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Patent Office UNITED STATES 2,233,025PATENT OFFICE ESTRADIO-1-MONOESTERS Karl Miescher, Riehen, and Caesar Scholz, Basel, Switzerland, assignors, by mesne assignments, to Ciba, Pharmaceutical Products, Incorporated, Summit, N.J., a corporation of New Jersey No Drawing. Application October 7, 1937, Serial No. 167,866. In Switzerland November 20, 1936 4 Claims. (CI. 260-397) This invention is based on the surprising ob servation that partially esterified compounds of ually passes into solution. This solution is acidi the dihydro-estrin series having a free phenolic fied and a precipitate is produced by the addi hydroxyl are obtained when completely esterified tion of 200 parts of water. This is filtered and 5 compounds of the dihydro-estrin series are treat Washed Successively with water, dilute sodium ed in careful manner with hydrolytically acting carbonate Solution and again with water. The agents. In this way only those acid residues are estradiol-17-mono-propionate which is already split off which are bound at the phenolic hy Very pure can be recrystallized from a mixture O droxyl-groups. of methyl alcohol and water. It melts at As hydrolytically acting agents there may be 199-200° C. used both those of an alkaline nature and those The time necessary for the reaction depends of an acid nature. Suitable alkaline agents are, on the temperature and the degree of dilution for example alkali hydroxides, alkali carbonates, used. 5. alkaline earth hydroxides, magnesia or the like. Eacample 2 As acid reagents hydrogen halide acids, Sulfuric A solution of 1 part of estradiol-3:17-dipro acid, phosphoric acid or the like may be used. pionate in 350 parts of methyl alcohol is mixed It is preferable to use a suitable solvent, espe with 0.15 part of potassium hydroxide and the cially an alcohol, for instance methyl alcohol, mixture...is allowed to stand at room temperature 20 ethyl alcohol, isopropyl alcohol, but also acetone, for SOme...time. After acidification and concen dioxane and the like may be used in the presence tration in a vacuum this solution is diluted with of Water if desired. v 300 parts of water. The crystalline precipitate, By compounds of the dihydroestrin series are thus produced is now further worked up as de meant estradiol, dihydroequilenin and estriol. Scribed in Example 1, the product again being Thus, there may be obtained when starting the estradiol-17-mono-propionate of melting from estradiol di-esters, for example, homogene point 199-200° C. ous estradiol-17-mono-esters. In like manner Eacample 3 from estriol tri-esters there are obtained estriol 16:17-di-ester. While the partial saponification 1 part of estradiol-3:17-di-n-butyrate (melting 30 of di-esters of the androstane diols leads to mix point 64-65 C.; obtainable for example by the tures, the constituents of which can be separated action of n-butyric anhydride on a pyridine so only with difficulty, the reaction on which this lution of estradiol) is mixed with 50 parts of a 30, invention depends is Surprisingly unitary and the solution of 0.5 per cent. strength of sodium car partially esterified compounds of the dihydro bonate in methyl alcohol of 95 per cent, strength estrin series with a free phenolic hydroxyl are and the whole is stirred at room temperature for obtained in practically quantitative yields. This some time. After acidification, precipitation happens even when the hydroxyl groups of the with water and the usual working-up the es 3. 5 parent material are all substituted by the same tradiol-17-mono-n-butyrate is obtained in slen acyl residue. With like result, however, mixed der crystalline needles and may be recrystallized esterified compounds of dihydro-estrin series may from a mixture of alcohol and water and melts 40 be partially split. at 166-167 C. The compounds obtainable by this invention In a similar manner there is obtained, for in 40 are intended for use in therapy. stance, the estradiol-17-mono-iso-butyrate of The following examples illustrate the invention melting point 183-183.5° C. the parts being by Weight: Eacample 4 Eacample 1 1 part of estradiol-3:17-n-divalerianate (boil 1 part of estradiol-3:17-dipropionate (melting ing point 0.01 mm.-220-230° C. bath tempera point 104-105° C.; made, for example, by action ture; made, for example, by the action of n 50 of propionic anhydride on estradiol in pyridine valeric anhydride on a solution of estradiol in solution) is mixed with 50 parts of a solution of pyridine) is mixed with 50 parts of a solution of 1 per cent. strength of potassium carbonate in 0.5 per cent. strength of potassium carbonate in 50 methyl alcohol of 90 per cent, strength and the methyl alcohol of 95 per cent. strength, and the mixture is stirred for. Some time at room tem Whole is stirred for some time at 20° C. The 55 perature. The estradiol-3:17-dipropionate grad oily n-di-valerianate passes gradually into solu tion. The solution is neutralized and the precip 55 2,233,025 2 is gradually dissolved. After neutralization itate is produced by the addition of about 200 Water is added to produce a precipitate and the parts of Water. This finely crystalline product treatment of the latter follows that described in is filtered and Washed successively with Water, Example 1. The fine crystalline needles thus dilute Sodium carbonate solution and again with obtained are estradiol - 17 - mono-n-butyrate. 5. water. It may be further purified by crystalliza They may be recrystallized from aqueous alco tion from a mixture of methyl alcohol and water. hol and then melt at 166-67° C. The estradiol-17-mono-n-valerianate melts at Instead of hydrochloric acid there may also 144-145 C. be used other hydrolytically acting agents, such The estradiol-17-mono-iso-Valerianate is pro as for instance hydrobromic acid, sulfuric acid, O 10 duced in quite similar manner. phosphoric acid and the like. In quite analogous manner other 17-mono Eacample 5 esters, for example caproate, stearate, palmitate 1 part of estradiol-3:17-dicaprate (oil; boil and corresponding carbonic acid esters of the ing point 0.001 mm.s-260-265 C. bath tempera type of estradiol, for example the estradiol-17 5 15, ture; made for example by the action of caprinyl mono-ethyl carbonate of melting point 171-172 chloride on estradiol in the presence of pyridine) C. or the 16:17-diester of the type of estriol may and 60 parts of a solution of 0.5 per cent, strength be obtained. It may be an advantage to start of potassium carbonate in methyl alcohol of 95 from mixed esters of which the phenolic hy per cent, strength are stirred together for some droxyl has been Substituted by especially easily 20 20 time at room temperature. The mixture is neu eliminated acid residues, for example the acetyl tralised with hydrochloric acid, water is added or the formyl residue. This is particularly so in to produce a precipitate and the latter is Worked making Compounds of the dihydroestrin series up in the usual manner. The estradiol-17-mono Which are Substituted in 17-position by aromatic caprate is thus obtained in fine crystalline lami residues, for instance the estradiol-17-mono 25 23 nae which may be recrystallized from a mixture benzoate which has been prepared for example of methyl alcohol and water and then melt at from estradiol-3-butyrate-17-benzoate or the like. 112-112.5Instead C.of potassium carbonate, barium hy Eacample 8 droxide, magnesia, or the like may be used. A Solution of 1 part of estradiol-3:17-pro 30 30, Eacample 6 pionate in 160 parts of ethyl alcohol is shaken 1 part of estradiol-3:17-dipropionate (melting in the presence of reduced platinum oxide which point 104-105 C.; obtainable, for example, by always contains alkali either adsorbed or chemi the action of propionic anhydride on estradiol in cally combined. After filtration and evapora 85 35 pyridine solution) is mixed with 100 parts of a tion of the alcohol in a vacuum there remains 0.5 N-Solution of hydrochloric acid in absolute an oil which rapidly crystallizes and may be re alcohol. The mixture is stirred for some time Crystallized from aqueous methanol. The estra at room temperature. The estradiol-3:17-di diol-17-monopropionate is thus obtained in the propionate passes slowly into solution. The mix form of lustrous crystalline laminae of melting 40 ture is then neutralized with sodium carbonate point 199-200° C. 40 solution and the product of reaction is precipi In a quite analogous manner there are obtained tated in the form of crystalline needles by gradual partial esterified dihydro-equilenine and estriol addition of 300 parts of water. The Crystalline With a free phenolic hydroxyl group when treat mass is washed successively with Water, a little ing completely esterified dihydro-equilenine or 45 dilute sodium carbonate solution and Water. For estriol with hydrolytically acting agents of an 5. further purification recrystallization from a mix alkaline or an acid nature. What we claim is: ture of methanol and water may be used. The 1. The estradiol-17-monoesters, the acid radi estradiol-17-mono-propionate melts at 199 cal of which contains from 4 to 5 carbon atoms, 200 C. and the melting points of which range from about 50 50 Eacample 7 1 part of estradiol-3:17-di-n-butyrate (melt 144° C. to about 183.5° C. ing point 64-65 C.; obtainable, for example, by 2.
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