Rubin, Martin; Wishinsky, Henry published an article in 1946, the title of the article was 1-Methyl-3-ethyl-4-(p-hydroxyphenyl)-Δ3-cyclohexenylethylcarbinol, an “open model” of estradiol.COA of Formula: C9H14O3 And the article contains the following content:
Johnson and Offenhauer (C.A. 39, 4067.1) have suggested 4-(p-hydroxyphenyl)hexahydropropio-phenone as an “open model” of estrone; [1-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenyl]ethylcarbinol (I) is now proposed as an open model of estradiol. γ-Methyl-γ-carboxypimelic acid (II) yields 80% of the Et ester, b0.1 128-31°, which is cyclized (75%) to Et 1-methyl-3-carbethoxy-4-ketocyclohexanecarboxylate (II), b0.2 125-30°, gives a violet color with FeCl3. II (10 g.) in 20 cc. AcOH, 5 cc. concentrated HCl, and 3 cc. H2O, refluxed 5 h., gives 78% of 1-methyl-4-ketocyclohexanecarboxylic acid (III), b0.5 130-5°, m. 78-9°. III results in 47% yield by refluxing 15 g. I and 30 g. Ac2O for 4 h. and heating the residue at 200-20°/30 mm. until CO2 evolution ceases. The Me ester (IV) of III b0.2 80-3°. II (130 g.), added to 11.5 g. Na in 300 cc. PhMe and refluxed until the Na has reacted, the solution treated with 100 g. EtI, and refluxed for 14 h., gives 92% of the 3-Et homolog of II, b0.1 120-5°; 130 g. in 400 cc. AcOH, 80 cc. concentrated HCl, and 32 cc. H2O, refluxed 18 h., gives 88% of the 3-Et homolog (V) of III, b0.1 140-50°; Me ester, b0.05 95°. The reaction product of 32 g. of V with p-MeOC6H4MgBr (from 35 g. p-MeO-C6H4Br) in ether (refluxing 2 h.), decomposed with dilute H2SO4, the ether layer extracted with 5% NaOH, the alk. extract acidified, extracted with ether, and the residue treated with CH2N2, gives 13 g. of the carbinol (with some dehydrated product), C18H26O4, b0.1 150-60°; dehydration with SOCl2-C5H5N and saponification with 10% NaOH in 50% MeOH give 15% of 1-methyl-3-ethyl-4-(p-methoxyphenyl)-3-cyclohexene-1-carboxylic acid (VI), m. 123-4°; this is resistant to catalytic hydrogenation over active Pt at room temperature and 30 lb. H pressure. VI (7 g.) in 50 cc. C6H6, treated with 10 cc. SOCl2 and a drop of C5H5N, allowed to stand overnight at room temperature, the residue in PhMe treated at 0-5° with an excess of Et2Zn in PhMe, the mixture allowed to warm to room temperature, and after 4 h. decomposed with EtOH and dilute HCl, gives 7 g. of 1-methyl-1-propionyl-3-ethyl-4-(p-methoxyphenyl)-3-cyclohexene, b0.1 150-5° (not anal. pure); this is not stable to acidic demethylation reagents but 5 g. with 5 g. KOH and 150 cc. C2H4-(OH)2, refluxed 4 h., gives 60% of I, pale yellow glass, b0.1 175-80° (p-nitrobenzoate, m. 127-8°). IV (34 g.) and p-MeOC6H4MgBr give 12 g. of 1-methyl-4-(p-methoxy-phenyl)-3-cyclohexene-1-carboxylic acid, (VII), m. 137-7.5°, and 6 g. of the lactone of 1-methyl-4-hydroxy-4-(p-methoxyphenyl)cyclohexanecarboxylic acid, m. 114-15°; the latter can be converted to VII by saponification with aqueous alkali, followed by distillation of the H2O in vacuo, then by heating with KHSO4 and tetralin for 1 h. Catalytic reduction of VII in AcOH over Pt oxide at room temperature and a pressure of 2 atm. gives 1-methyl-4-(p-methoxyphenyl)cyclohexane-carboxylic acid (VIII), m. 112-15°; Me ester, b0.1 140-5°. Reaction of the acid chloride of VIII with Et2Zn gives a crude 1-methyl-1-propionyl-4-(p-methoxyphenyl)cyclohexane, b0.03 140-5°; refluxed with 40% HBr in glacial AcOH, it yields 60% of 1-methyl-4-(p-hydroxyphenyl)-hexahydropropiophenone, m. 142-3°, purified through the benzoate, m. 96-7°. The experimental process involved the reaction of Methyl 1-methyl-4-oxocyclohexanecarboxylate(cas: 37480-41-4).COA of Formula: C9H14O3
Methyl 1-methyl-4-oxocyclohexanecarboxylate(cas:37480-41-4) belongs to ethers. Oxygen is more electronegative than carbon, thus the alpha hydrogens of ethers are more acidic than those of simple hydrocarbons. They are far less acidic than alpha hydrogens of carbonyl groups (such as in ketones or aldehydes), however. COA of Formula: C9H14O3
Referemce:
Ester – Wikipedia,
Ester – an overview | ScienceDirect Topics