methallenestril

Chemical properties

Crystals.Soluble in ether, vegetable oils.

Originator

Vallestril ,Searle,US,1952

The Uses of methallenestril

Medicine (estrogen).

Definition

ChEBI: Methallenestril is a member of naphthalenes.

Manufacturing Process

A first step involves the preparation of 2-cyano-6-methoxynaphthalene (cyanonerolin). 90 g of 2-bromo-6-methoxynaphthalene are heated with 60 g of cuprous cyanide in a metal bath at 240° to 250°C stirring for one hour. At the instant when the cuprous cyanide begins to react and dissolves, the mass turns brown, liquefies and heats up strongly. The molten mass is poured onto a cold surface, is pulverized and sifted. This powder is treated with dilute ammonia (1 liter of water to 300 cc of commercial ammonia solution). The solution is filtered on a Buchner filter and the precipitate that remains on the filter is washed with dilute ammonia and then with water.
After drying, the residue is treated in a Kumagawa extracting apparatus with boiling benzene. The benzene is evaporated and the residue is distilled in vacuo. About 50 g of cyanonerolin (BP = 205° to 208°C/14 mm) are obtained with a yield of about 70%. By recrystallization in 200 cc of methyl alcohol, 40 g of the product are obtained in absolutely pure state, in the shape of beautiful colorless needles (MP = 103°C with the Maquene block). By concentrating the mother liquor to half its original volume, a further 3.6 g of pure product are obtained.
The 2-cyano-6-methoxy-naphthaleneis in turn converted by successive reactions into: (a) β-ketonic ester, (b) ester-alcohol, (c) β-ethylene ester by dehydration, (d) saturated ester, and (e) [3-(6-methoxy-2-naphthyl)]2,2- dimethyl pentanoic acid which is the required product.
(A) Obtaining a β-Ketonic Ester by Reacting Ethyl Bromoisobutyrate with Cyanonerolin: 9 g of cyanonerolin are heated in a reflux apparatus for 40 minutes with 7 g of zinc and 19 g of ethyl bromoisobutyrate in the presence of 150 cc of anhydrous benzene. After cooling, the mixture is filtered to eliminate unreacted zinc and is hydrolyzed by stirring for one hour with dilute sulfuric acid (10 cc of sulfuric acid to 200 cc of water). The benzene layer is washed, dried and the solvent is eliminated. It is purified by recrystallization in methyl alcohol. 12.5 g of ketonic ester (MP = 72.5° to 73.5°C) are thus obtained in the form of large prismatic crystals.
(B) Obtaining an Ester-Alcohol by Reacting Magnesium Ethyl Bromide with the Previous Ketonic Ester: 10 g of the previous ester dissolved in 40 cc of anhydrous benzene are gradually poured while stirring into an iced solution of magnesium ethyl bromide prepared from 1.035 g of magnesium, 4.15 cc of ethyl bromide and 40 cc of anhydrous ether. After heating in a reflux apparatus for one-half hour, the mixture is poured into ice in the presence of ammonium chloride. After washing the ether-benzene layer, the solvents are eliminated in vacuo and an ester-alcohol is thus obtained with a yield of 98%, in the form of a transparent resin. This resin, if treated with petroleum ether, yields 6.35 g of ester-alcohol in the form of fine needles (MP = 66.68°C) which are very soluble in the chief organic solvents and in petroleum ether.
(C) Conversion into Ethyl [3(6-Methoxy-2-Naphthyl)] 2,2-Dimethyl-3- Pentanoate by Dehydrating the Previous Ester-Alcohol: The semi-oily raw product of the previous reaction is dehydrated by heating with its own weight of potassium bisulfate to 180°C until boiling stops. After cooling, the magma is removed from the anhydrous ether in small portions. The ether is then evaporated and an ethylene ester is obtained in the form of an oil which slowly solidifies, with a yield of 98%. The product, after being purified by chromatography, melts at 48° to 51°C.
(D) Obtaining Ethyl [3-(6-Methoxy-2-Naphthyl)] 2,2-Dimethyl Pentanoate by Hydrogenation of the Previous Ethylene Ester: 3.5 g of the previous ethylene ester, purified by chromatography, are hydrogenated in the presence of 3.6 g of platinum in 30 cc of ether. The quantity of hydrogen fixed corresponds to the theoretical quantity calculated. After filtering, the ether is evaporated, 3.45 g of ester are thus obtained in the form of an oil which quickly solidifies. Purification is effected by chromatography.
(E) Obtaining [3-(6-Methoxy-2-Naphthyl)] 2,2-Dimethyl Pentanoic Acid: 2.5 g of the previous ester are saponified by means of 15 cc of soda lye and 25 cc of methyl glycol. The mixture is boiled for one hour, diluted with water and, after cooling, is treated twice with ether in order to eliminate the remaining neutral fractions. The aqueous layer is precipitated by means of 15 cc of acetic acid. 2.1 g of raw acid are obtained. After effecting two crystallizations in 10 parts of acetic acid mixed with 3 parts of water, fine needles are obtained which are grouped in rosettes and melt at 131.5° to 132.5°C.

Therapeutic Function

Estrogen