Novel 17-[(hydroxymethyl)formamido methylene]-steroids of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms optionally substituted with halogen or an oxygen or nitrogen function and alkenyl and alkynyl of 2 to 4 carbon atoms, R.sub.2 is alkyl of 1 to 4 carbon atoms and the A,B,C and D rings may contain one or more double bonds and are optionally substituted with at least one member of the group consisting of hydroxy, keto, halogen, alkyl and alkoxy of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms and a process for their preparation which are intermediates for the preparation of the corresponding 17-hydroxyacetyl steroids.

STATE OF THE ART 
Chem. Berichte, Vol. 109, No. 12 (1976), p. 3964 describes compounds useful 
as starting materials for the process. 
OBJECTS OF THE INVENTION 
It is an object of the invention to provide the novel steroids of formula I 
and to provide a novel process for their preparation and novel 
intermediates. 
It is a further object of the invention to provide a novel process for the 
preparation of 17-hydroxyacetyl steroids. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel steroids of the invention are 17-[(hydroxymethyl)formamido 
methylene]-steroids of the formula 
##STR2## 
wherein R.sub.1 is selected from the group consisting of hydrogen, alkyl 
of 1 to 4 carbon atoms optionally substituted with halogen or an oxygen or 
nitrogen function and alkenyl and alkynyl of 2 to 4 carbon atoms, R.sub.2 
is alkyl of 1 to 4 carbon atoms and the A,B,C and D rings may contain one 
or more double bonds and are optionally substituted with at least one 
member of the group consisting of hydroxy, keto, halogen, alkyl and alkoxy 
of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms. 
Examples of R.sub.1 are alkyl such as methyl or ethyl; alkyl substituted 
with oxygen and nitrogen functions such as hydroxymethyl, hydroxyethyl, 
formyl, acetyl, cyano, aminomethyl and aminoethyl; haloalkyl such as 
halomethyl wherein the halogen is chlorine, bromine or fluorine; alkenyl 
such as vinyl the allyl; alkynyl such as ethynyl. Examples of R.sub.2 are 
methyl and ethyl. 
When the A,B,C and D rings contain one or more double bonds, the double 
bonds are preferably in 1(2), 3(4), 4(5) or 9(11) positions or a 
conjugated double bond system such as 3(4) and 5(6) or 4(5) and 6(7) or 
1(2) and 4(5) or an aromatic system such as 1,3,5 positions or a triple 
bond system such as 1(2), 4(5), 6(7). 
When the A,B,C and D rings are substituted with at least one hydroxy group 
they are preferably in the 3- and/or 11-positions. When the A,B,C and D 
rings are substituted with at least one keto groups, they are preferably 
in the 3- and/or 11-position. When the A,B,C and D rings contain at least 
one halogen, they are preferably fluorine, chlorine or bromine in the 6- 
and/or 9.alpha.-positions. 
When the A,B,C and D rings are substituted with at least one alkyl, they 
are preferably methyl or ethyl in the 2,6,7,16.alpha. and/or 
16.beta.-positions. When the A,B,C and D rings are substituted with at 
least one alkoxy, they are methoxy or ethoxy in the 3-and/or 
11.beta.-positions. When the A,B,C and D rings are substituted with at 
least one alkenyl, they are preferably vinyl or allyl in the 
11.beta.-position. When the A,B,C and D rings are substituted with at 
least one alkynyl, they are preferably ethynyl in the 11.beta.-position. 
Among the preferred compounds of formula I are those wherein R.sub.2 is 
methyl and those wherein R.sub.1 is hydrogen or methyl. 
Preferred compounds of the invention are those of the formula 
##STR3## 
wherein R.sub.2 is alkyl of 1 to 4 carbon atoms, R.sub.3 is alkyl of 1 to 
8 carbon atoms and the B,C and D rings optionally contain at least one 
double bond and are optionally substituted with at least one of the above 
indicated substituents. Preferably, the B,C and D rings are unsubstituted. 
Other preferred compounds of the invention are those of the formula 
##STR4## 
wherein R.sub.1 and R.sub.2 have the above definitions and R.sub.3 is 
alkyl of 1 to 8 carbon atoms and the A,B,C and D rings optionally contain 
at least one supplementary double bond and are optionally substituted with 
at least one of the above substituents. 
A most preferred group of compounds within formula I.sub.B includes 
compounds of the formula 
##STR5## 
wherein R.sub.1, R.sub.2 and R.sub.3 have the above definitions and X and 
Y are both hydrogen or together form a carbon-carbon double bond. 
Preferably, X and Y are hydrogen. 
The compounds of formula I have a very great industrial interest as they 
are directly prepared from the corresponding 17-keto compounds in good 
yields by a simple and economical process and are able to be transferred 
directly into the corresponding 17-hydroxyacetyl compounds in very good 
yields in a simple and economical manner. 
The compounds of formula I permit introduction of a hydroxyacetyl group 
beginning from 17-keto steroids in a rapid, simple and economical manner 
and it is a very generally applicable process for steroids having a ketone 
function in the 17-position. The compounds of formula I have in the 
17-position the group 
##STR6## 
and the A,B,C and D rings and the nature and number of the substituents 
may be varied greatly. 
The novel process of the invention for the preparation of a compound of 
formula I comprises reacting a compound of the formula 
##STR7## 
wherein R.sub.1 and R.sub.2 have the above definitions, R is alkyl of 1 to 
18 carbon atoms and the A,B,C and D rings optionally contain at least one 
double bond and are optionally substituted with at least one of the above 
substituents with a reducing agent to obtain the corresponding compound of 
formula I. If the compounds of formula II possess a 3-keto or a 3-hydroxy 
group, it is protected respectively in the form of an enol ether or in the 
form of an ether. 
The process of the invention for the preparation of a compound of formula 
I.sub.A comprises reacting a compound of the formula 
##STR8## 
wherein R, R.sub.2, R.sub.3, B, C and D have the above definition with a 
reducing agent to obtain the corresponding compound of formula I.sub.A. 
Particularly preferred starting compounds are the compounds of the formula 
##STR9## 
wherein R, R.sub.2 and R.sub.3 have the above definitions. 
The process of the invention for the preparation of compounds of formula 
I.sub.B comprises reacting a compound of the formula 
##STR10## 
wherein R,R.sub.1,R.sub.2,R.sub.3,B, C and D have the above definitions 
with a reducing agent to form the compound of formula I.sub.B. A preferred 
starting compound has the formula 
##STR11## 
wherein R,R.sub.1, R.sub.2 and R.sub.3 have the above definition and X and 
Y are both hydrogen or form a carbon-carbon double bond. Preferably, X and 
Y are hydrogen. 
The reducing agent may be an aluminum hydride or an alkali metal dihydro 
bisalkoxy aluminate of the formula 
EQU M--AlH.sub.2 (OAlk.sub.1 OAlk.sub.2).sub.2 
wherein M is an alkali metal and Alk.sub.1 and Alk.sub.2 are individually 
alkyl of 1 to 8 carbon atoms. Preferably, the reducing agent is lithium 
aluminum double hydride or sodium dihydro bis(2-methoxyethoxy) aluminate 
and the reduction is effected at a temperature near 0.degree. C. such as 
-5.degree. to 5.degree. C. R.sub.3 is preferably methyl or ethyl and R is 
preferably ethyl. 
The starting compounds of formula II are novel products except for ethyl 
(20 E) formamido-3-methoxy-19-nor-.DELTA..sup.1,3,5(10),17(20) 
-pregnatetrene-21-oate which is described by Schollkopf et al [Chem. Ber., 
Vol. 109 (1976), p. 3964]. The preferred intermediates of formula II are 
those wherein R.sub.1 is hydrogen or methyl and R.sub.2 is methyl. 
The compounds of formula II may be prepared by reacting a compound of the 
formula 
##STR12## 
wherein M is an alkali metal and R is alkyl of 1 to 18 carbon atoms with a 
compound of the formula 
##STR13## 
wherein R.sub.1 and R.sub.2 have the above definitions and the A,B,C and D 
rings optionally contain at least one double bond and are optionally 
substituted with at least one of the above discussed substituents. M is 
preferably potassium. 
Another process of the invention comprises reacting a compound of formula I 
with an acid hydrolysis agent to form the corresponding compound of the 
formula 
##STR14## 
wherein R.sub.1, R.sub.2 and the A,B,C and D rings are as discussed above. 
The preferred acid hydrolysis agents are hydrochloric acid and sulfuric 
acid. 
It is also possible to transform the compounds of formula II into the 
compounds of formula III without isolating the compounds of formula I and 
it is also a part of the invention to react a compound of formula II with 
a reducing agent to form a compound of formula I in situ which is then 
reacted with an acid hydrolysis agent. 
The compounds of formula III have a very great industrial interest as they 
are known to be very useful pharmaceutical products such as 
corticosterone, 19-nor-corticosterone, desoxycorticosterone, 
19-nor-desoxycorticosterone and 9(11)-dehydro-desoxycorticosterone. 
In the following examples there are described several preferred embodiments 
to illustrate the invention. However, it should be understood that the 
invention is not intended to be limited to the specific embodiments.

EXAMPLE 1 
3-methoxy-19-nor-.DELTA..sup.1,3,5(10) -pregnatriene-21-ol-3-one 
STEP A: (20E) 20-formamido-3-methoxy-19-nor-.DELTA..sup.1,2,5(10),17(20) 
-pregnetetraene-21-ol 
A solution of 1.6 g of ethyl (20E) 
20-formamido-3-methoxy-19-nor-.DELTA..sup.1,3,5(10),17(20) 
-pregnatetraene-21-oate [prepared by process of Schollkopf et al, Chem. 
Ber., Vol. 19 (1976), p. 3964] in 32 ml of anhydrous tetrahydrofuran was 
stirred at 0.degree. C. for 2 hours with 200 mg of lithium aluminum double 
hydride and 200 mg of potassium borohydride and then ethanol was added 
thereto dropwise to decompose excess lithium aluminum double hydride. The 
mixture was stirred at room temperature for one hour and was then diluted 
with a solution of Seignette salt (sodium potassium tartrate). The mixture 
was extracted with ethyl acetate and the organic phase was filtered. The 
filtrate was washed with water, dried and evaporated to dryness and the 
residue was triturated with isopropyl ether. The suspension was iced and 
was vacuum filtered. The product was washed with isopropyl ether and was 
dried in air to obtain 1.28 g of (20E) 
20-formamido-3-methoxy-19-nor-.DELTA..sup.1,3,5(10),17(20) 
-pregnetetraene-21-ol which was used as is for the next step. A sample of 
the product after crystallization from methanol melted at 191.degree. C. 
STEP B: 3-methoxy-19-nor-.DELTA..sup.1,3,5(10) -pregnatriene-21-ol-20-one 
1 ml of 5N hydrochloric acid was added to a suspension of 300 mg of the 
product of Step A in 10 ml of methanol and the mixture was stirred at room 
temperature for one hour. The mixture was then diluted with water and was 
filtered and the recovered product was washed with water and dried towards 
50.degree. C. to obtain 200 mg of 3-methoxy-19-nor.DELTA..sup.1,3,5(10) 
-pregnariene-21-ol-20-one. The filtrate was extracted with methylene 
chloride and the organic phase was evaporated to dryness to obtain another 
70 mg of the desired product for a total yield of 97%. After 
crystallization from methanol, the product melted at 
130.degree.-131.degree. C. 
Analysis: C.sub.21 H.sub.28 O.sub.3 ; molecular weight=328.455. 
______________________________________ 
Calculated: % C 76.79 % H 8.59 
Found: 76.6 8.5 
______________________________________ 
IR Spectrum (chloroform): Absorption at 3458 cm.sup.-1 (associated OH); at 
1706 cm.sup.-1 (20-keto); at 1610, 1577 and 1500 cm.sup.-1 (aromatic). 
Circular Dichroism (ethanol): 
______________________________________ 
Max. at 231 nm .DELTA..sub..epsilon. = +2.3 
Max. at 287 nm .DELTA..sub..epsilon. = +3.4 
______________________________________ 
NMR Spectrum (CDCl.sub.3): Peaks at 4.16-4.25 ppm (20-hydrogen); at 
3.17-3.25-3.33 ppm (hydrogen of --OH). 
EXAMPLE 2 
.DELTA..sup.4 -pregnene-21-ol-3,20-dione 
STEP A: Ethyl (20E) 20-formamido-3-ethoxy-.DELTA..sup.3,5,17(20) 
-pregnatriene-21-oate 
A solution of 2.25 g of ethyl isocyanate in 20 ml of anhydrous 
tetrahydrofuran was added with stirring at -10.degree. C. to a solution of 
2.15 g of potassium tert.-butylate in 50 ml of anhydrous tetrahydrofuran 
and after 15 minutes of stirring the mixture, a solution of 5.025 g of 
3-ethoxy-.DELTA..sup.3,5 -androstadiene-17-one in 80 ml of anhydrous 
tetrahydrofuran was slowly added thereto. The temperature was allowed to 
return to room temperature and the mixture was stirred for 15 hours and 
was then poured into an aqueous saturated ammonium chloride solution. The 
mixture was extracted with ether and the organic phase was washed with 
water, dried and evaporated to dryness. The residue was chromatographed 
over silica gel and was eluted with a 1-1 benzene-ethyl acetate mixture to 
obtain a first fraction of 4.71 g (69% yield) of ethyl (20E) 
20-formamido-3-ethoxy-.DELTA..sup.3,5,17(20) -pregnatriene-21-oate and 
0.97 g (14% yield) of the corresponding (Z) isomer. After crystallization 
from methanol, the E isomer melted of 204.degree. C. and the Z isomer 
melted at 172.degree. C. 
STEP B: (20E) 20-formamido-3-ethoxy-.DELTA..sup.3,5,17(20) 
-pregnatriene-21-ol 
150 mg of lithium aluminum double hydride were added in a plurality of 
small portions with stirring to a solution of 1.025 g of the (20E) isomer 
of Step A in 20 ml of anhydrous tetrahydrofuran in an ice bath and the 
temperature was then allowed to rise to room temperature. The mixture was 
stirred for 15 hours and 5 ml of ethanol were cautiously added thereto to 
destroy excess lithium aluminum double hydride to obtain a solution of 
(20E) 20-formamido-3-ethoxy-.DELTA..sup.3,5,17(20) -pregnatriene-21-ol 
which was used for the next step. 
STEP C: .DELTA..sup.4 -pregnene-21-ol-3,20-dione 
The reaction mixture of Step B and 5 ml of 5N hydrochloric acid were 
stirred at room temperature for 6 hours and the mixture was diluted with 
water. The mixture was extracted with ethyl acetate and the organic phase 
was washed with water, dried and evaporated to dryness to obtain 600 mg of 
.DELTA..sup.4 -pregnene-21-ol-3,20-dione which melted at 
141.degree.-142.degree. C. after crystallization from a methylene 
chloride-isopropyl ether mixture. 
EXAMPLE 3 
3-methoxy-19-nor-.DELTA..sup.1,3,5(10) -pregnatriene-21-ol-20-one 
STEP A: (20E) 20-formamido-3-methoxy-19-nor-.DELTA..sup.1,3,5(10),17(20) 
-pregnatetraene-21-ol 
3.5 ml of a 70% benzene solution of sodium dihydro bis-(2-methoxy ethoxy) 
aluminate were added over 10 minutes under nitrogen to a solution of 1.4 g 
of ethyl (20E) 20-formamido-3-methoxy-19-nor-.DELTA..sup.1,3,5(10),17(20) 
-pregnatetraene-21-oate in 30 ml of anhydrous tetrahydrofuran cooled in an 
ice bath and the mixture was stirred for one hour. Excess hydride was 
destroyed by careful addition of 10 ml of ethanol and then 0.35 g of 
potassium borohydride was added thereto. The reaction mixture was stirred 
for one hour to obtain a mixture containing (20E) 
20-formamido-3-methoxy-19-nor-.DELTA..sup.1,3,5(10),17(20) 
-pregnatetraene-21-ol which was used for the next step. 
STEP B: 3-methoxy-19-nor-.DELTA..sup.1,3,5(10) -pregnatriene-21-ol-20-one 
The mixture of Step A was acidified with 20 ml of 5N hydrochloric acid and 
was then stirred for 15 hours at room temperature and was diluted with 
water. The mixture was extracted with ethyl acetate and the organic phase 
was washed with water, dried and evaporated to dryness. The residue was 
chromatographed over silica gel and was eluted with a 9-1 benzene-ethyl 
acetate mixture to obtain 0.95 g of 3-methoxy-19-nor-.DELTA..sup.1,3,5(10) 
-pregnatriene-21-ol-20-one in the form of colorless crystals melting at 
130.degree.-131.degree. C. 
EXAMPLE 4 
2,2-dimethyl-13.beta.-ethyl-18,19-dinor-.DELTA..sup.4 
-pregnene-21-ol-3,20-dione 
STEP A: 
2,2-dimethyl-13.beta.-ethyl-17.beta.-[2'(RS)-tetrahydropyranyloxy)]-.DELTA 
..sup.4 -gonene-3-one 
20 ml of a solution of 1.4M potassium tert.-butylate in tetrahydrofuran 
were added dropwise over one hour with stirring under an inert atmosphere 
to a mixture of 1.860 g of 
13.beta.-ethyl-17.beta.-[2'(RS)-tetrahydropyranyloxy]-.DELTA..sup.4 
-gonene-3-one [described in U.S. Pat. No. 3.338.928], 10 ml of 
tetrahydrofuran and 4 ml of methyl iodide cooled to -70.degree. C. and the 
mixture was stirred at -70.degree. C. for 30 minutes and was then poured 
into an aqueous saturated ammonium chloride solution. The mixture was 
extracted with methylene chloride and the organic phase was dried and 
evaporated to dryness to obtain 2.2 g of raw 
2,2-dimethyl-13.beta.-ethyl-17.beta.-[2'(RS)-tetrahydropyranyloxy]-.DELTA. 
.sup.4 -gonene-3-one. 
STEP B: 2,2-dimethyl-13.beta.-ethyl-.DELTA..sup.4 -gonene-17.beta.-ol-3-one 
A solution of 2.2 g of the product of Step A, 20 ml of ethanol and 4 ml of 
2N hydrochloric acid was refluxed for one hour, cooled and poured into 
water. The mixture was extracted with methylene chloride and the organic 
phase was washed with water, dried and evaporated to dryness under reduced 
pressure. The residue was crystallized from isopropyl ether to obtain 735 
mg of 2,2-dimethyl-13.beta.-ethyl-.DELTA..sup.4 -gonene-17.beta.-ol-3-one 
melting at 168.degree. C. The mother liquors were evaporated to dryness 
and the residue was chromatographed over silica gel. Elution with an 8-2 
benzene-ethyl acetate mixture yielded 375 mg of product which was 
crystallized from isopropyl ether to obtain 290 mg of product melting at 
169.degree. C. The product was chromatographed over silica gel and was 
eluted with isopropyl ether-methylene chloride mixture to obtain 
2,2-dimethyl-13.beta.-ethyl-.DELTA..sup.4 -gonene-17.beta.-ol-3-one 
melting at 170.degree. C. 
STEP C: 2,2-dimethyl-13.beta.-ethyl-.DELTA..sup.4 -gonene-3,17-dione 
2.6 ml of Heilbron Jones solution were added dropwise at 0.degree. C. to a 
solution of 2.475 g of the product of Step B in 50 ml of acetone and the 
mixture was stirred for 15 minutes at 0.degree. C. 1 ml of methanol was 
added to the mixture which was then diluted with water and was vacuum 
filtered. The product was washed with water to obtain 2.380 g of 
2,2-dimethyl-13.beta.-ethyl-.DELTA..sup.4 -gonene-3,17-dione melting at 
195.degree. C. 
STEP D: 2,2-dimethyl-3-ethoxy-13.beta.-ethyl-.DELTA..sup.3,5 
-gonadiene-17-one 
0.25 ml of a solution of 0.2% sulfuric acid in ethanol was added to a 
mixture of 1 g of the product of Step C, 10 ml of anhydrous ethanol and 1 
ml of ethyl orthoformate and the mixture was refluxed under an inert 
atmosphere for 70 minutes and was then cooled. A few drops of 
triethylamine were added to the mixture which was diluted with aqueous 
sodium bicarbonate and was extracted with ether. The ether phase was 
washed with water, dried and evaporated to dryness under reduced pressure 
to obtain 1.250 g of residue. The latter was chromatographed over silica 
gel and was eluted with a 95-5 benzene-ethyl acetate mixture to obtain 
0.95 g of 2,2-dimethyl-3-ethoxy-13.beta.-ethyl-.DELTA..sup.3,5 
-gonadiene-17-one which was used as is for the next step. 
STEP E: Mixture of E and Z isomers of ethyl 
2,2-dimethyl-3-ethoxy-13.beta.-ethyl-20-formamido-18,19-dinor-.DELTA..sup. 
3,5,17(20) -pregnatriene-21-oate 
5.25 ml of ethyl isocyanoacetate were added dropwise under an inert 
atmosphere to a mixture of 3.36 g of the product of Step D, 15 ml of 
dioxane and 50 ml of 0.93M potassium tert.-butylate in dioxane and the 
mixture was heated at 80.degree. C. for 75 minutes and was cooled. The 
mixture was poured into aqueous monosodium phosphate solution and was 
extracted with ethyl acetate. The organic phase was washed with water, 
dried and evaporated to dryness under reduced pressure. The residue was 
chromatographed over silica gel and was eluted with a 9-1 benzene-ethyl 
acetate mixture and then with a 7-3 mixture to obtain 3.9 g of mixture of 
E and Z isomers of ethyl 
2,2-dimethyl-3-ethoxy-13.beta.-ethyl-20-formamido-18,19-dinor-.DELTA..sup. 
3,5,17(20) -pregnatriene-21-oate. 
STEP F: 
2,2-dimethyl-3-ethoxy-13.beta.-ethyl-20-formamido-18,19-dinor-.DELTA..sup. 
3,5,17(20) -pregnatriene-21-ol 
125 mg of lithium aluminum double hydride were added to a solution of 850 
mg of the product of Step E in 8.5 g of tetrahydrofuran cooled to 
0.degree. to -2.degree. C. and the mixture was held at 0.degree. C. for 
one hour. Then, 8.5 ml of ethanol and 125 mg of sodium borohydride were 
carefully added to the mixture which was then stirred at room temperature 
for 15 minutes and was diluted with ethyl acetate. An aqueous saturated 
sodium chloride solution was slowly added to the mixture to obtain a paste 
and the organic phase was decanted. The residue was taken up twice in 
ethyl acetate and the organic phase was washed with saturated sodium 
chloride aqueous solution, dried and evaporated to dryness under reduced 
pressure to obtain 710 mg of E and Z isomers of 
2,2-dimethyl-3-ethoxy-13.beta.-ethyl-20-formamido-18,19-dinor-.DELTA..sup. 
3,5,17(20) -pregnatriene-21-ol. 
STEP G: 2,2-dimethyl-13.beta.-ethyl-18,19-dinor-.DELTA..sup.4 
-pregnene-21-ol-3,20-dione 
2.8 ml of 2N hydrochloric acid were added to a solution of 710 mg of the 
product of Step F in 14 ml of methanol and the mixture was allowed to 
stand at room temperature for 20 hours. The mixture was diluted with water 
and was extracted with methylene chloride. The organic phase was washed 
with aqueous sodium bicarbonate solution, then with water, dried and 
evaporated to dryness under reduced pressure to obtain 525 mg of residue. 
The latter was chromatographed over silica gel and was eluted with an 8-2 
benzene-ethyl acetate mixture to obtain 340 mg of 
2,2-dimethyl-13.beta.-ethyl-18,19-dinor-.DELTA..sup.4 
-pregnene-21-ol-3,20-dione which was crystallized. 
EXAMPLE 5 
10.beta.-ethynyl-19-nor-.DELTA..sup.4,9(11) -pregnadiene-21-ol-3,20-dione 
STEP A: 3,3-ethylenedioxy-10.beta.-ethynyl-.DELTA..sup.9(11) 
-estrene-5.alpha.,17.beta.-diol 
8.24 g of lithium acetylide in ethylene diamine were added with stirring to 
a mixture of 4.12 g of 
3,3-ethylenedioxy-5.alpha.,10.alpha.-epoxy-17.beta.-benzyloxy-.DELTA..sup. 
9(11) -estrene (described in French Pat. No. 1,550,974) in 60 ml of 
ethylene diamine and the mixture was heated at 45.degree. C. under inert 
atmosphere for 24 hours. The mixture was cooled in ice and was extracted 
with methylene chloride. The organic phase was washed with water, dried 
and evaporated to dryness. The residue was chromatographed over silica gel 
and was eluted with a 7-3 benzene-ethyl acetate mixture to obtain 3 g of 
3,3-ethylenedioxy-10.beta.-ethynyl-.DELTA..sup.9(11) 
-estrene-5.alpha.,17.beta.-diol which melted at 213.degree. C. after 
crystallization from aqueous ethanol. 
STEP B: 3,3-ethylenedioxy-10.beta.-ethynyl-.DELTA..sup.9(11) 
-estrene-5.alpha.-ol-17-one 
4.5 g of pyridinium chlorochromate [Tetrahedron Letters, No. 31 (1975), p. 
2647-2650] were added to a solution of 3 g of the raw product of Step A in 
75 ml of methylene chloride containing 1% of pyridine and the mixture was 
stirred for one hour at room temperature. The mixture was chromatographed 
over silica gel and was eluted with ether to obtain 2.73 g of product. The 
latter was crystallized from aqueous ethanol, was washed and dried to 
obtain 2.43 g of 3,3-ethylenedioxy-10.beta.-ethynyl-.DELTA..sup.9(11) 
-estrene-5.alpha.-ol-17-one melting at 188.degree. C. 
STEP C: Ethyl 
3,3-ethylenedioxy-10.beta.-ethynyl-20-formamido-19-nor-.DELTA..sup.9(11),1 
7(20) -pregnadiene-5.alpha.-ol-21-oate 
10.3 ml of 1.75M potassium tert.-butylate in tetrahydrofuran and 2 ml of 
ethyl isocyanacetate were added with stirring under an inert atmosphere to 
a solution of 2.14 g of the product of Step B in 21 ml of tetrahydrofuran 
and the mixture was stirred at room temperature for one hour and was then 
poured into ice water. The mixture was extracted with methylene chloride 
and the organic phase was washed with water, dried and evaporated to 
dryness under reduced pressure to obtain 3.7 g of ethyl 
3,3-ethylenedioxy-10.beta.-ethynyl-20-formamido-19-nor-.DELTA..sup.9(11),1 
7(20) -pregnadiene-5.alpha.-ol-21-oate. 
STEP D: 
3,3-ethylenedioxy-10.beta.-ethynyl-20-formamido-19-nor-.DELTA..sup.9(11),1 
7(20) -pregnadiene-5,21-diol 
600 mg of lithium aluminum double hydride were added under an inert 
atmosphere in fractions with stirring at 5.degree. C. to a solution of 3.7 
g of the product of Step C in 90 ml of tetrahydrofuran and after stirring 
the mixture for 2 hours, ethanol was slowly added thereto to destroy 
excess hydride. 30 ml of ethanol were added and 0.5 g of sodium 
borohydride was added after which the suspension was stirred at room 
temperature for 20 minutes. 100 ml of ethyl acetate were added thereto 
followed by dropwise addition of aqueous sodium chloride solution to 
precipitate mineral salts in the form of a gummy residue. The organic 
phase was decanted and the residue was taken up twice in ethyl acetate. 
The combined organic phases were dried and evaporated to dryness to obtain 
2.8 g of 
3,3-ethylenedioxy-10.beta.-ethynyl-20-formamido-19-nor-.DELTA..sup.9(11),1 
7(20) -pregnadiene-5,21-diol. 
STEP E: 10.beta.-ethynyl-19-nor-.DELTA..sup.4,9(11) 
-pregnadiene-21-ol-3,20-dione 
A solution of 2.68 g of the product of Step D in 36 ml of methanol 
containing 3.6 ml of 6N hydrochloric acid was refluxed for 80 minutes and 
was cooled and diluted with ice water. The mixture was extracted with 
methylene chloride and the organic phase was dried and evaporated to 
dryness under reduced pressure. The residue was chromatographed over 
silica gel and was eluted with a 7-3 cyclohexane-ethyl acetate mixture. 
Different fractions were crystallized from a methylene chloride-isopropyl 
ether mixture to obtain 1.03 g of 
10.beta.-ethynyl-19-nor-.DELTA..sup.4,9(11) -pregnadiene-21-ol-3,20-dione 
melting at 162.degree. C. 
NMR Spectrum (CDCl.sub.3): Peaks at 0.68 ppm (18--CH.sub.3); at 2.23 ppm 
(C.tbd.CH); at 4.21 ppm (21--CH.sub.2); at 5.71-5.77-5.81 ppm 
(11-hydrogen); at 5.91 ppm (4-hydrogen). 
EXAMPLE 6 
19-nor-.DELTA..sup.4 -pregnene-21-ol-3,20-dione 
STEP A: Ethyl (20E) 3-ethoxy-20-formamido-19-nor-.DELTA..sup.3,5,17(20) 
-pregnatriene-21-oate 
A solution of 5 g of ethyl isocyanacetate in 30 ml of tetrahydrofuran was 
added at 10.degree. C. over 15 minutes to a solution of 5 g of potassium 
tert.-butylate in 60 ml of tetrahydrofuran and the mixture was stirred for 
10 minutes. A solution of 9 g of 3-ethoxy-.DELTA..sup.3,5 
-estradiene-17-one [described in U.S. Pat. No. 3,029,261] in 120 ml of 
tetrahydrofuran was added thereto and the mixture was stirred at room 
temperature for 4 hours and was poured into an aqueous saturated ammonium 
chloride solution. The mixture was extracted with ethyl acetate and the 
organic phase was washed with water, dried and evaporated to dryness under 
reduced pressure. The residue was crystallized from 20 ml of ether to 
obtain 10.9 g of ethyl (20E) 
3-ethoxy-20-formamido-19-nor-.DELTA..sup.3,5,17(20) -pregnatriene-21-oate 
melting at 165.degree. C. 
______________________________________ 
U.V. Spectrum (ethanol): 
Max. with 238 nm 
E.sub.1.sup.1 = 725 
.epsilon. = 30,000 
U.V. Spectrum (0.1NHCl in ethanol): 
Max. at 238 nm E.sub.1.sup.1 = 658 
.epsilon. = 27,200 
______________________________________ 
STEP B: (20E) 3-ethoxy-20-formamido-19-nor-.DELTA..sup.3,5,17(20) 
-pregnatriene-21-ol 
1.2 g of lithium aluminum double hydride and 1 g of sodium borohydride were 
added at 5.degree. C. to a solution of 5.5 g of ethyl (20E) 
3-ethoxy-20-formamido-19-nor-.DELTA..sup.3,5,17(20) -pregnatriene-21-oate 
in 100 ml of tetrahydrofuran and the mixture was stirred for 2 hours at 
5.degree. C. Then, 30 ml of ethanol were added thereto dropwise and the 
mixture was stirred at room temperature for 30 minutes. 20 ml of a 
solution of sodium potassium tartrate were added to the mixture which 
caused a precipitate in the solution and the surnageant was decanted. The 
precipitate was taken up several times in ethyl acetate and the combined 
organic phases were washed with aqueous saturated sodium chloride 
solution, dried and evaporated to dryness under reduced pressure. The 
residue was empasted with isopropyl ether and the mixture was vacuum 
filtered to obtain 4.3 g of (20E) 
3-ethoxy-20-formamido-19-nor-.DELTA..sup.3,5,17(20) -pregnatriene-21-ol 
melting at 202.degree. C. 
______________________________________ 
U.V. Spectrum (ethanol): 
______________________________________ 
Max. at 239 nm E.sub.1.sup.1 = 668 
.epsilon. = 24,800 
______________________________________ 
STEP C: 19-nor-.DELTA..sup.4 -pregnene-21-ol-3,20-dione 
A solution of 200 mg of the product of Step B, 5 ml of methanol and 1 ml of 
5N hydrochloric acid was stirred at room temperature for one hour and was 
then poured into aqueous saturated sodium bicarbonate solution. The 
mixture was extracted with ethyl acetate and the organic phase was dried 
and evaporated to dryness under reduced pressure. The residue was empasted 
with ether and the mixture was vacuum filtered to obtain 160 mg of 
19-nor-.DELTA..sup.4 -pregnene-21-ol-3,20-dione melting at 132.degree. C. 
After crystallization from isopropanol, the product melted at 133.degree. 
C. 
______________________________________ 
U.V. Spectrum (ethanol): 
______________________________________ 
Max. at 240-241 nm 
E.sub.1.sup.1 = 574 
.epsilon. = 18,200 
Inflex. towards 290 nm 
E.sub.1.sup.1 = 4 
______________________________________ 
EXAMPLE 7 
9.alpha.-fluoro-.DELTA..sup.4 -pregnene-11.beta.,21-diol-3,20-dione 
STEP A: Ethyl (20E) 
3-ethoxy-9.alpha.-fluoro-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11.beta.-ol-21-oate 
A solution of 5.7 g of ethyl isocyanacetate in 57 ml of tetrahydrofuran was 
added dropwise with stirring under an inert atmosphere over 15 minutes to 
a solution of 5.789 g of potassium tert.-butylate in 202 ml of 
tetrahydrofuran cooled to 0.degree. to 5.degree. C. and the mixture was 
stirred at 0.degree. to 5.degree. C. for 15 minutes. A solution of 6 g of 
3-ethoxy-9.alpha.-fluoro-.DELTA..sup.3,5 -androstadiene-11.beta.-ol-17-one 
[described in U.S. Pat. No. 3,968,132] in 120 ml of tetrahydrofuran was 
added thereto over 10 minutes and the mixture stood for 31/4 hours at room 
temperature. The mixture was cooled to 5.degree. to 10.degree. C. and 200 
ml of an aqueous saturated sodium chloride solution were added thereto. 
The mixture was extracted with ethyl acetate and the organic phase was 
washed with aqueous saturated sodium chloride solution, dried and 
evaporated to dryness. The residue was chromatographed over silica gel and 
was eluted with a 95-5 chloroform-methanol mixture to obtain 5.9 g of 
ethyl (20E) 3-ethoxy-9.alpha.-fluoro-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11.beta.-ol-21-oate. 
I.R. Spectrum (ethanol): 
______________________________________ 
Max. at 239 nm E.sub.1.sup.1 = 625 
.epsilon. = 28,800 
______________________________________ 
STEP B: (20E) 3-ethoxy-9.alpha.-fluoro-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11.beta.,21-diol 
2 g of lithium aluminum double hydride were added in small fractions over 
15 minutes at 0.degree. to 5.degree. C. to a solution of 4 g of the 
product of Step A in 80 ml of tetrahydrofuran and the mixture was stirred 
at 0.degree. to 5.degree. C. for 90 minutes. 4 ml of aqueous saturated 
ammonium chloride solution were added dropwise to the mixture which was 
then vacuum filtered and the filter was washed with a 7-3 
chloroform-methanol mixture. The filtrate was evaporated to dryness to 
obtain 2.070 g of residue. The latter was chromatographed over silica gel 
and was eluted with a 95-5 chloroform-methanol mixture containing 
0.5.degree./.sub..permill. triethylamine to obtain (20E) 
3-ethoxy-9.alpha.-fluoro-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11.beta.,21-diol. 
______________________________________ 
U.V. Spectrum (ethanol): 
______________________________________ 
Max. at 238-239 nm 
E.sub.1.sup.1 = 492 
.epsilon. = 20,600 
______________________________________ 
STEP C: 9.alpha.-fluoro-.DELTA..sup.4 -pregnene-11.beta.,21-diol-3,20-dione 
Using the procedure of Step C of Example 6, the product of Step B was 
reacted to obtain 9.alpha.-fluoro-.DELTA..sup.4 
-pregnene-11.beta.,21-diol-3,20-dione. 
EXAMPLE 8 
.DELTA..sup.4 -pregnene-11.beta.,21-diol-3,20-dione 
STEP A: ethyl (20E) 3-ethoxy-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11-one-21-oate 
A solution of 15.8 ml of ethyl isocyanacetate in 95 ml of tetrahydrofuran 
was added over 10 minutes with stirring under an inert atmosphere to a 
solution of 16.21 g of potassium tert.-butylate in 145 ml of 
tetrahydrofuran cooled to 0.degree. to 5.degree. C. and the mixture was 
stirred for 20 minutes at 0.degree. to 5.degree. C. A solution of 23.8 g 
of 3-ethoxy-.DELTA..sup.3,5 -androstadiene-11,17-dione [described in U.S. 
Pat. No. 3,055,917] in 130 ml of tetrahydrofuran was added to the mixture 
and after stirring the mixture at 0.degree. to 5.degree. C. for 45 
minutes, 500 ml of aqueous saturated ammonium chloride solution were added 
thereto. The mixture was extracted with ethyl acetate and the organic 
phase was washed with aqueous saturated ammonium chloride solution, dried 
and evaporated to dryness under reduced pressure. The residue was taken up 
in 100 ml of methylene chloride and the mixture was filtered. 500 ml of 
ethyl acetate were added to the filtrate and the methylene chloride was 
distilled off under reduced pressure. The mixture was iced and vacuum 
filtered and the product was washed with ethyl acetate to obtain 23.7 g of 
ethyl (20E) 3-ethoxy-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11-one-21-oate melting at 218.degree. C. The mother liquors 
were chromatographed over silica gel and were eluted with a 7-3 
benzene-ethyl acetate mixture. The product was crystallized from ethyl 
acetate to obtain another 4.814 g of the said product melting at 
218.degree. C. 
STEP B: (20E) 3-ethoxy-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11.beta.,21-diol 
2.266 g of potassium borohydride were added at 0.degree. to 5.degree. C. to 
a solution of 10 g of the product of Step A in 200 ml of tetrahydrofuran 
and then 2.266 g of lithium aluminum double hydride were added thereto in 
small fractions over 10 minutes. The mixture was stirred for 110 minutes 
at 0.degree. to 5.degree. C. under an inert atmosphere and then 10 ml of 
ethanol were carefully added thereto over 30 minutes. The mixture was 
stirred at 0.degree. to 5.degree. C. for 30 minutes and the temperature 
was allowed to rise over 30 minutes. 10 ml of aqueous saturated ammonium 
chloride solution were added to the mixture which was then vacuum 
filtered. The filtrate was washed with chloroform and evaporated to 
dryness under reduced pressure to obtain 9 g of (20E) 
3-ethoxy-20-formamido-.DELTA..sup.3,5,17(20) 
-pregnatriene-11.beta.,21-diol. 
______________________________________ 
U.V. Spectrum (ethanol): 
______________________________________ 
Max. at 237 nm E.sub.1.sup.1 = 540 
.epsilon. = 21,700 
______________________________________ 
STEP C: .DELTA..sup.4 -pregnene-11.beta.,21-diol-3,20-dione 
Using the procedure of Step C of Example 6, the product of Step B was 
reacted to obtain .DELTA..sup.4 -pregnene-11.beta.,21-diol-3,20-dione. 
Various modifications of the products and processes of the invention may be 
made without departing from the spirit or scope thereof and it is to be 
understood that the invention is intended to be limited only as defined in 
the appended claims.