Estradiol derivatives

Novel estradiol derivatives of the formula ##STR1## wherein R.sup.1 means an alkyl group of two or more carbon atoms, and R.sup.2 is hydrogen or an acyl group, have antiestrogen activity and are useful as antiestrogen drugs.

The present invention relates to novel and useful 16.beta.-alkylestradiol 
derivatives and to a process for producing the same. 
More particularly, the present invention relates to 
16.beta.-alkylestradiols represented by the formula (I): 
##STR2## 
wherein R.sup.1 means an alkyl group of two or more carbon atoms, and 
R.sup.2 is hydrogen or an acyl group, and to a process for producing the 
same. 
Hitherto, testosterone or derivatives thereof (e.g. testosterone 
propionate) have been used for the therapy of estrogen-dependent diseases 
(e.g. advanced breast cancer) as an antiestrogen drug. However the therapy 
is generally accompanied by the side effect of inducing masculine 
characteristics resulting from the androgenic potency of testosterone 
which leads the patient to discontinue the therapy. 
Under the circumstances, the present inventors studied and discovered that 
16.beta.-alkylestradiol derivatives have substantially no estrogen 
activity but rather than antiestrogen activity and that this propensity is 
particularly pronounced where the number of carbon atoms in the 
16.beta.-alkyl moiety is within the range of 2 to 4. The present invention 
is accomplished on the basis of the above findings. 
The principal object of the present invention is to provide a compound of 
the general formula (I), which is useful as an antiestrogen drug, and 
another object of the invention is to provide a process for producing the 
compound (I). 
Referring to the formula (I) and formula (II) described hereinafter, the 
alkyl group of two or more carbon atoms as designated by R.sup.1 may be 
straight-chain or branched, and saturated or unsaturated, thus being 
exemplified by lower alkyl groups having 2 to 4 carbon atoms, such as 
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, allyl, 
3-butenyl and so on. The acyl group as designated by R.sup.2, R.sup.2' and 
R.sup.3 is a hydrocarbon-carbonyl group whose hydrocarbon moiety has 1 to 
8 carbon atoms. The hydrocarbon-carbonyl group is exemplified by lower 
alkylcarbonyl groups whose alkyl moieties have 1 to 3 carbon atoms, e.g. 
acetyl, propionyl, butyryl, etc.; arylcarbonyl groups, e.g. benzoyl; and 
aralkylcarbonyl groups, e.g. phenylpropionyl, etc. Where R.sup.2 or 
R.sup.2' is an acyl group, the substituent --OR.sup.2 or --OR.sup.2' in 
17-position of formula (I) or (II) is an esterified hydroxyl group, and 
the corresponding compound is an 17-ester of compound (I) or (II). The 
hydrocarbon residue as designated by R.sup.3 in the formula (II) is an 
alkyl, aryl and aralkyl groups. The alkyl group mentioned for R.sup.3 may 
be a straight-chain or branched lower alkyl group of 1 to 3 carbon atoms 
such as methyl, ethyl, propyl, isopropyl or the like; the aryl group also 
mentioned for R.sup.3 may for example be phenyl or p-nitrophenyl; and the 
aralkyl group for R.sup.3 may for example be benzyl or benzhydryl. 
The compounds (I) of the present invention can be produced according to a 
known method. For example, the compounds (I) are produced according to the 
method illustrated as follows; 
##STR3## 
wherein R.sup.1 and R.sup.2 have the same meaning as defined above, 
R.sup.2' is hydrogen or an acyl group, and R.sup.3 is a hydrocarbon 
residue or an acyl group. Namely, the above method is carried out by 
subjecting the compound (II) to a reaction leading to a cleavage of an 
acyl group or hydrocarbon residue of the esterified or etherified hydroxyl 
group in 3-position thereof. 
By the present reaction, the acyl group or hydrocarbon residue of the 
esterified or etherified hydroxyl group in the 3-position is removed, thus 
leaving a free hydroxyl group in the 3-position. The hydrocarbon residue 
may be, for instance, alkyl having 1 to 3 carbon atoms, phenyl, 
p-nitrophenyl, benzyl, or benzhydryl. The acyl group may be, for instance, 
a lower alkylcarbonyl group whose alkyl moiety has 1 to 3 carbon atoms or 
an arylcarbonyl group. 
This reaction, where R.sup.3 is an alkyl or aryl group, that is to say 
where --OR.sup.3 is an etherified hydroxyl group, is carried out by 
reacting the compound (II) with a reagent capable of cleaving an ether 
linkage. This ether-cleaving reagent may be any reagent that is able to 
cleave the ether linkage of the etherified hydroxyl group in the 
3-position without affecting the steroid skeleton and the 16.beta.-alkyl 
group of the starting compound. Thus, for example, there may be mentioned 
acidic reagents, for example, hydrohalogenic acids such as hydrochloric 
acid, hydrobromic acid, hydroiodic acid, etc., halides of phosphorus, 
boron, aluminum, thallium and titanium, etc., preferably the corresponding 
chlorides and bromides (e.g. phosphorus tribromide, boron tribromide, 
aluminum chloride, titanium tetrachloride, etc.), pyridinium halide (e.g. 
pyridinium chloride); Grignard's reagents (e.g. methylmagnesium iodide, 
ethylmagnesium bromide); sodium iodide-dimethylsulfoxide and so forth. 
Generally, such ether-cleaving reagents are used in amounts within the 
range of about 1 to 10 moles per mole of the compound (II). While the 
reaction takes place in the absence of a solvent, the reaction is 
generally carried out in the presence of a solvent. As said solvent may be 
mentioned an organic solvent capable of dissolving steroid compounds, such 
as ethers (e.g. diethylether, tetrahydrofuran, etc.), halogenated 
hydrocarbons (e.g. dichloromethane, chloroform, chlorobenzene, 
dichloroethane, trichloroethylene, etc.), esters (e.g. ethyl acetate, 
butyl acetate, etc.), nitrobenzene, dimethylformamide, dimethylsulfoxide, 
hexamethylphosphoramide and so on. The reaction is generally conducted 
within the temperature range of -10.degree. to 250.degree. C when no 
solvent is employed, or at temperatures between -10.degree. C and the 
boiling point of the solvent employed when a solvent is employed. 
Following the reaction, the reaction mixture may be immediately treated 
with water to recover the contemplated compound. Where R.sup.3 is an 
aralkyl group, the cleavage reaction according to this invention is 
carried out by subjecting the compound (II) to catalytic reduction or 
hydrolysis. The catalytic reduction is carried out by means of a catalyst 
such as platinum oxide, palladium, Raney nickel or the like, generally in 
a solvent such as methanol, ethanol, ether or tetrahydrofuran at a 
temperature between about 10.degree. and 60.degree. C and at a pressure 
within the range of 1 to 100 kg/cm.sup.2. Where R.sup.1 is an unsaturated 
alkyl group, the conditions should be selected from, among the above, such 
that the unsaturated bond will not be reduced, e.g. reduction at normal 
temperature and atmospheric pressure. The hydrolysis is carried out with 
the same reagent as the ether-cleavage reagent to be employed where 
R.sup.3 is an alkyl or aryl group, or with a halogenoacetic acid such as 
trifluoroacetic acid, trichloroacetic acid or monochloroacetic acid under 
the same conditions as those employed for the ether-cleavage reaction 
where R.sup.3 is an alkyl or aryl group (e.g. as to the solvent, reaction 
temperature and other parameters). 
Where R.sup.3 is an acyl group, that is where --OR.sup.3 is an esterified 
hydroxyl group, the cleavage reaction according to this invention is 
carried out by subjecting the compound (II) to hydrolysis. This hydrolysis 
may be conducted by any procedure that enables us to cleave the ester 
linkage of the esterified hydroxyl group in the 3-position without 
affecting the steroid skeleton or the 16.beta.-alkyl group of starting 
compound (II). Thus, for example, the hydrolysis is conducted generally in 
a solvent. The solvent is a mixture of water and a solvent such as an 
alcohol (e.g. methanol, ethanol, t-butanol, n-propanol or the like), 
ether, ethyl acetate, tetrahydrofuran, dimethylsulfoxide or 
dimethylformamide. The hydrolysis is conducted by means of an inorganic or 
organic basic reagent such as an alkali metal hydroxide (e.g. sodium 
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, 
sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), 
triethylamine, triethylenediamine or the like, or an acid reagent such as 
an inorganic acid (e.g. hydrochloric acid, sulfuric acid, nitric acid, 
phosphoric acid, etc.) or an organic acid (e.g. formic acid, acetic acid, 
oxalic acid, p-toluenesulfonic acid, etc.). The reaction is generally 
conducted at a temperature within the range of 0.degree. to about 
80.degree. C. 
Where both R.sup.2' and R.sup.3 of starting compound (II) are acyl groups, 
both esterified hydroxyl group in the 3- and 17-positions thereof are 
generally hydrolyzed to free hydroxyl groups, but if desired, the 
substituent in the 3-position of compound (II) may be selectively 
hydrolyzed to convert the esterified hydroxyl group in the 3-position 
alone to a free hydroxyl group by selecting a mild set of hydrolyzing 
conditions, for example at a comparatively low temperature, e.g. room 
temperature, using a weakly basic reagent such as an alkali metal 
carbonate or alkali metal hydrogen carbonate. Compound (I) may also be 
produced by subjecting Compound (II) wherein R.sup.2' is an acyl group to 
Birch's reduction, for example. 
Following the cleavage reaction of this invention, the contemplated end 
compound (I) may be isolated and purified by procedures conventional per 
se (e.g. treatment with water, extraction, concentration, 
recrystallization, chromatography, etc.). 
The thus produced compounds (I) have antiestrogen activity, i.e. the 
inhibitory activity on the binding of estradiol to the estradiol-receptor 
protein isolated from the uterine tissues, and have substantially no 
estrogen activity and no androgen activity. Further the present compounds 
(I) are low in toxicity, and therefore, they are of use as antiestrogen 
drugs for the alleviation of highly estrogen-dependent diseases (e.g. 
functional uterine hemorrhage, mastitis, etc.) in said mammalian animals 
including mouse, rat and man. 
For example, the 16.beta.-ethylestradiol has an antiestrogen activity 
several times as potent as that of clomiphene and of testosterone, and can 
be used as an antiestrogen drug for said mammals including mouse, rat and 
man in the same usage manner as testosterone for alleviation of the above 
diseases. 
Compounds (I) except 16.beta.-ethylestradiol may also be employed, 
depending on the potency of their antiestrogen activity, as antiestrogen 
drugs in the same usage manner as testosterone for alleviation of the 
above disease. 
Where the compound (I) is employed as an antiestrogen drug, it may be 
orally or parenterally administered as it is or in admixture with a known 
excipient or carrier (e.g. lactose, calcium phosphate, corn starch, methyl 
cellulose, coconut oil, sesame oil, peanut oil, etc.) in such dosage forms 
as tablets, capsules, powders, suspensions or injections. 
These injections are prepared, for example, by dissolving or suspending the 
compounds (I) in vegetable oils (e.g. sesame oil, cottonseed oil, castor 
oil, olive oil, corn oil, peanut oil, etc.) in combination, if desired, 
with antiseptics (e.g. benzyl alcohol, benzyl benzoate, chlorobutanol, 
etc.), solubilizing agents, surface active agents, etc. Among the 
compounds (I), 17.beta.-ester derivatives are readily soluble in oils and 
exhibit relatively sustained anti-estrogenic action. When the compounds 
(I) are administered orally, they may be as powders, tablets, capsules, 
pills, liquids, syrups, elixirs, buccals, granules, etc. Some examples of 
prescription in which the compounds of this invention are utilized as 
antiestrogen drugs are as hereinafter. 
For example, where the compound (I) is administered parenterally as an 
antiestrogen drug for alleviation of breast cancer, the intramuscular dose 
range is between 10 and 400 mg, more preferably between 30 and 100 mg for 
an adult female human per week. The dose may be divided into 2 to 3 weekly 
doses of corresponding smaller amounts. 
The compound (I) wherein R.sup.2 is an acyl group, i.e. the 17-ester of 
16.beta.-alkyl estradiol (I) is, generally speaking, long-active, 
slow-active, stable in storage and/or easy to prepare dosage forms thereof 
in comparison with the 17-hydroxyl compound corresponding thereto. 
There may be exemplified compositions in which a compound of this invention 
is used an antiestrogen drug; 
______________________________________ 
Injections: 
(1) 16.beta.-ethylestradiol 
10 weight parts 
sesame oil 1000 volume parts 
(2) 16.beta.-ethylestradiol 
17-acetate 100 weight parts 
benzyl benzoate 20 volume parts 
sesame oil 1000 volume parts 
______________________________________ 
______________________________________ 
Capsules: 
16.beta.-ethylestradiol 17-acetate 
20 weight parts 
lactose 140 weight parts 
corn starch 50 weight parts 
sugar ester 4 weight parts 
calcium salt of carboxy- 
methylcellose 4 weight parts 
magnesium stearate 2 weight parts 
(220 mg/capsul) 
______________________________________ 
______________________________________ 
Tablets: 
16.beta.-ethylestradiol 17-acetate 
20 weight parts 
lactose 100 weight parts 
corn starch 90 weight parts 
sugar ester 4 weight parts 
calcium salt of carboxymethyl- 
cellose 4 weight parts 
magnesium stearate 2 weight parts 
(220 mg/tablet.) 
______________________________________ 
In the prescriptions, "weight part" corresponds the "gram", and "volume 
part" corresponds to "milliliter". 
The starting compound (II) for this invention may be produced by the method 
described in the specification of German Patent Application Laid-Open No. 
2100319.0, or by the method described in Chemical Pharmaceutical Bulletin 
Vol.21, 1393(1973), or a method analogous with such methods as above, from 
the estra-1,3,5(10)-trien-16-oxo-17.beta.-ols corresponding to the 
compound (II) or the compounds described in Tetrahedron Vol.30, 
2107(1974). It should be noted that, generally, said 
estra-1,3,5(10)-trien-16-oxo-17.beta.-ols or their derivatives may be 
produced by procedures similar to the procedures established for the 
species known among them. 
The starting compound (II), wherein both R.sup.2' and R.sup.3 are the same 
acyl group, can be produced by reacting the compound (I) wherein R.sup.2 
is hydrogen with an acylating agent according to per se known procedures 
established for acylation of alcoholic hydroxyl group. The acylating agent 
is exemplified by acid anhydrides (e.g. acetic anhydride, propionic 
anhydride, phenylpropionic anhydride)-organic or inorganic bases, acid 
halides (e.g. acetyl chloride, propionyl chloride, phenylpropionyl 
chloride, benzoyl chloride)-organic or inorganic bases, acids-dehydrating 
agents such as sulfuric acid, hydrochloric acid, dicyclohexylcarbodiimide, 
etc. For example, the acylating reaction is conducted in the presence of a 
catalyst which may be an alkaline catalyst such as, for example, pyridine, 
picolin, collidine, quinoline or a tertiary amine, e.g. triethylamine, or 
an acid catalyst such as; for example, a Lewis acid, e.g. boron 
trifluoride, zinc chloride or aluminum chloride, p-toluene sulfonic acid 
or potassium hydrogen sulfate. The raction is generally conducted in one 
of the common protoninert solvents for steroids which include, among 
others, halogenated hydrocarbons, e.g. chloroform, dichloromethane, etc., 
hydrocarbons, e.g. toluene, benzene, hexane, etc., esters, e.g. ethyl 
acetate etc., dimethyl formamide, pyridine, picoline, etc. Alternatively, 
use may be made of a large excess of the acylating agent such as organic 
acid anhydride or the like so that the acylating agent will also function 
as the necessary solvent. The reaction usually proceeds at 0.degree. C to 
room temperature, although the reaction may be hastened by heating the 
system to the neighborhood of 100.degree. C. After the reaction is 
complete, the reaction mixture may for example be treated with a large 
quantity of water so as to let the acyloxy derivatives crystallize or, 
alternatively, to subject to the extraction with an organic solvent to 
obtain the compound.

EXAMPLE 1 
To 1 g of 16.beta.-ethylestradiol 3-methyl ether is added 1.3 g of 
pyridinium chloride and the mixture is heated at 150.degree. C. After 2 
hours, the reaction mixture is poured into ice-water and the resultant 
crystals are collected by filtration. Recrystallized from ethyl acetate, 
16.beta.-ethylestradiol is obtained as needles melting at 173.degree. to 
174.degree. C. 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3410, 3150(OH), 1610, 1595(Ar, "Ar" 
means "Aryl"). 
NMR .delta. .sub.ppm.sup.d 6.sup.-DMSO : 0.68(3H,s,18-CH.sub.3), 
1.11(3H,t,J=6Hz, CH.sub.3), 3.57(1H,d,J=9Hz,17.alpha.-H),6.4-7.2(3H,m,Ar). 
Mass m/e 300(M.sup.+), 282, 213. 
Elemental analysis, for C.sub.20 H.sub.28 O.sub.2 : Calcd: C, 79.95; H, 
9.39. Found: C, 79.89; H, 9.24. 
EXAMPLE 2 
To a solution of 2.3 g of 16.beta.-ethylestradiol 3-methyl ether in 25 ml 
of ether is added an ethereal solution of methylmagnesium iodide (prepared 
by reacting 1.2 g of magnesium with 7.0 g of methyl iodide in 50 ml of 
ether). The resultant mixture is gently heated and the ether is gradually 
removed under reflux. Following removal of ether, the reaction mixture is 
further heated at 120.degree. C for 2 hours. After cooling, the residue is 
carefully poured into ice-water in a small portion. The aqueous mixture is 
adjusted to pH 2 with 5N-hydrochloric acid and the resultant crystals are 
collected by filtration. Recrystallized from ethyl acetate, 
16.beta.-ethylestradiol is obtained as needles. In melting point and IR 
spectrum, this product is in agreement with the product obtained in 
Example 1. 
EXAMPLE 3 
In 10 ml of methanol is dissolved 360 mg of 16.beta.-ethylestradiol 
3,17-diacetate(melting point: 148.degree. to 149.degree. C), followed by 
the addition of 2N-methanolic solution of potassium hydroxide. The mixture 
is heated at 50.degree. C for 3 hours. After cooling, water is added to 
the reaction mixture, and the resultant mixture is then adjusted to pH 2 
with 5N-hydrochloric acid. The separated crystals are recovered by 
filtration to yield 16.beta.-ethylestradiol. In melting point and IR 
spectrum, this compound is in agreement with the product obtained in 
Example 1. 
EXAMPLE 4 
(1) To a solution of 0.17 g of 16.beta.-ethylestradiol in 5 ml of pyridine 
is added 1 ml of acetic anhydride. After keeping the resultant mixture at 
50.degree. C for 8 hours, 10 ml of water is added to the reaction mixture, 
and the mixture is extracted with dichloromethane. The organic layer is 
washed with water, dried over anhydrous sodium sulfate and concentrated, 
whereupon pale yellow crude crystals are obtained. Recrystallization from 
methanol gives 16.beta.-ethylestradiol 3,17-diacetate as colorless needles 
melting at 148.degree. to 149.degree. C. 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 1760(OCOCH.sub.3), 1725(OCOCH.sub.3). 
(2) To a solution of 0.25 g of 16.beta.-ethylestradiol 3,17-diacetate in 15 
ml of methanol is added a solution of 19 mg of anhydrous potassium 
carbonate in 2 ml of methanol and the mixture is stirred at room 
temperature for 15 minutes. The reaction mixture is concentrated under 
reduced pressure and made acidic with 2N-hydrochloric acid, whereupon 
crystals separate. 
Recrystallized from ether-n-hexane(1:1), 16.beta.-ethylestradiol 17-acetate 
is obtained as colorless needles melting at 187.degree. to 188.degree. C. 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3400(OH), 1725(OCOCH.sub.3). 
Elemental analysis, for C.sub.22 H.sub.30 O.sub.3 : Calcd. C, 77.15; H, 
8.83. Found C, 77.19; H, 8.80. 
EXAMPLE 5 
(1) 16-Ketoestradiol 3-benzylether is reacted with ethyl magnesium iodide 
in ether to give 16.beta.-hydroxy-16.alpha.-ethylestradiol 3-benzylether. 
The product is treated with pyridine-acetic anhydride to give 
16.beta.-hydroxy-16.alpha.-ethylestradiol 17-acetate. The resultant 
17-acetate is heated with zinc powder in toluene at 130.degree. C for 5 
hours to give 16.beta.-ethylestrone 3-benzylether. The product is treated 
with sodium borohydride in methanol, whereupon 16.beta.-ethylestradiol 
3-benzylether is produced. 
(2) In 30 ml of methanol is dissolved 0.73 g of 16.beta.-ethylestradiol 
3-benzyl ether, followed by addition of 210 mg of platinum oxide. The 
catalytic reduction is thus conducted at atmospheric pressure and room 
temperature. After the absorption of hydrogen has completed, the platinum 
oxide is filtered off and the filtrates are concentrated under reduced 
pressure. By the above procedure is obtained 16.beta.-ethylestradiol as 
crude crystals. This crude product is recrystallized from ethyl acetate as 
in Example 1. In melting point and IR spectrum, this product is in 
agreement with the product obtained in Example 1. 
EXAMPLE 6 
To a solution of 0.93 g of 16.beta.-isopropylestradiol 3-methyl ether in 15 
ml of ether is added an ethereal solution of methylmagnesium iodide. The 
mixture is then treated in the same manner as Example 2, whereupon 
16.beta.-isopropylestradiol is obtained as crude crystals. The resultant 
crude crystals are recrystallized from ethyl acetate. Melting point: 
221.degree. to 222.degree. C. 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3400(OH), 1610, 1590(Ar). 
NMR .delta. .sub.ppm.sup.d 6.sup.-DMSO : 0.70(3H,s,18-CH.sub.3), 
0.83(3H,d,J=5Hz,CH.sub.3), 0.98(3H,d,J=5Hz,CH.sub.3), 
3.73(1H,d,J=9Hz,17.alpha.-H), 6.4-7.2 (3H,m,Ar). 
Elemental analysis, for C.sub.21 H.sub.30 O.sub.2 : Calcd. C, 80.21; H, 
9.62. Found C, 80.30; H, 9.67. 
EXAMPLE 7 
Under ice-cooling, 0.2 g of phosphorus tribromide is added in a small 
portion to a solution of 0.6 g of 16.beta.-ethylestradiol 3-methyl ether 
in 10 ml of dichloromethane. The resultant mixture is allowed to stand at 
room temperature for 4 hours. The reaction mixture is poured in a small 
portion into ice-water and extracted with dichloromethane. Upon removal of 
the solvent by concentration, 16.beta.-ethylestradiol is obtained as crude 
crystals. Recrystallization under the same conditions as Example 1 yields 
pure crystals. In melting point and IR spectrum, this product is in 
agreement with the product obtained in Example 1. 
In the similar manner as above, 16.beta.-allylesteradiol is obtained from 
16.beta.-allylestradiol 3-methyl ether. Melting point: 204.degree. to 
206.degree. C. 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3350(OH), 3080, 1640(allyl), 1610, 
1595(Ar). 
Elemental analysis, for C.sub.21 H.sub.28 O.sub.2 Calcd. C, 80.73; H, 9.03. 
Found C, 80.77; H, 9.10. 
EXAMPLE 8 
(1) To a solution of 0.3 g of 16.beta.-ethylestradiol in 2 ml of pyridine 
is added 0.6 ml of propionic anhydride. After keeping the resultant 
mixture at 50.degree. C for 10 hours, 10 ml of water is added to the 
reaction mixture, followed by extraction with dichloromethane. The organic 
layer is washed with water, dried over anhydrous sodium sulfate and 
concentrated, whereupon crude crystals are obtained. Recrystallization 
from methanol gives 16.beta.-ethylestradiol 3,17-dipropionate as colorless 
needles melting at 57.degree. C. 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 1760(OCOC.sub.2 H.sub.5), 
1725(OCOC.sub.2 H.sub.5). 
(2) To a solution of 0.2 g of 16.beta.-ethylestradiol 3,17-dipropionate in 
10 ml of methanol is added 16 mg of anhydrous potassium carbonate, 
followed by stirring at room temperature for 30 minutes. The reaction 
mixture is concentrated under reduced pressure, and the residue is made 
acidic with 2N-hydrochloric acid, whereupon crystals are obtained. The 
crystals are collected by filtration and recrystallized from hexane to 
give 16.beta.-ethylestradiol 17-propionate as colorless needles melting at 
176.degree. to 178.degree. C. 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3350(OH), 1700(OCOC.sub.2 H.sub.5). 
Elemental analysis for C.sub.23 H.sub.32 O.sub.3 : Calcd. C, 77.49; H, 
9.05. Found C, 77.48; H, 9.07. 
EXAMPLE 9 
(1) In a similar manner to Example 4-(1), 16.beta.-isopropylestradiol 
3,17-diacetate is obtained by acetylation of 16.beta.-isopropylestradiol 
with acetic anhydride-pyridine. Melting point: 115.degree. to 116.degree. 
C. IR .nu. .sub.max.sup.KBr cm.sup.-1 : 1765(OCOCH.sub.3), 
1735(OCOCH.sub.3). 
(2) According to a similar manner to Example 4-(2), 
16.beta.-isopropylestradiol 3,17-diacetate is hydrolized with anhydrous 
potassium carbonate to give 16.beta.-isopropylestradiol 17-acetate. 
Melting point: 193.degree. to 194.degree. C. IR .nu. .sub.max.sup.KBr 
cm.sup.-1 : 1350(OH), 1700(OCOCH.sub.3). 
Elemental analysis for C.sub.23 H.sub.32 O.sub.3 : Calcd. C, 77.49; H, 
9.05. Found C, 77.31; H, 9.11. 
EXAMPLE 10 
(1) To a solution of 0.2 g of 16.beta.-ethylestradiol 3-methylether 
17-acetate in 10 ml of dimethylsulfoxide is added 0.5 g of dried sodium 
iodide, and the mixture is refluxed for 3 hours under nitrogen gas stream. 
After cooling, 30 ml of water is added to reaction mixture, and the 
resultant mixture is extracted with ether. The ether layer is washed with 
water, dried over anhydrous sodium sulfate and concentrated, whereupon 
pale yellow crude crystals are obtained. Recrystallization from 
ether-hexane (1:1) gives 16.beta.-ethylestradiol 17-acetate. This product 
is in accordance with the product obtained in Example 4 in melting point 
and IR spectrum. 
(2) According to a similar manner to Example 7, 16.beta.-ethylestradiol 
3-methylether 17-acetate is treated with phosphorus tribromide to give 
16.beta.-ethylestradiol 17-acetate. 
EXAMPLE 11 
(1) To a solution of 0.3 g of 16.beta.-ethylestradiol in 10 ml of pyridine 
is added 0.5 g of 3-phenylpropionyl chloride, and the mixture is kept at 
room temperature for 12 hours. To the reaction mixture is added 10 ml of 
ice-water, and the mixture is extracted with ether. The ether layer is 
washed with 3N-aqueous solution of potassium carbonate, dried over 
anhydrous sodium sulfate and concentrated, whereupon 
16.beta.-ethylestradiol 3,17-diphenylpropionate is obtained. 
IR .nu. .sub.max.sup.Neat cm.sup.-1 : 1760, 1735(OCOCH.sub.2 CH.sub.2 
-C.sub.6 H.sub.5). 
(2) To a solution of the product obtained in the above experiment (1) in 10 
ml of methanol is added 0.1 g of potassium carbonate and the mixture is 
stirred at room temperature for 30 minutes. The reaction mixture is 
concentrated, and to the resultant residue is added 10 ml of water, 
followed by extraction with ether. The ether layer is washed with water, 
dried over anhydrous sodium sulfate and concentrated, whereupon crude oily 
product is obtained. The product is subjected to silica gel column 
chromatography using benzene-ether(3:1) as an eluent thereof to give 
16.beta.-ethylestradiol 17-phenylpropionate as colorless oil. IR : .nu. 
.sub.max.sup.Neat cm.sup.-1 : 3400(OH), 1700(OCOCH.sub.2 CH.sub.2 C.sub.6 
H.sub.5), 1605(Ar). Mass: m/e 432(M.sup.+, M=432 for C.sub.29 H.sub.36 
O.sub.3) 404(-28), 299(-133). 
EXAMPLE 12 
(1) In a similar manner to Example 11-(1), 16.beta.-ethylestradiol is 
reacted with benzoyl chloride to give crude crystals. Recrystallization 
from ether gives 16.beta.-ethylestradiol 3,17-dibenzoate melting at 
177.degree. to 178.degree. C. IR .nu. .sub.max.sup.KBr cm.sup.-1 : 1735, 
1720(OCOC.sub.6 H.sub.5). 
(2) According to a similar manner to Example 11-(2), 
16.beta.-ethylestradiol 3,17-dibenzoate is hydrolyzed with potassium 
carbonate to give 16.beta.-ethylestradiol 17-benzoate melting at 194 to 
196.degree. C. IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3450(OH), 
1695(OCOC.sub.6 H.sub.5). 
Elemental analysis for C.sub.27 H.sub.32 O.sub.3 Calcd. C, 80.16; H, 7.97. 
Found C, 79.87; H, 7.99. 
EXAMPLE 13 
(1) 16-Ketoestradiol 3-methylether is reacted with n-butylmagnesium iodide 
to give 16.beta.-hydroxy-16.beta.-n-butylestradiol: 
IR .nu. .sub.max.sup.Neat cm.sup.-1 : 3500(OH), 1605, 1590(Ar). Acetylation 
of the compound with acetic anhydride in pyridine gives the corresponding 
17-acetate: 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3450(OH), 1730(OCOCH.sub.3), 1605, 
1595(Ar). 
The 17-acetate is treated with zinc powder in toluene for 4 hours at 
130.degree. C to give 16.beta.-butylestrone 3-methyl ether: 
IR .nu. .sub.max.sup.Neat cm.sup.-1 : 1735(c=o), 1605, 1595(Ar), Reduction 
of 16.beta.-butylestrone 3-methyl ether with sodium borohydride in 
methanol gives 16.beta.-n-butylestradiol 3-methylether: 
IR .nu. .sub.max.sup.Neat cm.sup.-1 : 3500(OH), 1605, 1595(Ar). 
According to a similar procedure to the above experiment (1), 
16.beta.(3-butenyl)-estradiol 3-methylether is produced from 
16-ketoestradiol 3-methylether and 3-butenylmagnesium bromide. IR .nu. 
.sub.max.sup.Neat cm.sup.-1 : 3500(OH), 1635(c=c), 1605, 1590(Ar). Mass: 
m/e 340(M.sup.+), 325(-15), 322(-18). 
(2) According to a similar manner to Example 2, 16.beta.-n-butylestradiol 
3-methylether is reacted with methylmagnesium iodide gives 
16.beta.-n-butylestradiol melting at 148 to 150.degree. C 
(recrystallization from hexane). 
IR .nu. .sub.max.sup.KBr cm.sup.-1 : 3400(OH), 1605(Ar). 
Elemental analysis for C.sub.22 H.sub.32 O.sub.2 : Calcd. C, 80.44; H, 
9.83. Found C, 80.40; H, 9.99. 
In a similar manner to above experiment (2), 16.beta.-(3-butenyl)-estradiol 
is obtained from 16.beta.(3-butenyl)-estradiol 3-methylether. Melting 
point: 154.degree. to 156.degree. C. IR .nu. .sub.max.sup.KBr cm.sup.-1 : 
3400(OH), 3050, 1635(c=c), 1605(Ar) 
Elemental analysis for C.sub.22 H.sub.30 O.sub.2 Calcd. C, 80.93; H, 9.26. 
Found C, 80.62; H, 9.58.