Estrone 3-methyl ether

A McMurry coupling of (176, X = O Y = /5H) provides ( )-9,ll-dehydroesterone methyl ether [1670-49-1] (177) in 56% yield. 9,11-Dehydroestrone methyl ether (177) can be converted to estrone methyl ether by stereoselective reduction of the C —double bond with triethyi silane in triduoroacetic acid. In turn, estrone methyl ether can be converted to estradiol methyl ether by sodium borohydride reduction of the C17 ketone (199,200). 

The solubility of many steroids in ammonia-tetrahydrofuran-/-butyl alcohol is about 0.06 A/, a higher concentration than has been reported in other solvent systems. Still higher concentrations may be possible in particular cases by suitable variation in the solvent ratios Procedure 3 (section V) describes such a reduction of estradiol 3-methyl ether at a 0.12 M concentration. A few steriods such as the dimethyl and diethyl ketals of estrone methyl ether are poorly soluble in ammonia-tetrahydrofuran-/-buty] alcohol and cannot be reduced successfully at a concentration of 0.06 even with a 6 hour reduction period. The diethyl ketal of estrone methyl ether is reduced successfully at 0.12 M concentration using a two-phase solvent system of ammonia-/-amyl alcohol-methylcyclohexane (Procedure 4, section V). This mixture probably would be useful for any nonpolar steroid that is poorly soluble in polar solvents but is readily soluble in hydrocarbons. 

Estrone methyl ether (100 g, 0.35 mole) is mixed with 100 ml of absolute ethanol, 100 ml of benzene and 200 ml of triethyl orthoformate. Concentrated sulfuric acid (1.55 ml) is added and the mixture is stirred at room temperature for 2 hr. The mixture is then made alkaline by the addition of excess tetra-methylguanidine (ca. 4 ml) and the organic solvents are removed. The residue is dissolved in heptane and the solution is filtered through Celite to prevent emulsions in the following extraction. The solution is then washed threetimes with 500 ml of 10 % sodium hydroxide solution in methanol to remove excess triethyl orthoformate, which would interfere with the Birch reduction solvent system. The heptane solution is dried over sodium sulfate and the solvent is removed. The residue is satisfactory for the Birch reduction step. Infrared analysis shows that the material contains 1.3-1.5% of estrone methyl ether. The pure ketal may be obtained by crystallization from anhydrous ethanol, mp 99-100°. Acidification of the methanolic sodium hydroxide washes affords 10-12 g of recovered estrone methyl ether. 

The crude ketal from the Birch reduction is dissolved in a mixture of 700 ml ethyl acetate, 1260 ml absolute ethanol and 31.5 ml water. To this solution is added 198 ml of 0.01 Mp-toluenesulfonic acid in absolute ethanol. (Methanol cannot be substituted for the ethanol nor can denatured ethanol containing methanol be used. In the presence of methanol, the diethyl ketal forms the mixed methyl ethyl ketal at C-17 and this mixed ketal hydrolyzes at a much slower rate than does the diethyl ketal.) The mixture is stirred at room temperature under nitrogen for 10 min and 56 ml of 10% potassium bicarbonate solution is added to neutralize the toluenesulfonic acid. The organic solvents are removed in a rotary vacuum evaporator and water is added as the organic solvents distill. When all of the organic solvents have been distilled, the granular precipitate of 1,4-dihydroestrone 3- methyl ether is collected on a filter and washed well with cold water. The solid is sucked dry and is dissolved in 800 ml of methyl ethyl ketone. To this solution is added 1600 ml of 1 1 methanol-water mixture and the resulting mixture is cooled in an ice bath for 1 hr. The solid is collected, rinsed with cold methanol-water (1 1), air-dried, and finally dried in a vacuum oven at 60° yield, 71.5 g (81 % based on estrone methyl ether actually carried into the Birch reduction as the ketal) mp 139-141°, reported mp 141-141.5°. The material has an enol ether assay of 99%, a residual aromatics content of 0.6% and a 19-norandrost-5(10)-ene-3,17-dione content of 0.5% (from hydrolysis of the 3-enol ether). It contains less than 0.1 % of 17-ol and only a trace of ketal formed by addition of ethanol to the 3-enol ether. 

Under certain conditions surface catalytic deuterations can lead to the exchange of benzylic hydrogens. An example in the steroid field is the exchange of the benzylic hydrogens in estrone methyl ether (42) with deuterium in the presence of palladized charcoal." " According to mass spectrometric analysis, the product (43) contains three deuteriums (83 %), which have been assigned to the 6- and 9a-positions on the basis of NMR evidence." " ... 

The alkynylation of estrone methyl ether with the lithium, sodium and potassium derivatives of propargyl alcohol, 3-butyn-l-ol, and propargyl aldehyde diethyl acetal in pyridine and dioxane has been studied by Miller. Every combination of alkali metal and alkyne tried, but one, gives the 17a-alkylated products (65a), (65c) and (65d). The exception is alkynylation with the potassium derivative of propargyl aldehyde diethyl acetal in pyridine at room temperature, which produces a mixture of epimeric 17-(3, 3 -diethoxy-T-propynyl) derivatives. The rate of alkynylation of estrone methyl ether depends on the structure of the alkyne and proceeds in the order propar-gylaldehyde diethyl acetal > 3-butyn-l-ol > propargyl alcohol. The reactivity of the alkali metal salts is in the order potassium > sodium > lithium. 

Methoxy-cis-19-norpregna-l,3,5(10),17(20)-tetraene A solution of 31 g (109 mmolesi of estrone methyl ether in 600 ml of benzene is added rapidly to a solution of 469 mmoles of ethylidenetriphenylphosphorane in 1.2 liters of DMSO. After heating under nitrogen at 60° overnight, the reaction is cooled, poured into ice water, and extracted with three portions of hexane, backwashed with three portions of water and the hexane removed. The crude product, dissolved in petroleum ether (bp, 30-60°), is filtered through 225 g of alumina (activity I). The residue from the eluate consists of 95 % cis- and 5 % tran5-isomers, as determined by vpc analysis. After recrystallization from ether-methanol, 26.3 g (82%) of cw-isomer is obtained mp 76.5-77.5° [a]o 60°. 

Ethoxyacetylene A solution of 7 g of estrone methyl ether in tetra-hydrofuran (80 ml) is slowly added with stirring to ethoxyethynylmagnesium bromide (from ethoxyacetylene, 9 g, and 3 M ethereal methyhnagnesium bromide, 32 ml) and the mixture is refluxed overnight with stirring. Aqueous... 

The reaction of ethyl a-bromoacetate with 17-keto steroids such as estrone methyl ether or dehydroepiandrosterone acetate " under standard Reformatsky conditions is stereospecific, producing the 17 -ol in up to 80% yields. Ethyl a-bromopropionate reacts similarly but the yields are somewhat lower. 

Methoxy-D-Homo-estra-l,3,5(10)-trien-17a-one (96)" (/) Acetic acid (6.4 ml) is added to a stirred solution of estrone methyl ether (93 1.1 g) in ethanol (35 ml) containing potassium cyanide (6 g) at 0°. After being stirred for 1 hr at 0° and 2.5 hr at room temperature, the reactants dissolve and potassium acetate preciptates. Water (65 ml) is added to the reaction mixture and the precipitated solid is collected by filtration. The crude product is dissolved in ethyl acetate and the ethyl acetate solution is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. Recrystallization of a portion of the crude product from cyclohexane-acetone gives 3-methoxy-17a-cyano-estra-l, 3,5(10)-trien-17j5-ol (94a) as needles mp 158.5°. 

During 1961-2 four independent groups almost simultaneously reported the first syntheses of D-norsteroids, based on the photolysis of 16-diazo-17-ketones. In a typical procedure. Cava and Moroz ° convert the 16-oximino-17-one (93) derived from estrone methyl ether (92) to the diazoketone (94)... 

Reaction of estrone methyl ether with methyl Grignard reagent followed by Birch reduction and hydrolysis of the intermediate enol ether affords the prototype orally active androgen in the 19-nor series, normethandrolone (69). ° (Note that here again the addition of the methyl group proceeded stereoselectively by approach from the least hindered side.) The preparation of the ethyl homolog starts by catalytic reduction of mestranol treatment of the intermediate, 70, under the conditions of the Birch reduction and subsequent hydrolysis of the intermediate enol ether yields norethandrolone (71). ... 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

Clinical trials of these orally active progestins showed that they were effective as contraceptives with a success rate that exceeded 99%. These compounds were then marketed as obtained from the reaction sequence after appropriate purification. As the analytical methodology improved it became apparent that a small amount of an impurity was present in all active samples. An examination of the reaction scheme allowed ready identification of that by-product. Any unreduced estradiol methyl ether (13-1) will go to estrone methyl ether on oxidation this will then afford the potent orally active estrogen mestranol (9-1) on ethynylation. Subsequent... 

One of the important mechanisms by which orally administered steroids are inactivated involves the formation of water-soluble derivatives at the 17 position, a process that is greatly reduced in 17a-alkyl-17(3-hydroxy derivatives. Extensive use of the resulting orally active compounds has since revealed that 17 alkylation also leads to increased liver toxicity. Preparation of the first of these compounds, nor-methandrolone (32-3), starts by addition of methylmagnesium iodide to estrone methyl ether (9-1) to give the 17a methyl derivative. Birch reduction followed by acid hydrolysis leads to normethandrolone (32-3) [16]. 

This orientation also obtains in cycloaddition with citraconic anhydride (6). These results arc difficult to rationalize in any case the reaction of 1 with quinones such as 2 provides a route to D-homosteroids with substituents at either C,j or C14. In fact, the adduct 5 was converted to (//-estrone methyl ether. 

The reaction provides the key step in a stereoselective synthesis of estrone methyl ether (6) from 5.b... 

Androst-4-ene-3,ll,17-trione, 88, 377, 409 di-Androst-5-en-3/3-oI, 199 Androst-5-en-17-ol-3-one, 32 Androst-l-en-3-one, 152 Androst-4-en-3 -one, 152 5a-Androst-8-en-l 1-one, 189 5 -Androst-8(14)-en-15-0ne, 155 Anhydrous hydrogen fluoride, 425 Aqueous hydrogen fluoride, 435 Argentic picolinate, 241 17a-aza-D-homo-estrone methyl ether, 163... 

Bamford-Stevens decomposition of tosylhy-drazones, 351 p-Benzoquinone, 308 Benzyl ether hydrogenolysis, 139 Benzyl thioenol ethers, 87 Birch reduction, 11, 49, 50 Birch reduction of estrone methyl ether diethyl ketal, 51... 

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