US3925487A - Substituted diphenyl ethene - Google Patents

Substituted diphenyl ethene Download PDF

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US3925487A
US3925487A US887335A US88733569A US3925487A US 3925487 A US3925487 A US 3925487A US 887335 A US887335 A US 887335A US 88733569 A US88733569 A US 88733569A US 3925487 A US3925487 A US 3925487A
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ethenes
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diphenyl
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Bernt Borretzen
Knut Gunnar Olsson
Bertil Sundbeck
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Pharmacia Animal Health Inc
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Ferrosan AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/02—Magnesium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • 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
    • C07C45/70—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 with functional groups containing oxygen only in singly bound form
    • C07C45/71—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 with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/02—Lithium compounds

Definitions

  • ABSTRACT relates to a new process for the preparation of unsymmetrical substituted dihydroxy diphenyl ethenes or esters thereof comprising both new and known compounds and having valuahlc pharmacological activity. According to the new process acetals oi the dihydroxy diphenyl ethenes are used instead of their esters for protecting the phenol groups.
  • the monoor diaeetals ol' the earhinols corresponding to the desired diphenyl ethenes are dehydrated in a manner known per se to form mono or diacetals. of the desired diphenyl ethenes and either cleaving said acetals in a way known per se to form the desired dihydroxy diphenyl ethenes and, if desired, esterifying said dihydroxy compounds in a way known per se. or converting said acetals directly in a way known per se to the desired esters of the dihydroxy di phenyl ethenes.
  • the dehydration step and the cleavage step or the conversion step resp. may be combined into a single step.
  • the invention also relates to certain new dihydroxy diphcnyl ethenes pre pared according to the invention.
  • the present invention relates to a new process for the preparation of unsymmetrical substituted diphenyl ethenes having the general formula or esters thereof with suitable acids such as saturated aliphatic carboxylic acids having from I to 18 carbon atoms such as e.g.
  • Dihydroxy diphenyl ethenes of formula I and their esters are previously known from the U.S. Pat. Nos. 3,237,200; 3,406,209 and 3,287,397. Said compounds have pharmacological activity comprising estrogenic and antiestrogenic activity and inhibition of the secretion of gonadotropins from the pituitary gland.
  • the process according to the invention for the preparation of the diphenyl ethenes of formula I is characterized in that mono or diacetals having the general formula wherein R, and R, have the above-mentioned meaning and R represents a group having the general formula R, c
  • the cleavage of the mono or diacetals of formula IV occurs very easily, preferably with an alcoholic acid, e.g. I ethanolic hydrochloric acid, said acetals of formula IV being converted to the diphenols of formula I.
  • the cleavage may also be carried out in such a way that the esters of the phenols of formula I are obtained directly from the acetals of formula IV, e.g. with the aid of lower acid anhydrides.
  • Acetic acid anhydride in pyridine gives e.g., the diacetate of a diphenol of formula I.
  • the cleavage may also, when R is not hydrogen, be carried out by vigorous heating, the acetal groups being removed as vinyl ethers with the formation of diphenols of formula I.
  • the dihydroxy diphenyl ethenes of formula I are, as already mentioned, previously known from the U.S. Pat. Nos. 3,237,200; 3,406,209 and 3,287,397 according to which they are prepared by another process with the fundamental difference that the protecting group used for the protection of the phenol groups instead of being an acetal group as in the process of the present invention is a lower alkyl group, generally a methyl group.
  • This difference is of decisive importance. While the acetal group easily can be removed e.g., as already mentioned above, by short boiling in diluted alcoholic acid the removal of the methyl group in the first place is carried out by treating with alkali (NaOI-I, KOI-I) in alcoholic solution at 200C.
  • carbinols of formula II which are used as starting materials in the process of the present invention can be prepared by reacting esters having the general formula wherein R and R have the above-mentioned meaning and R represents a lower alkyl group,
  • metal-organic compounds containing the group 5 eg compounds having the formula R0 Q-Lt VI VII ' wherein R represents an acetal group with the abovementioned meaning and Y represents halogen, preferably bromine.
  • R represents an acetal group of formula Ill, ammonium chloride solution, preferably a saturated with ketones having the general formula no- CH wherein R and R, have the above-mentioned meaning
  • R in formula VI represents an acetal group
  • 1 mole of metal-organic compound is used per mole of ketone
  • R in formula Vlll represents hydrogen
  • 2 moles of metal-organic compound per mole of ketone are used since I mole of the metalorganic compound will be consumed by the phenol group of the ketone.
  • the carbinols of formula [I are either extracted as such or as acetals of formula IV after the dehydration.
  • the extraction is in both cases carried out with a suit- VIII 5 able organic solvent, e.g. an ether, a ketone or a hydrocarbon.
  • the carbinols of formula [I can be isolated by evaporation of the solvent and are dehydrated either already at slightly above room temperature or through heating up to from to C. at water pump suction vacuum.
  • the acetals of formula [V are isolated in a conventional manner, such as by distillation at low pressure (0.000l to 0.02 mm Hg). They can also be purified by chromatography, reprecipitation or by recrystallization. The acetals are obtained as oils or as crystallized solids in good yields and in a pure state.
  • the dihydroxy diphenyl ethenes of formula I can also be prepared by treating the crude product from, e.g., a Grignard reaction directly with alcoholic hydrochloric acid whereupon the diphenol formed is isolated in a known manner.
  • the pharmacological activity of the dihydroxy diphenyl ethenes of formula I are disclosed in the US. Pat. No. 3,237,200 as well as different preparation forms of the compounds and different ways of administration.
  • the pharmacological activity is probably due to the free phenols in all cases, but the esters of the diphenols of formula I may modify the essential pharmacological activity while not influencing its general nature, i.e., estrogenicity, antiestrogenicity, pituitary gland inhibition etc. This modification may be due to a variable hydrolysis rate, excretion rate, etc., and increases the pharmacological and pharmaceutical applicability of the compounds.
  • the modification can also change the solubility, the emulsifying properties, the storability etc.
  • esters of lower alkane carboxylic acids are used, e.g., acetic acid and propionic acid. Even phosphates can be used.
  • the esters are prepared from the free diphenols by treating these with reactive acid derivatives, e.g., acetic acid anhydride, and catalytic amounts of acid, acid chlorides in pyridine etc.
  • the acyl compounds can also be prepared directly from the acetals of formula IV or from crude products from the metal-organic reaction which also may contain carbinols of formula II, by treating with reactive acid derivatives, e.g., acetic acid anhydride in pyridine.
  • dihydroxy diphenyl ethenes of the invention have come into clinical used in the humane as well as in the veterinary medicine.
  • Bis(p-acetoxyphenyl)-cyclohexylidene methane is used under the name CYKLOFENIL as an ovulation stimulating agent [Sv. farm. tidskr. 73 (I969) 233].
  • This compound was prepared from methyl t-butyiacetate as described in Example 2 a). The product was obtained in a yield of 80% and with a boiling point of l85187C. at 0.01 mm Hg.
  • the corresponding phenol was prepared from the methoxymethoxy compound as described in Example 2 b). 58 g of the crude phenol (m.p. l80l82C.) was dissolved in 230 ml of acetic anhydride, and a trace of cone. sulphuric acid was added. The reaction mixture, which immediately became warm, was heated for 30 minutes on a steam bath. After cooling, the mixture was poured into water and the acetylated compound, which had separated as an oil, was taken up in ether and washed with a saturated solution of sodium bicarbonate and twice with a sodium chloride solution. The solvent was evaporated and the product was distilled at 177-180C./0.02 mm Hg. Yield: 75 g. After recrystallization from ethanol, the product was obtained with a melting point of 86.5-87.5C.
  • the total amount of crude ethoxyethoxy compound was dissolved in 1000 ml of ethanol and 6 ml of cone. hydrochloric acid, whereupon the mixture was refluxed for 2 minutes.
  • the reaction mixture was poured into 3 liters of water and the crude phenol crystallized immediately. This was filtered, washed with water, dried and further washed with 2 X 200 ml of a boiling mixture of methylene chloride and carbontetrachloride (1:9) and dried.
  • the product was obtained in a yield of 250 g with a melting point of 216220C. After recrystallization from methanol-water (1:1), the product was obtained with a melting point of 221-222C.
  • This compound was prepared from the phenol (m.p. 216-220C.) from Example 4 b) as described in Example 3 b). The product was obtained in a yield of 90 and with a melting point after recrystallization from ethanol of 101103C.
  • This compound was prepared from ethyl Z-methylcylcopentylcarboxylate as described in Example 4 a). The crude product was obtained in a yield of 90 and this substance was used directly for acetylation.
  • This compound was prepared from the crude ethoxyethoxy compound described in Example 5 a) by acetylation according to Example 3 b) using about 0.1 ml of cone. H 80, to 100 ml of acetic anhydride. The product was obtained in a yield of 60% (calculated on the basis of the ethyl ester of Example 5 a)). The melting point of the product after recrystallization from 90% ethanol was 74-75C.
  • EXAMPLE 6 a Preparation of l,l-bis(pyranyloxyphenyl)-2-ethyll-pentene.
  • EXAMPLE 8 a Preparation of bis(p-methoxyethoxyphenyl)-2-ipropylcyclohexylidene methane.
  • This compound was prepared from p-bromobutoxyethoxy benzene and ethyl cyclohexane carboxylate as described in Example 2 a).
  • the crude oil was dried at 8090C. and 0.0002 mm Hg. Thereupon it was dissolved in a mixture of ether and petroleum ether (l:l) and chromatographed on neutral aluminum oxide (Wohler). The first fraction was discarded and the second, after evaporation of the solvent, dried at 80-90C./0.0002 mm Hg and then distilled at 95-97C./0.0001 mm Hg.
  • This compound was prepared according to Example 4 b) and c
  • the product was obtained in a yield of 60% and with a melting point after recrystallization from ethanol of l35l36C. (Lit. l37l38C. Mixed m.p. 135-l37C.).
  • This compound was prepared from pbromoisobutoxyethoxy benzene and ethyl cyclobutane carboxylate as described in Example 2 a).
  • This compound was prepared according to Example 5 b) in a yield of and with a melting point of l39-l40C. (Lit. l39-l41C.).
  • This compound was prepared under the conditions described in Examples 4 b) and 3 b). The product was obtained with a melting point of l36-l37c.
  • This compound was prepared from the methoxymethoxy compound of Example 13 a) as described in Example 2 b). After recrystallization from ethanol the product was obtained with a melting point of l78l80C.
  • This compound was prepared from ethyl 2-methylcyclohex-4-ene carboxylate as described in Example 2 a). The product was obtained with a boiling point of 2l0-215C. at 0.07 mm Hg. n 1.5700.
  • This compound was prepared as described in Example 2 a) from bis(p-methoxymethoxyphenyl)-2-methylcyclohex-4-enylidene methane, prepared according to Example 14 a). After recrystallization from methanol the product was obtained with a melting point of 229-23 lC.

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Abstract

The present invention relates to a new process for the preparation of unsymmetrical substituted dihydroxy diphenyl ethenes or esters thereof comprising both new and known compounds and having valuable pharmacological activity. According to the new process acetals of the dihydroxy diphenyl ethenes are used instead of their esters for protecting the phenol groups, whereupon the mono- or diacetals of the carbinols corresponding to the desired diphenyl ethenes are debydrated in a manner known per se to form mono- or diacetals, of the desired diphenyl ethenes and either cleaving said acetals in a way known per se to form the desired dihydroxy diphenyl ethenes and, if desired, esterifying said dihydroxy compounds in a way known per se, or converting said acetals directly in a way known per se to the desired esters of the dihydroxy diphenyl ethenes. In all said cases the dehydration step and the cleavage step or the conversion step resp. may be combined into a single step. The invention also relates to certain new dihydroxy diphenyl ethenes prepared according to the invention.

Description

United States Patent I l Borretzen et al.
]lll 3,925,487
[ Dec. 9, 1975 I'll] Appl. No.: 887,335
I30] Foreign Application Priority Data Dec, 24. [968 United Kingdom. (il474/(1X I52] tJ.S Cl 260/619 A; 260/479 R; 260/47) S. 260/463 R; 260/46) R, 260/457; 260/965;
]51 I Int. Cl. (107C 39/[2 ]58] Field of Search 260/619 A. 6| R [56] References Cited UNITED STA'I'ES PA'IEN'IS l.7t ).352 l/l93l (arswell ZhU/(il 3 l) l 7)2.7l(i 2/l93l Stocltclhaci. 260/613 D X 2,873,297 ZIIISJ Ramsden t Mill/(v13 l) 3.237.200 2/l9hh llarany et al 260/013 R X 3.287.397 l l/lQfih ()lsson ct alv 2(1tl/fil3 R X 33106.20) Ill/I968 llarany i i, IOU/fil 3.500.653 4/l97ll Fried i r r r r r ZhU/(il) A X FOREIGN PAlENTS OR APPIJCA'IIONS 537.976 7/IU4I United Kingdom loll/til) A Shelton ct al., .lour. Amer. (he-m. Soc. Vol. 75 (I953) 54915405.
Primary I:.\mn1'nvrBernard Hell'in AHurm'y, Agent. or l"irm--Blum MUSLUVllY. Friedman 8L Kaplan 57] ABSTRACT The present invention relates to a new process for the preparation of unsymmetrical substituted dihydroxy diphenyl ethenes or esters thereof comprising both new and known compounds and having valuahlc pharmacological activity. According to the new process acetals oi the dihydroxy diphenyl ethenes are used instead of their esters for protecting the phenol groups. whereupon the monoor diaeetals ol' the earhinols corresponding to the desired diphenyl ethenes are dehydrated in a manner known per se to form mono or diacetals. of the desired diphenyl ethenes and either cleaving said acetals in a way known per se to form the desired dihydroxy diphenyl ethenes and, if desired, esterifying said dihydroxy compounds in a way known per se. or converting said acetals directly in a way known per se to the desired esters of the dihydroxy di phenyl ethenes. In all said cases the dehydration step and the cleavage step or the conversion step resp. may be combined into a single step. The invention also relates to certain new dihydroxy diphcnyl ethenes pre pared according to the invention.
l Claim, N0 Drawings SUBSTITUTED DIPI-IENYL ETHENE DESCRIPTION OF THE INVENTION The present invention relates to a new process for the preparation of unsymmetrical substituted diphenyl ethenes having the general formula or esters thereof with suitable acids such as saturated aliphatic carboxylic acids having from I to 18 carbon atoms such as e.g. formic acid, acetic acid, propionic acid, trimethylacetic acid, caproic acid, palmitic acid and stearic acid; cyclohexane carboxylic acid; aromatic or araliphatic carboxylic acids such as benzoic acid and cinnamic acid; polyhydric organic acids such as succinic acid, tartaric acid, citric acid and hexahydrophthalic acid; sulphuric acid or a phosphoric acid such as orthophosphoric acid, in which formula R represents hydrogen or a straight or branched alkyl group having from 1 to 4 carbon atoms, and R, represents a straight or branched alkyl or alkenyl group having from 2 to 5 carbon atoms, wherein the substituents R and R may be connected to an alicyclic ring.
Dihydroxy diphenyl ethenes of formula I and their esters are previously known from the U.S. Pat. Nos. 3,237,200; 3,406,209 and 3,287,397. Said compounds have pharmacological activity comprising estrogenic and antiestrogenic activity and inhibition of the secretion of gonadotropins from the pituitary gland.
The process according to the invention for the preparation of the diphenyl ethenes of formula I is characterized in that mono or diacetals having the general formula wherein R, and R, have the above-mentioned meaning and R represents a group having the general formula R, c|-|, o-cH- III wherein R,, R and R have the above-mentioned meaning, whereupon the mono or diacetals of formula IV are cleaved in a way known per se to form the corresponding diphenols of formula I which, if desired, are esteritied in a way known per se, or the mono or diacetals of formula IV are converted directly in a way known per se to the esters of the diphenols of formula I, in which case the dehydration of the compounds of formula II and the cleavage of the compounds of formula IV or the direct conversion of these to the esters also may be carried out in a single step.
The cleavage of the mono or diacetals of formula IV occurs very easily, preferably with an alcoholic acid, e.g. I ethanolic hydrochloric acid, said acetals of formula IV being converted to the diphenols of formula I. However, the cleavage may also be carried out in such a way that the esters of the phenols of formula I are obtained directly from the acetals of formula IV, e.g. with the aid of lower acid anhydrides. Acetic acid anhydride in pyridine gives e.g., the diacetate of a diphenol of formula I. The cleavage may also, when R is not hydrogen, be carried out by vigorous heating, the acetal groups being removed as vinyl ethers with the formation of diphenols of formula I.
The dihydroxy diphenyl ethenes of formula I are, as already mentioned, previously known from the U.S. Pat. Nos. 3,237,200; 3,406,209 and 3,287,397 according to which they are prepared by another process with the fundamental difference that the protecting group used for the protection of the phenol groups instead of being an acetal group as in the process of the present invention is a lower alkyl group, generally a methyl group. This difference is of decisive importance. While the acetal group easily can be removed e.g., as already mentioned above, by short boiling in diluted alcoholic acid the removal of the methyl group in the first place is carried out by treating with alkali (NaOI-I, KOI-I) in alcoholic solution at 200C. In this case several side reactions occur [cf. Miquel et al: J. Med. Chem. 6 I963) 774], and discolouration is always obtained. The yield is also reduced by the repeated recrystallizations which often are necessary to obtain a pure uncoloured end product.
Some of the compounds which can be obtained by the process of the present invention can on the whole not be prepared by the method disclosed in the US. Pat. Nos. 3,237,200; 3,406,209 and 3,287,397. This applies e.g., to l, l -bis( p-acetoxyphenyl 3,3-dimethyl-l-butene, bis(p-acetoxyphenyl)-2-methyl-cyclopentylidene methane and l,l-bis(p-hydroxyphenyl )-2-methyll ,4-pentadiene.
The carbinols of formula II which are used as starting materials in the process of the present invention can be prepared by reacting esters having the general formula wherein R and R have the above-mentioned meaning and R represents a lower alkyl group,
with metal-organic compounds containing the group 5 eg compounds having the formula R0 Q-Lt VI VII ' wherein R represents an acetal group with the abovementioned meaning and Y represents halogen, preferably bromine.
TABLE I 1 R5 CH, CHJ CH H cm,- CH,=CHCH, CH, CH,- CH, cHl CH- cl-l, CH,-
il.......-..- R H- f CH H -CH H 3 C,H,
/ After the reaction with the I Grignard reagent and the water removal CH,
is obtained Another method for the preparation of the starting compounds of formula I] involves the reaction of a metal-organic compound containing the group TABLE ll RI R! R CH- H H CH CH;, CH=CH,-CH; H
/CH, on ui, c,i-|,., ,H= l
CH, CH
R mm- H- R R? CH OCH C H 3 cnaocn- After the reaction with the Grignard reagent and the water CH removal /CHCH,OCH
is obtained wherein R represents an acetal group of formula Ill, ammonium chloride solution, preferably a saturated with ketones having the general formula no- CH wherein R and R, have the above-mentioned meaning In case that R in formula VI" represents an acetal group, 1 mole of metal-organic compound is used per mole of ketone, while in the case R in formula Vlll represents hydrogen, 2 moles of metal-organic compound per mole of ketone are used since I mole of the metalorganic compound will be consumed by the phenol group of the ketone.
one.
The carbinols of formula [I are either extracted as such or as acetals of formula IV after the dehydration. The extraction is in both cases carried out with a suit- VIII 5 able organic solvent, e.g. an ether, a ketone or a hydrocarbon.
The carbinols of formula [I can be isolated by evaporation of the solvent and are dehydrated either already at slightly above room temperature or through heating up to from to C. at water pump suction vacuum.
The acetals of formula [V are isolated in a conventional manner, such as by distillation at low pressure (0.000l to 0.02 mm Hg). They can also be purified by chromatography, reprecipitation or by recrystallization. The acetals are obtained as oils or as crystallized solids in good yields and in a pure state.
The removal of water from the compounds of formula [l occurs very easily and under conditions being so similar to those used in the removal of the acetal groups, e.g., by treating with diluted acids or by heat- 7 ing, so that it is not necessary to prepare the acetals of formula [V in a pure state.
The dihydroxy diphenyl ethenes of formula I can also be prepared by treating the crude product from, e.g., a Grignard reaction directly with alcoholic hydrochloric acid whereupon the diphenol formed is isolated in a known manner.
The pharmacological activity of the dihydroxy diphenyl ethenes of formula I are disclosed in the US. Pat. No. 3,237,200 as well as different preparation forms of the compounds and different ways of administration. The pharmacological activity is probably due to the free phenols in all cases, but the esters of the diphenols of formula I may modify the essential pharmacological activity while not influencing its general nature, i.e., estrogenicity, antiestrogenicity, pituitary gland inhibition etc. This modification may be due to a variable hydrolysis rate, excretion rate, etc., and increases the pharmacological and pharmaceutical applicability of the compounds. The modification can also change the solubility, the emulsifying properties, the storability etc. Usually esters of lower alkane carboxylic acids are used, e.g., acetic acid and propionic acid. Even phosphates can be used. Preferably the esters are prepared from the free diphenols by treating these with reactive acid derivatives, e.g., acetic acid anhydride, and catalytic amounts of acid, acid chlorides in pyridine etc. The acyl compounds can also be prepared directly from the acetals of formula IV or from crude products from the metal-organic reaction which also may contain carbinols of formula II, by treating with reactive acid derivatives, e.g., acetic acid anhydride in pyridine.
Some of the dihydroxy diphenyl ethenes of the invention have come into clinical used in the humane as well as in the veterinary medicine.
Bis(p-acetoxyphenyl)-cyclohexylidene methane is used under the name CYKLOFENIL as an ovulation stimulating agent [Sv. farm. tidskr. 73 (I969) 233].
Bis(p-hydroxyphenyl)-cyclohexylidene methane has clinically shown a good effect in the treatment of prostate cancer [Nylanderz Opusc. Med. 11 (1966) 226].
Bis(p-acetoxyphenyl)-2-methylcyclohexylidene methane has showed a good effect as a fertility controlling substance. The pharmacology is described by N. Einar-Jensen, Diss. Kungl. Veterinfirhiigskolan, Stockholm, I968.
The invention is further illustrated by means of the following non-limiting examples.
EXAMPLE 1.
a. Preparation of p-methoxymethoxy-Z-ethylbutyrophenone.
Note: For convenience, the term p-methoxymethoxy is taken to mean p-CH OCH,O; this terminology will be used similarly in the other examples. Furthermore, the word acetal which actually is a noun designating a specific type of compound, for convenience has already been used as an adjective to indicate the group having the general formula III and will so be used below.
To a solution of 184 g of p-hydroxy-2-ethylbutyrophenone in 300 ml of butanone, 200 g of potasvigorous agitation, g of chlorodimethylether. Upon completion of the addition, the reaction mixture was refluxed for V2 hour with agitation, and was then cooled. Thereupon 300 ml of water and 200 ml ofether were added. The etheral layer was separated and washed with 2 X 200 ml of 2N NaOH, with water, dried over anhydrous sodium sulphate and distilled. The product was obtained in a yield of g and with a boiling point of ll5l20C. at O.l mm Hg.
b. Preparation of l-(p-methoxymethoxyphenyl)-l- (p-ethoxyethoxyphenyl )-2-ethyll -butene.
To a solution of 37 g of p-methoxymethoxy-Z-ethylbutyrophenone in 100 ml of ether a Grignard solution was added, prepared from 40 g of p-ethoxyethoxybromo benzene and 4.1 g of magnesium in a mixture of 20 ml of tetrahydrofurane and 30 ml of ether. Upon completion of the addition, the reaction mixture was refluxed for 2 hours with agitation, and was then cooled. Thereupon, 25 ml of water was added and the organic layer was separated and dried over sodium sulphate and distilled. The product was obtained in a yield of 52% and with a boiling point of 79-8 1C. at 0.0005 mm Hg. The substance was an oil.
c. Preparation of l,l-bis(p-hydroxyphenyl)-2-ethyll-butene.
4 g of the compound prepared according to Example 1 b) was dissolved in 50 ml of ethanol, and 2 ml of conc. hydrochloric acid was added. The mixture was refluxed for 15 minutes and the reaction mixture was poured into a mixture of ice and water. The phenol crystallized immediately and after recrystallization from 50% ethanol, the substance was obtained with a melting point of l79l80C. and in a yield of 2.5 g. lLit. l79l80C. according to Miquel et al: J. Med. Chem. 6 (1963) 774.]
EXAMPLE 2 a. Preparation of bis(p-methoxymethoxyphenyl)- cyclohexylidene methane.
To a Grignard solution, prepared from 24 g of magnesium and 210 g of p-methoxymethoxybromo benzene in a mixture of 100 ml of tetrahydrofurane and ISO ml of ether, there was added, dropwise, with vigorous agitation, 50 g of ethyl cyclohexane carboxylate. Upon completion of the addition, the reaction mixture was boiled for 2.5 hours with agitation, and was then cooled. Thereupon, ml of water and 150 ml of ether were added. The etheral layer was separated, washed with water, dried over sodium sulphate and distilled. The crude product was obtained in a yield of I00 g and with a boiling point of 200-2l0C. at 0.0l mm Hg. After recrystallization from 70% ethanol, the substance melted at 70-7 1C.
b. Preparation of bis(p-hydroxyphenyl)-cyclohexylidene methane.
40 g of the crude substance prepared according to Example 2 a) was dissolved in 250 ml of ethanol, and 15 ml of conc. hydrochloric acid was added at once. The solution was refluxed for 15 minutes and then poured into 500 ml of water. The phenol was precipitated, filtered and recrystallized from methanol and water l l The product was obtained in a yield of 25 g and with a melting point of 234-235C. [Lit. 235-236C. according to J. Med. Chem. 6 (1963) sium carbonate was added and then, dropwise, with 5 774].
EXAMPLE 3.
:1. Preparation of l,1-bis(p-methoxymethoxyphenyl)- 3,3-dimethyl-1-butene.
This compound was prepared from methyl t-butyiacetate as described in Example 2 a). The product was obtained in a yield of 80% and with a boiling point of l85187C. at 0.01 mm Hg.
b. Preparation of l,l-bis(p-acetoxyphenyl)-3,3- dimethyl-l-butene.
The corresponding phenol was prepared from the methoxymethoxy compound as described in Example 2 b). 58 g of the crude phenol (m.p. l80l82C.) was dissolved in 230 ml of acetic anhydride, and a trace of cone. sulphuric acid was added. The reaction mixture, which immediately became warm, was heated for 30 minutes on a steam bath. After cooling, the mixture was poured into water and the acetylated compound, which had separated as an oil, was taken up in ether and washed with a saturated solution of sodium bicarbonate and twice with a sodium chloride solution. The solvent was evaporated and the product was distilled at 177-180C./0.02 mm Hg. Yield: 75 g. After recrystallization from ethanol, the product was obtained with a melting point of 86.5-87.5C.
EXAMPLE 4 a. Preparation of bis(p-ethoxyethoxyphenyl)-2- methylcyclohexylidene methane. Note: The term pethoxyethoxy indicates the following group "p-CH,CH,OCHO
To a Grignard solution, prepared from 72 g of magnesium and 686 g of p-ethoxyethoxybromo benzene in 600 ml of tetrahydrofurane and 1000 ml of ether, there was added with agitation 206 g of methyl Z-methylcyclohexane carboxylate dissolved in 300 ml of ether. Thereupon, the reaction mixture was boiled for 2 hours and cooled. The Grignard complex was decomposed with 200 ml of water and the organic layer was separated, washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off at 80C. and 0.01 mm Hg. The yield of crude ethoxyethoxy compound was 622 g.
b. Preparation of bis(p-hydroxyphenyl)-2-methylcyclohexylidene methane.
The total amount of crude ethoxyethoxy compound was dissolved in 1000 ml of ethanol and 6 ml of cone. hydrochloric acid, whereupon the mixture was refluxed for 2 minutes. The reaction mixture was poured into 3 liters of water and the crude phenol crystallized immediately. This was filtered, washed with water, dried and further washed with 2 X 200 ml of a boiling mixture of methylene chloride and carbontetrachloride (1:9) and dried. The product was obtained in a yield of 250 g with a melting point of 216220C. After recrystallization from methanol-water (1:1), the product was obtained with a melting point of 221-222C.
c. Preparation of bis(p-acetoxyphenyl)-2-methylcyclohexylidene methane.
This compound was prepared from the phenol (m.p. 216-220C.) from Example 4 b) as described in Example 3 b). The product was obtained in a yield of 90 and with a melting point after recrystallization from ethanol of 101103C.
EXAMPLE 5 a. Preparation of bis(p-ethoxyethoxyphenyl)2- methylcyclopentylidene methane.
This compound was prepared from ethyl Z-methylcylcopentylcarboxylate as described in Example 4 a). The crude product was obtained in a yield of 90 and this substance was used directly for acetylation.
b. Preparation of bis(p-acetoxyphenyl)-2-methy1cyclopentylidene methane.
This compound was prepared from the crude ethoxyethoxy compound described in Example 5 a) by acetylation according to Example 3 b) using about 0.1 ml of cone. H 80, to 100 ml of acetic anhydride. The product was obtained in a yield of 60% (calculated on the basis of the ethyl ester of Example 5 a)). The melting point of the product after recrystallization from 90% ethanol was 74-75C.
EXAMPLE 6 a. Preparation of l,l-bis(pyranyloxyphenyl)-2-ethyll-pentene.
To a Grignard solution, prepared from 5 g of magnesium and 51.4 g of p-bromopyranyloxy benzene in 200 ml of tetrahydrofurane, 14.4 g of ethyl a-methylvalerate was added dissolved in 100 ml of ether. The reaction mixture was refluxed for 2 hours with vigorous stirring, cooled and decomposed with 100 ml of a saturated ammonium chloride solution. The organic layer was separated, washed with water, and dried over sodium sulphate. After removing the solvent at a pressure of 0.01 mm Hg and 80C., the crude product was obtained in a yield of 30 g. After recrystallization from ethanol, the product was obtained with a melting point of 5859C.
b. Preparation of 1,1-bis(p-hydroxyphenyl)-2-ethyll-pentene.
15 g of the crude compound from Example 6 a) was distilled at 0.01 mm giving a fraction from dihydropy rane and at 220230C. a further fraction which after recrystallization from benzene melted at 173-174C. and was identical with a known sample of l,l-bis(phydroxyphenyl)-2-ethyl-l-pentene (mixed melting point and IR).
EXAMPLE 7 a. Preparation of bis(p-ethoxyethoxypheny1)-2-ethylcyclohexylidene methane.
EXAMPLE 8 a. Preparation of bis(p-methoxyethoxyphenyl)-2-ipropylcyclohexylidene methane.
To a Grignard solution, prepared from 68 g of magnesium and 55 g of p-bromomethoxyethoxy benzene in 40 ml of tetrahydrofurane and ml of ether, 18.4 g of methyl 2-i-propylcyclohexylcarboxylate, dissolved in 40 m1 of ether, was added with stirring. Upon completion of the addition, the mixture was boiled for 2 hours.
After cooling, the Grignard complex was decomposed with I ml of water. The yield of crude compound was 50 g. After distillation at 89-95C./0.0002 mm Hg the compound was recrystallized from methanol and melted at 6062C.
b. Preparation of bis(p-acetoxyphenyl)-2-i-propylcyclohexylidene methane.
40 g of the crude compound from Example 8 a) was dissolved in l00 ml of ethanol and 1 ml of cone. hydrochloric acid. The solution was boiled for minutes and poured into water. The dark brown oil which separated was dissolved in 5N NaOH. The solution was extracted with ether and acidified with 5N HCl. The phenol was taken up in ether, and washed with water. The solution was dried over sodium sulphate and the ether was evaporated. The crude phenol was acetylated as described in Example 3 b). After distillation at 200-2l5C./0.00l mm Hg and two recrystallizations from ethanol, the product was obtained with a melting point of l39-l4lC.
EXAMPLE 9 a. Preparation of cyclohexylidene methane.
This compound was prepared from p-bromobutoxyethoxy benzene and ethyl cyclohexane carboxylate as described in Example 2 a). The crude oil was dried at 8090C. and 0.0002 mm Hg. Thereupon it was dissolved in a mixture of ether and petroleum ether (l:l) and chromatographed on neutral aluminum oxide (Wohler). The first fraction was discarded and the second, after evaporation of the solvent, dried at 80-90C./0.0002 mm Hg and then distilled at 95-97C./0.0001 mm Hg.
b. Preparation of bis(p-acetoxyphenyl)-cyclohexylidene methane.
This compound was prepared according to Example 4 b) and c The product was obtained in a yield of 60% and with a melting point after recrystallization from ethanol of l35l36C. (Lit. l37l38C. Mixed m.p. 135-l37C.).
bis( p-butoxyethoxyphenyl)- EXAMPLE 10 a. Preparation of bis(p-isobutoxyethoxyphenyl)- cyclobutylidene methane.
This compound was prepared from pbromoisobutoxyethoxy benzene and ethyl cyclobutane carboxylate as described in Example 2 a).
b. Preparation of bis(p-acetoxyphenyl)-cyclobutylidene methane.
This compound was prepared according to Example 5 b) in a yield of and with a melting point of l39-l40C. (Lit. l39-l41C.).
EXAMPLE 11 bis(p-ethoxyethoxyphenyl dium sulphate. The solvent was distilled off. The crude product was obtained in a yield of 7 g.
b. Preparation of bis(p-hydroxyphenyl)-cyclohexylidene methane.
This compound was prepared under the conditions described in Example 4 b). The product was obtained with a melting point after recrystallization of 235-236C. The yield was 1.7 g (45%).
c. Preparation of bis(p-acetoxyphenyl)-cyclohexylidene methane.
This compound was prepared under the conditions described in Example 3 b). The melting point of the product after recrystallization was 136-l 37C. and the yield was [.5 g (90%).
EXAMPLE 12 a. Preparation of bis(p-methoxymethoxyphenyl)- cyclohexylidene methane.
To a solution of p-methoxymethoxyphenyl lithium, prepared from 6.5 g of p-bromomethoxymethoxy benzene, 0.42 g oflithium l.4 g 30% Li dispersion) and ml of ether, there was added with stirring 2.0 g of ethyl cyclohexane carboxylate dissolved in 15 ml of ether. After addition of the ester the mixture was refluxed for one hour. The metal-organic compound was decomposed with water and the organic layer was separated, washed with water and dried over sodium sulphate. The solvent was evaporated and the crude product was distilled at 200-2l0C./0.0l mm Hg. The fraction obtained was recrystallized from ethanol. The product was obtained in a yield of l .5 g and with a melting point of 70-7lC.
b. Preparation of bis(p-acetoxyphenyl)-cyclohexylidene methane.
This compound was prepared under the conditions described in Examples 4 b) and 3 b). The product was obtained with a melting point of l36-l37c.
EXAMPLE l3 a. Preparation of l,1-bis( p-methoxymethoxyphenyl)- Z-methyll ,4-pentadiene.
This compound was prepared from ethyl 2-methyl pentene-4-oate as described in Example 2 a). The product was obtained in a yield of 85% and with a boiling point of l40l45 C. at 0.03 mm Hg. n,,"'= 1.5796.
b. Preparation of l,1-bis(p-hydroxyphenyl)-2-methyll ,4-pentadiene.
This compound was prepared from the methoxymethoxy compound of Example 13 a) as described in Example 2 b). After recrystallization from ethanol the product was obtained with a melting point of l78l80C.
EXAMPLE 14 a. Preparation of bis(p-methoxymethoxyphenyl)-2- methyl-cyclohex-4-enylidene methane.
This compound was prepared from ethyl 2-methylcyclohex-4-ene carboxylate as described in Example 2 a). The product was obtained with a boiling point of 2l0-215C. at 0.07 mm Hg. n 1.5700.
b. Preparation of bis(p-hydroxyphenyl)-2-methylcyclohex-4-enylidene methane.
This compound was prepared as described in Example 2 a) from bis(p-methoxymethoxyphenyl)-2-methylcyclohex-4-enylidene methane, prepared according to Example 14 a). After recrystallization from methanol the product was obtained with a melting point of 229-23 lC.
l3 14 c. Preparation of bis(p-acetoxyphenyl)-2-methylthe product was obtained with a melting point of cyclohex-4-enylidene methane. l l8-l19C.
This compound was prepared as described in Exam- What we claim is: ple 3 b) from bis(p-methoxymethoxyphenyl)-2-rnethyll. The compound bis(p-hydroxyphenyl)-2-methylcyclohex-4-enylidene methane prepared according to cyclohex-4-enylidene methane. Example 14 a). After recrystallization from methanol

Claims (1)

1. THE COMPOUND BIS(P-HYDROXYPHENYL)-2-METHYLCYCLOHEX-4-ENYLIDENE METHANE.
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US2873297A (en) * 1955-11-28 1959-02-10 Metal & Thermit Corp Process of reacting olefin oxides with specified organomagnesium chlorides
US3237200A (en) * 1959-02-25 1966-02-22 Barany Ernst Herbert Carboxylic acid esters
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US3406209A (en) * 1966-02-08 1968-10-15 Ernst H. Barany 1, 1-bis(p-oh-phenyl)-2, 2-disubstituted ethylenes
US3506653A (en) * 1966-09-12 1970-04-14 Syntex Corp Non-steroid hormonal agents

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US2873297A (en) * 1955-11-28 1959-02-10 Metal & Thermit Corp Process of reacting olefin oxides with specified organomagnesium chlorides
US3237200A (en) * 1959-02-25 1966-02-22 Barany Ernst Herbert Carboxylic acid esters
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US3406209A (en) * 1966-02-08 1968-10-15 Ernst H. Barany 1, 1-bis(p-oh-phenyl)-2, 2-disubstituted ethylenes
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