted into ether, the
solution dried, and the ether distilled on. The residue is 2,4-di-(p-methoxy phenyl)-3-ethyl hexane. It is a colorless 011.
Step V.--A mixture of 7 grams or 2,4-di-(pmethoxy phenyl) -3-ethyl hexane (as prepared in StepIV) with 14 grams of potassium hydroxide and 25 cc. of ethanol is heated. at 200 C.'for 18 hours in a rocking autoclave. The resulting thick, clear liquid is diluted with water and filtered with charcoal to remove a slight turbidity, and the filtrate is acidified. The precipitate is extracted into ether, the solution dried and. the ether distilled oil. The residue may be sublimed in a high vacuum. From this sublimate two isomeric compounds can be obtained by fractional crystallization from benzene. Both" are white solids and have the structure 2,4-di-(p-hydroxy phenyl) -3-ethyl-hexane. One of the isomers has a melting point of 160 C. and theother a melting aration of the racemic mixtures is eifected by slowly to a well-stirred solution of grams (1.8 65
moles) of ethyl magnesium bromide in l200'cc.
of dry ether maintained below 'l C. After addition is complete stirring is continued for three hours at room temperature and the mixture is then poured into 3 liters of ice water containing cc. of concentrated sulfuric acid. The ether fractional crystallization, it is evident that where warranted, other methods of separation, e. g. distillation, use of selective solvents and any suitable method of fractionation may be em loyed, as will be apparent to those skilled in the art in the light of the invention herein described and claimed. In some cases the mixtures crystallize out as two solid isomers, in which case fractional crystallization may be resorted to. When the isomers are both liquid, fractional distillation may frequently be employed.
As stated at the beginning, the radicals R in the formulas may be any alkyl radicals. In support of this generic statement the following specific examples of compounds having estrogenie is then distilled at mm. pressure and the distil- 1| and bactericidal properties are given. These compounds and their corresponding ethers can be prepared by the methods above disclosed. The ethers and esters can be prepared by applying standard etherification or esteriflcationtechnique CH: 51H: 11 2:
a a. Cfla... a. in. he. in. in. no if i: on i... i... n
It is preferred that the number of carbon atoms in each of the alkyl substituents on the propane bridge .be'not greater than five, although the activity of compounds having substituents higher in the series is demonstratedby numerous examples, some of which are included herein.
A specific example of the conversion of one of the hydroxy compounds to the corresponding ester is as follows:
One gram of 2,4-di-(p-hydroxy phenyl) -3- ethyl hexane is refluxed for 3% hours with a mixture of cc. of propionic anhydride and 0.5 gram of fused sodium propionate. The reaction mixture is diluted with water and made alkaline with potassium hydroxide, and the prodnot is extracted in ether. After removal of the ether the desired ester is obtained as a thick yellow oil which has a boiling point of 185-190 C. at 0.5 mm. pressure.
As many apparently widely diiferent embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be understood that we do not limit ourselves to the specific embodiments thereof except as defined in the appended claims.
we claim:
1. Process for preparing estrogenic compounds which comprises treating with wherein R is allryl and R1 is selected from the class consisting of H and alkyl, in the presence of an agent selected from the class consisting of inorganic mineral acids and inorganic bases, thereby forming a compound of the formula no OR treating the latter in the cold with RzMgX, wherein R: is alkyl and X is any halide except fluoride, thereby forming solid and liquid isomers of a diphenyl propanone represented by the formula 5 Hr -WU separating the solid from the liquid isomers thereof, treating the solid isomers under refiux ing conditions with RaMgX, where R: is an alkyl group and X is the same as before, thereby producing a compound of the formula ititif hydrogenating the latter in presence of a hydrogenation catalyst to a compound of the formula with wherein R is alkyl and R1 is selected from the class consisting of H and alkyl, in the presence of an agent selected from the class consisting of inorganic mineral acids and inorganic bases, thereby forming a compound of the formula treating the latter in the cold with Rmgx, wherein R: is alkyl and X is any halide except fluoride, thereby forming a mixture of stereoisomers of a diphenyl propanone represented by the formula ir-Z separating the stereoisomers into racemic pairs. subjecting the pairs separately to a course of treatment comprising reacting a racemic pair of stereoisomers under refluxing conditions with mwhmniisanalkylgroupandxisthe same as before, thereby producing a compound oi the formula no on Dry-gsg I l I hydrogenating the latter in presence of a hydror genation catalyst to a compound of the formula no on and deetherifying thiscompound in the presence of a material selected from the group consisting which comprises 4. Process for preparing estrogenic compounds treating ROOCO 01mm with .wherein R is alkyl and R1 is selected from the class consisting of H and alkyl, in the presence of inorganic mineral acids and inorganic bases.
thereby forming a eompound'of the formula no on IE I FiK-iH-iH-O 3. Process for preparing estrogenic compounds which comprises treating BOGCHO wherein R is alkyl and Bi is selected from the class consisting of H and alkyl, in the presence of an. agent selected from the class consisting of inorganic mineral acids and inorganic bases,
thereby forming a mixture of stereoisomers of a .diphenyl propanone represented by the formula it-t0 separating the stereoisomers into racemic pairs, subjecting the. pairs separately to a course of treatment comprising reacting a raeemic pair of of an agent selected from the class consisting of inorganic mineral acids and inorganic bases,
thereby forming a compound of the formula treating the latter in the cold with mmx, wherein R2 is alkyl and x is any halide except fluoride,
thereby forming solid and liquid isomers of a diphenyl propanone represented by the formula separating the solid from the liquid isomers thereof, treating the solid isomers under refluxing conditions with RaMgX, where R: is an allryl group and x is the same as before, whereby there is produced a compoimd of the formula hydrogenating the latter in. presence of a hydrogenation catalyst to a compound of the formula and deetherifying this compound in the presence of a material selected from the group consisting of inorganic mineral acids and inorganic bases,
thereby forming a compound of the formula stereoisomers under refluxing conditions with Rslilgx, where R: is an alkyl group and]! isthe same as before, whereby there is produced a compound of the formula r BOGKZHEHOOR hydrogenating the latter in presence of a hydrogenation catalyst to a compound of the formulav 30003423 01100 11! 1 i and deetherifying this compound in the presence of a material selected from the group wnsisting of inorganic mineral acids and inorganic bases,
thereby forming a compound of the formula HoOin-in-in-Oom 5. Process for preparing estrogenic compounds wnien comprises treating anisaldehyde with pride, thereby forming solid and liquid isomers of methoxy butyrophenone in the presence of hydrogen halide, thereby forming iA-dimethoxyalpha-ethvlchalcone; treating the latter in the cold with ethyl magnesium halide except the fluol,3-di(p-methoxyphenyl) 2 ethyl pentanone- 1; the solid from the liquid isomers thereof, treating the solid isomers under refluxing conditions with methyl magnesium halide except I the fluoride, whereby there is produced 2,4-di(pmethoxyphenyl) -3-ethyl hexene; hydrogenating the latter compound in the presence of a hydrogenation catalyst to 2,4-diip-meth'onphenyl) -3- ethyl hexane; and dee s the last named eon't oumiinthepreseneeo'fitznttteriaiseieeteuv from the class consisting of inorganic mineral acids and inorganic bases. thereby forming 2,4- di(p-hydro xyphcnyl) -3-ethyi hexane.
RAIPB C. TAU-MAN.
strain a. smear.
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Application Number | Priority Date | Filing Date | Title |
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US538090A US2400034A (en) | 1944-05-30 | 1944-05-30 | Racemic estrogenic compounds |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US538090A US2400034A (en) | 1944-05-30 | 1944-05-30 | Racemic estrogenic compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US2400034A true US2400034A (en) | 1946-05-07 |
Family
ID=24145446
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US538090A Expired - Lifetime US2400034A (en) | 1944-05-30 | 1944-05-30 | Racemic estrogenic compounds |
Country Status (1)
Country | Link |
---|---|
US (1) | US2400034A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2447917A (en) * | 1946-03-22 | 1948-08-24 | Edwin A Strattman | Spirally contractable mop wringing attachment for scrub buckets |
US2476679A (en) * | 1945-10-18 | 1949-07-19 | Morren Henri | Production of p,p'-dihydroxy-3, 4-diphenylhexane of mesoid form |
US2686199A (en) * | 1949-07-19 | 1954-08-10 | Firestone Tire & Rubber Co | Reaction product of bisphenol-a and salicylic acid |
-
1944
- 1944-05-30 US US538090A patent/US2400034A/en not_active Expired - Lifetime
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2476679A (en) * | 1945-10-18 | 1949-07-19 | Morren Henri | Production of p,p'-dihydroxy-3, 4-diphenylhexane of mesoid form |
US2447917A (en) * | 1946-03-22 | 1948-08-24 | Edwin A Strattman | Spirally contractable mop wringing attachment for scrub buckets |
US2686199A (en) * | 1949-07-19 | 1954-08-10 | Firestone Tire & Rubber Co | Reaction product of bisphenol-a and salicylic acid |
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