US3865883A - 1,2,3,4,9,12-Hexahydrophenanthrenes - Google Patents

1,2,3,4,9,12-Hexahydrophenanthrenes Download PDF

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US3865883A
US3865883A US235808A US23580872A US3865883A US 3865883 A US3865883 A US 3865883A US 235808 A US235808 A US 235808A US 23580872 A US23580872 A US 23580872A US 3865883 A US3865883 A US 3865883A
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methyl
ethyl
methoxy
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hexahydrophenanthrene
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John A Edwards
John H Fried
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Roche Palo Alto LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/21—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen
    • C07C51/23—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups
    • C07C51/235—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with molecular oxygen of oxygen-containing groups to carboxyl groups of —CHO groups or primary alcohol groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/29—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ
    • 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
    • C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
    • 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
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/42—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the rings
    • C07C57/44—Cinnamic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • 260/520 R 260/600, 260/611 F, 260/6l7.5, 260/930, 260/951, 260/952, 260/953,
  • ABSTRACT New compounds of the l,2,3,4,9,12-hexahydrophenanthrene class, useful as estrogenic and antifertility agents, and methods for their preparation.
  • la- Ethyl-Za-carboxy-ZB-methylJ-methoxy-1,2 ,3,4,9,12- hexahydrophenanthrene is exemplified as illustrative of the class.
  • R is methyl or ethyl
  • R is carboxy and the alkali metal salts thereof, carb (lower)-alkyloxy, formyl, or hydroxymethyl and the conventional hydrolyzable esters and ethers thereof;
  • R is methyl or ethyl
  • R is lower alkyloxy, hydroxy or the conventional hydrolyzable esters and ethers thereof.
  • R is hydrogen or methyl
  • lower alkyloxy denotes the group OAlkyl, alkyl being a straight or branched chain saturated hydrocarbon group containing from I to 6 carbon atoms, inclusive, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, amyl, hexyl, and the like.
  • hydrolyzable esters and ethers refers to those physiologically acceptable hydrolyzable ester groups and labile ether groups conventionally employed in the pharmaceutical art such as acetate, propionate, butyrate, trimethylacetate, valerate, methylethylacetate, caproate, butylacetate, 3-methylpentanoate, enanthate, caprylate, triethylacetate, pelargonate, decanoate, undecanoate, benzoate, phenylacetate, diphenylacetate, cyclopentylpropionate, methoxyacetate, aminoacetate, diethylaminoacetate, trichloroacetate, B-chloropropionate, bicyclo [2.2.2]octane-l-carboxylate, adamantoate, dihydrogen phosphate, dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate,
  • the wavy lines in at the C-l position of the phenanthrene nucleus indicates the configuration alpha or beta or mixtures thereof.
  • the compounds of the present invention can exist in two d and two lforms, that is, d-cis, dtrans, l-cis, and l-trans.
  • two racemates are possible, that is, dl-cis and dl-trans. While each or mixtures are included within the scope hereof, the dlcis racemate is preferred.
  • the process of the present invention by which the compounds are prepared generates both the individual alpha and beta isomers or mixtures thereof.
  • the individual 12a and 12B isomers are separable by chromatography and each and the mixture thereof are included within the scope of the present invention.
  • the position of the R substituent is designated and defined as the C-10 ring position.
  • the compounds of the present invention possess estrogenic and anti-fertility activity. They are accordingly useful in replacement therapy for estrogen deficiencies and in the control and regulation of fertility and in the management of various menstrual disorders and are ,employed in accordance with these uses in the same manner as known estrogenic and anti-fertility agents. Thus, they can be administered in conjunction with one or more pharmaceutically non-toxic excipients, whether orally or parenterally, and at dosage levels appropriate for the condition being treated or effect desired, the most favorable dosage being determinable by one of ordinary skill in the art taking into consideration the particular condition being treated and the observed response to treatment.
  • Useful pharmaceutical excipients include water, polyalkylene glycols, vegetable oils, lactose, talc, magnesium stearate, gelatin, starches, flavoring agents and the like.
  • the compounds of the present invention are used in the adopted manner customary with compounds having like utility.
  • R is as defined by R, exclusive of hydroxy and the esters thereof.
  • the pentaene starting material (I) is reduced with an alkali metal such as sodium, potassium and lithium and a lower monohydric alcohol in a lower alkyl amine or diamine, for example, methyl amine, diethyl amine, and the like or in liquid ammonia to obtain the triene intermediate compound (II).
  • the triene intermediate (II) is aromatized such as with pyridinium hydrobromide perbromide to obtain the final product tetraene (Ill).
  • the first step reduction involves reacting a l,2,3,4- tetrahydrophenanthrene compound together with sodium, potassium, or lithium metal and a lower monohydric alcohol in a lower alkyl amine or diamine, for example, methyl amine, diethyl amine, and the like or in liquid ammonia.
  • Suitable lower monohydric alcohols include those straight or branched alkanols containing from I to 6 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec.-butanol, isobutanol, t-butanol, n-amyl alcohol, and n-hexanol.
  • reaction is conveniently conducted in organic liquid reaction media in admixture with the alcohol.
  • Suitable media include the common organic solvents such as tetrahydrofuran, dioxane, toluene, benzene, n-hexane, diethyl ether, glyme, diglyme, and the like.
  • the reaction is conducted at temperatures ranging from about 80C. to about C. and, preferably, at the boiling point of the reaction mixture and under reflux and for a period of time sufficient to complete the reaction ranging from about 1 hour to about 14 days.
  • the second step aromatization involves reacting a l,- 2,3,4,5,8,9,l2-octahydrophenanthrene compound together with pyridinium hydrobromide perbromide.
  • This reaction is conveniently conducted in organic liquid reaction media. Suitable media include those listed hereinabove which are useful in the reduction step.
  • the reaction is conducted at temperatures ranging from about 80C. to about 25C. or more and for a period of time sufficient to complete the reaction ranging from about 1 minute to about 12 hours.
  • the reactants are contacted and maintained together in any convenient order or fashion. They are then maintained within or about the cited temperature range for a period of time sufficient to produce the product.
  • the product is recovered and isolated from the reaction mixture following conventional techniques such as decantation, filtration, distillation, extraction, evaporation, and chromatography.
  • the given reactions consume the respective reactants in the ratio of one mole of starting compound per four moles of alkali metal and one mole of intermediate triene compound per mole of pyridinium hydrobromide perbromide.
  • the amounts of the reactants to be employed are not critical, some of the desired prod not being obtained when employing any proportions thereof.
  • the appropriate reactants are employed in amounts ranging from about four moles to about one hundred moles of the alkali metal per mole of starting compound, the am monia or amine being employed in large excess, and amounts ranging from about 0.9 moles to about 1.5 moles of pyridinium hydrobromide pe'rbromide per mole of starting compound.
  • the triene intermediate (ll) is obtained directly upon reduction of (I), it is possible, if desired, to obtain and isolate a tetraene derivative of partial formula (I-a) by reduction of compound (I) as described. This compound can be isolated and reduced further as described to obtain the triene intermediate (ll) by way of twostep methodology.
  • each ofR, R, R R and R are as defined hereinabove and R is lower alkyl; R is a conventional hydrolyzable ether; and R is a conventional hydrolyzable ester or ether.
  • the above depiction represents the various useful sequences In the acid series (C-2a), the sequence of formula l 2 3 is employed to arrive at the C-7 ether final products.
  • the C-7 substituent (R) preferably is, or is converted to, the tetrahydropyran-2-yloxy ether which is cleaved upon reaction with lithium iodide in collidine at about 180C.
  • the C-7 esters are derived from the C7 hydroxy compounds.
  • the acids are also useful for the preparation of the corresponding esters (formula 5) via the intermediate acid chloride and appropriate alcohol.
  • the corresponding 7-hydroxy derivatives of the latter esters are preferably obtainable through the 7-tetrahydropyran 2-yloxy compounds, as described above.
  • hydroxymethyl (R compounds formula 8).
  • a 2-carb(lower)alkyloxy ester (formula 6) can be employed and reduced in the first step to the hydroxymethyl grouping (formula 7).
  • the hydroxymethyl products (formula 8) can be conventionally esterified or etherified (formula 13) and the esters or ethers converted to the corresponding 7-hydroxy compounds (formula 4; R conventional hydrolyzable ester or ether of hydroxymethyl) preferably through the 7-tetrahydropyran-Z-yloxy derivatives, as described above.
  • the aldehydes can be further oxidized to the acids (formula 3) or converted to the 7-hydroxy compound (formula 4; R formyl), preferably through the 7-tetrahydropyranyl ether.
  • ester starting compounds can be reduced by reaction with lithium aluminum hydride (THF) to form the corresponding hydroxymethyl compounds (formula 10).
  • THF lithium aluminum hydride
  • These can be con ventionally etherified (formula 1 l or they can be converted as described above to the products (formulas 8 and 13). These products are, in turn, convertable to the corresponding 7-hydroxy compounds (formula 4), as described above.
  • R is lower alkyloxy or a conventional hydrolyzable ether; R is methyl or ethyl;
  • R is carboxy, hydroxymethyl and the conventional hydrolyzable ethers thereof; R is methyl or ethyl; and R is hydrogen or methyl; are novel compounds of the present invention useful as intermediates, as herein set forth, in the preparation of l,2,3,4,9, l 2-hexahydrophenanthrene products hereof.
  • l,2,3,4-tetrahydrophenanthrene starting compounds hereof are known in the art or can be prepared in accordance with known processes. See, for example, Helv. Chim. Acta. 28, 1506 (1945) and Helv. Chim.
  • ethers of the hydroxymethyl compounds follows upon etherification with dihydropyran (for the tetrahydropyran-Z-yl ethers and dihydrofuran (for the tetrahydrofuran-2-yl ethers) and 4-methoxy-5,6-dihydro-2H-pyran (for the 4-methoxytetrahydropyran-4-yloxy ethers) with acid catalyst in inert solvent.
  • Cyclopentyl ethers are prepared upon reaction of the hydroxy compound with sodium hydride and Cyclopentyl bromide.
  • the corresponding esters are prepared by reacting the hydroxymethyl compound with a hydrocarbon carboxylic acid anhydride in the presence of pyridine.
  • the C-lO methyl starting compounds are prepared in accordance with the procedure described in U.S. Pat. Application Ser. No. 638,648, filed May 15, 1967 by Edwards and Fried for Phenanrhrene-2-Carb0xy1ic Acids, which is hereby incorporated by reference.
  • This ,method involves reacting a 2-(3-methyl-l,2,3,4-tetrahydronaphthyliden)-ethyl isothiouronium acetate together with a tetronic acid in an aqueous organic solution at about room temperature to prepare the corresponding a-[2-(3-methyl-l ,2,3,4-tetrahydronaphthaliden)-ethyl]-tetronic acid compound.
  • This compound is then contacted with a strong acid optionally in an organic solvent at a temperature of from about room temperature to about reflux to prepare the corresponding 7-methyll 6-oxaestra-l ,3,5( lO),8,l4- pentaen-l7-one steroid.
  • a strong acid optionally in an organic solvent at a temperature of from about room temperature to about reflux to prepare the corresponding 7-methyll 6-oxaestra-l ,3,5( lO),8,l4- pentaen-l7-one steroid.
  • This can be subjected to carbonyl reduction and thence converted to
  • PREPARATION l A solution of l g. of 3-methoxybenzoic acid in 50 ml. of benzene is treated with 2 g. of thionyl chloride. The mixture is heated at reflux under anhydrous conditions for 2 hours and then evaporated under reduced pressure. The residue is dissolved in 20 ml. of benzene and this solution is evaporated to dryness to yield 3- methoxybenzoyl chloride.
  • a suspension of 0.5 g. of palladium-on-charcoal catalyst in 50 ml. of methanol is hydrogenated for 30 minutes.
  • a solution of l g. of the latter compound and 200 ml. of methanol is added and hydrogenated with agitation until the uptake of hydrogen has ceased.
  • the catalyst is removed by filtration and the solution is evaporated to yield 3-(3-methoxybenzoyl) butanoic acid.
  • a mixture of l g. of 3-methyl-6-methoxy-l-tetralone in ml. of acetic acid is saturated with hydrogen bromide gas.
  • the mixture is then allowed to stand for 24 hours and then the reaction mixture is concentrated.
  • the thus-obtained residue, 25 ml. of 95% methanol and 0.5 g. of potassium hydroxide is refluxed for 1 hour.
  • the reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3-,methyl-6-hydroxy-ltetralone.
  • a freshly prepared solution of 3 g. of vinyl bromide in 3 ml. of tetrahydrofuran is added to 0.5 g. of magnesium in 5 ml. of tetrahydrofuran to prepare a vinyl magnesium Grignard reagent.
  • To this mixture is then added a solution of l g. of 3-methyl-6-methoxy-l-tetralone in 25 ml. of tetrahydrofuran and 10 ml of ether and resulting mixture is held at room temperature for a period of 24 hours, then heated at reflux for one hour and then cooled.
  • the reaction mixture is then poured into water, acidified with hydrochloric acid and stirred vigorously to decompose any excess Grignard reagent.
  • a mixture of l 1.8 g. of thiourea and 100 ml. of acetic acid is warmed on a steam bath until the mixture becomes homogeneous.
  • the solution is then cooled to room temperature and to it is then added 32 g. of 3- methyl--methoxy-l-vinyl-l-tetralol.
  • the resulting mixture is agitated until the mixture again becomes homogeneous.
  • the acetic acid is then removed by heating (50-60C.) under reduced pressureto afford a syrup.
  • the syrup is poured with stirring into ml. of ether.
  • the xylene mixture is allowed to cool and then concentrated to a smaller volume and upon cooling deposited a precipitate of org-dimethyl tetraonic acid which is collected by filtration and recrystallized from benzene:- hexane.
  • ether ex-' tracts are combined, washed with water, and then dilute aqueous sodium thiosulfate solution, dried and evaporated to furnish the methyl ester of cis 7- methoxyl-acetyl-2, l O-dimethyl-l ,2,3 ,4- tetrahydrophenanthrene-2-carboxylic acid which can be crystallized from benzene-hexane.
  • a current density of 0.02 amps/cm. is applied for a period of 5 hours.
  • the reaction mixture is then removed from the cell and concentrated under reduced pressure to a small volume which is then extracted several times with ether.
  • the ether extracts are combined, washed with water and a 5% aqueous sodium bicarbonate solution, dried and evaporated to dryness to furnish the methyl ester of cis acidified by the addition of dilute aqueous hydrochloric acid and extracted several times with the ethyl acetate.
  • EXAMPLE 1 Liquid ammonia which has been dried over sodium metal and distilled (600 ml.), 300 ml. dry tetrahydrofuran, and 150 ml. of dry ethanol are mixed together 10 with stirring. Ten g. of la-ethyl-Za-carboxy-2/3-methyl- 7-methoxy-l,2,3,4-tetrahydrophenanthrene (cis bisdehydrodoisynolic acid methyl ether) are then added to the mixture while continuing the stirring. To the resultant mixture are added 54 g. of lithium wire in ca.
  • the resultant mixture is extracted with ethyl acetate, washed with water and then saturated NaCl and evaporated.
  • the concentrate after evaporation is recrystallized from methanol to provide the la-ethyl-Za- 45 carboxy-2B-methyl-7-methoxy-l ,2,3,4,9,l2a-hexahy- 55 fied mixture extracted with ethyl acetate.
  • the extracts are dried over magnesium sulfate and evaporated to provide a concentrate which is fractionally crystallized from methanol/H O to obtain the la-ethyl-2a-carboxy- 2,8-methyl-7-hydroxy-l ,2,3,4,9,l Za-hexahydro- 6O phenanthrene product.
  • EXAMPLE 2 Liquid ammonia which has been dried over sodium metal and distilled (600 ml.), 300 ml. dry tetrahydro- 5 furan, and ml. of dry ethanol are mixed together with stirring. Ten g. of la-ethyl-Za-carboxy-ZB-methyl- 7-methoxyl ,2,3,4-tetrahydrophenanthene(cis bisdehydrodoisynolic acid methyl ether) are then added to the mixture while continuing the stirring. To the resultant mixture are added 54 g. of lithium wire in ca. 2.0 g. portions with concommitant addition of 500 ml. of ethanol in 20 ml. portions over a total period of ca.
  • the resultant mixture is extracted with ethyl acetate, washed with water and then saturated NaCl and evaporated to provide the 12a and 12B epimers of lOl-BthYl- 2oz-carboxy-2B-methyl-7-methoxy-l ,2,3,4,9,12-hexahydrophenanthrene.
  • the concentrate after evaporation is crystallized from methanol to provide the laethyl-Za-carboxy-2B-methy1-7-methoxy 1 ,2 ,3 ,4 ,9 12a-hexahydrophenanthrene product.
  • the mother. liquor is subjected to thin-layer chromatography to obtain the la-ethyl-Za-carboxy-2B-methyl-7-methoxyl,2,3,4,9, l 2B-hexahydrophenanthrene.
  • EXAMPLE 3 A mixture of 1a-ethyl-Za-carbomethoxy-2B-ethy1-7- methoxy-l,2,3,4-tetrahydrophenanthrene (104 mg.) in 300 mg. oft-butanol is dispersed in a mixture of 25 ml. of ammonia and ml. of tetrahydrofuran with stirring. Lithium wire mg.) is then added to the resultant solution in a portion-wise fashion at reflux. After the blue color of the resultant mixture has faded (about minutes), the ammonia is allowed to evaporate. After evaporation period, water and diethyl ether are added to the resultant mixture.
  • the ether layer is separated and washed with water, dried and evaporated to obtain a residue which is recrystallized from ether hexane to obtain the la-ethyl-2a-hydroxymethyl-2B-methyl-7 -methoxy-l,2,3,4,5,8-hexahydrophenanthrene product.
  • a solution is prepared by dispersing 500 mg. of 1aethyl-2a-hydroxymethyl-2B-methy1-7-methoxy- 1,2,3,4,5,8-hexahydrophenanthrene in 100 ml. of tetrahydrofuran and 100 ml. of ammonia. Lithium wire (500 mg.) and 10 ml. of t-butanol are added portionwise thereto over a period of 5 days at a rate sufficient to maintain a blue color. After the blue color of the reaction mixture has faded, water and ether are added.
  • the ether layer is separated and washed with water. dried and evaporated to provide an isomeric mixture of la-ethyl-2a-hydroxymethyl-2B-methyl7-methoxy- 1,2,3 ,4,5 ,8 ,9, 1 Z-octahydrophenanthrene.
  • the pyridine is evaporated by passing a stream of nitrogen through the reaction mixture and the resultant residue partitioned between diethyl ether and water.
  • the ether extracts are washed with water, dried and evaporated to obtain the la-ethyl-Za-hydroxymethyll5 2B-methyl-7-methoxy-l,2,3,4,9,12-hexahydrophenanthrene epimeric products.
  • the residue is subjected to thin-layer chromatography to separate the --1a-ethyl-Za-hydroxymethyl- 2B-methyl-7-methoxy- 1 ,2,3,4,9,l 2a-hexahydro- 20 phenanthrene product and the corresponding 126 product.
  • la'Ethyl-2 a-carbotetrahydropyran-Z -yloxy-2B- methyl-7-tetrahydropyran-2-yloxy-1,2,3 ,4-tetrahydrophenanthrene is reacted with 100 equivalents of sodium metal and ammonia in the presence of t-butanol as otherwise set forth in Example 3 to obtain first the la-ethyI-Za-hydroxymethyl-2/3-methyl-7- tetrahydropyran-2'-yloxy-l ,2,3,4,5,8-hexahydrophenanthrene product and second the la-ethyl-2ahydroxymethyl-2,8-methyl-7-tetrahydropyran-2'-yloxy 1,2,3,4,5.8,9,1Z-octahydrophenanthrene products.
  • the isomeric mixture of the latter product is reacted with pyridinium hydrobromide perbromide as set forth in Example 3 to obtain the 1a-ethyl-2a-hydroxymethyl- 2,8-methyl-7-tetrahydropyran-2 yloxy-l ,2.3 ,4,9,12- hexahydrophenanthrene products.
  • Each isomer can be treatd in accordance with the procedure of Example 1 to provide the 1a-ethyl-Za-hydroxymethyl-Zfimethyl 7-hydroxy-l ,2,3,4,9,12-hexahydrophenanthrene products.
  • la-ethyl- 2a-hydroxymethyl-2B-methyl-7-tetrahydropyran-Z'- yloxy-l ,2,3,4,9,12-hexahydrophenanthrene product is obtainable by employing the corresponding methyl, ethyl, n-propyl, and n-butyl esters in lieu of the carbo ester starting material.
  • Za-propionyloxymethyl, -butroyloxymethyl, -caproyloxymethyl, and -trimethylacetoxymethyl compounds otherwise corresponding to the acetoxymethyl product of the foregoing paragraph are prepared by using the corresponding acylating agent.
  • the other acyloxymethyl compounds of the present invention are prepared by utilizing the corresponding acylating agent.
  • dihydropyran Two milliliters of dihydropyran are added to a solution of 1 g. of la-ethyl-Za-hydroxymethyl-2B-methyl- 7-methoxy-l,2,3,4,9,l2-hexahydrophenanthrene in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days,
  • a solution of one chemical equivalent of la-ethyl- 2a-hydroxymethyl-2B-methyl-7-methoxy-1,2,3,4,9,l2- hexahydrophenanthrene in ml. of benzene is heated to reflux and about 2 ml. removed by distillation to eliminate moisture.
  • the mixture is cooled to room temperature and two chemical equivalents of sodium hydride are added, followed by the dropwise addition of two chemical equivalents of cyclopentyl bromide in 10 ml. of benzene over a period of 20 minutes.
  • the ethers of la-ethyl-Zahydroxymethyl-2/3-methyl-7-methoxy-1 ,2,3,4-tetrahydrophenanthrene are prepared in accordance with paragraphs 3, 4 and 5 of this example and the resultant compounds are treated in accordance with the procedures of Example 1 above to prepare the 20:- tetrahydropyran-Z'-yloxymethyl-tetrahydrofuran-2'- yloxymethyl, -4'-methoxy-tetrahydropyran-4- yloxymethyl, and -cyclopentyloxymethyl compounds in the la-ethyl-ZB-methyl-7-methoxy-l ,2,3,4,9. l 2-hexahydrophenanthrene series.
  • EXAMPLE 6 i Twenty ml. of liquid ammonia, 10 ml. of tetrahydrofuran, and 5 ml. of ethanol are mixed together. To the resultant mixture are added 300 mg. of la-ethyl-2aacetoxymethyl-2,B-methyl-7-methoxy-1,2,3,4-tetrahydrophenanthrene with stirring. To the resulting mixture are added 50 equivalents of sodium metal in a portionwise fashion and with stirring. After the addition period of about 72 hours, the reaction mixture is worked up as set forth in Example 1 to provide the laethyl-2ahydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,5,8,9,l2- octahydrophenanthrene products. The use of potassium metal in t-butanol and lithium metal in isopropanol affords similar results.
  • EXAMPLE 7 To a solution of 3 g. of la-ethyl-Za-carboxy-ZB- methyl-7-methoxy-l,2,3,4,9,12a-hexahydrophenanthrene in 50 ml. of methylene chloride are added an excess of diazomethane in ether (obtained from nitrosomethylurea) and a few drops of methanol. The reaction mixture is maintained at room temperature for 18 hours and the excess reagent is then decomposed by the addition of acetic acid.
  • EXAMPLE 8 To a solution of 14.2 mg. of la-ethyl-2ahydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,9,l2a' hexahydrophenanthrene in ml. of dry dimethylsulfoxide is added a solution of 49.6 mg. of dicyclohexylcarbodiimide in 300g of dimethylsulfoxide, followed by the addition of a solution of 2,1. of trifluoroacetic acid, 3.8;1. of pyridine and 50p. of dimethylsulfoxide. After reaction, the mixture is partitioned between water and diethyl ether. The ether extracts are washed with water, dried and evaporated.
  • the residue is subjected to thin-layer chromatography to obtain the laethyl-Za-formyl-2B-methyl-7-meth0xy-l ,2,3,4,9, l 2&- hexahydrophenanthrene product.
  • EXAMPLE 9 To a stirred solution of l g. of lB-ethyl-Za-formyl- ZB-methyl-7-cyclopentyloxy-1,2,3,4,9,l2-hexahydrophenanthrene in 10 ml. of acetone, cooled to C., is added under nitrogen a solution of 8N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 ml. of concentrated sulfuric acid and diluting with water to 100 ml.) until the color of the reagent persists in the mixture. The mixture is then stirred for 5 minutes at O-5C. and diluted with water.
  • 8N chromic acid prepared by mixing 26 g. of chromium trioxide with 23 ml. of concentrated sulfuric acid and diluting with water to 100 ml.
  • lB-ethyl-Za-hydroxymethyl-2,8-methyl-7-n-propoxy- R is methyl or ethyl:
  • R is hydroxymethyl or the hydrolyzable hydrocarbon carboxylic acid esters thereof wherein the carboxylic acid moiety has from 2 to 14 carbon atoms;
  • R is methyl or ethyl
  • R is lower alkyloxy wherein the alkyl moiety has from 1 to 6 carbon atoms, hydroxy, the hydrolyzable hydrocarbon carboxylic acid esters of said hydroxy group wherein the carboxylic acid moiety has from 2 to 14 carbon atoms, tetrahydropyran- 2'-yloxy, tetrahydrofuran-Z-yloxy, 4- methoxytetrahydropyran-2'-yl.oxy, or cyclopentyloxy; and R is hydrogen or methyl.
  • R is ethyl; R is methyl; and R is lower alkyloxy.
  • R is methoxy; la-ethyl-2a-hydroxymethyl-2B-methyl-7- methoxy-l ,2,3,4,9, l 2a-hexahydrophenanthrene.

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Abstract

New compounds of the 1,2,3,4,9,12-hexahydrophenanthrene class, useful as estrogenic and anti-fertility agents, and methods for their preparation. 1 Alpha -Ethyl-2 Alpha -carboxy-2 Beta methyl-7-methoxy-1,2,3,4,9,12-hexahydrophenanthrene is exemplified as illustrative of the class.

Description

United States Patent Edwards et al.
l,2,3,4,9,IZ-HEXAHYDROPHEN ANTH- RENES Inventors: John A. Edwards, Los Altos; John H. Fried, Palo Alto, both of Calif.
Assignee: Syntex Corporation, Apartado,
Panama, Panama Filed: Mar. 17, 1912 Appl. No.: 235,808
Related U.S. Application Data Division of Ser. No. 883,582, Dec. 9, 1969, Pat. No. 3,681,427.
U.S. Cl 260/613 R, 260/345.8, 424/308, 424/311, 260/345.9, 424/312, 424/341, 260/347.4, 424/346, 260/347.8, 260/410.5, 260/457, 260/468 R, 260/468 G, 260/468.5, 260/473 F, 260/476 C, 260/479 R, 260/479 S, 260/482 R-, 260/484 R, 260/487, 260/488 B, 260/488 CD, 260/5l4.5, 260/520,
260/520 R, 260/600, 260/611 F, 260/6l7.5, 260/930, 260/951, 260/952, 260/953,
Int. Cl. C07c 171/07 [58] Field of Search 260/396 R, 396 N, 613 R,
260/479 R, 488 CD, 617.5, 476 C, 410. 487, 482 R, 484, 345.8, 345.9, 347.4, 347.8, 468 R, 468 G [56] References Cited UNITED STATES PATENTS 2,938,056 5/1960 Nathan et a1. 260/613 R 3,275,691 9/1966 Goldberg et a1. 260/613 R 3,483,226 12/1969 Baran 260/613 R 3,716,578 2/1973 Johnk 260/613 R Primary Examiner-Vivian Garner Attorney, Agent, or Firm Tom M. Moran; Joseph J. Hirsch; Walter H. Dreger [57] ABSTRACT New compounds of the l,2,3,4,9,12-hexahydrophenanthrene class, useful as estrogenic and antifertility agents, and methods for their preparation. la- Ethyl-Za-carboxy-ZB-methylJ-methoxy-1,2 ,3,4,9,12- hexahydrophenanthrene is exemplified as illustrative of the class.
8 Claims, No Drawings 1 l,2,3,4,9, IZ-HEXAHYDROPHENANTHRENES In the foregoing and succeeding formulas,
R is methyl or ethyl;
R is carboxy and the alkali metal salts thereof, carb (lower)-alkyloxy, formyl, or hydroxymethyl and the conventional hydrolyzable esters and ethers thereof;
R is methyl or ethyl;
R is lower alkyloxy, hydroxy or the conventional hydrolyzable esters and ethers thereof; and
R is hydrogen or methyl.
In the presentspecification and claims, the term lower alkyloxy denotes the group OAlkyl, alkyl being a straight or branched chain saturated hydrocarbon group containing from I to 6 carbon atoms, inclusive, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, amyl, hexyl, and the like. The expression conventional hydrolyzable esters and ethers, as used herein, refers to those physiologically acceptable hydrolyzable ester groups and labile ether groups conventionally employed in the pharmaceutical art such as acetate, propionate, butyrate, trimethylacetate, valerate, methylethylacetate, caproate, butylacetate, 3-methylpentanoate, enanthate, caprylate, triethylacetate, pelargonate, decanoate, undecanoate, benzoate, phenylacetate, diphenylacetate, cyclopentylpropionate, methoxyacetate, aminoacetate, diethylaminoacetate, trichloroacetate, B-chloropropionate, bicyclo [2.2.2]octane-l-carboxylate, adamantoate, dihydrogen phosphate, dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate, tetrahydropyran-Zyl ether, tetrahydrofuran-Q-yl ether, 4-methoxytetrahydropyran-4-yl ether, cyclopentyl ether, and the like. The expression carboxy" denotes the -CO H group and formyl the --Cl-IO group.
In the present specification and claims, the wavy lines (in at the C-l position of the phenanthrene nucleus indicates the configuration alpha or beta or mixtures thereof. Thus, the compounds of the present invention can exist in two d and two lforms, that is, d-cis, dtrans, l-cis, and l-trans. In addition, two racemates are possible, that is, dl-cis and dl-trans. While each or mixtures are included within the scope hereof, the dlcis racemate is preferred.
With respect to the other center of symmetry present at the C-12 position, the process of the present invention by which the compounds are prepared generates both the individual alpha and beta isomers or mixtures thereof. The individual 12a and 12B isomers are separable by chromatography and each and the mixture thereof are included within the scope of the present invention.
For the purposes of the present invention, the conventional numbering of the various carbon positions on the phenanthrene nucleus is employed, as depicted by the following partial formula:
For example, as used herein, the position of the R substituent is designated and defined as the C-10 ring position.
The compounds of the present invention possess estrogenic and anti-fertility activity. They are accordingly useful in replacement therapy for estrogen deficiencies and in the control and regulation of fertility and in the management of various menstrual disorders and are ,employed in accordance with these uses in the same manner as known estrogenic and anti-fertility agents. Thus, they can be administered in conjunction with one or more pharmaceutically non-toxic excipients, whether orally or parenterally, and at dosage levels appropriate for the condition being treated or effect desired, the most favorable dosage being determinable by one of ordinary skill in the art taking into consideration the particular condition being treated and the observed response to treatment. Useful pharmaceutical excipients, solid or liquid, include water, polyalkylene glycols, vegetable oils, lactose, talc, magnesium stearate, gelatin, starches, flavoring agents and the like. In general, the compounds of the present invention are used in the adopted manner customary with compounds having like utility.
The compounds of the present invention are prepared in accordance with the following reaction sequence of partial formulas:
sf m
(III) In the above and succeeding formulas, R is as defined by R, exclusive of hydroxy and the esters thereof.
With reference to the reaction scheme outlined above, the pentaene starting material (I) is reduced with an alkali metal such as sodium, potassium and lithium and a lower monohydric alcohol in a lower alkyl amine or diamine, for example, methyl amine, diethyl amine, and the like or in liquid ammonia to obtain the triene intermediate compound (II). The triene intermediate (II) is aromatized such as with pyridinium hydrobromide perbromide to obtain the final product tetraene (Ill).
The first step reduction involves reacting a l,2,3,4- tetrahydrophenanthrene compound together with sodium, potassium, or lithium metal and a lower monohydric alcohol in a lower alkyl amine or diamine, for example, methyl amine, diethyl amine, and the like or in liquid ammonia. Suitable lower monohydric alcohols include those straight or branched alkanols containing from I to 6 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec.-butanol, isobutanol, t-butanol, n-amyl alcohol, and n-hexanol. The
. reaction is conveniently conducted in organic liquid reaction media in admixture with the alcohol. Suitable media include the common organic solvents such as tetrahydrofuran, dioxane, toluene, benzene, n-hexane, diethyl ether, glyme, diglyme, and the like. The reaction is conducted at temperatures ranging from about 80C. to about C. and, preferably, at the boiling point of the reaction mixture and under reflux and for a period of time sufficient to complete the reaction ranging from about 1 hour to about 14 days.
The second step aromatization involves reacting a l,- 2,3,4,5,8,9,l2-octahydrophenanthrene compound together with pyridinium hydrobromide perbromide. This reaction is conveniently conducted in organic liquid reaction media. Suitable media include those listed hereinabove which are useful in the reduction step. The reaction is conducted at temperatures ranging from about 80C. to about 25C. or more and for a period of time sufficient to complete the reaction ranging from about 1 minute to about 12 hours.
In carrying out these reactions, the reactants are contacted and maintained together in any convenient order or fashion. They are then maintained within or about the cited temperature range for a period of time sufficient to produce the product. Following the respective reaction, the product is recovered and isolated from the reaction mixture following conventional techniques such as decantation, filtration, distillation, extraction, evaporation, and chromatography.
The given reactions consume the respective reactants in the ratio of one mole of starting compound per four moles of alkali metal and one mole of intermediate triene compound per mole of pyridinium hydrobromide perbromide. However, the amounts of the reactants to be employed are not critical, some of the desired prod not being obtained when employing any proportions thereof. In the preferred embodiments hereof, the appropriate reactants are employed in amounts ranging from about four moles to about one hundred moles of the alkali metal per mole of starting compound, the am monia or amine being employed in large excess, and amounts ranging from about 0.9 moles to about 1.5 moles of pyridinium hydrobromide pe'rbromide per mole of starting compound.
Although under the conditions of this process, the triene intermediate (ll) is obtained directly upon reduction of (I), it is possible, if desired, to obtain and isolate a tetraene derivative of partial formula (I-a) by reduction of compound (I) as described. This compound can be isolated and reduced further as described to obtain the triene intermediate (ll) by way of twostep methodology.
The following depiction provides more detailed reference to the manner by which the compounds hereof are prepared.
In the above, each ofR, R, R R and R are as defined hereinabove and R is lower alkyl; R is a conventional hydrolyzable ether; and R is a conventional hydrolyzable ester or ether.
By way of further explanation of the processes hereof by which the present compounds are prepared, the above depiction represents the various useful sequences In the acid series (C-2a), the sequence of formula l 2 3 is employed to arrive at the C-7 ether final products. In the preparation of the corresponding 7-hydroxy compounds (formula 4), the C-7 substituent (R) preferably is, or is converted to, the tetrahydropyran-2-yloxy ether which is cleaved upon reaction with lithium iodide in collidine at about 180C. (See Harrison, Chemical Communications, No. 11, p. 616 (1969) or with an 80% oxalic acid in aqueous methanol solution at room temperature or with 80% aqueous acetic acid at room temperature. The C-7 esters are derived from the C7 hydroxy compounds.
The acids (formula 3) are also useful for the preparation of the corresponding esters (formula 5) via the intermediate acid chloride and appropriate alcohol. The corresponding 7-hydroxy derivatives of the latter esters (formula 4; R carb(lower)alkyloxy) are preferably obtainable through the 7-tetrahydropyran 2-yloxy compounds, as described above.
A similar sequence follows for the preparation of the hydroxymethyl (R compounds (formula 8). In this instance, a 2-carb(lower)alkyloxy ester (formula 6) can be employed and reduced in the first step to the hydroxymethyl grouping (formula 7). The hydroxymethyl products (formula 8) can be conventionally esterified or etherified (formula 13) and the esters or ethers converted to the corresponding 7-hydroxy compounds (formula 4; R conventional hydrolyzable ester or ether of hydroxymethyl) preferably through the 7-tetrahydropyran-Z-yloxy derivatives, as described above. the hydroxymethyl products (formula 8) can also be converted to the corresponding 7-hydroxy compounds (formula 4; R =hydroxymethyl or oxidized to the aldehydes (formula 9) with chromicacid in pyridine. The aldehydes can be further oxidized to the acids (formula 3) or converted to the 7-hydroxy compound (formula 4; R formyl), preferably through the 7-tetrahydropyranyl ether.
Alternatively, the ester starting compounds (formula 6) can be reduced by reaction with lithium aluminum hydride (THF) to form the corresponding hydroxymethyl compounds (formula 10). These can be con ventionally etherified (formula 1 l or they can be converted as described above to the products (formulas 8 and 13). These products are, in turn, convertable to the corresponding 7-hydroxy compounds (formula 4), as described above.
The process of the present invention can be practiced upon starting materials bearing the substituents defined by R, R, R R and R In accordance withordinary level of skill in the art, certain of the substituents are introduced at a time subsequent to the principal reactions in order to avoid chemical interference or competition. Thus, the C-7 hydroxy andl ester compounds are .prepared as last steps as set forth above. The C-Za esoff)-..
wherein R is lower alkyloxy or a conventional hydrolyzable ether; R is methyl or ethyl;
R is carboxy, hydroxymethyl and the conventional hydrolyzable ethers thereof; R is methyl or ethyl; and R is hydrogen or methyl; are novel compounds of the present invention useful as intermediates, as herein set forth, in the preparation of l,2,3,4,9, l 2-hexahydrophenanthrene products hereof. The novel compounds of the present invention of the formula:
l l (w to prepare the corresponding compound of partial formula (II): g Q
ha k/ (II) and aromatizing the compound of formula (II) wherein, R is R exclusive of hydroxy or a conventional hydrolyzable ester thereof; followed by, in optional order and to the extent desired or required:
1. cleaving any ester or ether group to the corresponding alcohol,
2. converting any carboxylic acid to the corresponding ester,
3. converting any carboxylic acid to the corresponding salt,
4. reducing any ester to the corresponding alcohol,
5. hydrolyzing any acid ester to the corresponding acid,
6. oxidizing any alcohol to the corresponding aldehyde,
7. oxidizing any aldehyde to the corresponding acid,
8. esterifying any hydroxyl group, and
9. etherifying any hydroxyl group,
The l,2,3,4-tetrahydrophenanthrene starting compounds hereof are known in the art or can be prepared in accordance with known processes. See, for example, Helv. Chim. Acta. 28, 1506 (1945) and Helv. Chim.
Acta. 30, 777 (i947) and U.S. Pat. application by Edwards Serial No. 589,494, filed Oct. 26, 1966 for Ethers Containing a Phenanthrene Nucleus, and the references cited in each, and Medicinal Chemistry, Vo-
Ilumne ll, John Wiley and Sons, Inc., New York, 1956.
Thus, for further example, preparation of the ethers of the hydroxymethyl compounds follows upon etherification with dihydropyran (for the tetrahydropyran-Z-yl ethers and dihydrofuran (for the tetrahydrofuran-2-yl ethers) and 4-methoxy-5,6-dihydro-2H-pyran (for the 4-methoxytetrahydropyran-4-yloxy ethers) with acid catalyst in inert solvent. Cyclopentyl ethers are prepared upon reaction of the hydroxy compound with sodium hydride and Cyclopentyl bromide. The corresponding esters are prepared by reacting the hydroxymethyl compound with a hydrocarbon carboxylic acid anhydride in the presence of pyridine.
The C-lO methyl starting compounds are prepared in accordance with the procedure described in U.S. Pat. Application Ser. No. 638,648, filed May 15, 1967 by Edwards and Fried for Phenanrhrene-2-Carb0xy1ic Acids, which is hereby incorporated by reference. This ,method involves reacting a 2-(3-methyl-l,2,3,4-tetrahydronaphthyliden)-ethyl isothiouronium acetate together with a tetronic acid in an aqueous organic solution at about room temperature to prepare the corresponding a-[2-(3-methyl-l ,2,3,4-tetrahydronaphthaliden)-ethyl]-tetronic acid compound. This compound is then contacted with a strong acid optionally in an organic solvent at a temperature of from about room temperature to about reflux to prepare the corresponding 7-methyll 6-oxaestra-l ,3,5( lO),8,l4- pentaen-l7-one steroid. Dehydrogenation thereof with palladium catalyst forms the corresponding 6,7- dehydro derivative thereof or treatment of the steroid with an alkali metal hydroxide aqueous organic solution at about room temperature prepares the corresponding l-acetyl-l0-methyl-l,2,3,4- tetrahydrophenanthrene-2-carboxylic acid alkali metal salt. This can be subjected to carbonyl reduction and thence converted to the acid ester with an alkyl iodide which can be converted to the free acid upon base hydrolysis.
Representative starting compounds are the following:
I[3,2B-dimethyl-2a-carboxy-7-methoxy-l ,2,3,4-tetrahydrophenanthrene,
la-ethyl-Za-carbomethoxy-2l3-methyl-7-ethoxyl 0- methyl-l ,2,3 ,4-tetrahydrophenanthrene,
la-methyl-Za-hydroxymethyl-2B-ethyl-7-methoxy- 1,2,3,4-tetrahydrophenanthrene,
lB,2B-diethyl-2a-tetrahydropyran-2-yloxymethyl-7- cyclopentyloxy-l ,2,3,4-tetrahydrophenanthrene,
lB,2,8lO-trimethyl-2a-carboxy-7-methoxy-, l,2,3,4- tetrahydrophenanthrene,
la-ethyl-Za-carboethoxy-2B-methyl-7- tetrahydropyran-Z-yloxy-l ,2,3,4-tetrahydrophenanthrene,
la,lO-dimethyl-Za-hydr0xymethyl-2B-ethyl-7- ethoxy-l ,2,3 ,4-tetrahydrophenanthrene,
la,2/3-diethyl-2a-cyclopentyloxymethyl-7- tetrahydropyran-2 -yloxy-l ,2,3,4-tetrahydrophenanthrene,
lB-methyl-2oz-carboxy-2,B-ethyl-7-n-propyloxyl,2,3,4-tetrahydrophenanthrene, and
1B-ethyl-Za-tetrahydropyran-Z -yloxymethyl-2B, l O -dimethyl-7-tetrahydropyran-2'-yloxy-l ,2,3,4-tetrahydrophenanthrene.
tetrahydrophenanthrene The following preparation and examples further illustrate the manner by which the present invention can be practiced and represent, in one aspect, the best mode for carrying out the invention. As such, however, they should be construed merely as illustrative and not as limitative upon the overall scope hereof.
PREPARATION l A solution of l g. of 3-methoxybenzoic acid in 50 ml. of benzene is treated with 2 g. of thionyl chloride. The mixture is heated at reflux under anhydrous conditions for 2 hours and then evaporated under reduced pressure. The residue is dissolved in 20 ml. of benzene and this solution is evaporated to dryness to yield 3- methoxybenzoyl chloride.
A solution of 1 g. of the latter compound in 50 ml. of anhydrous ether is heated to reflux and a solution of 5 g. of diethyl cadmium and 50 ml. of anhydrous ether is added. After being heated to reflux for 20 hours the mixture is extracted with ether. These extracts are washed with water to neutrality and evaporated to yield 3-methoxy propiophenone.
A mixture of l g. of the latter compound and 0.5 g. of glyoxylic acid in a solution of 0.5 g. of potassium hydroxide in l ml. of water and I0 ml. of ethanol is allowed to stand at room temperature for a period of [8 hours. The solid which forms is collected by filtration, washed with water and dried to yield 3-(3'-methoxybenzoyl)-2-butenoic acid.
A suspension of 0.5 g. of palladium-on-charcoal catalyst in 50 ml. of methanol is hydrogenated for 30 minutes. A solution of l g. of the latter compound and 200 ml. of methanol is added and hydrogenated with agitation until the uptake of hydrogen has ceased. The catalyst is removed by filtration and the solution is evaporated to yield 3-(3-methoxybenzoyl) butanoic acid.
A mixture of l g. of the latter compound, 2 g. of hydrazine hydrate, 1.2 g. of potassium hydroxide, 1.2 ml.
of water and 1.2 ml. of diethylene glycol is heated for 45 minutes at reflux, then in an open flask until the temperature of the reaction mixture is 200C, and finally for an additional 2 hours at reflux. The mixture is cooled, water added and the product isolated by extraction with ether. These extracts are dried over sodium sulfate and evaporated to yield 3-(3'- methoxybenzyl) butanoic acid.
A mixture of l g. of the latter material in 10 ml. of polyphosphoric acid is heated on a steam bath for a period of about 8 hours. The reaction mixture is then poured into ice water and the mixture is extracted several times with ether. The ether extracts are combined and evaporated to dryness to give 3-methyl-6-methoxyltetrulonc.
A mixture of l g. of 3-methyl-6-methoxy-l-tetralone in ml. of acetic acid is saturated with hydrogen bromide gas. The mixture is then allowed to stand for 24 hours and then the reaction mixture is concentrated. The thus-obtained residue, 25 ml. of 95% methanol and 0.5 g. of potassium hydroxide is refluxed for 1 hour. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3-,methyl-6-hydroxy-ltetralone.
A freshly prepared solution of 3 g. of vinyl bromide in 3 ml. of tetrahydrofuran is added to 0.5 g. of magnesium in 5 ml. of tetrahydrofuran to prepare a vinyl magnesium Grignard reagent. To this mixture is then added a solution of l g. of 3-methyl-6-methoxy-l-tetralone in 25 ml. of tetrahydrofuran and 10 ml of ether and resulting mixture is held at room temperature for a period of 24 hours, then heated at reflux for one hour and then cooled. The reaction mixture is then poured into water, acidified with hydrochloric acid and stirred vigorously to decompose any excess Grignard reagent. The organic phase is then separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed with water to neutrality, dried over sodium sulfate and evaporated to dryness to yield the crude 3-methyl-6-methoxy- 1 -vinyll -tetralol.
A mixture of l 1.8 g. of thiourea and 100 ml. of acetic acid is warmed on a steam bath until the mixture becomes homogeneous. The solution is then cooled to room temperature and to it is then added 32 g. of 3- methyl--methoxy-l-vinyl-l-tetralol. The resulting mixture is agitated until the mixture again becomes homogeneous. The acetic acid is then removed by heating (50-60C.) under reduced pressureto afford a syrup. The syrup is poured with stirring into ml. of ether. The resulting precipitate is collected and dried to yield 2-(3-methyl-6-methoxy-l,2,3,4-tetrahydronaphthyliden)ethyl isothiouronium acetate which can be recrystallized from methanolzether.
To a well-stirred solution of 16.8 g. of ethyl oz-propionyl propionate in l00 ml. of anhydrous ether is added dropwise l7 g. of bromine at such a rate that the solution continually remains clear. After completion of the bromine addition, stirring is maintained for an additional 2 hours. At the end of the reaction time, the ether is evaporated under reduced pressure and the re' sulting oil is then dissolved in 65 ml. of xylene, and the resulting xylene mixture is refluxed for 17 hours. The xylene mixture is allowed to cool and then concentrated to a smaller volume and upon cooling deposited a precipitate of org-dimethyl tetraonic acid which is collected by filtration and recrystallized from benzene:- hexane.
To a solution of 12.5 g. of 2-(3-methyl-6-methoxyl,2,3,4-tetrahydronaphthyliden)ethyl isothiouronium acetate in a mixture of ml. ethanol, and ml. of water, is added a solution of 5.1 g. of a,7-dimethyl tetronic acid in 20 ml. ethanol. Immediately, the reaction mixture is diluted by adding an additional 80 ml. of water, stirred and allowed to stand at room temperature for a period of 16 hours. The reaction mixture is then cooled to 5C. for 2 hours, and the thus-formed precipitate collected by filtration to yield oz-[2-(3-methyl- 6- methoxy-l ,2,3,4-tetrahydronaphthyliden )-ethyl]-a,'ydimethyl tetronic acid.
Nine grams of a-[2-(3-methyl-6-methoxy-l,2,3,4- tetrahydronaphthyliden)-ethyl]-a,y-dimethyl tetronic acid and 460 mg. of p-toluenesulfonic acid in ml. of benzene is heated at reflux for four hours, during which time water is continuously removed from the reaction mixture by a Dean-Stark trap. After cooling, the reaction mixture is filtered through a short column of silica gel and evaporated under reduced pressure to yield 3-methoxy-7, l 5-dimethyl l 6-oxaestral,3,5(lO),8,l4-pentaen-l7-one which is recrystallized from ether.
A mixture of 0.5 g. of 3-methoxy-7,l5-dimethyl-l6- oxaestra-l,3,5(l0),8,l4-pentaen-l7-one and 5 mg. of 5% palladium-on-charcoal catalyst. and 75 ml. of xylene is heated at reflux for 36 hours. The mixture is then cooled, filtered to remove the catalyst and the filtrate is evaporated under reduced pressure to yield a residue 1 6-oxa-estra-1 ,3,5
containing predominantly 3-methoxy-7, l 5-dimethyl-6- oxaestra-l,3,5(l),6,8,l4-hexaen-l7-one and a small amount of 3-methoxy-7, 1 S-dimethyl-l 6-oxal 4B-estral,3,5(10),6,8-pentaen-l7-one. The residue is purified by preparative thin layer chromatography and crystallized from methanol to yield 3-methoxy-7,l5-dimethyl- (l0),6,8,l4-hexaen-l7-one. 3- methoxy-7, l S-dimethyll 6-oxaestra-l ,3 ,5( l0),8, l 4- pentaen-l 7-one, 0.4 g. of maleic acid and 0.25 g. of 5% palladium-on-charcoal catalyst and 75 ml. of benzene is heated at reflux for about 24 hours. The mixture is then cooled to room temperature and filtered. The filtrate is then washed with dilute aqueous sodium bicarbonate solution, dried and evaporated to yield 3- methoxy-7,l5-dimethyl-l6-oxaestra-l,3,5(10),6,8,l4- hexaen-l7-one which is crystallized from methanol.
A mixture of 250 mg. of 3-methoxy-7,l5-dimethyll6-oxaestra-l,3,5(l0),6,8,l4-hexaen-l7-one in 25 ml. of absolute ethanol and ml. of 1N aqueous sodium hydroxide solution is allowed to stand at room temperature for 24 hours. The reaction mixture is then filtered and the thus-collected crystalline residue is washed with water and dried to yield the sodium salt of cis 7- methoxyl -acetyl-2, l O-dimethyl-l ,2,3 ,4 -tetrahydrophenanthrene-Z-carboxylic acid.
A mixture of 307 mg. of sodium salt of cis 7- methoxyl-acetyl-2, l O-dimethyl-l ,2,3 ,4- tetrahydrophenanthrene-Z-carboxylic acid, 1 ml. of methyl iodide and 7 ml. of dimethylacetamide is stirred in the dark for 5 hours. Then, excess methyl iodide is removed by evaporation under reduced pressure. The reaction mixture is then poured into water and the mixture extracted several times with ether. The ether ex-' tracts are combined, washed with water, and then dilute aqueous sodium thiosulfate solution, dried and evaporated to furnish the methyl ester of cis 7- methoxyl-acetyl-2, l O-dimethyl-l ,2,3 ,4- tetrahydrophenanthrene-2-carboxylic acid which can be crystallized from benzene-hexane.
Into the cathode compartment of a divided electrolysis cell provided with a cellulose dialysis membrane, lead electrodes (each electrode measuring 2 cm. X 5 cm. X 1.6 mm.) and a stirrer, there is added 20 mg. of methyl ester of cis 7-methoxy-l-acetyl-2,IO-dimethyll,2.3,4-tetrahydrophenanthrene-Z-carboxylic acid and a mixture of ml. of dioxane and 15 ml. of 10% aqueous sulfuric acid (by weight). An additional amount of a mixture of 15 ml. of dioxane and 15 ml. of 10% aqueous sulfuric acid is added to the cell. A current density of 0.02 amps/cm. is applied for a period of 5 hours. The reaction mixture is then removed from the cell and concentrated under reduced pressure to a small volume which is then extracted several times with ether. The ether extracts are combined, washed with water and a 5% aqueous sodium bicarbonate solution, dried and evaporated to dryness to furnish the methyl ester of cis acidified by the addition of dilute aqueous hydrochloric acid and extracted several times with the ethyl acetate.
EXAMPLE 1 Liquid ammonia which has been dried over sodium metal and distilled (600 ml.), 300 ml. dry tetrahydrofuran, and 150 ml. of dry ethanol are mixed together 10 with stirring. Ten g. of la-ethyl-Za-carboxy-2/3-methyl- 7-methoxy-l,2,3,4-tetrahydrophenanthrene (cis bisdehydrodoisynolic acid methyl ether) are then added to the mixture while continuing the stirring. To the resultant mixture are added 54 g. of lithium wire in ca.
15 2.0 g. portions with concommitant addition of 500 ml.
of ethanol in ml. portions over a total period of ca. 24 hours while maintaining the reaction mixture at reflux (ca. 20). After this period, the ammonia is allowed to evaporate and 2 l. of a saturated, aqueous solution of sodium dihydroorthosphosphate is added to the concentrate. The resultant mixture is then extracted with ethyl acetate and the extract is dried over sodium sulfate and evaporated. The concentrate, after evaporation, is then fractionally crystallized from ethyl acetate to provide the la-ethyl-2a-carboxy-2B-methyl- 7-methoxy-l ,2,3,4,5 ,8,9, l 2a-octahydrophenanthrene product.
Pyridine (0.5 ml.) and chloroform (2 ml.) are mixed and maintained together at room temperature. To the resultant mixture are added mg. of la-ethyl-Zacarboxy-2fl methyl-7-methoxyl ,2,3 ,4,5 ,8,9,12oz. octahydrophenanthrene, while maintaining the mixture at room temperature. After the addition, the resultant mixture is cooled to C. with stirring. While continuing the stirring of the cooled mixture, 87 mg. of pyridinium hydrobromide perbromide are added. After -the addition, the reaction mixture is allowed to warm to room temperature with stirring. After this time, the reaction solution is poured into 5% l-lCl ice water. The resultant mixture is extracted with ethyl acetate, washed with water and then saturated NaCl and evaporated. The concentrate after evaporation is recrystallized from methanol to provide the la-ethyl-Za- 45 carboxy-2B-methyl-7-methoxy-l ,2,3,4,9,l2a-hexahy- 55 fied mixture extracted with ethyl acetate. The extracts are dried over magnesium sulfate and evaporated to provide a concentrate which is fractionally crystallized from methanol/H O to obtain the la-ethyl-2a-carboxy- 2,8-methyl-7-hydroxy-l ,2,3,4,9,l Za-hexahydro- 6O phenanthrene product.
EXAMPLE 2 Liquid ammonia which has been dried over sodium metal and distilled (600 ml.), 300 ml. dry tetrahydro- 5 furan, and ml. of dry ethanol are mixed together with stirring. Ten g. of la-ethyl-Za-carboxy-ZB-methyl- 7-methoxyl ,2,3,4-tetrahydrophenanthene(cis bisdehydrodoisynolic acid methyl ether) are then added to the mixture while continuing the stirring. To the resultant mixture are added 54 g. of lithium wire in ca. 2.0 g. portions with concommitant addition of 500 ml. of ethanol in 20 ml. portions over a total period of ca. 24 hours while maintaining the reaction mixture at reflux (ca. -20). After this period, the ammonia is allowed to evaporate and 2 l. of a saturated, aqueous solution of sodium dihydroorthophosphate is added to the concentrate. The resultant mixture is then extracted with ethyl acetate and the extract is dried over sodium sulfate and evaporated to provide the 1201 and 12B epimers of la-ethyl-Za-carboxy-ZB-methyl-7- methoxy-1,2,3,4,5,8,9,12-octahydrophenanthrene.
Pyridine (0.5 ml.) and chloroform (2 ml.) are mixed and maintained together at room temperature. To the resultant mixture are added 75 mg. of the 120: and 12,8 epimers of la-ethyl-2acarboxy-2,B-methyl-7-methoxyl,2,3,4,5,8,9,l2-oetahydrophenanthrene, prepared as described above, while maintaining the mixture at room temperature. After the addition, the resultant mixture is cooled to -80C. with stirring. While continuing stirring of the cooled mixture, 87 mg. of pyridiuium hydrobromide perbromide are added. After the addition, the reaction mixture is allowed to warm to room temperature with stirring. After this time, the reaction solution is poured into HCl ice water. The resultant mixture is extracted with ethyl acetate, washed with water and then saturated NaCl and evaporated to provide the 12a and 12B epimers of lOl-BthYl- 2oz-carboxy-2B-methyl-7-methoxy-l ,2,3,4,9,12-hexahydrophenanthrene. The concentrate after evaporation is crystallized from methanol to provide the laethyl-Za-carboxy-2B-methy1-7-methoxy 1 ,2 ,3 ,4 ,9 12a-hexahydrophenanthrene product. The mother. liquor is subjected to thin-layer chromatography to obtain the la-ethyl-Za-carboxy-2B-methyl-7-methoxyl,2,3,4,9, l 2B-hexahydrophenanthrene.
The 1a-ethyl-Za-carboxy-ZB-methyl-7-methoxy- 1,2,3,4,9, l 2a-hexahydrophenanthrene thus prepared is treated with lithium iodide as described in Example 1 to obtain the 1a-ethyl-2a-carboxy-2B-methyl-7- hydroxy-l ,2,3,4,9,1Za-hexahydrophenanthrene product.
EXAMPLE 3 A mixture of 1a-ethyl-Za-carbomethoxy-2B-ethy1-7- methoxy-l,2,3,4-tetrahydrophenanthrene (104 mg.) in 300 mg. oft-butanol is dispersed in a mixture of 25 ml. of ammonia and ml. of tetrahydrofuran with stirring. Lithium wire mg.) is then added to the resultant solution in a portion-wise fashion at reflux. After the blue color of the resultant mixture has faded (about minutes), the ammonia is allowed to evaporate. After evaporation period, water and diethyl ether are added to the resultant mixture. The ether layer is separated and washed with water, dried and evaporated to obtain a residue which is recrystallized from ether hexane to obtain the la-ethyl-2a-hydroxymethyl-2B-methyl-7 -methoxy-l,2,3,4,5,8-hexahydrophenanthrene product.
A solution is prepared by dispersing 500 mg. of 1aethyl-2a-hydroxymethyl-2B-methy1-7-methoxy- 1,2,3,4,5,8-hexahydrophenanthrene in 100 ml. of tetrahydrofuran and 100 ml. of ammonia. Lithium wire (500 mg.) and 10 ml. of t-butanol are added portionwise thereto over a period of 5 days at a rate sufficient to maintain a blue color. After the blue color of the reaction mixture has faded, water and ether are added.
The ether layer is separated and washed with water. dried and evaporated to provide an isomeric mixture of la-ethyl-2a-hydroxymethyl-2B-methyl7-methoxy- 1,2,3 ,4,5 ,8 ,9, 1 Z-octahydrophenanthrene.
5 The epimeric mixture of 1a-ethyl-Za-hydroxymethyl- 2Bmethyl-7-inethoxy-1,2,3,4,5,8,9,12- octahydrophenanthrene (103 mg.) is dispersed in 1 ml. of pyridine and 100 mg. of pyridinium hydrobromide perbromide in 0.5 m1. of pyridine are added dropwise.
10 The pyridine is evaporated by passing a stream of nitrogen through the reaction mixture and the resultant residue partitioned between diethyl ether and water. The ether extracts are washed with water, dried and evaporated to obtain the la-ethyl-Za-hydroxymethyll5 2B-methyl-7-methoxy-l,2,3,4,9,12-hexahydrophenanthrene epimeric products. The residue is subjected to thin-layer chromatography to separate the --1a-ethyl-Za-hydroxymethyl- 2B-methyl-7-methoxy- 1 ,2,3,4,9,l 2a-hexahydro- 20 phenanthrene product and the corresponding 126 product.
Similarily as described above, the 12a epimer in the Za-hydroxymethyl-l,2,3,4,5,8,9,12- octahydrophenanthrene series is isolated.
hydroxy-l,2,3,4-tetrahydrophenanthrene in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromato-- graphed on neutral alumina, eluting with hexane, to yield let-ethyl- 2a-carbotetrahydropyran-2-yloxy-2B-methyl-7- tetrahydropyran-2'-yloxy-1 ,2,3,4-tetrahydrophenanthrene which is recrystallized from pentane.
la'Ethyl-2 a-carbotetrahydropyran-Z -yloxy-2B- methyl-7-tetrahydropyran-2-yloxy-1,2,3 ,4-tetrahydrophenanthrene is reacted with 100 equivalents of sodium metal and ammonia in the presence of t-butanol as otherwise set forth in Example 3 to obtain first the la-ethyI-Za-hydroxymethyl-2/3-methyl-7- tetrahydropyran-2'-yloxy-l ,2,3,4,5,8-hexahydrophenanthrene product and second the la-ethyl-2ahydroxymethyl-2,8-methyl-7-tetrahydropyran-2'-yloxy 1,2,3,4,5.8,9,1Z-octahydrophenanthrene products. The isomeric mixture of the latter product is reacted with pyridinium hydrobromide perbromide as set forth in Example 3 to obtain the 1a-ethyl-2a-hydroxymethyl- 2,8-methyl-7-tetrahydropyran-2 yloxy-l ,2.3 ,4,9,12- hexahydrophenanthrene products. Each isomer can be treatd in accordance with the procedure of Example 1 to provide the 1a-ethyl-Za-hydroxymethyl-Zfimethyl 7-hydroxy-l ,2,3,4,9,12-hexahydrophenanthrene products.
In a manner similar to that set forth above, la-ethyl- 2a-hydroxymethyl-2B-methyl-7-tetrahydropyran-Z'- yloxy-l ,2,3,4,9,12-hexahydrophenanthrene product is obtainable by employing the corresponding methyl, ethyl, n-propyl, and n-butyl esters in lieu of the carbo ester starting material.
EXAMPLE A mixture of l g. of la-ethyl-2a-hydroxymethyl-2B- methyl-7-methoxyl ,2,3 ,4,9, l 2-hexahydrophenanthrene, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield la-ethyl-Za-acetoxymethyl- 2,B- methyl-7-methoxy-l ,2,3 ,4,9, l 2-hexahydrophenanthrene which may be further purified through recrystallization from acetonezhexane.
In like manner, the Za-propionyloxymethyl, -butroyloxymethyl, -caproyloxymethyl, and -trimethylacetoxymethyl compounds otherwise corresponding to the acetoxymethyl product of the foregoing paragraph are prepared by using the corresponding acylating agent. In like manner, the other acyloxymethyl compounds of the present invention are prepared by utilizing the corresponding acylating agent.
Two milliliters of dihydropyran are added to a solution of 1 g. of la-ethyl-Za-hydroxymethyl-2B-methyl- 7-methoxy-l,2,3,4,9,l2-hexahydrophenanthrene in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days,
and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield la-ethyl-2a-tetrahydropyran-2 yloxymethyl-2B-methyl-7-methoxyl ,2,3,4,9, l 2-hexahydrophenanthrene which is recrystallized from pen tane.
By employing the method of the preceding paragraph using dihydrofuran in lieu of dihydropyran, there is prepared the corresponding la-ethyl-Zwtetrahydrofuran- 2-yloxymethyl-2B-methyl-7-methoxy-l ,2,3,4,9,l 2- hexahydrophenanthrene product. Similarly, the lotethyl-2a-(4-methoxy-tetrahydropyran-4'-yloxymethyl)-2B-methy1-7-methoxy-l,2,3,4-tetrahydrophenanthrene product is prepared by utilization of the foregoing procedure employing 4-methoxy-5,6- dihydro-2H-pyran in lieu of dihydropyran.
A solution of one chemical equivalent of la-ethyl- 2a-hydroxymethyl-2B-methyl-7-methoxy-1,2,3,4,9,l2- hexahydrophenanthrene in ml. of benzene is heated to reflux and about 2 ml. removed by distillation to eliminate moisture. The mixture is cooled to room temperature and two chemical equivalents of sodium hydride are added, followed by the dropwise addition of two chemical equivalents of cyclopentyl bromide in 10 ml. of benzene over a period of 20 minutes. The mixture is allowed to reflux for 20 hours after which time the precipitate of sodium bromide is removed by filtration and the organic phase dried and evaporated to yield la-ethyl-2a-cyclopentyloxymethyl-2B-methyl-7- methoxyl ,2,3,4,9, l 2-hexahydrophenanthrene which is further purified upon recrystallization from pentane.
Alternatively, the ethers of la-ethyl-Zahydroxymethyl-2/3-methyl-7-methoxy-1 ,2,3,4-tetrahydrophenanthrene are prepared in accordance with paragraphs 3, 4 and 5 of this example and the resultant compounds are treated in accordance with the procedures of Example 1 above to prepare the 20:- tetrahydropyran-Z'-yloxymethyl-tetrahydrofuran-2'- yloxymethyl, -4'-methoxy-tetrahydropyran-4- yloxymethyl, and -cyclopentyloxymethyl compounds in the la-ethyl-ZB-methyl-7-methoxy-l ,2,3,4,9. l 2-hexahydrophenanthrene series.
Similarly, the foregoing methods are used to prepare the corresponding C-7 esters and ethers of the l,2,3,4,- 9,12-hexahydrophenanthrene products hereof.
The methods of the foregoing procedures can be practiced utilizing a 7-tetrahydropyran-Z-yloxy compound in lieu of the 7-methoxy starting compound set forth therein to provide the corresponding 7- tetrahydropyran-Z'-yloxy-l ,2,3,4,9,1 2-hexahydrophenanthrene product. These compounds can then be hydrolyzed as set forth in paragraph 3, Example 1.
EXAMPLE 6 i Twenty ml. of liquid ammonia, 10 ml. of tetrahydrofuran, and 5 ml. of ethanol are mixed together. To the resultant mixture are added 300 mg. of la-ethyl-2aacetoxymethyl-2,B-methyl-7-methoxy-1,2,3,4-tetrahydrophenanthrene with stirring. To the resulting mixture are added 50 equivalents of sodium metal in a portionwise fashion and with stirring. After the addition period of about 72 hours, the reaction mixture is worked up as set forth in Example 1 to provide the laethyl-2ahydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,5,8,9,l2- octahydrophenanthrene products. The use of potassium metal in t-butanol and lithium metal in isopropanol affords similar results.
The latter product is treated with pyridinium hydrobromide perbromide to obtain the corresponding laethyl-2a-hydroxymethyl-2B-methyl-7-methoxyl,2,3,4,9,12-hexahydrophenanthrene products.
EXAMPLE 7 To a solution of 3 g. of la-ethyl-Za-carboxy-ZB- methyl-7-methoxy-l,2,3,4,9,12a-hexahydrophenanthrene in 50 ml. of methylene chloride are added an excess of diazomethane in ether (obtained from nitrosomethylurea) and a few drops of methanol. The reaction mixture is maintained at room temperature for 18 hours and the excess reagent is then decomposed by the addition of acetic acid. The resulting mixture is poured into water and the organic layer is separated, washed with water to neutrality and evaporated to dryness to yield la-ethyl-Za-carbomethoxy-2B-methyl-7- methoxy-l,2,3,4,9,lZa-hexahydrophenanthrene product.
In a manner similar to the above, the other corresponding Za-carboalkyloxy compounds of the present invention are prepared.
EXAMPLE 8 To a solution of 14.2 mg. of la-ethyl-2ahydroxymethyl-2B-methyl-7-methoxy-l,2,3,4,9,l2a' hexahydrophenanthrene in ml. of dry dimethylsulfoxide is added a solution of 49.6 mg. of dicyclohexylcarbodiimide in 300g of dimethylsulfoxide, followed by the addition of a solution of 2,1. of trifluoroacetic acid, 3.8;1. of pyridine and 50p. of dimethylsulfoxide. After reaction, the mixture is partitioned between water and diethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is subjected to thin-layer chromatography to obtain the laethyl-Za-formyl-2B-methyl-7-meth0xy-l ,2,3,4,9, l 2&- hexahydrophenanthrene product.
EXAMPLE 9 To a stirred solution of l g. of lB-ethyl-Za-formyl- ZB-methyl-7-cyclopentyloxy-1,2,3,4,9,l2-hexahydrophenanthrene in 10 ml. of acetone, cooled to C., is added under nitrogen a solution of 8N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 ml. of concentrated sulfuric acid and diluting with water to 100 ml.) until the color of the reagent persists in the mixture. The mixture is then stirred for 5 minutes at O-5C. and diluted with water. The solid which forms is collected by filtration, washed with water and dried under vacuum to yield lB-ethyl-2a-carb0xyl2/3- methyl-7-cyclopentyloxyl ,2,3 ,4,9, l 2-hexahydrophenanthrene which may be further purified by recrysl5 tallization from acetone: hexane.
EXAMPLE 10 To a solution of IO g. of la-ethyl-2a-carboxy-2B,l0- -carboxyacetone:hexane dimethyl-7-methoxy 2Q l,2,3,4,9, lZ-heXahydrophenanthrcne in 200 ml. of ethanol is added the theoretical amount of potassium hydroxide dissolved in 200 ml. of 90% ethanol. The reaction mixture is then concentrated in vacuum giving potassium lmethyl-2B,lO-dimethyl-7-methoxy- 25 12.3.4.9, l 2-hexahydrophenanthrene-20z-carboxylate.
In accordance with the foregoing methods, the following are prepared:
la-methyl-2a-carboxy-2B-ethyl-7-methoxyl,2,3,4,9, l2-hexahydrophenanthrene,
l,8-ethyl-2a-carboethoxy-7-methoxyl O-methyll,2,3.4,9, l 2-hexahydrophenanthrene,
la-ethyl-2a-carbo-n-propoxy-ZB-methyl-7-(4'- methoxytetrahydropyran-4-yloxy)-l ,2,3,4,9, l 2-hexahydrophenanthrene,
l B-ethyl-2a-tetrahydropyran-2 'yloxy-2B-methyl-7- hydroxy-- l ,2,3,4,9, l 2-hexahydrophenanthrene,
la-methyl-Za-formyl-2,B-ethyl-7-propionyloxy- 1,2,3 ,4,9, l 2-hexahydrophenanthrene,
sodium la-ethyl-ZB-methyl-7-methoxy-l ,2,3,4,9,l2- 40 hexahydrophenanthrene-Za-carboxylate,
l,B-ethyl-2a-carbo-n-butoxy-ZB-ethyl-7-hydroxy l,2,3.4,9,l2-hexahydrophenanthrene,
1121,23,] 0-trimethyl-2a-carboxy-7-hydroxyl ,2,3,4,9,12-hexahydrophenanthrene.
1B,lO-dimethyl-2a-pentanoyloxymethyl-2B-ethyl-7- cyclopentyloxyl ,2,3,4,9, l 2-hexahydrophenanthrene, l,B,2B-diethyl-Za-cyclopentyloxymethyl-7-acetoxy- 1,2,3,4,9,l2-hexahydrophenanthrene,
potassium la-ethyl-ZB-methyl-7-acetoxyl,2,3,4,9, l 2-hexahydrophenanthrene-2a-carboxylate,
lB-ethyl-Za-carboxy-2/3-methyl-7-tetrahydropyran- 2 '-yloxy-l ,2,3,4,9, l 2-hexahydrophenanthrene,
lB-methyl-2a-formyl-2B-ethyl-7-ethoxyl,2,3,4,9, l 2-hexahydrophenanthrene,
lB-ethyl-Za-hydroxymethyl-2,8-methyl-7-n-propoxy- R is methyl or ethyl:
R is hydroxymethyl or the hydrolyzable hydrocarbon carboxylic acid esters thereof wherein the carboxylic acid moiety has from 2 to 14 carbon atoms;
R is methyl or ethyl;
R is lower alkyloxy wherein the alkyl moiety has from 1 to 6 carbon atoms, hydroxy, the hydrolyzable hydrocarbon carboxylic acid esters of said hydroxy group wherein the carboxylic acid moiety has from 2 to 14 carbon atoms, tetrahydropyran- 2'-yloxy, tetrahydrofuran-Z-yloxy, 4- methoxytetrahydropyran-2'-yl.oxy, or cyclopentyloxy; and R is hydrogen or methyl. 2. A C-lZa compound according to claim 1. 3. A compound according to claim 1 wherein R is ethyl; R is methyl; and R is lower alkyloxy.
4. A compound according to claim 3 wherein R is hydrogen.
5. A compound according to claim 4 wherein R hydroxymethyl.
6. The compound according the claim 5 wherein R is methoxy.
7. A C-l2a compound according to claim 1 wherein R is ethyl; R is hydroxymethyl; R is methyl; R is lower alkyloxy; and R is hydrogen.
8. The compound according to claim 7 wherein R is methoxy; la-ethyl-2a-hydroxymethyl-2B-methyl-7- methoxy-l ,2,3,4,9, l 2a-hexahydrophenanthrene.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Q Patent 3,865,883 Dated February 11, 1975 Invent0r(s)JOHN A. EDWARDS et al It is certified that error appears in the above-identified patent Q and that said Letters Patent are hereby corrected as shown below:
Column 2, line 4, change "symmetry to asymmetry--.
Column 5, line 39, change "quences In" to quences. In.
I Column 7, line 5, change R to R e 2' 2 Column 7, line 22, change "R to R Column 8, line 9, change "ethers to ethers)-.
Column 16, lines 59, 60 and 61, change "11" to --ul-. 8
Column 17, line 12, change "carboxy l26" to carboxy-2B- Column 17, line 20, delete "carboxy-acetone:hexane".
Column 18, line 4, change "2c" to 26- C Signed and Scaled this ninth Day Of September 1975 [SEAL] e I Altesr:
RUTH C. MASON C. MARSHALL DANN Arresting Officer (mnml'ssiuner uj'Palents and Trademarks Q

Claims (9)

1. A PROCESS FOR PREPARING GLYOXAL WHICH COMPRISES IN THE
1. A COMPOUND SELECTED FROM THE GROUPS OF COMPOUNDS REPRESENTED BY THE FOLLOWING FORMULA: PRESENCE OF WATER REACTING CHLORACETALDEHYDE WITH A DIALKYL SULFOXIDE, EACH OF SAID ALKYL GROUPS, WHICH MAY BE THE SAME OR
2. A C-12 Alpha compound according to claim 1.
3. A compound according to claim 1 wherein R1 is ethyl; R3 is methyl; and R4 is lower alkyloxy.
4. A compound according to claim 3 wherein R5 is hydrogen.
5. A compound according to claim 4 wherein R2 is hydroxymethyl.
6. The compound according the claim 5 wherein R4 is methoxy.
7. A C-12 Alpha compound according to claim 1 wherein R1 is ethyl; R2 is hydroxymethyl; R3 is methyl; R4 is lower alkyloxy; and R5 is hydrogen.
8. The compound according to claim 7 wherein R4 is methoxy; 1 Alpha -ethyl-2 Alpha -hydroxymethyl-2 Beta -methyl-7-methoxy-1,2, 3,4,9,12 Alpha -hexahydrophenanthrene.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2938056A (en) * 1957-11-27 1960-05-24 Upjohn Co 2, substituted-1-methyl-7-methoxy-1, 2, 3, 4, 9, 10-hexahydrophenanthrenes
US3275691A (en) * 1962-04-11 1966-09-27 Hoffmann La Roche Dodecahydrophenanthrene derivatives
US3483226A (en) * 1967-06-12 1969-12-09 Searle & Co 16-oxa and 17 - oxa - d - homoestra - 1,3,5(10)-trien-3-ols and d-nor-seco-diols corresponding,ethers and esters thereof
US3716578A (en) * 1969-04-03 1973-02-13 Novo Terapeutisk Labor As Hexahydrophenanthrene derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2938056A (en) * 1957-11-27 1960-05-24 Upjohn Co 2, substituted-1-methyl-7-methoxy-1, 2, 3, 4, 9, 10-hexahydrophenanthrenes
US3275691A (en) * 1962-04-11 1966-09-27 Hoffmann La Roche Dodecahydrophenanthrene derivatives
US3483226A (en) * 1967-06-12 1969-12-09 Searle & Co 16-oxa and 17 - oxa - d - homoestra - 1,3,5(10)-trien-3-ols and d-nor-seco-diols corresponding,ethers and esters thereof
US3716578A (en) * 1969-04-03 1973-02-13 Novo Terapeutisk Labor As Hexahydrophenanthrene derivatives

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