A compound of the formula ##STR1## wherein R.sub.1 is hydrogen or methyl, R.sub.2 is methyl or ethyl, and A,B,C and D rings optionally containing at least one double bond and optionally substituted with at least one member of the group consisting of optionally protected --OH, .dbd.O, alkyl and alkoxy of 1 to 4 carbon atoms, halogen and alkenyl and alkynyl of 2 to 4 carbon atoms, R is selected from the group consisting of halogen, --OH, alkylthio and alkoxy of 1 to 6 carbon atoms, aralkoxy, arylthio and aralkylthio of 7 to 15 carbon atoms and ##STR2## R.sub.3 and R.sub.4 are individually hydrogen, or alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 15 carbon atoms or taken together with the nitrogen form a heterocycle optionally containing another nitrogen or oxygen atom, excepting the product in which R is methoxy, R.sub.1 and R.sub.2 each represent methyl, A ring carries a 3.beta.-acetoxy function and B ring contains a double bond in 5(6) useful as intermediates for the preparation of 20-keto-pregnanes.

STATE OF THE ART 
Related prior art includes U.S. Pat. No. 4,500,460; No. 2,445,006; No. 
2,495,735 and No. 2,180,095 and JACS, Vol. 74 (1952), p. 5814-5817. 
OBJECTS OF THE INVENTION 
It is an object of the invention to provide the novel compounds of Formula 
I and a process for their preparation. 
It is another object of the invention to provide a novel process for the 
preparation of 20-keto-pregnanes and novel intermediates formed therein. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel compounds have the formula 
##STR3## 
wherein R.sub.1 is hydrogen or methyl, R.sub.2 is methyl or ethyl, the A, 
B, C and D rings optionally containing at least one double bond and 
optionally substituted with at least one member of the group consisting of 
optionally protected --OH, .dbd.O, alkyl and alkoxy of 1 to 4 carbon 
atoms, halogen and alkenyl and alkynyl of 2 to 4 carbon atoms, R is 
selected from the group consisting of halogen, --OH, alkylthio and alkoxy 
of 1 to 6 carbon atoms, aralkoxy, arylthio and aralkylthio of 7 to 15 
carbon atoms and 
##STR4## 
R.sub.3 and R.sub.4 are individually hydrogen, or alkyl of 1 to 6 carbon 
atoms or aralkyl of 7 to 15 carbon atoms or taken together with the 
nitrogen form a heterocycle optionally containing another nitrogen or 
oxygen atom, excepting the product in which R is methoxy, R.sub.1 and 
R.sub.2 each represent methyl, A ring carries a 3.beta.-acetoxy function 
and B ring contains a double bond is 5(6). 
When the A, B, C and D rings carry at least one double bond, it is 
preferred for the double bonds to be at 1(2), 4(5), 5(6) or 9(11) or for a 
system of conjugated double bonds at 3(4) and 5(6) or at 4(5) and 6(7) or 
for an aromatic system of three double bonds 1, 3, 5, or for a system of 
three double bonds 1(2), 4(5), 6(7). However, it is preferred to use 
products which do not include double bonds. When the A, B, C and D rings 
are substituted by at least one hydroxyl, it is preferred for there to be 
hydroxyls at 3, 6, 7, 11 and/or 12. When the A, B, C and D rings are 
substitued by at least one ketone, it is preferred for there to be a 
ketone function at 3, 7, 11 or 12. 
When the A, B, C and D rings are substituted by at least one halogen, it is 
preferred for there to be a fluorine, chlorine or bromine atom at position 
6 or 9.alpha.-, for example. When the A, B, C and D rings are substituted 
by at least one alkyl, it is preferred for methyl or ethyl to be 2, 6, 7, 
or at 16.alpha.- or 16.beta.-. When the A, B, C and D rings are 
substituted by at least one alkyloxy, it is preferred for methoxy or 
ethoxy at 3 or 11.beta.-. When the A, B, C and D rings are substituted by 
at least one alkenyl, it is preferably vinyl or allyl in position 
11.beta.-, for example. When the A, B, C and D rings are substituted by at 
least one alkynyl, it is preferably ethynyl in 11.beta.-position, for 
example. 
The hydroxyl groups can be protected in the usual ways known in the 
literature. There can be cited, for example, acetonides, cyclic 
carbonates, orthoesters, cyclic sulfites, ether formed with 
tetrahydropyrannyl, trityl or benzyl and acyls such as acetyl, succinyl or 
formyl. 
The ketone groups can also be protected by standard protector groups such 
as ketals, more specially ethylene ketal, thioacetals, hemithioacetals, 
enol ethers, enol acetates, enamines and oximes. However, ketal groups are 
preferred, especially ethylene ketal, to protect the ketones. When the 
products of Formula I have a 3-ketone group, this group is very 
preferentially protected. 
R may be a halogen, preferably chlorine or bromine; R may be alkoxy 
preferably methoxy or ethoxy, but also propyloxy, isopropyloxy, butyloxy, 
sec-butyloxy, tert-butyloxy, pentyloxy, or hexyloxy; benzyloxy or 
phenethoxy. 
R.sub.3 and R.sub.4 can individually be hydrogen or methyl, ethyl, propyl, 
isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl or benzyl, or 
R.sub.3 and R.sub.4 together with the nitrogen atom to which they are 
bonded form morpholine, piperidine or pyrrolidine. R may also be 
methylthio or ethylthio or alkylthio derived from the alkyls or alkoxys 
indicated above as well as phenylthio or benzylthio. 
The preferred products of Formula I are those wherein R.sub.1 and R.sub.2 
are methyl, and the A, B, C and D rings carry an optionally protected 
3-hydroxyl and, optionally at least one other function chosen from the 
optionally protected hydroxyl functions in the 6, 7, 11 and 12 positions, 
and the optionally protected ketone in position 7, 11 and 12, and R is 
hydroxy alkoxy of 1 to 4 carbon atoms, or 
##STR5## 
wherein R'.sub.3 and R'.sub.4 are hydrogen, alkyl of 1 to 4 carbon atoms 
or R'.sub.3 and R'.sub.4 together with the nitrogen atom to which they are 
bonded form piperidino, pyrrolidino or morpholino and more especially, the 
products of Formula I wherein the A, B, C and D rings carry at position 3 
an optionally protected hydroxyl and optionally at least one other 
function chosen from optionally protected 12-hydroxyl and optionally 
protected 11- or 12-ketone and R is hydroxyl, methoxy or ethoxy, or 
morpholino. 
Other preferred products are particularly advantageous the sub-family of 
products constituted by the products of Formula I wherein the A, B, C and 
D rings carry an optionally protected 3-hydroxyl, and optionally at least 
one other function chosen from optionally protected hydroxyl functions in 
position 6, 7 or 12 and optionally protected ketone in position 7, 11 or 
12. 
In the last family, there can be cited the products including, as skeleton 
of the rings A, B, C and D, products derived from the natural or 
semi-synthetic biliary acids which products are enumerated in the 
following table: 
##STR6## 
wherein R' is hydroxyl, methoxy, ethoxy or morpholino, and R.sub.6 R.sub.7 
and R.sub.12 have the following significances: 
______________________________________ 
R.sub.6 R.sub.7 R.sub.12 
______________________________________ 
H .alpha.-OH .alpha.-OH 
H .beta.-OH .alpha.-OH 
H H H 
H H .alpha.-OH 
H .alpha.-OH H 
.alpha.-OH H H 
H .beta.-OH H 
.alpha.-OH .alpha.-OH H 
.beta.-OH .alpha.-OH H 
.beta.-OH .beta.-OH H 
H H .alpha.-OH 
H .alpha.-OH .alpha.-OH 
______________________________________ 
In these products, the hydroxyls may also be protected, notably the 
3-hydroxyl. The preferred protector group is acetyl or formyl. 
Among the products including at least one ketone, the following products 
are preferred: 
##STR7## 
wherein R' is hydroxyl, methoxy, ethoxy or morpholino and the substituents 
in position 3, 7, 11 and 12 have the following significances: 
3 protected ketone 
-13.alpha.-OH, 7-keto, 12.alpha.-OH 
-3.alpha.-OH, 11-keto 
-3.alpha.-OH, 7.alpha.-OH, 12-keto 
-3.alpha.-OH, 7-keto 
-3.alpha.-OH, 7.beta.-OH, 12-keto 
-3-OH, 11-keto, 12-OH 
3-OH, 11-keto. 
Naturally, the hydroxyls may be protected and the same applies to the 
ketones in position 7 or 12. The preferred protector group for the ketone 
group is a cyclic or non-cyclic ketal. 
Specific preferred compounds of the invention are 
4-[3.alpha.-acetyloxy-5.beta.-cholan-11,23,24-trione-24-yl]-morpholine, 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid, the methyl ester of 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid and 
3.alpha.-acetoxy-5.beta.-cholan-11,23-dione-24-oic acid. 
The novel process of the invention for the preparation of a compound of 
Formula I comprises reacting a compound of the formula 
##STR8## 
wherein A, B, C, D, R.sub.1 and R.sub.2 have the above definition with a 
reagent to form the halide, then with a tertiary base, then with thionyl 
chloride and optionally then with a member of the group consisting of 
water, alkanol, or aralkanol, alkylthiol, arylthiol, aralkylthio, or 
##STR9## 
wherein R.sub.3 and R.sub.4 have the above definition to form a compound 
of the formula 
##STR10## 
wherein A, B, C, D, R, R.sub.1 and R.sub.2 have the above definition and 
reacting the latter either (a) with an aqueous acid or an oxidant or (b) 
with a halogenation reagent, then with a basic hydrolysis agent and where 
R is --OH, optionally reacting the product with a reactant to form the 
acid halide, alkanol, aralkanol, alkylthiol, arylthiol, aralkylthiol or 
##STR11## 
wherein R.sub.3 and R.sub.4 have the above definition, to obtain the 
corresponding compound of Formula I. 
In a preferred mode of the invention, the reagent of the formation of the 
acid halide is oxalyl chloride or oxalyl bromide and most preferably, 
thionyl chloride. 
The tertiary base used is chosen from triethylamine, methylethyl-pyridine, 
pyridine, diazabicyclo-octane, diazabicyclo-nonene, diazabicyclo-undecene, 
and preferably triethylamine or pyridine. The preferred alkanol or 
aralkanol is methanol, ethanol or benzyl alcohol. The primary or secondary 
amine used is chosen from methyl- or ethylamine, diethylamine, morpholine, 
piperidine, pyrrolidine, and preferably morpholine. Naturally, the 
corresponding thiol can be used. The alkylthiol, arylthiol or aralkylthiol 
used is chosen preferably from methanethiol, ethanethiol and thiobenzyl 
alcohol. The preferred aqueous acid to convert the products of Formula III 
into products of Formula I is sulfuric acid, but another mineral or 
organic acid such as hydrochloric acid or acetic acid can also be used. 
When an oxidant is used, it may be potassium permanganate, hydrogen 
peroxide, ozone, a perborate or a persulfate. Generally, the action of an 
aqueous acid or an oxidant on the products of Formula III leads to a 
product of Formula I in which R is hydroxyl. If necessary and if desired, 
other products of Formula I can then be prepared for example, by reacting 
an alkanol such as methanol separately or simultaneously to obtain a 
product of Formula I in which R is alkoxy or a primary or secondary amine 
such as morpholine to obtain the products of Formula I in which R is 
##STR12## 
as well as the corresponding thiols. In a preferred way, acid hydrolysis 
or oxidation is carried out in the presence of the alkanol or the primary 
or secondary amine of which it s desired to obtain the derivative of 
Formula I. 
Naturally, an agent for an acid halide chosen from the list indicated above 
can also be made to act on a product of Formula I in which R is --OH. The 
reactions mentioned above for the preparation of products of Formula III 
can preferably be carried out in a solvent or a mixture of solvents 
miscible slightly or not at all with water such as methylene chloride, and 
chloroform. 
The standard blocking or unblocking reactions for the functional groups 
optionally on the rings A, B, C and D can be carried out at the beginning 
of the synthesis, on the products of Formula II or on the products 
obtained of formula I. For example, the products of Formula I in which the 
A ring includes a 3-hydroxyl protected by an acyl such as acetyl or formyl 
can be submitted to a standard saponification reaction to obtain the 
corresponding product in which the A ring has a free hydroxyl. The 
operation is done by the usual methods by reaction, for example, of a base 
such as sodium hydroxide, potassium hydroxide or potassium carbonate in a 
solvent such as methanol, methylene chloride, water or a mixture of such 
solvents. 
Inversely, the products of Formula I can also be submitted to the action of 
a derivative of a protector group such as acetic anhydride to protect a 
free hydroxyl, for example in the 3-position. 
Another object of the invention is a process for the preparation of a 
compound of the formula 
##STR13## 
wherein A, B, C, D, R.sub.1 and R.sub.2 have the above definitions 
comprising reacting a compound of Formula I with a strong oxidizing agent 
to obtain a compound of the formula 
##STR14## 
reacting the latter with a reagent to form the acid halide and reacting 
the latter with a tertiary base and then thionyl chloride and then 
optionally with a member of the group consisting of water, alkanol, 
aralkanol, alkylthiol, arylthiol, aralkylthiol and 
##STR15## 
wherein R.sub.3 and R.sub.4 have the above definition to obtain a compound 
of the formula 
##STR16## 
wherein A, B, C, D, R, R.sub.1 and R.sub.2 have the above definition and 
Hal is halogen and reacting the latter with a dehydrohalogenation reagent 
and then an oxidizing cleavage agent to obtain the corresponding compound 
of Formula VI. 
The strong oxidizing agent may be Jones' reagent (chromic and sulfuric acid 
in water), lead tetra acetate, hydrogen peroxide and potassium dichromate. 
The agent for formation of an acid halide is chosen from the list indicated 
above, preferably thionyl chloride. The other reagents are also chosen 
from the lists above. The halogenation reagent is a halogen such as 
bromine or a halogenation reagent such as sulfuryl chloride. The 
deshydrohalogenation agent is preferably a strong basic agent such as 
Triton B, 
##STR17## 
an alkali metal alcoholate such as sodium or potassium ethanolate, 
potassium tert-butylate or a sodium or potassium amide. Utilizing a base 
such as sodium or potassium hydroxide at reflux in an alkanol such as 
methanol or ethanol or glyme is also possible or a basic resin such as 
Amberlite. The oxidizing cleavage agent is chosen from ozone and an 
oxidant such as ruthenium oxide or manganese oxide. 
The action of a dehydrohalogenation reagent on the products of Formula V 
gives rise to a product of the following formula 
##STR18## 
which product is then able, after oxidizing cleavage, to lead to the 
products of the Formula VI. 
Natually, in the preparation of the products of Formula VI, the standard 
reactions of blocking and unblocking the functional groups which the rings 
A, B, C and D may include can be carried out either on the starting 
products of Formula I or on the intermediate products of the synthesis. 
Especially, in the case where the dehydrohalogenation reaction carried out 
on the intermediate products of Formula V leads to a saponification of the 
acyl protector group such as acetyl or formyl, the product having a free 
hyroxyl may be re-acylated by means, for example, of acetic anhydride in 
the presence of pyridine. 
Also, the processes described above, the formation agent of an acid halide 
is thionyl chloride. 
As the formation reaction of the sulfine function includes the use of 
thionyl chloride, the linking together of the reagents indicated above, 
namely: 
(a) action of a formation agent of an acid halide, 
(b) tertiary base, then 
(c) thionyl chloride, 
in the preferred form where the formation agent of an acid halide is 
thionyl chloride, amounts to the action on the product of Formula II of 
thionyl chloride in the presence of a tertiary base. Finally, the products 
of Formula V are a subject of the invention, as new industrial products 
and especially as industrial products for the utilization of the products 
of Formula I. 
The starting products of Formula II are known products, for many of the 
natural products of the biliary acid series, or of the products which can 
be prepared by the usual methods starting with these natural products. 
The products of Formula VI are products of the progesterone series and 
these products possess interesting pharmacological properties. 
Furthermore, thes products can serve as starting material for the 
reconstruction of the deoxycortisone chain 
##STR19## 
or for other chains in the position 17.

In the following examples, there are described several preferred 
embodiments to illustrate the invention. However, it is to be understood 
that the invention is not intended to be limited to the specific 
embodiments. 
EXAMPLE 1 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid 
Step A: 3.alpha.-acetyloxy-5.beta.-cholan-11-one-24-oic acid 
200 g of 5.beta.-cholan-3.alpha.-ol-11-one-24-oic acid and 400 ml of acetic 
anhydride are mixed together and the mixture was heated to 45.degree. C. 2 
g of p-toluene sulfonic acid and 20 ml of acetic acid were introduced all 
at once and the temperature rose to 63.degree. C. in 5 minutes. The 
mixture was kept at 60.degree. C. for one hour and then was brought down 
to 55.degree. C. Over about 1 hour, 400 ml of distilled water were added 
at +55.degree. C. and after cooling to +10.degree. C., the precipitate 
formed was separated, washed and dried under reduced pressure to obtain 
211 g of 3.alpha.-acetyloxy-5.beta.-cholan 11-one-24-oic acid melting at 
225.degree. C. (purity near to 99%). 
106 g of the product obtained were dissolved in methylene chloride, 
filtered on silica and eluted with a mixture of methylene chloride and 
ethyl acetate (9/1) to obtain 105 g of purified product melting at 
225.degree. C. 
I.R. Spectrum (chloroform in cm.sup.-1) 
##STR20## 
NMR Spectrum (CDCl.sub.3) in ppm. 
______________________________________ 
H of CH.sub.3 at position 18 
0.62 H of ACO 2.03 
H of CH.sub.3 at position 21 
0.88-0.93 H in position 3 
4.72 
H of CH.sub.3 at position 19 
1.2 H of COOH 8.71 
______________________________________ 
Stage B: 
4-[3.alpha.-(acetyloxy)-11,23,24-trioxo-5.beta.-cholan-24-yl)-morpholine 
Under an inert atmosphere, 68 g of the product of Step A, 250 ml of 
methylene chloride and 0.35 ml of N,N-dimethylformamide were mixed 
together and at reflux of the methylene chloride, 12.8 ml of thionyl 
chloride were added over about 15 minutes. Reflux was maintained for 45 
minutes, followed by concentration to dryness by distilling under reduced 
pressure. 250 ml of methylene chloride were added to the crystallized acid 
chloride and at -15.degree. C., 12.8 ml of thionyl chloride were added. At 
-25.degree. C. and over about 90 minutes, a mixture of 46.5 ml of 
triethylamine and 46.5 ml of methylene chloride were added, and the 
suspension was stirred for 30 minutes. While maintaining the temperature 
at -25.degree. C. and over about 30 minutes, a mixture of 35.5 ml of 
morpholine and 50 ml of methylene chloride were added, with stirring for 
thirty minutes. Then, over about 10 minutes, 350 ml of water were added, 
while allowing the temperature to rise towards 0.degree. C. 4.7 ml of 
acetic acid were added, and at +2.degree. C./+5.degree. C., over about 90 
minutes, 49.6 g of potassium permanganate were added. The mixture was 
diluted during this introduction with 240 ml of water, and stirring was 
maintained to +2.degree./+5.degree. C. for one hour. At 
+5.degree./+10.degree. C. and over about 30 minutes, 43 g of sodium 
bisulfite, and simultaneously, a solution of 12 ml of concentrated 
sulfuric acid in 150 ml of iced water were added. After decanting, the 
methylene chloride phase was washed with water and dried, and 5 g of 
magnesium sulfate and then 60 g of aluminium CBT.sub.1 were added under 
good stirring at 20.degree. C. for 90 minutes. Stirring was maintained for 
a further 90 minutes at ambient temperature, then after filtering, the 
filtrate was concentrated to dryness by distilling under reduced pressure. 
80 ml of ethyl acetate were added to the residue, followed by 
concentrating to dryness by distilling under reduced pressure to expel the 
residual methylene chloride, and 100 ml of ethanol were added to the 
residue. Solution occurred by stirring at about 40.degree. C. and then the 
solution was cooled to 0.degree. C., and crystallization was initiated. 
After standing for 16 hours, 57.6 g of 
-4-[3.alpha.-(acetyloxy)-11,23,24-trioxo-5.beta.-cholan-24-yl)-morpholinne 
melting at 122.degree.-123.degree. C. were obtained. The mother liquors 
were concentrated to dryness, and a residue of 22 g titrating 83.5% of the 
expected product were obtained. 
IR Spectrum (chloroform) in cm.sup.-1. 
##STR21## 
NRM Spectrum (CDCl.sub.3) in ppm. 
______________________________________ 
H of CH.sub.3 in position 18 
0.67 
H of CH.sub.3 in position 21 
0.9-1.0 
H of CH.sub.3 in posiiton 19 
1.17 
H of ACO 2.0 
H in position 3 4.7 
H of the morpholine 
3.4-3.8 
______________________________________ 
STEP C: 5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid 
Under an inert atmosphere, 0.5 g of the product of Step B, 5 ml of methanol 
with 5% of water, and 0.75 g of sodium hydroxide in pastilles were mixed 
together and left for 24 hours at ambient temperature. The solution became 
clear, and a 2N aqueous solution of hydrochloric acid was added until the 
pH showed acid, then extraction was done with ethyl acetate. The extracts 
were dried, concentrated to dryness by distilling under reduced pressure 
to obtain 0.4 g of 5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid. 
IR Spectrum (chloroform) in cm.sup.-1 
______________________________________ 
3 hydroxy OH 3605 Region C.dbd. O 
1781 
3 forms of acid 
3410 ep 1750 
1781 1700 
3510 monomer 1710 
1703 
______________________________________ 
EXAMPLE 2 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid 
Stage A: 3.alpha.-formyloxy-23-sulfinyl-5.beta.-cholan-11-one-24-oic acid 
83.7 g 3.alpha.-formyloxy-23-sulfinyl-5.beta.-cholan-11-one-24-oic acid, 
840 ml of methylene chloride and 168 ml of pyridine were mixed together, 
cooled to +10.degree. C., and over about 5 minutes while allowing the 
termperature to rise to +20.degree. C., 32 ml of thionyl chloride were 
introduced. After stirring at 20.degree. C. for one hour, over about 5 
minutes, 84 ml of water were added with stirring at 20.degree. C. for 15 
minutes. The reaction mixture was then poured into an iced aqueous 
solution of hydrochloric acid, and after stirring, then decanting, 
extraction was done with methylene chloride. The extracts were treated 
with active charcoal, then concentrated to dryness by distilling under 
reduced pressure to obtain 98.5 g of the crude expected product with an 
Rf.=0.45 [eluting with a mixture of chloroform, isopropanol and acetic 
acid (85/14/1)]. 
Analysis: C.sub.25 H.sub.36 O.sub.6 S; molecular weight 464.60 Calculated: 
C% 64.82 H% 7.81 S% 6.90 Found: 64.8 7.7 7.00 
UV Spectrum (ethanol). 
Max. at 282 nm. E.sup.1.sub.1 =157 .epsilon.=6400 that is -77% in sulfine. 
Step B: Methyl ester of 5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid 
Under an inert atmosphere, 2 g of the product of Step A, 20 ml of methanol 
and 0.4 ml of concentrated sulfuric acid were mixed together and refluxed 
for 2 hours, then poured into a mixture of water and ice, and extracted 
with ethyl acetate. The extracts were washed with water, dried and 
concentrated to dryness by distilling under reduced pressure. The residue 
was chromatographed on silica and eluted with a mixture of methylene 
chloride and ethyl acetate (9/1) to obtain 0.64 g of product which was 
crystallized from a mixture of methylene chloride and isopropyl ether, to 
obtain methyl ester of 5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid 
melting about 75.degree. C. with an Rf.=0.32 [eluting with a mixture of 
methylene chloride and ethyl acetate (85/15)]. 
IR Spectrum (chloroform) 
Absence of formate--Presence of OH, ketone not conjugated and ester band 
wide. 
H of position 18 Me.: 0.67 
H of position 20 Me.: 0.9-1.0 
H of position 19 Me.: 1.14 
H.sub.3 : 3.67 
H of COOCH.sub.3 : 3.9 
Step C: 5.beta.-cholan-3-ol-11,23-dione-24-oic acid 
Under an inert atmosphere, 0.5 g of the product of Step C, 5 ml of 
methanol, 1.3 ml of water, and 135 mg of sodium hydroxide in pastilles 
were mixed together and stirred at 20.degree. C. for 20 hours. The 
reaction mixture was then poured into a mixture of N hydrochloric acid and 
ice, and after stirring, the precipitate formed was separated, washed with 
water, dissolved in methylene chloride, dried, concentrated to dryness by 
distilling under reduced pressure to obtain 0.43 g of 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid. 
IR Spectrum (chloroform) in cm.sup.-1. 
##STR22## 
EXAMPLE 3 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid 
Step A: 3.alpha.-formyloxy-22,23-dibromo-5.beta.-cholan-11-one-24-oic acid 
Under an inert atmosphere, 20.9 g of 
3.alpha.-formyloxy-5.beta.-cholan-11-one-24-oic acid, 200 ml of methylene 
chloride and 32 ml of pyridine were mixed together and over about 5 
minutes at +5.degree. C. and while allowing the temperature to rise to 
+20.degree. C., 8 ml of thionyl chloride were added with stirring at 
20.degree. C. for 1 hour, followed by cooling to 10.degree. C. Over about 
5 minutes, 8 ml of bromine were introduced and the mixture was stirred at 
20.degree. C. for one hour. The reaction mixture was poured into a mixture 
of water and ice, stirred, decanted, and extracted with methylene 
chloride. The extracts were dried, treated with active charcoal with a 
little aluminum, filtered and concentrated to dryness by distilling under 
reduced pressure. 40 ml of formic acid were added to the residue, and 
after heating to boiling point for 5 minutes, the formic acid was 
eliminated by distilling under reduced pressure. 40 ml of isopropyl ether 
were added slowly, and after cooling, 24.6 g of 
3.alpha.-formyloxy-22,23-dibromo-5.beta.-cholan-11-one-24-oic acid melting 
at 248.degree. C. and with a Rf.=0.40 [eluting with a mixture of 
chloroform, isopropanol and acetic acid (85/14/1)] were obtained. 
Analysis: C.sub.25 H.sub.36 O.sub.5 Br.sub.2 molecular weight=576.38 
Calculated: C% 52.09 H% 6.30 Br% 27.73 Found: 52.0 6.3 27.4 
Step B: 5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid 
Under an inert atmosphere, 46.6 g of the product of Step A and 930 ml of N 
sodium hydroxide were mixed together and the suspension was heated at 
100.degree. C. for 4 hours. After cooling, ice was added, then 100 ml of 
hydrochloric acid, followed by concentrating and extracting with ethyl 
acetate. The extracts were dried, treated with active charcoal with a 
little aluminum, then filtered, and the filtrate was concentrated to 
dryness by distilling under reduced pressure. Methylene chloride was added 
to the residue, and crystallization took place to obtain 25.4 g of 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid melting at about 
155.degree. C. 
The product was chromatographed on silica and eluted with a mixture of 
chloroform, isopropanol and acetic acid (80/18.5/1.5). The interesting 
fractions were concentrated and ethyl acetate was added. After washing 
with water, drying, and concentrating to dryness by distilling under 
reduced pressure, they were crystallized from a mixture of acetone and 
petroleum ether (b.p.=60.degree. to 80.degree. C.) to obtain the desired 
product melting at 130.degree. C. with a Rf.=0.35 [eluting with a mixture 
of chloroform, isopropanol and acetic acid 78/20/2]. 
IR Spectrum (chloroform). 
Presence of OH, 11-keto, and 
##STR23## 
NMR Spectrum (CDCl.sub.3) in ppm. 
H of position 18 Me: 0.68 
H of position 20 Me: 0.9-1.0 
H of position 19 Me: 1.18 
Mobile H's: 4.4 
EXAMPLE 4 
3.alpha.-(acetyloxy)-5.beta.-cholan-11,23-dione-24-oic acid 
Under an inert atmosphere, 141 mg of 
5.beta.-cholan-3.alpha.-ol-11,23-dione-24-oic acid, 0.3 ml of acetic 
anhydride, and 3 mg of toluene sulfonic acid were mixed together and 
stirred for a further 15 minutes. After extracting with ethyl acetate, the 
extracts were washed with water, dried, and concentrated to drynes by 
distilling under reduced pressure. The residue was chromatographed on 
silica nd eluted with a mixture of methylene chloride, isopropanol and 
acetic acid (87-12.5-0.5) to obtain 80 mg of 
3.alpha.-(acetyloxy)-5.beta.-cholan-11,23-dione-24-oic acid 
IR Spectrum (chloroform), in cm.sup.-1. 
##STR24## 
EXAMPLE 5 
3.alpha.-acetoxy-5.beta.-pregnane-11,20-dione 
Stage A: 3.alpha.-(acetyloxy)-24-nor-5.beta.-cholan-11-one-23-oic acid 
Under an inert atmosphere, 893 mg of 
3-(acetyloxy)-5-cholan-11,23-dione-24-oic acid and 6 ml of acetic acid 
were mixed together, and at +15.degree. C., over about 20 minutes, 4.5 ml 
of Jones' oxidizing solution (prepared from 267 g of CrO.sub.3, 230 ml of 
H.sub.2 SO.sub.4 and water to 1000 ml) were introduced with stirring at 
+15.degree. C. for 5 minutes. The reaction mixture was poured into iced 
water, and extracted with methylene chloride. The extracts were washed 
with a 0.1M aqueous solution of sodium thiosulfate, then with water, 
dried, and concentrated to dryness by distilling under reduced pressure. 
The residue was chromatographed on silica and eluted with a mixture of 
methylene chloride and acetone 9/1 to obtain 680 ml of impure 
3.alpha.-(acetyloxy)-24-nor-5.beta.-cholan-11-one-23-oic acid melting at 
110.degree.-120.degree. C. 
IR Spectrum (chloroform) 
Presence of acetate, 11-oxo and acid. 
NMR Spectrum (CDCl.sub.3) in ppm. 
H of position 18 Me: 0.66 
H of position 21 Me: 0.97-1.02 
H of position 19 Me: 1.18 
H of ACO: 2.0 
H.sub.3 : 4.68 
Step B: 
4-[3.alpha.-(acetyloxy)-22,22-dibromo-11-oxo-24-nor-5.beta.-cholan-23-yl)] 
-morpholine 
Under an inert atmosphere, 4.1 g of the product of Step A, 41 ml of 
methylene chloride and 6.35 ml of pyridine were mixed together, and at 
0.degree./+5.degree. C., 1.57 ml of thionyl chloride were added. Then 
immediately 1.6 ml of bromine were added with stirring at 20.degree. C. 
for one hour. At 0.degree./-5.degree. C., over about 15 minutes, 8.5 ml of 
morpholine were added with stirring for 1 hour, while allowing the 
temperature to return to 20.degree. C. The reaction mixture was poured 
into 400 ml of 2N iced hydrochloric acid and was extracted with 
chloroform. The extracts were washed with water, dried, concentrated to 
dryness by distilling under reduced pressure. The 6.5 g of residue were 
chromatographed on silica and eluted with a mixture of cyclohexane and 
ethyl acetate (8/2) to obtain 2.075 of 
4-[3.alpha.-(acetyloxy)-22,22-dibromo-11-oxo-24-nor-5.beta.-cholan-23-yl)] 
-morpholine. 
IR Spectrum (chloroform) in cm.sup.-1. 
______________________________________ 
OAC 1724 
1364 
C--O complex 1267-1251-1235 
11-oxo 1704 
amide 1645 
______________________________________ 
NMR Spectrum (CDCl.sub.3) in ppm. 
H of position 18 Me: 0.74 
H of position of 19 Me: 1.16 
H of position 21 Me: 1.34-1.42 
H of ACO: 1.8 
H of the morpholine: 3.76 
H.sub.3 : 4.7 
Analysis: C.sub.29 H.sub.43 Br.sub.2 NO.sub.5 ; molecular weight=645.48 
Calculated: C% 53.96 H% 6.71 N% 2.17 Br% 24.76 Found: 53.9 6.7 2.1 24.6 
Step C: 3.alpha.-acetoxy-5.beta.-pregnane-11,20-dione 1.degree. 
Debromohydration 
Under an inert atmosphere, 250 mg of the product of Step B, 2.5 ml of 
methanol, and 2.5 ml of triton B (or benzyl trimethyl ammonium hydroxide) 
at 40% in aqueous solution were mixed together and refluxed for 1 hour. 
After cooling, the reaction mixture was poured into iced water, and 
extracted with methylene chloride. The extracts were washed with water, 
dried and concentrated to dryness by distilling under reduced pressure to 
obtain 120 mg of 3.alpha.-acetoxy-5.beta.-pregnane-11,20-dione, which was 
used as is for the following reaction. 
2.degree.. Acetylation. 
Under inert atmosphere, the said product, 1.2 ml of pyridine and 0.48 ml of 
acetic anhydride were mixed together and left in contact for 20 hours. The 
mixture was then poured into iced water, and after 30 minutes, was 
extracted with methylene chloride. The extracts were washed with water, 
dried, and concentrated to dryness by distilling under reduced pressure to 
obtain 170 mg of the expected acetylated product which was used as is for 
the following reaction. 
3.degree.. Ozonolysis 
Under an inert atmosphere, the acetylated product, 2.5 ml of 
1,2-dichlorethane, and 1 ml of acetic acid were mixed together, and at 
-5.degree. C., a current of ozonized oxygen was passed for 15 minutes. The 
excess of ozone was eliminated by bubbling nitrogen through and then the 
reaction mixture was poured slowly into an excess of an aqueous solution 
of sodium bicarbonate. Extraction was done with methylene chloride and the 
extracts were washed with water, dried and concentrated to dryness by 
distilling under reduced pressure to obtain 115 mg of 
3.alpha.-acetoxy-5.beta.-pregnane-11,20-dione. The crude product was 
chromatographed on silica and eluted with a mixture of cyclohexane and 
ethyl acetate (8/2) to obtain 16 mg of the purified product, of which the 
infra-red spectrum was identical to that of an authentic sample. 
EXAMPLE 6 
3.alpha.-acetoxy-5.beta.-pregnane-11,20-dione 
1.degree. Bromination. 
Under an inert atmosphere, 3.2 g of 
3.alpha.-acetoxy-24-nor-5.beta.-cholan-11-one-23-oic acid (titer 85%) from 
Stage A of example 5, 32 ml of methylene chloride and 6.1 ml of pyridine 
were mixed together, and at -5.degree. C., over about 10 minutes, 1.2 ml 
of thionyl chloride were added dropwise. Then, at -10.degree. C. over 10 
minutes, 0.6 ml of bromine were added and after stirring for 150 minutes 
at 20.degree. C., 8 ml of diethylamine were introduced at -5.degree. C. 
over about 20 minutes. The mixture was stirred for 1 hour at 20.degree. C. 
and then was poured into 2N iced hydrochloric acid with stirring for 15 
minutes. Extraction was done with methylene chloride and the extracts were 
washed with water, dried, treated with active charcoal, and taken to 
dryness by distilling under reduced pressure to obtain 5.1 g of crude 
brominated product which was used as is for the following reaction. 
2.degree. Treatment with Triton B (debromohydration) 
Under an inert atmosphere, 1.5 g of the crude brominated product, 15 ml of 
methanol and 12 ml of Triton B (benzyl trimethyl ammonium hydroxide) at 
40% in aqueous solution were mixed together and refluxed for 90 minutes, 
then cooled, poured into water, and extracted with methylene chloride. The 
extracts were washed with water saturated with sodium chloride, with a 
0.5M aqueous solution of monosodium phosphate, and with water saturated 
with sodium chloride, then dried and concentrated to dryness by distilling 
under reduced pressure to obtain 837 mg of crude product which was used as 
is for the following reaction. 
3.degree.. Acetylation 
Under an inert atmosphere, the 837 mg of said product, 3 ml of pyridine and 
1.5 ml of acetic anhydride were mixed together and stirred at 20.degree. 
C. for 20 hours. A few ml of water were added, and after stirring for 1 
hour, the reaction mixture was poured into water saturated with sodium 
chloride, and extracted with methylene chloride. The extracts were washed 
with water saturated with sodium chloride, dried, and concentrated to 
dryness by distilling under reduced pressure to obtain 954 mg of crude 
acetylated product which was used as is for the following reaction. 
4.degree.. Ozonization. 
The 954 mg of crude acetylated product, 15 ml of methylene chloride and 8 
ml of acetic acid were mixed together, and at 0.degree. C., a current of 
ozonized oxygen was passed for 1 hour. Then, the reaction mixture was 
poured into water and extracted with methylene chloride. The extracts were 
washed with water saturated with sodium chloride, dried, and concentrated 
to dryness by distilling under reduced pressure to obtain 992 mg of crude 
ozonized product. The crude product was chromatographed on silica and 
eluted with a mixture of cyclohexane and ethyl acetate (75/25) to obtain 
106 mg of 3.alpha.-acetoxy-5.beta.-pregnane-11,20-dione. 
IR Spectrum (chloroform) 
The spectrum was identical to that of an authentic sample of 
3.alpha.-acetoxy-11,20-dioxo-5.beta.-pregnane. 
Various modifications of the products and processes of the invention may be 
made without departing from the spirit or scope thereof and it should be 
understood that the invention is intended to be limited only as defined in 
the appended claims.