CA1199907A - PROCESS FOR THE PREPARATION OF 5.alpha. - HYDROXYL STEROIDS DERIVATIVES AND DERIVATIVES THUS OBTAINED - Google Patents

Abstract

The invention relates to a process for the preparation of a compound of general formula (II): (II) <IMG> in which K represents a blocked ketone group, R1 represents an organic radical containing from 1 to 18 C, containing at least a nitrogen, phosphorus or silicon atom, the atom immediately adjacent to carbon at 11 being a carbon atom, R2 represents a hydrocarbon radical containing from 1 to 8 C and X represents the remainder of a pentagonal or hexagonal cycle unsubstituted or substituted and possibly carrying unsaturation. The compounds of formula II are especially useful as starting reagents in the preparation of steroid derivatives substituted in 11.beta. and endowed with anti-glucocorticoid properties.

Description

9 ~ 7 This is a division of Canadian patent demand No. 393.808 filed January 8, 1982.
~ a present invention relates to a method for the preparation of a compound of general formula (II):

X ~ II) L
K ~ I
GH
in which K represents a keto grouping blocks under form of ketal, thiocetal, d 7 oxime or methyloxime, Rl represents an organic radical containing from 1 to 18 atoms of carbon, containing at least one nitrogen, phosphorus or of silicon, the atom immediately adjacent to the carbon at 11 being a carbon atom, R2 represents a hydro-carbon containing 1 ~ carbon atoms and X represents the remainder of a non-substituted pentagonal or hexagonal cycle or substitutes and can be carrying unsaturation ~
The present invention also relates to these compounds of formula II obtained by the implementation of the process below mentionned.
This procedure according to the invention which is the subject of the present application, is characterized in that we submit a compound of formula general (III ~:

¦ ~ X (III) OJ
K

in which ~, R2 and X keep the same meaning that previously, ac ~ ion of a compound selected dan ~ the group consisting of the compounds of formula (R1 ~ 2 Cu Li, of formula RlMg Hal and formula RlLi, ~ which ones ~ are ~ preserved the same meaning as before and Hal represents a halogen atom, if applicable, in the presence of halide cui ~ reux, to obtain the compound of formula (II ~ sought.
R2 preferably represents a radic ~ l saturated alkyl, linear or branched, containing 1 to 4 carbon atoms, for example a methyl, ethyl, n-propyl or butyl radical.
Advantageously, R2 represents a methyl radical.
X preferably represents the rest of a pentagonal cycle possibly substituted.
Advantageously, X represents the remainder of a cycle of formula:

~ ~ R

where R2 retains the same meaning as before, the dotted line in 16-17 symbolizes the possible presence of a double bond, Y represents a radical rR5 ~

-LR6! N
where n represents the number 1 or 2, R5 represents a hydrogen atom, an alkyl radical containing 1 ~ 8 carbon atoms, an alkenyl or alkynyl radical containing of 2 ~ 8 carbon atoms, an aryl radical containing 6 to 14 carbon atoms or an aralkyl radical containing from 7 to 15 carbon atoms, R6 identical or different from R5, .S3 ~ 7 can take one of the values indicated for R5 and can equal-ment represent a radic ~ l hydroxyl, R3 and Rg ~ identical or different, represent either a hydrogen atom, or an OH, Oalc4, O-CO-alc5, alc4 and alc5 radical representing a alkyl radical containing ~ carbon atoms or aralkyl containing from 7 to 15 carbon atoms, ie a radical alkenyl or alkynyl containing 2 ~ 8 carbon atoms, either a radical - C - CH20H, or a xadical -COCH20COalc5, in which alc6 represents an alkyl radical containing the 8 carbon atoms possibly substituted or a radical aralkyl containing from 7 to 15 carbon atoms, ie a radical CO-CO2H or CO-CO2alc7 in which alc7 represents a radical alkyl containing from 1 to 8 carbon atoms, i.e. a radical H IHalc8 ~ C = OJ is a radical -C = O ~ in which alc8 represents a alkyl radical containing from 1 to 8 carbon atoms or one aralkyl radical containing 7 to 15 carhone atoms, ie a radical -C_N, i.e. R3 and R4 together form a radical c ~ 3 ~ CO Zl in which Zl represents a hydrogen atom, a _ ~ --Z
alkyl radical or an acyl radical containing from 1 to 8 atoms of carbon and Z2 an alkyl radical containing from 1 to 8 atoms carbon ~
R5 is preferably different from R6.
When R5 and R6 represent an alkyl radical, it it is preferably a methyl or ethyl radical.
When R5 or R6 represents an alkenyl radical, it it is preferably the vinyl, isopropenyl or allyl radical.

When R5 or R ~ x represents an alkynyl radical, it it is preferably the ethynyl or propynyl radical.
When R5 or R6 represents an aryl radical or aralkyl, it is preferably a phenyl or benzyl radical.
Lor5que R3 or R4 represents an Oalc ~ or OCOalc5 radical, alc ~ and alc5 preferably represent a methyl radical, ethyl, n-propyl, butyl, pentyl, hexylP or benzyl.
When R3 or R4 represents an alkenyl radical, it preferably the vinyl, isopropenyl, allyl or

2-methylallyl.
When R3 or R ~ represents ~ an alkynyl radical, it this is pxeference of the radical -C-CH, or -CC alcg, alcg preferably representing a methyl, ethyl, propyl radical, isopropyl, isopropenyl, butyl, benzyl or trifluoromethyl.
Alc6, alc7 and alc8 preferably represent one of the preferential values of alc4 or alc5.
Preferably, ltin ~ ention relates to a process for the preparation of compounds where the radicals R3 and R4 are ~ different except in the case where R3 and R4 each represents a hydrogen atom Parml the preferred values of the radical ~ C

we can cite the radicals OH OH OH

--1 ";--I"; --I "
~ C _ C CH ~~ C - CH 'CC - CF3 R ~ C ~ 2H / ~ - CH20H Cll-NH (CH) 2CH3 'OH ~ / OH

I /

or f ~ \ Zl in which Zl represents an atom ~ 2 hydrogen, an alkyl radical containing 1 to 8 carbon atoms bone or an acyl radical containing 2 to 8 carbon atoms, for example an acetyloxy or benzoyl radical and Z2 represents a alkyia radical containing from 1 to 8 carbon atoms ~ one, for example a methyl radical. Advantageously, R5 and R6 represent a hydrogen atom and n is ega ~ a 1.
More particularly, the invention relates to a method for the preparation of compounds of formula II in which Rl represents a hydrocarbon radical containing 1 ~ 18 atoms of carbon and containing at least one nitrogen atom.
Paxmi these compounds, we can cite very specially the compound ~ for which R1 represents a primary alkyl radical, secondary or tertiary, containing from 1 to 8 carbon atoms, having one or more heteroatoms selected from the group constitutes by oxygen ~ nitrogen and sulfur, of which at least one nitrogen atom, or substituted by a heterocycle containing the minus one nitrogen atom.
By alkyl radical ~ means preferably, the radicals methyl ethyl, n-propyl, isopropyl, butyl, isobutyl, terbutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclo penty ~ e or cyclohexyl.
By heterocycle containing at least one nitrogen atom, we may mention the radicals 3,4- or 2 ~ pyridyle, the radicals thiazolyl or piperidinyl.
Mention may also be made, as preferred compounds obtained by a process according to the invention, the compounds for which R
represents a heterocyclic radical comprising at least one nitrogen atom, optionally substituted by an alkyl radical '7 containing 1 to 8 carbon atoms.
By heterocyclic radical is meant preferably one of the radicals men ~ ionnes above.
I, when Rl represents a heterocyclic radical comprising as long as at least one nitrogen atom, substituted by an alkyl radical, it is most often a heterocycle substituted by a methyl, ethyl or n-propyl radical.
Among the preferred compounds obtained by a process according to the invention, mention may also be made of the compounds, for which R1 represents an aryl or aralkyl radical bearing an amine function / ~ 7 \ R
in which R7 and R8 represent an alkyl radical containing from 1 to 8 carbon atoms, or a primary alkyl radical, secondary QU tertiary containing 1 to 8 carbon atoms, with one or more heteroatom ~ selected from the group consisting of oxygen, nitrogen and sulfur, of which at least a nitrogen atom, or substituted by a heterocycle comprising at least one nitrogen atom.
By alkyl radical is preferably meant one of the radicals mentioned above.
By aryl or aralkyl radical ~ means preferably the phenyl or benzyl radical.
The term heterocyclic radical preferably means one heterocyclic radicals mentioned above.
The invention particularly relates to a process to prepare compounds for which R1 represents a 2,3 or 4-pyridyl radical, a radical 9g) 7 : CH3 (2 ~ n CH3 (n ~ 31 a radical ~ / \ ~ 0 - \

a radical ~ 3 \

a radical NOT

or a radical The subject of the invention is also in particular a process for preparing compounds for which R1 represents a radical (3) 3 `, ~
~, In an entirely preferred embodiment of the process of the invention:
- the reaction takes place at room temperature, - the compound of formula (III) is subjected to the action of a compound of formula RlMg Hal in the presence of copper salts.
The invention particularly relates to a process for the preparation of a compound of general formula (II '):

Rl ~ ~ R3 ~ R ~ (II ') OH

in which Rl, R2 and K are defined as above, R'3 represents a hydroxy radical or an ORC radical in which Rc represen ~ e the r ~ ste alc ~ of an ether group or COalc5 of a ester group, alc4 and alc5 representing an alkyl radical containing 1 to ~ carbon atoms or aralkyl containing from 7 to 15 carbon atoms and R'4 represents an atom a ~ hydrogen or an alkenyl or alkynyl radical comprising 2 to 8 carbon atoms ~ characterized in that we submit a compound of formula (IV):

~ R

J: ' in which K and R2 are defined as above, at the action of a compound chosen from the group consisting of compounds of formula ~ Rl) 2 Cu Li, of formula RlMgHal and formula RlLi, in which Rl is defined as above and Hal represents an atom of halogen, if appropriate in presence of cuprous halide, to o ~ hold a compound of formula (V): R
: 2 . I (V) , ~ III
~ ~, \
K

OH
in the ~ uelle K, Rl and R2 are defined as above, which we then submit - either ~ the action of a reducing agent to obtain the corresponding 17-hydroxy compound, - SGit to the action of an appropriate manager to obtain the corresponding compound 17 ~ -hydroxy 17a-substituted, - or ~ the action of an organometallic derivative such as a lithian or a potassium derivative, to obtain the compound 17 ~ -hydroxy 17 ~ substitute corresponding, - either to the action of a cyanidation agent to obtain the compound 17 ~ -cyano 17 ~ -hydroxy corresponding, which is protected the hydroxy function, then to the action of an organometallic derivative _ 9 _ ~; as described above, to obtain compound 17 ~ -hydroxy 17a-substituted corresponding, and that, if necessary, we submit either of the 17-hydroxy compounds obtained above, has the action of an esterification or e-therification agent, and that, if necessary, one or the other of the compounds is subjected 17-substituted obtained above, in which the substituent in 17 comprises a triple bond, ~ the action of a reducing agent, to obtain the corresponding ethylenic.
In a preferred embodiment of the 17 invention process tion, the reaction of the compound ~ IV3 with the compound RlMg Hal, (Rl) 2 Cu Li or Rl Li is carried out under the conditions already described above.
The dif ~ erents reactifs ~ ue we react on the com--pose of formula ~ V3 are well known in the chemistry of steroids. The experimental part below describes some one of the reactions with the compound of formula (V).
Among the compounds of formllle (II) as well as the compounds of formula (V), there may be mentioned more particularly:
- 11 ~ - ~ 4- ~ trimethylsilyl ~ phenyl7 3,3- / 1,2-ethanediyl bis (oxy) / 17a- (prop-1-ynyl1 estr-9-en 5a, 17 ~ -diol, - 11 ~ - (4-pyri ~ yl) 3J3- / 1,2-ethanediyl bis (oxy) / 17a-(prop-l-ynyl) estr-3- ~ n 5a, 17 ~ -diol, ; ~
; - 11 ~ - / 3- (N, N-dimethylamino ~ propyl7 3,3-Ll, 2-ethanediyl bis (oxy) / 17a- (prop-1-ynyl) estr-9-en 5a, 17 ~ - diol, - ll ~ dimethylaminophenyl) 3,3- / 2-ethanediyl bis (oxy) 7 17a- (prop-1-ynyl) estr-9-en 5a, 1 / ~ -diolf -. _ - 3,3- ~ ethanediyl bis ~ oxy) 7 11 ~ / 4- (N, N-dimethylaminoethyl-oxy) phenyl7 17N- (prop-l-ynyl) estr-9-en 5 ~, 17 ~ -diol, - 1R 21 chloro 3,3- / 1,2-ethanediyl bis (oxy) 7 11 ~ - (4-dimethyl-aminophenyl) (17 ~) l9-nor pregn-9-en-20-yn 5 ~, 17 ~ -diol, - 11 ~ - (4-dimethylaminophenyl) 3,3-L1,2-ethanediyl bis (oxy) /
17a-prop-2-ynyl) estr-9-en 5 ~ rl7 ~ -diol.
The compounds of formula (III) and in particular, among these, the compounds of formula (IV), used to prepare the compounds of formula (II) or ~ V) are products known in a way general, which can be prepared by submitting the compounds ~ 5 (10 ~, 9 (11) corresponding to the action of an epoxidation agent selective of the double bond 5 ~ 10). This is how we can subject compounds ~ 5 (10 ~ 9 (11) for example to action oxygenated water used in the presence of hexachloroacetone or of hexafluoroacetone, according to the process described and claimed in French Patent No. 2,423,486. 3,3-L1, 2-ethanediyl bis (oxy) 7 17 ~ - (1-propynyl) estr-9 ~ en 5 ~, 10 ~ -epoxy 17 ~ -ol is a product not described, the preparation of which is given below in the experimental part.
The compounds of formula II which are the subject of the present invention are particularly useful for preparing according to the method of main request, compounds of formula (I '):
Rl R2 X (I ') ~ ~ / ~
1 ~ CI
/ ~ \ ~

in which R1 represents an organic radical containing from 1 to 18 carbon atoms, containing at least one atom nitrogen, phosphorus or silicon, the atom immediately adjacent to carbon in 11 being a carbon atom, R2 represents sen ~ e a hydrocarbon radical containing from 1 to 8 atoms of carbon, X represents the remainder of a pentagonal or hexagonal cycle possibly substituted and possibly carrying unsatura-tion, the group C = A in position 3 represents a group oxo, free or blocks in the form of cetal, a grouping HHH
C \, C`, C \, a group C = ~ lOH, OH Oalc1 O-CO-alc a group C = NO-alc3 or a group C ~ 2, alcl, alc2 and alc3 representing an alkyl radical containing from 1 to 8 atoms of carbon or an aralkyl group containing from 7 to 15 carbon atoms and B and C together a double bond or an epoxy bridge.
These compounds of formula (I ') and their salts of addition with acceptable pharmaceutical acids are particularly interesting products from the point of view pharmacological; in particular they have a remarkable -These compounds of formula (I '), subject of the invention of the main application, are obtained by a charac-terise in that we submit a compound of general formula (II) r object of the present invention;

Rl R2 ¦ X (II ~
~ ~ 1 ~
I
~ ' , K
,, I
OH

: l in which K represents a blocked konic grouping in the form of cetal, thiocetal, oxime or methyloxime, Rl, R2 and X keep the same meaning as before, the action of a dehydrating agent capable of releasing the ketone function, to obtain a compound of formula (I'A):

Rl l X (I ~ A) / /) ~ ' in which Rl, R2 and X keep the same meaning that previously, that we submit, if applicable, either ~ the action of a cetalisation agent to obtain the compound of formula (I'B) in which the catone function in 3 ~ 13 is blocked in the form of cetal, R ~
l X (I '~) ~ J

cetal in which Rl, R2 and X keep the same meaning as ~
previously, either to the action of hydroxylamine NH2OH free, or blocked in NH2-O ~ alc3 form in which alc3 retains its significance previous fication, to obtain the compound of formula VS

1 ~ tI'c) in which R represents a hydrogen atom or a group alc3, Rl, R2 and X retain the same significance tion that previously, either to the action of a rec3uction agent capable of reducing selectively the ketone function in 3, to obtain the pose of formula (I'D) ~ Rl 2 1 / `- ~
l X (IID ~
~ \ `~ ~ /

HO

in which Rl, R2 and X keep the same meaning ~ ue previously, that one submits, if applicable, or the action of an etherification agent capable of to produce the radical alcl pvur to obtain a compound of for-mule (I'E) Rl 2 / \ / ---- \

~ X (I ~ E

alclo in which alcl, Rl, R2 and X keep the same meaning fi ~ ation that previously, that we submit, if necessary, or the action of an esterifying agent liable to introduce the group CO alc2 in which alc2 retains the previous meaning, to obtain a compound of formula (I

_ 15 Rl ~ 2 /
l X (I'F) `~ J
alc2COO

in which alc2, Rl, R2 and X conser ~ ent the same meaning as above, or composed of formula (I'A) I which we transform, if necessary, according to known methods, derivative for which C = A represents a group pement ~ H2 and, composed of formulas (I'A), (I'B ~, ¦I'C), (I'D), ~ I'E ~ or (I'F) that, if necessary, we submit ~ to the action of a pharmaceutically acceptable acid to obtain a salt, or ~
the action of an oxidizing agent, to obtain either, if the radical Rl comprises a nitrogen atom, a drift comprising at 11 ~
a radical whose nitrogen atom is oxide and in which the radicals B and C eventually form an epoxy bridge, that is, if the radical Rl does not contain a nitrogen atom, a derivative in which the radicals B and C form an epoxy bridge, and, composes in which ~ both the radical Rl contains a nitrogen atom oxide and B and C together form an epoxy bridge that, where if necessary, we selectively reduce to the level of the nitrogen atom oxide contained in the radical Rl and that, if necessary, we subjected to the action of a pharmaceutically acceptable acid for get a salt.
In a preferred embodiment of the method of the main demand for obtaining compounds of formula I ', the dehydrating agent capable of releasing the ketone function is a sul ~ onic resin (acid form), by -.16 -example, a commercial sulfonic resin with a poly-styrene or styrene / di ~ inylbenzene polymer support; But one can also use a mineral acid such as acid hydrochloric or sulfuric acid in a lower alkanol or perchloric acid in acetic acid, or an acid sulfonic like paratoluene sulfonic acid.
The ketalizing agent is preferably a alcohol or a dialcohol in the presence of an organic acid, com ~ e for example oxalic acid or paratoluene acid-sulfonic.
The agent for reducing the ketone function is preferably an alkali metal hydride. (See on this subject the article by ER ~ Walkis in Chemical Society Reviews 1976, Flight. 5, no 1, page 23.) The etherification agent is preferably a alkyl halide in the presence of a base.
The esterifying agent is preferably a de-side of carboxylic acid, for example a chloride or a anhydride, in the presence of a base such as pyridine.
It goes without saying that when one of the radicals R3 or R4 of the products of formula II ') obtained previously represented feels an OH radical, we can subject said OH radical to these products of formula (I ′), to the action of an agent of ethé-rification or esterification.
This etherification or esterification agent is preferably one of those mentioned above.
When R3 or R4 represents an acyloxy radical in 17, we can possibly saponify this grouping acyloxy. The saponification agent used is preferably contains a base such as soda, potash, starch potassium or potassium terbutylate, the reaction of saponification being carried out preferably within dlun , `
alcohol in ~ rieur like methanol or ethanol, it can also be lithium acetylide in ethyl ~ do diamine.
The oxidizing agent is preferably a peracid like metachloroperbenzoic acid, paracetic acid or perphthalic acid or oxygenated water alone or in the presence of hexachloro or hexafluoroacetone. When f` 1 ~ we want to obtain a compound in which only the atom r of nitrogen in the radical Rl is oxidized, an equivalent is used - oxidizing agent. When you want to get a compound in which, in addition, B and C form an epoxy bridge, u ~ ilise two equivalents of oxidizing agent.
The Selective Function Reduction Agent N-oxide is preferably triphenylphosphine and one can operate for example within acetic acid.
Example 1: Preparation of 11 ~ - (4-pyridyl-3 3,3-a, 2-ethanediyl bis (oxy) ~ 17 ~ - tproP-l-ynyl3__estr-g-en 5h ~ 17 ~ -diol and ap ~ Plica-tion of this compound in the preparation of 17 ~ -hydroxy 17 ~ -_. _. . _ _. _ [prop-l-ynyl) 11 ~ - (4-pyridyl) estra-4,9-dièn 3-one.
Stage A ~ p ~ aration of 11 ~ - (4-pyridyl ~ 3,3-Ll, 2-ethaned ~ bis (oxy) J 17 ~ - (prop-l- yl ~ estr-9-en 5a, 17 ~ diol.
At 20 ° C., 100 cm 3 of a solution of 4-chloropyridinyl magnesium bromide in tetrahydro-furan ~ 0.5 - 0.6 M solution prepared from 15 g of 4-chloropyridine and 6 g of magnesium ~ in a solution containing 6.16 g of dimethyl sulfide complex, bromide copper in 40 cm3 of tetrahydrofuran. Shake 20 minutes at room temperature SOllS inert atmosphere and add in 10 minutes a solution containing 3.7 g of

3,3- ~ 1,2-ethanediyl bis (oxyl ~ 5 ~, 10 ~ -epoxy 17 ~ - (prop ~
l-ynyl ~ estr ~ 9 (11) -èn 17 ~ -ol. Shake for an hour : ~ room temperature and poured into a mixture of water and ammonium chloride ~ The mixture is stirred reaction for half an hour at room temperature and ~ x extracted with ether ~ Washed with a saturated solution of sodium chloride, dried and concentrated to dryness under pressure scaled down. 6 ~ of a product are obtained which is chromatographed on silica, eluting with the methylene chloride mixture acetone 1-1 containing 1 per thousand of triethylamine. We isolate thus 3.15 g of product which is dried under a vacuum of 0.1 mm of mercury around 60C. This produces the product sought ~ D ~ -52 + 1.5 (c = 1% CHC13) Stage B: / yl ~ c ~ a ~ u compos ~ pr ~~~ dtr ~ At obtained at preparation of 17 ~ -hydroxy 17 ~ (prop ~ nYl) 11 ~ ( estra 4,9-di ~ n-3 one.
Stir for 3 hours at room temperature under an inert atmosphere a solution containing 2.9 g of the pro- -duit prepared in stage A, 14 cm3 of methanol and 7 cm3 of acid hydrochloric 2N. We then add a solution containing 200 cm3 of ether and 90 cm3 of a saturated carbonate solution sodium acid. We act for 15 minutes at temperature ambient, decante and ether extract. Wash the extracts with a saturated solution of sodium chloride, then dries and concentrates to dryness under reduced pressure. We obtain 2.3 g of a product which is chromatographed on silica eluting by the methylene chloride-acetone mixture 6-4. We isolate 1.7 g of product which is dried under pressure of 0.1 mm of mercury for 24 hours including 8 hours ~ 80C. We thus obtain the research product ~ 7D = + 305 ~ 1 ~ c = 1% CHC13).
In the same way we can prepare the 17 ~ -hydroxy, 17 ~ - ~ prop-1-ynyl) 11 ~ - (3-pyridyl) estra 4,9-dienn 3-one (~ 7D = + 14 c = 1 ~ CHC13) and 17 ~ -hydroxy 17 ~ - (prop-1-ynyl) 11 ~ -t2 pyridyl) es ~ ra-4,9-di ~ n 3-one ~ 7D = -2 (c = 1% CHC13) Example 2: Pr ~ ation of 11 ~ - ~ 3- (N, N-dimethylamino) propyl ~

3.3 ~ 2-ethanediyl bis (oxy ~ 17 ~ - (prop-1-yn ~ l? Estr-9-en 5 ~, 17 ~ -diol and application of this compound to ~ preparation of 17 ~ -hydroxy 11 ~ 3- (N, N-dimethyl amino) proleylJl? ~ - (prop-l-ynyl) estra-4,9-dien 3-one.
Stage A: Preparation of 11 ~ - ~ 3- (N, N dimethylamino) propy ~ 7 3.3-1,2-ethanediyl_bls (oxy ~ __7 ~ - ~ rop-1-ynyl) estr-9-en 5u, 17 ~ -diol.
12.33 g of complex are added over 5 minutes to 0C
copper dimethyl sulfide bromide in 141 cm3 of chloride 3- (N, N-dimethylamino) propyl magnesium, ~ 0.85 M solution prepared from 42 g of chloro 3-N, N-dimethylamino propane and 10.5 g of magnesium. Stirring is continued for 25 minutes at 0C and introduced drop ~ drop 3.70 g of 3.3-L1, 2-ethanediyl bis (oxy) J 5 ~, 10 ~ epoxy 17 ~ propynyl) estra-9 (11) -en -17 ~ -ol dissolved in 50 cm3 of tetrahydrofuran. We maintain the reaction mixture for 3 hours at 0C with stirring and pour it into a mixture containing 40 g of ammonium chloride nium and 200 cm3 of ice water. Shake for 15 minutes at the room temperature, then extracted with ether. We wash with a saturated solution of sodium chloride, dried and concentrated be dry under reduced pressure. 4.6 g of a product are obtained which is chromatographed on silica, eluting with a mixture methylene chloride - methanol ~ 8 - 2). We isolate 2.55 g of product.
~ 7D = -86 ~ 1.5 ~ c ~ in chloroform. J
Stage B; Application_of the compound previously obtained at the preparation of 17 ~ -hydroxy 11 ~ ~ 3- (N! N_dimethylamino) pro y V
17 ~ (prop-1-ynyl) estra 4,9-dien-3-one.
Stir at room temperature for 4 hours under an inert atmosphere, 2.4 g of the product prepared in stage A, 14 cm3 of methanol and 7 cm3 of 2N hydrochloric acid. We then add 200 cm3 of isopropyl ether and 90 cm3 of a saturated solution of sodium hydrogen carbonate. We shake a a9 ~ (~ 7 half hour at room temperature, decant and extract ~
e ~ her. Wash with saturated chloride solution sodium and dry. It is concentrated to dryness under reduced pressure and 1.8 g of a product are obtained which is chromatographed on silica, eluting with a chloroform-methanol mixture 8 - 2.
This gives 1.30 g of a product which is dried ~ 30 - 40C
~; approximately under reduced pressure of 0.1 mm of mercury. We obtain ; thus 1.25 g of research product fi ~ 1D = - 114 + 2.5 (c - 1% CHC13).
; 10 Exem21e_3_ _Preparation of 3,3-ethanediyl_bis (oxy ~ [4-(N, ~ -dimethyl amlno ethyloxy) pheny17 17 ~ - (pro ~ l = y3 ~ L ~ tr ~
9-in 5 ~, 17 ~ -diol and ctpplication of this compound to la_ ~ reparat on from 11 ~ - ~ 4 = ~ N, N-dim ~ ethyl amino ethy oxy) pheny ~ 7 17 ~ -hydrox ~
17 ~ - (prop-1-yn ~ estra 4,9-dièn-3-one.
Sta ~ e A: _ Preparation of 3,3-ethanedlyl bis (ox ~ y) 11 ~ - ~ 4- (N, N-dimethyl amino ~ thyloxy) pheny ~ 7 17 ~ - (prop-1-ynyl) estra-9-en 5a, 17 ~ -diol.
a) magnesian of 4- ~ N, N-dim ~ thylamino ethyloxy) bromo-ben ~ ene.
A dropwise introduction is made in 45 minutes solution containing 24 g of 4- (N, N-dimethylamino ethyloxy) bromobenzene in 90 cm3 of anhydrous tetrahydrofuran. We catalyzes the reaction by adding 0 "2 cm3 of 1,2-dibro-moethane. The introduction is finished, we still stir for one hour at 25C. This gives a 0.7M solution that llon uses it as is.
b) condensation We add the solution previously prepared in a solution ren ~ ermant 6.16 g of dimethyl sulfide complex, copper bromide in 20 cm3 of tetrahydrofuran. We shake 20 minutes at room temperature and add, drop to drop, in a few minutes, 3.7 g of 3,3-L1,2- (ethanediyl 3g9 ~ 7 bis ~ oxy3J 5a, 10a-epoxy 17 ~ - (prop-1-ynyl) estra- 9 (11 ~ ~ n 17B-ol in 50 cm3 of tetrahydrofuran. Then shake for one hour under an inert atmosphere, then pour the same reaction mixture in a solution containing 15 y of ammonium chloride in 200 cm3 of ice water. We extract with ether and wash with a saturated aqueous solution of chlo-sodium rure. It is dried and concentrated under reduced pressure.
18.3 g of an oil are thus obtained which is chromatographed on alumina, eluted with chloroform and thus obtains 4.5 g of product sought.
f ~ JD = ~ 44 + 1.5 ~ (c = 1% CHC13) Stage B Application of the com ~ ose previously obtained a_la ? ~ paration du 11 ~ -f4- (N, N-dimethylamino ethylox ~ phen ~ l ~ 17 ~~
hydroxy 17 ~ - (prop-1-ynyl) estra 4,9-dien-3-one.
9.5 cm3 of 2N hydrochloric acid are added to a solution containing 4.5 g of the product prepared at the stage A in 20 cm3 of methanol. The solution is kept under stirring for 2 hours at room temperature and add 260 cm3 of ether and 110 cm3 of a saturated solution sodium bicarbonate. we keep stirring for 15 minutes at room temperature, decant and ether extract. It is dried and concentrated to dryness under reduced pressure. 3.3 g of a product are obtained.
chromatography on silica eluting with the chlo- mixture methylene rure - methanol 192.5 - 7.5). We thus obtain 1.8 g of expected amorphous product.
~ 7D = + 71 (C = 1% CHC13) Example 4: Pre ~ aration of 11 ~ (4 ~ dimethylamino phenxl) 3.3- ~ 2-ethane_iyl bix (oxy) ~ 17 ~ (prop-1-ynyl) estr 9-en-5 ~, 17 ~ diol and application of this compound ~ the preparation of 17 ~ -hydroxy , _. . . _ _ 11 ~ - (4-dimethylamino phenyl) 17 ~ - (prop-1-ynyl) estra 4 ~ 9-dièn-... _ _ .. .... ~ _.
3-one.

Stage A 11 ~ (4-dimethylamino phenyl? 3,3- ~ 1,2-ethanediyl .
bis (oxy) ~ 17 ~ (prop-1-yn ~ l) estr 9-en-5 ~, 17 ~ -diol.
A solution containing 38 mmol of p-dimethylamino phenyl magnesium bromide in tetra-hydrofuran to a suspension containing 4.1 g of complex copper bromide-dimethyl sulfide in 20 cm3 of tetrahydro-furan. 2.45 g of 3.3-L1.2-ethanediYlbis are then added (oxy) ~ 5 ~, 10 ~ epoxy 17 ~ - (prop-1-ynyl ~ estr 9 (11) ene 17 ~ -ol in solution in tetrahydrofuran. We maintain the reaction mixture with stirring for 10 minutes, hydrolysis with 50 cm3 of a sa ~ uree chloride solution ammonium. We decant, extracted at lYether, the ~ e phase organic ~ water and dry. The solvents are evaporated under reduced pressure and 11 g of product obtained sought crude that we chromatograph on silica eluting by the mixture cyclohexane-ethyl acetate 6 - 40. We thus obtains 1.8 g of the research product (11 ~) and 750 mg of product lla. Recrystallized from 17 isopropyl ether and ethyl acetate F - 210C ~ 7D = - 665 (1 ~ CHC13).
Stage B _ Application of the compound previously obtained at the preparation_du 17 ~ -hydrox ~ - (4-dime-thylamino phenyl ~ 17 ~ -(prop-1-ynyl) _estra-4,9-dien-3-one.
2 cm3 of a hydrochloric acid solution are added.
concentrated in a solution containing 1.53 g of the product prepared in stage A in 60 cm3 of methanol. Shake 30 minutes at room temperature ~ and add 150 cm3 of ether, then 50 cm3 of an aqueous sodium hydroxide solution M. Stirred the reaction medium for 15 minutes and decanting, dries the organic phase. The solvents are evaporated under reduced pressure and 1.4 g of crude product are obtained, it is purified on silica, eluting with the cyclohexane mixture-ethyl acetate (7 - 3). We obtain 0.932 g of the product sought at F = 150C
C ~ 7D = +138.5 (C = 0.5% CHC13) Example 5: Preparation of 11 ~ (4-trimethylsi ~ yl) phenyl ~ 3.3L ~, 2-ethanediylbis (oxy ~ 17 ~ - (prop ~ n ~ estr-9-en 5 ~, _17B-diol and a lication of this compound ~ to the preparation of 17 ~ -PP .. ~
hydroxy 17a- [prop-1-ynyl) 11 ~ (4-trimethylsilyl) phenyL7 will be 4,9-dien-3-one_.
Stage A. Pre ~ aration_du ll ~ r (4-trimethylsilyl? Pheny V 3.3 ~ 1.2-éthanedlylbis _ (oxy) ~ 17 ~ - (prop ~ nyl) estr-9-en-5a, 17 ~ _diolO
We add ~ 30C under an atmosphere in 45cm3 of a 0.65 M solution of 4-trimethylsilyl bromide phenyl magnesium in tetrahydrofuran, 200 mg of cuprous chloride, then drop by drop, maintaining the tem ~ erature ~ -20C, a 3.3 g solution of 3J3 ~ 1.2 ethanediylbis (oxy) ~ 5 ~, 10 ~ -epoxy 17a- (prop-1-ynyl) estr 9 (11 ~ -in 17 ~ -ol in 25 cm3 of tetrahydrofuran. After one hour r hydrolysis using an aqueous solution ammonium chloride, ether extract, dry and evaporate solvents under reduced pressure. We chromatograph on silica, eluting with a methylene chloride mixture acetone (94 - 6) with 0.1% triethylamine. We isolate 2,087 g of the research product which is purified by recrystallization in isopropyl ether then in ethyl acetate F = 226C.
f ~ J ~ = - 60 ~ 1.5 (c = 0.9% CHC13).
Stage B: Application of the compound previously obtained at the preparation of 17 ~ -hydroxy 17 ~ - (pro ~ -1-ynyl) 11 ~ - ~ (9-trimethyl-silyl) pheny ~ 7 estra-4,9-dlèn-3-one.
1.7 g of Redex sul ~ onic resin are added to a solution containing 1.68 g of the product prepared at the stage A in 17 cm3 of 90 boiling alcohol. We heat at reflux for 30 minutes, wring out the resin, rinse with chloride of methylene, e ~ evaporates the filtrate under reduced pressure.
The residue thus obtained is taken up in methylene chloride, dry and flush the solvent under reduced pressure. We chromatography the residue obtained on silica, eluting with the benzene-ethyl acetate mixture (85 - 15 ~ We obtain thus 1.217 g of the research product melting at 212C.
~ a ~ 94 (c = 0.3 ~ CHC13) In the same way, we prepared the 17 ~ -hydroxy-17 ~ - (prop-1-ynyl) 11 ~ - ~ (3-trimethylsilyl) phenyl ~ estra-4,9-dien-3-one.
~ 7D = ~ 52.5 + 2 Ic = 1 ~ CHC13) The starting material for Stage A has been prepared as follows:
Stage a: 3! 3-l ~, 2-ethanedi ~ l_bis_ ~ oxy) _1 17 ~ - (pro ~ n ~
estra 5 (10) 911) - diene 17 ~ -ol.

..... _. . _ _ _ Cooled to 0C, with stirring, 207 cm3 of a solution of 7 ethyl magnesium bromide in tetrahydro-furan at 1.15 ~, bubbled for 1 hour 30 minutes at 0C, propyne gas previously dried over chloride calcium. Leave to return to room temperature and stir for another 1 hour while maintaining the bubbling. We then add at 20 - 25C in half an hour, a solution containing 30 g of 3.3- ~ 1,2-ethanediyl bi ~ (oxy) ~ estra 5 (10 9 (11) di ~ ne 17-one in 120 cm3 of tetrahydrofuran anhydrous and a drop of anhydrous triethylamine. We shake at room temperature for 2 hours and poured into a mixture of distilled water, ammonium chloride and ice.
Stir ae ~ trait with ethyl ether three times. We wash the organic phase with water, dries it, and concentrates it under reduced pressure. The residue is dried under vacuum. We cb-holds 35.25 g of the product sought.
NMR spectrum CDC13ppm 0.83 H of methyl in 18 1.85 H of methyl at C - C-CH3 5.65 H of carbon in 11

4 H of ethylene cetal Stage b: 3.3- ~ 1,2-ethylenedioxy bl (oxy) ~ 17 ~ - (prop-1-yn ~ l) estr 9 (11) -in 5 ~, 10 ~ -epoxy 17 ~ -ol.
Introduced with stirring and bubbling a ~ ote 30 g of product prepared in stage a in 150 cm3 of chloride of methylene. Cool to 0C then add in one times 1.3 cm3 of hexafluoroacetone sesquihydrate, then under stirring 4.35 cm3 of 85% oxygenated water. We maintain the reaction mixture with stirring and ~ nitrogen spraying 0C for 72 hours. Then pour the reac- solution tional in a mixture containing 250 g of ice and 500 cm3 of 0.2N sodium thiosulfate moments then extracted with methylene chloride ~ Washed the organic phase with distilled water, dried over sulfate soda in the presence of pyridine, then concentrated under pres-reduced sion. The residue is dried under reduced pressure.
31.6 g of a product are obtained, which is chromatographed on silica, eluent benzene - ethyl acetate 90 - 10. We thus obtains the product sought.
NMR spectrum CDC13ppm 0.82 H of methyl in 18 1,83 H of the methyl of the radical c - C -CH3 6.1 H of carbon in 11 3.92 H of cetal the 6th: Pre ~ aration of 3,3-dimethoxy 5 ~ -17 ~ -hydroxy 11 ~ -_ (4-dimethyla ~ 17 ~ -ethYnyl estr-9-ene and ap ~ lication of this composition ~ the ~ reParation of 17 ~ -ethYnvl 17 ~ -hydroxy 11 ~ -. .
[4-dimethylaminophenyl) estra 4,9-diene 3-one.

Stage A: 3,3-dimethoxy 5a-17 ~ -hydroxy 11 ~ - (4-dimethyl m ~ -_ nyl ~ 17 ~ -ethynyl estr-9-ene ~
2.8 g of 3.3-dimethoxy are mixed under inert gas 5a- 10a-epoxy 17 ~ -ethynyl 17 ~ -hydroxy estr-9 ~ ene, 56 cm3 anhydrous tetrahydrofuran and 80 mg of cuprous chloride anhydrous. Shake for ~ 5 minutes at room temperature then place in an ice water bath and add drop ~
drop 33 cm3 of a 0.95 M solution of (4-dimen-thylaminophenyl ~ magnesium in tetrahydrofuran. We then let rise to room temperature.
To a suspension of the copper bromide-sulphate complex dimethyl fure (6.15 g) in 30 cm3 of tetrahydrofuran anhydrous, 63 cm3 of (4-dimethylaminophenyl) bromide are added magnesium so that the temperature stays lower at 28 ~ 5. It is left for 30 minutes with stirring, then add the solution obtained above drop by drop. We maintains for 18 hours with stirring at temperature ambient, pour into a saturated chloride solution ammonium hydroxide, stirred for 10 minutes, extracted with chloroform, wash the organic phase with water, dry it and evaporate 1 ~ sol-boast. The residue is chromatographed on silica, eluting with petroleum ether-ethyl acetate mixture fl-l) to 0.5 per thousand of triethylamine, obtains 1.28 g of product ~ On purifies this product again by chromatography on silica eluting with the same mixture, and obtain 0.84 g of product expected.
Stage B: A ~ lication_du compose p ~
paration of 17 ~ -ethynyl 17a-hydroxy 11 ~ - (4-di ~ thy ~ minophenyl) will be 4,9-dien-3-one.
0.76 g of the product obtained in stage A is mixed with 15 cm3 of methanol and 1.6 cm3 of 2N hydrochloric acid.
Stir for 1 hour and a half then pour into a solution t saturated aqueous sodium bicarbonate, extracted with chloroform, dry the organic phase and evaporate the solvent.
0.76 g of crude product is obtained which is chromatographed on silica, eluting with an ether-petroleum-acetate mixture ethyl (1-13 then eluting with ethyl ether mixture-petroleum ether (3-1 ~. 0.435 g of product is obtained expected, which is crystallized from isopropyl ether.
F = 14 ~ C.
~ 7 ~ = ~ 235.5 + 4.5 (c = 0.45 ~ chloroform).
The starting product of stage A was prepared co ~ ne follows:
Stage a: 3,3-dimethoxy 17 ~ -hydroxy 17B-ethynyl estra 5 (10) 9 (11) diene.
Stir for 5 minutes at room temperature a mixture of 16.8 g of 3,3-dimethoxy 17 ~ -hydroxy 17 ~ -ethynyl estra 5 (10) 9- (11) diene, 175 cm3 of tetrahydrofuran anhydrous, 4.35 g of lithium bromide then cools ~ -60C
and add 37 cm3 of a 1.35 M solution of butyllithium in hexanne. Leave for 30 minutes under agitation then add 3.9 cm3 of methane sulfonyl chloride and leaves for 1 hour at -60C with stirring. We pour then in 500 cm3 of a saturated aqueous solution of ammonium chloride, stirred for 10 minutes, extract with methylener chloride dries the organic phase, adds 2.5 cm3 of pyridine then evaporated to dryness under reduced pressure you have 0C. 75 cm3 of tetrahydrofuran are added to the residue obtained, then 12.5 cm3 of water containing 0.75 g of nitrate silver. It is maintained for 18 hours ~ -30C, then for 4 hours at room temperature. We pour into 500 cm3 of a semi-saturated aqueous chloride solution ammonium, containing 5 g of sodium cyanide. We shake for 30 minutes at 20C, extracted with chloro ~ elm, washed i ~ ~ a951l0 ~

with a saturated aqueous solution of sodium chloride, dries and evaporates the solvent. Chromatography on silica eluting with the petroleum ether-ethyl acetate mixture (9-1).
3 g of expected product are obtained. F ~ 150C.
t ~ 7D = + 125 + 2.5 (c = 1% chloroform).
Stage b: 3,3-dimethoxy 5 ~ -10 ~ -epoxy 17 ~ -ethynyl 17 ~ -hydroxy estr-9 (11 ~ -ene.
2.6 g of the product obtained in stage b are mixed, 12 cm3 of methylene chloride and a drop of pyridine.
Cool to 0C, add 0.12 cm3 of hexachloroacetone and 0.65 cm3 of hydrogen peroxide (200 volumes ~. After one hour with stirring, 13 cm 3 of chloroform are added and then-follows the agitation for 18 days. We pour in 100 cm3 of saturated sodium thiosulfate solution, stirred for 10 minutes, extract with chloroform, wash the phase organic with saturated aqueous chloride solution sodium, dry and evaporate the solvent. 2.8 g of expected product, used as is for the next stage A
lThe product contains a small proportion of epoxide ~.
Example 7: Preparation of_3,3- ~ 1,2-ethanediyl bis loxy) ~ 5 ~, 17 ~ -dihydroxy 11 ~ - (4-dimethylaminophenyl ~ 17 ~ -phenyl est_ 9-ene and application of this compound to the preparation of 17 ~ -hydroxy 17 ~ -pheny ~ (4-dimethylaminophenyl) estra 4,9-dien-3-one.
Stage A_ 3.3-fl, 2-ethanediyl bis ~ oxy) ~ 4-dimeth ~ lamino-phenyl) estr-9-ene ~ -hydrox ~ 17-one.
a) preparation of the ma ~ nesien.
29 g of an inert gas mixture are mixed under magnesium and 50 cm3 of anhydrous tetrahydrofuran. We in-produced in 2.5 hours maintaining the temperature ~ 35C _ 5C, a mixture of 200 g of 4-dimethylamino bromo benzene in 950 cm3 of anhydrous tetrahydrofuran. We thus obtains a 0.8 M solution of magnesium expected.

_ 29 -b) a _ tion of the magnesian.
25 g of 3.3-L ~, 2-ethanediyl are mixed under inert gas bis (oxy) ~ ~ -10 ~ -epoxy estr-9 (11) -ene 17-one, 500 cm3 anhydrous tetrahydrofuran and 0.757 g of cuprous chloride.
Cool to 0, ~ 5C and add drop by drop in 1 hour 15 minutes 284 cm3 of the solution of my ~ neesien prepared above above. Then stir for 15 minutes, pour into a saturated solution of ammonium chloride, extracted a ~ ethyl acetate, wash the organic phase with a solution saturated with ammonium chloride and then with a saturated solution sodium chloride ree. The organic phase is dried and evaporates ~ dry under reduced pressure. We obtain 46 g of crude product which is chromatographed on silica eluting with petroleum ether-ethyl acetate mixture ~ 1-1) to 1 for thousand of triethylamine, 17.76 g of product are obtained.
of. F = 178C.
The impure fractions of product obtained are new chromatography on silica, eluting with a mixture acetone petroleum ether (8 ~ 2) has 1 per thousand of triethyla-mine. Qn again obtains 6.35 g of the expected product. F - 176C. The product thus obtained is used as is for the next stage ~
Stage B: 3.3-rl, 2-ethanediyl bis (o ~ y ~ 5 ~, 17 ~ -dihydroxy 11 ~ - (4 ~ dimethylaminophen ~ 1) 17 ~ _phenyl estr-9-ene.
Is added in 30 minutes ~ + 25C to a solution of 33.3 cm3 of phenyllithium (1.5M), a solution of 4.51 g of the product obtained in stage A in 45.1 cm3 of tetrahydrofu-anhydrous ranne. Stir for 4 hours at temperature room, pour a saturated aqueous solution of chloride of ammonium, extracted with ether, washing the organic phase with a saturated aqueous solution of sodium chloride, dry and evaporates the solvent. 5.6 g of crude product are obtained ; ~ ~
which is chromatographed on silica, eluting with a mixture methylene chloride-acetone (9 1) ~ 1 per thousand d ~ sort-thylamine. 1.16 g of expected product are obtained, which crystallizes in the mixture of methyl chloride ~ ne-ether isopropyl. F = 240C.

C ~ 7D - ~ 53 ~ 2.5 (C = 0.5 ~ Ch1OrOfOrm2).
Stage C_ _ ~ ication du_compose obtained previously ~ la preparation of 17 ~ -hydroxy 17 ~ -phenyl 11 ~ - (4-dimethylamino ~ xl estra 4l9-di ~ n-3-one.
~ - _ 1.5 g of the product obtained are mixed under inert gas in stage B, in 45 cm3 of methanol. We cool to 0, ~ 5C and introduced 3 cm3 of 2N hydrochloric acid. We stir for one hour at 0, + 5C, then add 90 cm3 of d7ether i and 90 cm3 of a 0.5 ~ 5 M aqueous solution of bicarbonate sodium. Agitate for 5 minutes, decant, extract with ether, wash the organic phase with an aqueous solution saturated with sodium chloride dry and evaporate the solvent.
, 1.30 g of product are obtained which llon purifies by chroma-tography on silica eluting with petroleum ether mixture-ethyl acetate (1-1 ~. 0.93 g of product is obtained-of, which is crystallized from the mixture of methyl chloride isopropyl thylene ether. F = 226C. C ~ 7D = 151.5 `Ic = 0.4 ~ chlo ~ oforme).
The starting material from stage A has been repaired as follows.
~ `We mix 11.18 g of 3.3- ~ 1,2-ethanediyl bis `(oxy ~ estr-5 l10) 9 (11) dien-17-one and 56 cm3 of chloride methylene, add 2 drops of pyridine, cool to 0C and introduced 4.3 cm3 of hexafluoroacetone sesquihydrate, then add 1.6 cm3 of oxygenated water to 85 ~. We keep under stirring and under inert gas at 0C for 23 hours ~ s. We then pour into a mixture containing 200 cm3 of solution 0-5M sodium thiosulfate and 200 g of ice. We main-hold for 30 minutes SOU5 agitation then extract methyl chloride ~ not containing a trace of pyridine.
The organic phase is washed with water, dried and evaporated the solvent. 11.4 g of expected product are obtained, used as is for the next stage.
Example 8: Preparation of 3 ~ 3 ~ 2-ethanediyl bis (oxy) l (4-dimethylaminopheny]? 23-m th ~ l (17 ~) 19,21-dinorchola-9.23-dl n-20-yn-5 ~ -17 ~ -d ~ ol_et a ~ plication de_ce compose à la preparation of 11 ~ - (4-dimethylaminophenyl ~ 17 ~ -hydroxy 23-methyl ~ 17 ~) 19.21-dinorchola-4,9,23-trien-20-yn-3-one.
Stage A: Preparation of 3,3- ~ 1,2-ethanediyl bis ~ oxy ~ 7 11 ~ -(4-dimethylaminoph2nyl ~ 23-meth ~ l (17a) 19,21-dinorchola-9,23-di ~ n-20-yn-5a-17 ~ -diol.
4.5 g of terbutylate of potassium with 90 cm3 of anhydrous tetrahydrofuran. We cools ~ -10C and adds 10.61 cm3 ~ e 2-methyl l ~ butèn 3-yne. Stir for 15 minutes at -10C, then add in 15 minutes a solution of 4.5 g of product obtained at stage A of example 7, in 45 cm3 of tetrahydrofuran anhydrous. Stir for 30 minutes at -10C and then for 4 hours at 0, + 5C. A solution is poured into 500 cm3 saturated aqueous ammonium chloride, extracted with acetate ethyl tate, wash the organic phase with a solution saturated aqueous sodium chloride, dries and evaporates to dry. 5.56 g of crude expected product are obtained.
F = 205C. The product is used as is for the following synth ~ se ~
The crude product, chromatography on silica in eluting with methylene chloride-ethyl acetate mixture (9 ~ 1 per thousand of triethylamine then recrystallizes in ethyl acetate, melts at 215C.

_ 32 _ 9 ~ 17 Stage B: _ Application of the compound previously obtained ~ the preparation of 11 ~ -l4-dimethylaminophenyl) 17 ~ -hydroxy 23-meth ~ 1 (17 ~) 19.21-dinorchola 4,9,23-trien-20-yn-3-one.
5 g of the product obtained are mixed under inert gas.
stage A with 300 cm3 of methanol and 10 cm3 of chlorhy-drique 2N. We have it for 15 minutes at 20 ~ C, add 300 cm3 of methylene chloride then 300 cm3 of a solution 0.2SM aqueous sodium bicarbonate. After 10 minutes with stirring, decanting, extract with methylene chloride ~
wash the organic phase with water, dry and evaporate to dryness.
4.5 g of crude expected product are obtained, which product is chromatographed.

written on silica using a petroleum ether mixture - -ethyl acetate (1-1 ~. We obtain after recrystallization of the product in diisopropyl ether, 2.01 g of product expected. F = 185C.
Ca ~ D = +88.5 ~ 1.5 (c = 1% chloroform).
Example 9: Method for the preparation of 11 ~ (4-dimethylamino-phen ~ l) 17 ~ -methoxy 23-methyl ~ 17 ~ 19.21 - dinor ~ --hola -4 r9 ~ 23 ~
trièn-20- ~ n-3-one_in the ~ uelle a compound of formula II is a reactional intermediary _. _ r Mixed under inert gas 4 ~ 5 g of tert-butoxide of potassium in 90 cm3 of anhydrous tetrahydrofuran O On cools the suspension to -10C then adds, drop ~ drop, 10 ~ 61 cm3 of 2-methyl 1-buten-3-yne. Shake for 15 minutes at -10C, then add in 15 minutes 4.5 g of the pro-product obtained in stage A of Example 7, in 45 cm3 of tetra-anhydrous hydrofuran. Stir for 30 minutes at -10C, then for 4 hours at 0, ~ 5C. 7.5 cm3 are then added methyl iodide and then maintained for 30 minutes under stirring in an ice bath. Then pour the mixture in 500 cm3 of hydrochloric acid 0.1 lN. We have for 30 minutes at room temperature, extracted ~ a-_ 33 9 ~ C ~ 7 ethyl cetate, wash the organic phase with a saturated aqueous solution of sodium bicarbonate, then with a saturated aqueous solution of sodium chloride.
The solvent is dried and evaporated. We chromatograph the residue on silica, eluting with a chloride mixture ethylene methylene acetate (95 5). 2.7 g of expected product, which is recrystallized from methanol.
F = 105C.
Example 10 Preparation of 21-chloro 3,3Ll ~ 2-ethanediyl bis (oxy V 11 ~ (4 dimethylaminophenyl ~ (17a) 19-nor pregna-9-en 20-yn 5a, 17 ~ -diol and application of this compound to the preparation 21-chloro 17 ~ -hydroxy 11 ~ (4-dimethylaminophenyl ~ (17a) 19-. ~
nor regna-4 9-dièn-20-yn 3-one.
Stage ~ A: 21-chloro 3.3 ~ 1,2-ethanediyl bis (o ~ y) J11 ~ (4-dimethyl-aminophenyl) (17 ~) 19-nor pregna-9-en 20-yn 5 ~, 17 ~ -diol.
Lithian preparation 77.5 cm3 of an solution are mixed under inert gas 1M of butyllithium in hexane with 310 cm3 of ether ethy-anhydrous liquor. Cool to 0, + 5C and add in 45 minutes are a solution of 7 cm3 of trichlorethylene in 28 cm3 anhydrous ethyl ether. Shake for an hour leaving the temperature to return to 20C.
Condensation The mixture obtained above is cooled to 0, + 5C.
and there is ~ drop by drop, in thirty minutes, a solution tion of 7 g of the product obtained in skacle A of Example 7 in 70 cm3 of tetrahydrofuran. Shake for thirty minutes, at 0, + 5C, then let the temperature return to 20C, pour slowly into a saturated aqueous solution of ammonium chloride, decante, methyl chloride extract lene, wash the organic phase with water, dry it and evaporate the solvent. 8.5 g of crude product are obtained (F = 220C) which is introduced into 42.5 cm3 of diisopropyl ether.
The mixture is stirred for 30 minutes, drained and 6.38 g of expected product. F = 230C.
The product can be purified by chromatography on silica eluting with benzene - ethyl acetate mixture 17 ~ 3) has 1 per thousand of triethylamine. By dissolution of this product in methylene chloride and addition of oxide diisopropyl ~, we obtain a melting crystallized product at 240C.
~ 7D = 83.5 + 1.5 (c = 1% chloroform).
Stage B: _Application of the compound previously obtained ~ the preparation of 21-chloro 17 ~ -hydroxy 11 ~ (4-dimethylamino-phenyl) _ (17 ~ Ll9_nor ~ re ~ na-4,9-dièn 2-yn 3-one.
6.38 g of the product obtained are mixed under inert gas at the previous stage and 191.4 cm3 of ethanol at 95 ~ is added 15 cm3 of 2N hydrochloric acid, stirred for 1 hour, add 300 cm3 of methylene chloride then 200 cm3 of a 0.25 M aqueous sodium bicarbonate solution. Wave-cante, extract with methylene chloride, wash the phase organic with water, dries and evaporates the solvent. We obtain 6 g of crude product which is chromatographed on silica ~ eluting with a benzene-ethyl acetate mixture (7-13). We o ~ holds 3.95 g of expected product, which is crystallized in ethyl acetate. F = 240C. ~ a ~ D = ~ 111 + 2 (c = 1% chloroform2).
Example 11 Preparation of 21-phenyl 3.3L ~ 12-ethanediyl bis (oxy ~ -l4-dimethylamino phenyl) 5 ~ -17 ~ -dihydroxy (17 ~) l9-nor-pregn-9- n-20-yne and application of this compound to the preparation 17 ~ -hydroxy 11 ~ - (4-dimethylaminophenyl) _21-phenyl ~ 17a) 19-nor-pregna-4,9-dien-20-yn-3-one.
Stage A: Preparation of 21-phenyl 3.3L ~! 2-ethanediYl bis (oxy ~ 7 11 ~ - (4-dimethylamino phenyl) 5 ~ -17B-dihydroxy (17 l9-nor-pregn-9-en-20- ~ ne.

4.17 g of te.rbutylate are mixed under inert gas of potassium in 83 cm3 of anhydrous tetrahydrofuran. We stir for 5 minutes then cool ~ -10C and add drop ~ drop 4.5 cm3 of phenyl acetylene. We shake it `` suspension for 5 minutes then add drop by drop ~
at -10C, a solution of 4.17 g of product obtained in the stage In Example 7 in 41 cm3 of anhydrous tetrahydrofuran.
At the end of the introduction, the temperature is brought to 0C, then after 1 hour the mixture is poured into a solution.
saturated ammonium chloride. We extract ~ ether, wash the gold ~ anic phase using an aqueous solution saturated with sodium chloride, dry, concentrate ~ dry and 4.7 g of product are obtained which is chromatographed on silica eluting with the methylene chloride-acetone mixture ~ 95-5 ~.
3.71 g of expected product are obtained. F = 168C.
; ~ 7 ~ = -119.5 + 2 (c = 1% chloroform).
Stage B Application of the preceding compound ~ obtained at the ~ pre ~ ation of l? ~ -hydroxy 11 ~ - ~ 4-dimethyl minophenyl) 21-phenyl (17 ~) 19-nor-pr-e - gna-4 ~ 9-dièn-2o-yn-3-one ~
: 20 3.49 g of product obtained as described are dissolved in the previous stage, in 68 cm3 of methanol then add 6.3 cm3 of 2N hydrochloric acid. After 30 minutes under stirring, it is poured into a mixture of 180 cm3 of ether ethyl and 90 cm3 of a 0 ~ 25 M bicarbonate solution , sodium. Agitate for 5 minutes, decante, extract ether, wash the organic phases with a solution 0.25 M sodium bicarbonate pUi5 with a saline solution turee of sodium chloride. Dry, evaporate the solvent . and obtains 4.35 g of product which is purified by chromatography written on silica, eluting with a mixture of methyl chloride : lene-acetone (95-5). 2.13 g of product are obtained.
du, after crista ~ lisat, ion in isopropyl ether.

~ 7 ~ = ~ 22.5 + 1 (c = 1 ~ chloroform).
Example 12._ Preparation of 11 ~ - (4-dimethYlaminophenyl) 3,3-Ll, 2-ethanediyl bis (oxy ~ 17 ~ - ~ propa ~ 1,2-dienyl) estr -9-en 5a-17 ~ dioletll ~~ (4-dimethylaminophen 1) 3,3-L ~, 2-ethanediyl bls (oxy) ~ 17 ~ - ~ prop-2-ynyl) str -9-en-5a-17 ~ -diol and applica-tion of these compounds to the ~ repair of 17 ~ -hydroxy 11 ~ - (4-dimethylaminophenyl) 17 ~ -_ (propa-1,2-dienyl) estra-4,9-dien-3 ~ ne, and 17 ~ -hYdroxY 11 ~ - (4-dimethYlamunoPh ~ nYl) 17 a (proP-2-Ynyl) estra 4.9-- dian-3-one.
Stage A: Preparation of 11 ~ - (4-dimethylaminophenyl ~ 3,3-2-ethanediyl bis ~ oxy ~ 7 17a- (propa-1,2-dienYl) estr -9-en-

5 ~ -17 ~ diol and 11 ~ - (4-dimethylamino ~ hényl3 3,3-f ~, 2-ethanedixl bis (oxyL7 17a- (prop-2-ynyl) estr -9-en-5a-17 ~ -diol.
Preparation of the lithian.
In 50 cm3 of anhydrous tetrahydrofuran at 0 ~ 5C, bubbling Allene until absorption of 2.1 g.
Cool to -70C and add in 15 minutes 23.9 cm3 of a 1.3M solution of butyllithium in hexane. We shake the mixture obtained for 15 minutes at -70C.
Condensation -~ the lithian solution obtained above, we add at -70C in 25 minutes a solution of 3 ~ 5 g of product obtained in stage A of Example 7 in 35 cm3 of te-anhydrous trahydrofuran. Stir for 1 hour at -70C, slowly pour into an ice-cold saturated aqueous solution, ammonium chloride. We extract the ether, wash the pha-gets organic with a saturated solution of sodium chloride dium, dry and evaporate the solvent. 3.4 g of product which is chromatographed on silica, eluting with mixture of petroleum ether-ethyl acetate ~ 1-1) to 1 for thousand of triethylamine. We isolate as follows:

a) 1.73 g of isomer 17 ~ - (propa-1,2-dienyl) F = 178C. r ~ 7D = -32 + 2 (c = 0.7% chloroform);

~ g ~

b) 1.5 g of 17 ~ - (prop-2-ynyl) isomer F = 150C [~? D = -15 + 2 (c = 0.9% chloroform ~.
Stage B: ApE ~ ication of 11 ~ - (4 imethylaminophenyl) 3,3-L ~, 2-ethanedi 1 bis (ox) ~ 17 ~ - (ro ~ -1,2-dien 1) estr -9-en-5 ~ -17 ~ -Y _Y P ~ ~
n of 17 ~ -hydroxy 11 ~ (4-dimethylaminophenyl) 17 ~ -Ipropa-1,2-dienyl) estra-4,9 dien ~ 3-one.

Is mixed under inert gas 1.73 ~ isomer 17 ~ -(propa-1,2-dienyl) obtained in stage A, 51.8 cm3 of ethanol at 95% and 3.5 cm3 of 2N hydrochloric acid. We stir at 20C
for 1 hour, add 50 cm3 of methylene chloride then 50 cm3 of a 0.25 M solution of sodium bicarbonate;
decanted, extracted with methylene chloride, washed with water ~
dries and evaporates the solvent. 1.51 g of product are obtained which is dissolved in 10 cm3 of methylene chloride to hot ~ We add 15 cm3 of isopropyl ether, concen ~
be and let rest. Is isolated ~ thus 1.23 g of product as we crystallize again in the mixture isopropyl methylene ether chloride. We obtain finally 1.11 g of expected product. F = 228C.
~ JD = +139.5 + 3 (c = 0.8% chloroform).
Stage B ': Application of 11 ~ -14-dimethylaminophenyl ~ 3.3 ~ 2-ethanediyl bis (oxy) 3 17 ~ - (prop-2-ynyl) estr -9-en-5 ~ -17 ~ -diol has the preparation of 17 ~ -hydroxy 11 ~ - (4-dimethylaminophenyl ~
17 ~ - (prop-2-ynyl) estra-4,9-dien-3-one.
0.94 g of isomer 17a- (prop-2-ynyl) ob-held in Stage A of Example 15, 28.2 cm3 of 95% ethanol and 2 cm3 of 2M hydrochloric acid. We stir at 20C for 1 hour, add 50 cm3 of methylene chloride and 50 cm3 0.25 M sodium bicarbonate solution, act for 5 minutes, decant and extract with methylene chloride.

The organic phase is washed with water, dried and the solvent. The product obtained is chromatographed on silica eluting with the petroleum ether-ethyl acetate mixture (1-1). 0.42 g of expected amorphous product is thus obtained.
~ a ~ D = +143 + 3 (c = 0.8% chloroform).
~ 3 ~ 13: Preparation of 17a-ethyrlyl 3,3- ~ ethanediyl bis (oxy) ~ (4 ~ dimethylamino ~ henyl) estr-9-en-5a-17 ~ -diol and application of this compound to the preparation of 17a ~ ethynyl 17 ~ -hydxoxy ll ~ - (4-dimethylamlnophenyl) estra_4,9-dien-3-one.
Preparation of 17a-ethynyl 3,3- ~ ethanediyl bis_ (oxy ~
(4-dimethylaminophenyl) estr-9-en-5 ~ -17 ~ -diol.
Sta ~ e A: _17 ~ -cyano 11 ~ - ~ 4-dimethylaminophen 1) 3.3 L ~ f2-ethanediyl bis (oxy ~ J 17 ~ - (trimethyl silyloxy) estr-9-en-5 ~ -ol.
Is added under inert gas at room temperature, ; ~ a suspension of 2.05 g of copper bromide complex-dimethyl sulfide in 10 cm3 of anhydrous tetrahydrofuran, a solution of 18 m / m ~ bromide of (4-dimethylaminophe-nyl) magnesium in anhydrous tetrahydrofuran, then on stir for 20 minutes and add 20 cm3 of triethylamine anhydrous. Then, 0.95 g of 17 ~ -cyano 17a- (tri-methyl silyloxy) 3,3-f ~ 2-ethanediyl bis (oxy) ~ 5 ~ -lOa-epoxy estr-9- (11) ene in solution in tetrahydrofuran anhydrous, stirred for 15 hours at room temperature, pour a saturated ammonium chloride solution into 50 cm3 nium, decant, ether extract ~ wash the organic phase with water, dry and evaporate the solvent. We purify the residue by chromatography on silica, eluting with a benzene mixture ethyl acetate (8-2). 1 ~ 1 g of product is obtained.
which is recrystallized from isopropyl ether.
F = 247C.
fa ~ D = -12.5 (c = 1% chloroform).
Stage B: 17a-ethynyl 3.3- ~ ethanediyl bis (oxy) ~ - (4 ~ dime-thylaminophenyl) estr-9-en-5a-17 ~ -diol.
- 3 ~ -A 0.8 g of product obtained in stage A in 8 cm3 of e-thylene diamine, we have ~ 1 g of acetylide complex ; lithium ethylene diamine, then keeps stirring and under inert gas at ~ 50C for 1 hour and a half. We re-cools to 20 ~ C then pours into a chloride solution ammonium. Extracted with ether and me chloride ~
thylene. The organic phase is dried and the solvent is evaporated.
The residue is chromatographed on silica, eluting with the medium.
benzene-ethyl acetate mixture (7-33, recrystallizes the product obtained in isopropyl ether and obtains 0.43 g of expected product. F = 199 c.
r ~ 7D = ~ 43 ~ + 1.5 ~ c = 1 ~ chloroform 3.
Stade_C- Appllcation of the compound previously obtained at the pre-~ aration du 17 ~ -éthYnvl 17 ~ -hvdroxY 11 ~ - (4-diméthYlaminoPhenvl ~
estra-4,9-dien-3-one.
To a solution of 0.25 g of product obtained in the stage B, in 6 cm3 of methanol, 1 cm3 of chlorhy-drique 2N. We have 40 minutes at 20C, pour into water containing 2.5 cm3 of lN sodium hydroxide, extracted with ether, dry the organic phase and evaporate the solvent.
The residue is chromatographed on silica, eluting with a mixture benz ~ ne-ethyl acetate (7-3), and obtains 0.25 g of product expected.
Ana_yse C28H33N2 ~ 415 ~ 54) Calculated: C ~ 80/92 H ~ 8.00 N ~ 3.37 Found: 80.7 8.1 3.1 Example ~ ation of 11 ~ - (4-dimethylaminophén ~ l) 3 ~ 3 ~, 2-ethanedi 1 his (ox 37 5 ~ -17 ~ -dihydro ~ Y 17 ~ -ethynyl estr-9-ene _ _ ~. Y _ _ ..
and aPPlication of this compound to the pre ~ aration of l? -ethynyl 17th-hydrox 11 ~ - (4-dimethylamino ~ hényl) estra 4,9-di ~ n-3-one.
Y. __ Stage A: Preparation of 11 ~ - (4-d ~ thylaminophenyl) 3,3- / 1,2-ethanediyl bis (oxy) ~ 5 ~ -17 ~~ dihydroxy 17a- ethynyl estr-9-ene.

_ 40 ~

6 g of product obtained are dissolved under inert gas.
stage A of Example 7, in 180 cm3 of tetrahydrofuran, then add 12.25 g of the lithium-ethyl acetilure complex ~ do diamine. The temperature is brought to 55C, stirred for 4 hours, cools, then pours into 600 cm3 of a solution saturated ice cold ammonium chloride. We extract with ether, wash the organic phase with a saturated solution of chloro-sodium rure, dries and evaporates the solvent. We purify the r ~ sidu obtained by chromatography on silica, eluting with benzene-ethyl acetate mixture (7-3) at 1 per thousand of triethylamine and obtains 4 ~ 5 g of the expected product we ~ had recrystallize from the chloride mixture of me ~
thylene diisopropyl oxide. F = 202C.
~? D = 47l5 ~ f 1.5 tc = 1 ~ chloroform) Stage B: Application of the compound previously obtained at the pre ~ aration of 17 ~ -ethynyl 17 ~ -hydroxy 11 ~ - (4-dimethylamino-phenyl) estra 4,9-di ~ n-3-one.
2 g of the product obtained in stage A are mixed in 50 cm3 of 95% ethanol. We add ~ to the suspension 5 cm3 2N hydrochloric acid. Stirring is maintained during 1 hour fi 20C / add 100 cm3 of ethyl ether then 100 cm3 of a 0.25M solution of sodium bicarbonate.
Decanted, extracted with ether, washing the organic phase with a saturated aqueous solution of sodium chloride, dry and evaporates to dryness. The residue obtained is chromatographed on silica eluting with petroleum ether-e acetate mixture thyle ~ 6 4 ~ and isolates 1.52 g of the expected product which is can recrystallize from diisopropyl ether.
F = 172C.
~ 720 = fl82 f 2.5 IC = 1% chloroform) O
Example 15: _ Preparation of 11 ~ - (3-dimethyl ~ aminophenyl) 3,3-J
1,2-ethanediyl bis (oxy) ~ 17 ~ - (prop-1-ynyl) estr-9-en-5 ~ -17 ~ -diol and application of this com ~ dares to prepare the 17 ~ -hy_rcx ~ (3-dimethylamino ~ nyl) estra-4,9-dien-3-one.
Stage A: Preparatlon du 11 ~ -l3-d ~ thylaminophe ~ l) 3,3, 2-ethanediyl bis (oxy) 717 ~ nyl? estr-9-en-5 ~ -173 diol.
Preparation of magneslum.
1.46 g of magnesium are mixed under inert gas and 5 cm3 of anhydrous tetrahydrofuran. We introduce in 45 minutes maintaining the temperature around 50C, 10 g of metahromodimethylaniline in 45 cm3 dP tetrahydrofuran anhydrous. (The reaction was started by adding di-bro ~ .omethane). Maintained for 1 hour under agitation-tion and obtains a 0.95 M solution of the expected magnesian.
Condensation Mixed under inert gas 3.7 g of 3.3-L ~, 2-ethylene dioxy bis (oxy) ~ 17 ~ - (prop-1-ynyl) estr-9 (11) en-5 ~ -10 ~ -epoxy 17 ~ -ol, 74 cm3 of anhydrous tetrahydrofuran and 9g mg of cuprous chloride. We cool to 0, + 5C, PUI5 adds 42.2 cm3 of magnet solution in 30 minutes hers obtained above. Stir for 30 minutes at 0, + 5C, poured into a saturated aqueous solution of chloride of ammonium, extracted with ether, washing the organic phase with a saturated aqueous solution of sodium chloride, dry and the solvent is evaporated off. The residue is chromatographed on silica eluting with methylene chloride-acetone mixture (9-1) at 1 per thousand of triethylamine. We get 3.5 g of expected product.
F = 262C
~ 7D = -64 + 1.5 (c = 1 ~ chloroform).
Is also isolated 0.66 g of the 5 ~ 0H isomer cor-respondent. F ~ 210C. ~ 7D = +32.5 + 1 (c = 0.8%
chloroform).

Stage B: Application of the compound previously obtained preparation of 17 ~ -hydroxy 11 ~ - (3-dimethylaminophenyl) 17 ~ - (prop-l-ynyl) estra 4,9-dien-3-one.
3.3 g of the product obtained are mixed under inert gas in stage A with 100 cm3 of methanol, cools ~ 0, + 5C
and adds 10 cm 3 of 2N hydrochloric acid. Shake for 1 hour at 0, + 5C, add 200 cm3 of diethyl ether, then 200 cm3 of a 0.25 M solution of sodium bicarbonate.
Agitation is carried out for 5 minutes, decanting, extracting with oxide of diethyls, la ~ e the organic phase with a saturated solution of sodium chloride, dries and evaporates the solvent. We obtains 3 g of product which is chromed ~ ography on silica eluting with a benzene-ethyl acetate mixture (7-3). We isolates 1.43 g of expected amorphous product.
[~ 7D = +43 ~ 2.5 (c = 1 ~ chloroform).
Example 16- Method for the_preparation of 11 ~ - (4 = dimethyl-aminophenyl) 17 ~ -hydroxy estra 4,9-dien 3-one, in which a compound of formula II is a reaction intermediate.
1 g of the product obtained in stage A of Example 7 in 20 cm3 of tetrahydrofuran at 10 ~ dleau.
After dissolution, 106 g of borohydride are added.
sodium, stirred for 1 hour ~ pour into ~ 00 cm3 of water, extract with methyl8ne chloride, wash the organic phase with saturated sodium chloride solution, dry and evaporates the solvent. We obtain 1 ~ 3 g of product 5 ~ -17 ~ -dihydroxyO
0.63 g of product obtained above is introduced in a mixture of 12 cm3 of methanol and 2.4 cm3 of acid hydrochloric 2N. Stir for 1 hour 30 ~ tempera-room ture, pour into a solution of hicarbonate sodium, ether extract, wash the organic phase with a saturated solution of sodium chloride, dry and eva-pore the solvent. The residue is chromatographed on silica eluting with the petroleum ether-ethyl acetate mixture (6-4 ~. The residue is triturated in petroleum ether, wring it out and obtained 0.38 ~ of expected product. F = 130C.
~ aJD = 277 ~ 5 (c = 0.5% chloroform).
Example 17: Preparation of 3,3- ~~, 3-ethanediyl bis (oxy) ~
11 ~ _ (4-dimethylamin ~ phenyl) 17a- (pro ~ -2-enyl) estra -9-ene 5 ~ -17 ~ -diol and application of this compound to the preparation of ; 17 ~ -hydroxy_11 ~ - (4-dimethylaminophenyl) 17 ~ e ~ = a = ~
will be 4,9-dlen-3-one.
Stad ~ A- Pre ~ ration of 3_3- / 2- thane ~ iyl bis (o ~ y? 7 11 ~ - ~ 4 ~ ethYlamino-phenyl) 17 ~ - ~ prop-2-enyl) estra-9-ene 5 ~ -17 ~ -diol.
In 55.5 cm3 of 0.7 M bromide solution allyl magnesium in ether, introduced under inert gas ~ 20C in 15 minutes ~ a solution of 3.5 g of the product i ~ obtained in stage A of Example 7 in 35 cm3 of te-trahydro-furan. Stir at 20C for 1 hour, pour into a saturated aqueous solution of ammonium chloride, extract with ether, wash the organic phase with an aqueous solution saturated with sodium chloride, dries and evaporates the solvent.
The residue obtained is dissolved in 10 cm 3 of methyl chloride.
thyl ~ ne. 15 cm3 of diisopropyl ether are added thereto, center, then leave to rest. We wring the cistals for-mes, rinse with diisopropyl ether, dry and 2.76 g of expected product is obtained. F = 198C.
Y 31 43 4 ( Calculated: C% 74.72 H ~ 8.78 N% 2.83 Found: 74.0 8.7 2.9 Stage B: _A ~ cation of the compound previously_obtained ~ at the preparation of 17 ~ -hydroxy 11 ~~ (4-dimethylaminophenyl) 17 ~ -(prop-2-enyl) estra 4,9-di ~ n-3-one.
2.2 g of the product obtained are suspended - ~ 4 -s ~ ade A in 66 cm3 of methanol, then add 4.5 cm3 of a-; 2N hydrochloric acid. Stir for 30 minutes at 20C, add 132 cm3 of diethyl ether, then 132 cm3 of a 0.25 M aqueous solution of sodium bicarbonate ~ We decan te, extracted with diethyl ether, washed with a solution saturated aqueous sodium chloride, dries and evaporates the solvent The residue is chromatographed on silica, eluting with the benzene-ethyl acetate mixture (7-3), take up the pro-product obtained in a mixture of 15 cm3 of diisopropyl ether e ~ 7.5 cm3 of methylene chloride, concentrate then leave ~ at rest. We spin and rinse with diisopropyl ether ; the crystals obtained, and obtains 1.365 g of the expected product.
F = 1 ~ 2C.
r ~ 7D = + 20 ~, 5 + 3 (c = 1% chloroorme).
xample 18: Preparation of 3 t 3- ~ 1,2-ethanediyl bis (oxy 4- (N, N-dimethylaminomethyl) phenylJ 17 ~ - (prop-1-ynyl) estr-9-en-5 ~ -17 ~ -diol and application of this co ~ pose_à la _ preparation of 17 ~ -hydroxy 11 ~ - ~ 4- (N, N-dimethylaminomethyl3 pheny V 17 ~ - (prop-1-ynyl) estra 4,9-dien-3-one.
Stage A: Preparation of 3.3- ~ 1-aminomethyl) pheny ~ 7 17 ~ - (prop-1-ynyl) estr-9-en-5 ~ -17 ~ -diol.
Preparation of the magnesian.
5.5 g of magnesium are mixed under inert gas and 10 cm3 of anhydrous tetrahydrofuran. We introduce in 1 hour 30 minutes maintaining the temperature at + 45 / + 50C, 42.8 g of 4- ~ N, N-dimethylaminomethyl ~ bromobenzene in 190 cm3 of anhydrous tetrahydrofuran. The reaction was initiated by addition of dibromoethane. After the end of troduction, stirring is continued for 1 hour. The expected 0.85 M magnesian solution is thus obtained.

~.

- 45 ~

9 ~

10 g of 3.3- ~ 1.2- are mixed under inert gas ~ thanediyl bis (oxy) ~ 17 ~ - (prop-1-ynyl) estr-9, (ll) -en-5 ~ -10 ~ -epoxy 17 ~ -ol, 200 cm3 of anhydrous tetrahydrofuran and 0.27 g of cuivous chloride. Cool to 0, + 5C
and introduced in 1 hour 127 cm3 of the magnesium solution prepared above. Then stir for 15 minutes, pour into a saturated aqueous solution of ammonium chloride, ex ~ -treated with ether, washing the organic phase with a solution saturated aqueous sodium chloride, dries and evaporates sol ~ an ~. The residue is chromatographed on silica in elu ant to methylene chloride-methanol mixture (9-1) to 1 per thousand of triethylamine. We o ~ hold 10.1 gd ~ product which is crystallized by dissolution in chloride of methylene and addition of a few cm3 of methanol then diisopropyl ether. After concentration and maintenance at rest for 6 hours ~ the product obtained is wrung and 7.37 g of expected product is obtained. F = 186C.
~ 7D = -63 + 2.5 (c = 0.5% chloroform).
Stage B: Application of the compound previously obtained to the preparation of 17 ~ -hydroxy 11 ~ - ~ 4- (N, N-dimethylaminomethyl) phenyl ~ 17a- (prop-1-ynyl) estra 4,9-dien-3-one.
3n mixture under inert gas 7.37 g of the product obtained naked in stage A in 147! 4 cm3 of methanol and 15 cm3 of acid hydrochloric 2N. Stir at 20C for 1 hour, add 300 cm3 of diethyl ether and 300 cm3 of an aqueous solution 0.25 M sodium bicarbonate, decant, extract ~
diethyl ether, wash the organic phase with a so-aqueous solution saturated with sodium chloride, dry and evaporates the solvent. The product obtained is recrystallized by dissolving it in a mixture of diisopropyl ether and methylene chloride and then concentrating the solution tion and leaving to rest. We spin and dry them crystals forms. 3.74 g of product are thus obtained.
of. F = 190C.
~ J ~ = +84.5 + 2 (c = O, 8% chloroform).
Example 19: Preparation of 3,3-L ~ 2-ethanediyl bis (ox 11 ~ - (4-pyrrolidinyl pheny ~ 17 ~ - (prop-1 ynyl) estr-9-en-5a ~ 173-diol and application of this compound to the preyaration of 17 ~ -hydroxy 11 ~ - (4-pyrrolidi ~ l phenyl 17 ~ - (prop-1-ynyl) will be 4,9-dien-3-one.

-Stage A Pré ~ aration of 3.3 h, 2- thanedi ~ l bis (oxy ~ J 11 ~ -(4- ~ y ~ _oli ~ yl phenyl ~ 17 ~ pro ~ Pl- vl ~ estr-9-en 5a-17 ~ -diol.
Preparation of the magnesian.
4 g of magnesium are mixed under inert gas and 10 cm3 of anhydrous tetrahydrofuran. We introduce in 1 hour keeping the temperature at 45-50C, 34 g of 4-pyrrolidinyl bromo benzene in 140 cm3 of tetrahydro-furan-anhydrous. The reaction was initiated by addition dibromoethane. This gives a 1M solution of magnesian expected.
Condensation on the epoxy.
8 g of 3.3- ~ 1.2-ethanediyl are mixed under inert gas bis (oxy) J 5a-10a-epoxy 17a- (prop-1-ynynl ~ estr-9 (11) en-17 ~ -ol, 160 cm3 of anhydrous tetrahydrofuran and 216 mg of copper chloride. Cool to 0, + 5C and introduce in 1 hour 30 minutes 86.4 cm3 of the magnesium solution prepared above. Shake for 1 hour, pour into a saturated aqueous solution of ammonium chloride, extracted with diethyl ether, wash the organic phase with a saturated aqueous solution of ammonium chloride then with a saturated aqueous solution of sodium chloride, dry and evaporates the solvent. The residue is purified by chromatography.
written on silica, eluting with a methyl chloride mixture lene acetone (95-5) has 1 per thousand of triethylamine. We - ~ 7 -9'3 ~ 7 thus obtains 8.3 y of expected product which is recrystallized in a methylene chloride-isopropyl ether mixture.
,; F - 185C.
/ ~ -7D = -67 + 1.5 (c = 1% chloroform3.
Stage B: Application of the compound previously obtained to the preparation , ration du 17 ~ -hvdro ~ y 11 ~ - (4-pyrrolidinylphenyl3 17r ~ rop-l-ynyl ~ estra 4,9-dien-3-one.
6.4 g of product obtained in stage A are dissolved in 128 cm 3 of methanol and then adds 13 cm3 of 2N hydrochloric acid. We stir at 20 ~ C for 1 hour, then add 256 cm3 of oxide diethyle and 256 cm of 0.25 M aous solution of bicarbonatP
of solium. Decante7 extracted with diethyl ether, washed ~ phase o ~ gani-than with a 0.25M aqueous solution of sodium bicarbonate, then with a saturated aqueous sodium chloride solution, dries and evaporates the solvent.
Chrcmat ~ graphie the resiau on silica by el ~ ant with ether mixture of petroleum-aceta ~ e of ethyl (1-1) and obtains ~ 5.25 g of the expected product which recrystallized from a methylene chloride-oxide mixture diisopropyl, F = 190C.

/ ~ 7 = +120 + 2.5 (c = 1.2 ~ chloroform) ~
- - D
Example 20: Preparation of 3,3- / 1,2-ethanediyl bis (oxy) 7 11 ~ -(4-dimethylaminophenyl) 17 ~ -ethenyl estr-9-en-5 ~ -17 ~ -diol and ap ~ lication of this comp se to the preparation of _ ~ -hydroxy 11 ~ -(4-dimeth laminophenyl3 17a-ethén ~ estra 4,9-dien-3-one.
Stage A: Preparation of 3,3- / 192-ethanediyl bis (oxy3 / 11 ~ -(4-dimethylaminophenyl) 17 ~ -éthenyl estr-9-en ~ 5 ~ -17 ~ -diol.
3 g of product obtained in stage B of the example are mixed 13 with 60 cm of pyridin ~ anhydrous and add 0.6 g of palladium 5% on calcium carbonate. We pass a current of hydrogen in the mixture at room temperature ~ for 1 hour The catalyst is drained, the filtrate is evaporated to dryness, takes up the toluene residue and evaporates again to dryness. We 2.94 g of expected product thus obtained, used as it is : for the rest of the synthesis. F = 181C. The product can be recrystallized from a methylene chloride-oxide mixture X diisopropyl. F = 182C.
/ a / = -6.5 + 2 (c = 0.7% chloroform).
- - D
Stage B: Application of the previously obtained compound to the preparation ration of 17 ~ -h ~ dro_y 11 ~ -14-dim thylamlnophenyl) 17 ~ -ethenyl will be 4,9-dien-3-one.
2.94 g of the product obtained are mixed under inert gas.
stage A with 60 cm3 of methanol then add 6.2 cm3 of aid hydrochloric 2N. The solution is stirred at 20C for 1 hour, add 120 cm3 of ether and 120 cm3 of an aqueous solution at 0 / 25M
sodium bicarbonate, keep stirring for 10 minutes, decant and extract with ether. The organic phase is washed than with a 0.25M aqueous solution of sodium bicarbonate then with a saturated aqueous solution of sodium chloride.
We dry ~ -evaporate the solvent. -Get 2.65 g of product which is chromatographed on silica, eluting with a benzene mixture-ethyl acetate (7-3) and then crystallized from a mixture diisopropyl ether-methylene chloride. We get final-1.51 g of expected product F = 150C.
- ~ -7D = +243 ~ 3 (c = 0.8 ~ chloroform) Example? 1: Preparation of 3.3- / 1.2 ethanediyl bis (_xy37 11 ~ -(4-diethylaminophenyl) 17 ~ - ~ prop-1-ynyl) es r-9-en 5 ~ -17 ~ -diol and application of this compound to the preparation of 17 ~ ~ ydroxy 11 ~ - (4-d _thy amin ~) 17 ~ ro ~ ynyl) estra 4.9 dien-3- ~ ne . _ _ _ _.
Stage A: Pre ~ aration_du 3,3- / 1,2-ethanediyl bis (ox ~? 7 11 ~ -~ 4-diethylaminophenyl) _ 17 ~ - (prop-1-ynyl) estr-9 en 5 ~ - 17 ~ -diol.
Maynesian training.
Mixed under inert yaz 3.9 g of magnesium in 10 cm3 of te ~ rahydrofuranne. 34.2 g are added dropwise of 4- (N, N-diethylamino) bromo benzene in 110 cm tetrahydrofuran by maintaining the temperature ~ approx.
35C. A 1M solution of the expected magnesium is obtained.
Condensation.
~ _. . _ _ 7.4 g of 3.3- ~ 1.2-ethanediyl bis are dissolved (oxy ~ 5 ~ - 10 ~ - epoxy 17 ~ - (prop-1-ynyl ~ estr-9 tll) ene 17 ~ -vl in 150 cm3 of anhydrous tetrahydrofuran O is added 0.25 g of cuprous chloride. Stir at 0 ~ 5C under gas inert and slowly add 80 cm3 of the ma-gnesian prepared above. We maintain for 17 hours with stirring at 20C, poured into an aqueous solution of ammonium chloride, extracted with ether, washing the gold phase ganic with an aqueous solution of sodium bicarbonate, s ~ che and evaporates the solvent. We ether the residue with ether of petroleum then treats it with activated carbon in ether and recrystallizes it from isopropyl ether. We obtain thus 4 g of expected product.
r ~ 7 ~ = -61 + 2.5 ~ c = 0.7 ~ chl ~ roform ~.
Stage B: Application of the previously dared com ~ obtained to the pre ~ aration of 17 ~ - ~ ydroxy ll ~ -diethylaminophenyl) 17 ~ -~ prop-l- ~ nyl) estra 4,9-di ~ n-3 ~ one.
To a solution of 3.12 g of product obtained at stage A in 45 cm3 of methanol, 8 cm3 of acid are added hydrochloric 2N and stirred at 20C under inert gas for 45 minutes. Pour into water, neutralize by addition 2N sodium hydroxide, extracted with methyl chloride ~ ne, ; dries and evaporates the solvent. The residue is chromatographed on silica ~ n eluting with the benzene-ethyl acetate mixture (1-1) and obtains 1.34 g of the expected product.
~ 7D = 144 ~ 5 ~ 3 ~ (c = 0.8 ~ chloroform).
Analysis: C31H39NO2 (457.63) Calculate ~ C ~ 81.36 H% 8.59 N% 3.06 Found: 81.7 8.8 2.09 4- (N, N-diethylamino) bromo benz ~ not used at the start of stage A was prepared as follows.
To an 86 y solution of N, N-diethylaniline in 400 cm3 of acetic acid, 93 g are added dropwise bromine. After the end of the introduction, we pour into a water-ice mixture ~ extract with methyl chloride ~ ne, wash the organic phase with an aqueous solution of bi-sodium carbonate, dries it and evaporates the solvent ~ On obtains 125 g of the expected product. Eb: 0.6 = 97 ~ C.
Example 22: Preparation of 3,3-L ~, 2-ethanediy ~ bis (oxy) ~
~ 4- ~ m_thyl (3-methyl butyl) amino ~ pheny1 ~ l? ~ - ~ propl-ynyl) estr-9-ene 5 ~ -17 ~ -diol and a lication of this com dared to PP ~ P
preparation _u 17 ~ -hydroxy ~ -c4- ~ methyl (3-methylbutyl) amin ~ pheny ~ J 17 ~ - ~ prop-1-ynyl) estra 4,9-dien-3-one.
Stage A: Preparation_of 3.3- h, 2-ethaned yl bis (oxy) ~ _ll ~ -~ 4-methyl (3-methyl butyl) amin ~ pheny ~ 1 17 ~ -1erop-1-yny ~ l`
estr-9-en 5a-17 ~ -diol.
Preparation of the magnesian.
50US inert gas is mixed 4.12 g of magnesium and 10 cm3 of tetrahydrofuran. We introduce a few cm3 of N-methyl N- (3-methylbutyl) 4-bromo benzene in solu-tion in tetrahydrofuran and initiates the reaction by addition of C, 2 cm3 of 1,2-dibromoethane. Then we add in 40 minutes the rest of the N-methyl N- (3-methyl-butyl) 4-bromo benzenamine in anhydrous tetrahydrofuran (32.6 g in 90 cm3). Then let it return to tempera-ambient temperature and then stirred for 1 hour.
This gives a 0.9 M solution of the expected magnesian.
Condensation 8 g of 3.3- {1,2-ethanediyl bis (oxy) are mixed.
5 ~ -10 ~ -epoxy 17 ~ (prop-1-ynyl) estr-9 (11) in 17 ~ -ol with 30 cm3 of anhydrous tetrahydrofuran and 3.77 g of chloride copper. Stir for 20 minutes at + 5C under gas inert, then add 100 cm3 of the magnesium solution prepared above. Then pour the mixture into a aqueous ammonium chloride solution, ether extract added with triethylamine then with methylene chloride triethylamine. The combined organic phases are washed with a saturated aqueous solution of sodium chloride, dry and evaporates to dryness. 31.2 g of expected product are obtained, use as is for the next stage. We can purify the product by chromatography on silica, eluting with a chloride mixture of methylene-acetone-triethylamine (96.5-4.5-0.5 ~.
~ 1D ~ ~ 59 ~ 5 t 2.5 (c = 0.7% chloroform).
Stage B ~ 3 ~ 1 _______ of the compound previously obtained ~ the preparation_du 17 ~ -hydroxy 11 ~ ~ 4- ~ methyl (3-methylbutyl) aminQ7 pheny ~ 17a- (prop-1-ynyl) estra _4,9-dien-3-one.
26 g of product obtained in stage A are dissolved in 200 cm3 of methanol then add 52 cm3 of hydrochloric acid than 2N. After 1 hour with stirring, pour the mixture in an aqueous solution of sodium bicarbonate, extracted with ether, then with methylene chloride, wash the phases organic combined with a saturated aqueous solution of sodium chloride, dries and evaporates the solvent. We purify the product by chromatography on silica, eluting with toluene-ethyl acetate mixture (92-8) and obtains 3.23 g of expected product.
~ a ~ D = +125 + 3.5 (c = 0.6 ~ chloroform).
AnalySe: C33 ~ 43 NO2 ( Calculated ~ C% 81.6 H ~ 8.92 N ~ 2.88 Found: 81.4 9.0 2.7 The amine used at the start of stage A has been prepared as follows.

Stage a: N-methyl N- (3-m ~ lbutyl ~ aniline.

86 g of N-methyl aniline, 500 cm3 of anhydrous benzene and 81 g of anhydrous triethylamine. We add drop by drop 121 g isoamyl bromide, brings to the reflux for 100 hours. We filter the mixture, wash it filtrate with water, dry and evaporate the solvent. We distill the residue and obtains 90 g of at ~ endu product. Eb 18 = 132C.
Stage b N ~ methyl N- (3-meth ~ lbutyll 4 br ~ n ~ c ~ LiAG

_ 64 g of product obtained in stage a are mixed with 300 cm3 of acetic acid, then add dropwise per hour at around 15C, 58 g of bromine in solution in 60 cm3 acetic acid. The temperature is brought to 80C, stirred for for 8 hours, pour ensu-l ~ e into ice water, extract with methylene chloride, wash the organic phase with a sodium bicarbonate solution then with water, dry and evaporates the solvent. Distill the residue and obtain 70 g -of expected product. Eb. 0.5 = 119C.

Example 23 ~ Preparation of 3,3-L ~, 2-ethanediYl bis (oxy) ~

[4-! N, N-dimethylaminoethylthio) pheny V 17 ~ - (prop-1-ynyl) estr-9 ~ en 5 ~ -17 ~ -diol and application of this component ~ L ~ e ~ e ~

at 17 ~ -hydroxy 11 ~ - ~ 4-N, N-dimethylaminoethylthio) pheny ~ 7 17 ~ -_rop-1-ynyl3 estra 4,9-dien 3-one.

Stage A: _Preparation of 3,3- ~ lr2-ethanediyl bis (ox ~

4- (N, N-dimethylaminoethylthio) phenyl7 17 ~ - (prop l-ynyl) estr-9-en_5a-17 ~ -diol.

Preparation of the magnesian.
;

2 g of magnesium are mixed under inert gas and 15 cm3 of anhydrous tetrahydrofuran. Then we introduce in 45 minutes letting the temperature rise to 56C a solution of ~ 0 g of 4- (NrN-dimethylaminoethylthio) l-bromobenzene in 40 cm3 of anhydrous tetrahydrofuran.
The reaction was initiated by the addition of 1,2-dibromoethane.
It is then left to return to 20C and then maintained under agitation.

~ g ~

tation for 45 minutes under inert ga ~. We obtain thus a 1.05 M solution of the expected magnesian.
Conaensatio ~
Cooled ~ -20C under inert gas 38 cm3 of the svlution of maynesian obtained above. We add 1.730g of chlorurous ~ copper, keeps stirring for 20 minutes then add 5 g of 3.3- ~ 1,2-ethanediyl bis (oxy) ~ 5 ~ -10 ~ -epoxy 17 ~ - (prop-1-ynyl) estr-9 (11) in 17 ~ -ol in 50 cm3 of anhydrous tetrahydrofuran. We main-holds at 20C under inert gas for 2 hours 45 minutes.
The mixture is poured into 600 cm3 of ice water, containing 60 g of ammonium chloride. Keep stirring for 45 minutes, decanting, extracting the aqueous phase by diethyl ether with added triethylamine, washed the organic phases united by an aqueous solution saturated with sodium chloride, dries and evaporates the solvent.
The residue is chromatographed on alumina, eluting with a methylene chloride-acetone mixture (95-53 and 10.3 g of expected product.
IR spectrum.
Absorption at 3600 cm ~ OH), 2240 cm (C = C) 1705 e ~ 1670 cm 1 (C) and CO conjugate) 1615 and 1490 cm 1 (aromatic bands).
Stage B: A ~ plication of the compound previously obtained ~
preparation of 17 ~ -hydroxy 11 ~ - ~ 4- (N, N-dimethylaminoethylthio phenylJ 17 ~ - (prop-1-ynyl) estra 4,9-dièn-3-one.
10.3 g of product obtained are mixed under inert gas.
held in stage A with 72 cm3 of methanol and then adds 20.6 cm3 2N hydrochloric acid. Stirring is maintained at 20C for 1 hour 15 minutes, neutralized by addition a saturated aqueous solution of sodium bicarbonate, add 200 cm3 of diethyl ether, decant, extract ~

diethyl ether, washing the combined organic phases with a saturated aqueous solution of sodium chloride, dry and concentrated to dryness. The residue is chromatographed on silica, eluting with methyl chloride mixture ~ ne-methanol ~ 9-1 ~ and obtains 3 g of pxoduit expected that one crystallizes-by empatage in diisopropyl ether. F = 145C.
[~ 7D - +125 ~ 2 (c = 1 ~ chloroform ~.
The amine used at the start of stage A was pre-prepared as follows.
20 g of sodium hydroxide tablets are dissolved in 500 cm3 of ethanol. 23.5 g of chlorhy- are also dissolved.
chloroethyldimethylamine drate in 75 cm3 of ethanol, then add 160 cm3 of the sodium hydroxide solution prepared above above ~ We also dissolve 30 g of parabromothiophenol in 100 cm3 of ethanol then add 160 cm3 of the solution of soda prepared above. We then add in 2 minutes at 20C, the amine solution prepared above. We wear at reflux for 3 hours, evaporate the solvent, add water, extracted with methylene chloride, washes the gold phase ganic with 0.1 N aqueous sodium hydroxide solution and then water, dry and evaporate the solvent. The residue is distilled and obtains ~ 5.5 g of the expected product. Eb. 0.1 = 110C.
Example 24: Preparation of 11 ~ - (4-dimethylaminophenyl ~ _ 3.3 ~ 1, 2-ethanediyl bis (oxy) ~ 21- (trimethylsilyl ~ (17 ~) l9-nor pregn-9-en-20-yn 5a- 17 ~ -diol_et application de ce_ o ~ dose a the preparation of 11 ~ - (4-dimethylaminophenyl) 17B-hydroxy 21-(trimethylsilyl) (17 ~) 19-nor pregna 4,9-dien-20-yn-3-one.
Stage A: Preparation of 11 ~ - (4-dimethylaminophenyl) 3C3- ~ 1,2-ethanediy1 bis (oxy3 ~ 21- (trimethylsilyl) (17 ~) l9-nor pr ~
9-in-20 = yn 5 ~ -_17 ~ -diol.
We mix under inert gas 13 cm3 of a solution 1.6M of ethyl magnesium bromide in ttrahydrofuran, with 13 cm3 of anhydrous -tetrahydrofuran. We stir while - 55 ~

for 5 minutes ~ 0, + 5C then add 3.4 cm3 drop by drop of trimethylsilyl acetylene. Let the temperature rise cross off at 20C and continue stirring for ~ 0 minutes, then dropwise a solution of 1.12 g of product obtained in stage A of Example 7 in 10 cm3 of tee anhydrous trahydrofuran. It is maintained for 15 hours at room temperature with stirring, poured into a solution aqueous ammonium chloride, stirred for 10 minutes at room temperature, extract with methylene chloride, wash the organic phase with a saturated aqueous solution sodium chloride, dries and evaporates the solvent. We chromatograph the residue on silica, eluting with a mixture petroleum ether-ethyl acetate (6-4) and obtains 680 mg of expected product.
~ 7D = -76.5 ~ 3 (c = 0.5% chloroform).
Stage B: Application of the Precedent Compound Obtained in the Preparation of _. ... . _ _ ~ - (4-dim ~ ethylaminophenyl) 17 ~ -hydroxy 21- ~ trimethylsilyl) (17 ~) ~ j. _. ... _ _ _. . .
l9-nor ~ r ~ a 4,9-dièn-20-yn-3-one ~
Gn mixture 562 ~ .g of product obtained in stage A to ~ ec 15 cm3 of methanol and 1 cm3 2N hydrochloric acid. We keep shaking at room temperature for 40 mLnutes, worm ~ e in a ~ aqueous-solution of sodium bicarbonate, extracted with ether, washed ~ the phase ~ rganic with a saturated aqueous solution of sodium chloride, s ~ che and evaporates the solvent. The residue is chromatographed on silica eluting with the mixture of petroleum ether-ethyl acetate-(6-4) and obtains 364 mg of the expected product.
[~ 7D = + 9715 ~ + 3 (c - 0.35 ~ chloroform).
Analysis: C31 H41 NO2Si (487.76) Calculates: C% 76.33 H% 8.47 N% 2.87 Found: 76.4 8.7 2.8 Example 25: Preparation of 3,3- ~ 1,2-ethanediyl bis (oxy) ~
, 4- (N! N-di ~ ropy ~ amino) pheny ~ 7 17a- (prop-1 ynyl) estr-9-en 5 ~ -17 ~ -diol and application of this ingredient to the preparation du 17 ~ -hydroxy ll ~ -f ~ - (N, N-dipropylamino) pheny ~ 7 17 ~ - ~ prop-1-ynYl) will be 4,9-dien-3-one.
Stage A: 3,3-L1, 2-ethanediyl bis (oxy ~ J ll ~ -f4- (N, N-dipro-pylamino) phenyl7 17 ~ - (prop-1-ynyl ~ estr ~ 9- ~ n 5 ~~ 17 ~ -diol.

_ Preparation of the corneal.
5 g of magnesium are mixed under inert gas with 15 cm3 of anhydrous tetrahydrofuran. We add drop to drop a solution of 52 g of 4-bromo N, N-dipropylaniline in 110 cm3 of tetrahydrofuran while maintaining the temperature-ture at 40C. This gives a 1.1 M solution of magne-his attPndu.
Condensation Melan ~ e under inert gas a solution of 5 ~ 55 g 3.3 ~ 1,2-ethanediyl bis ~ oxy) ~ 5 ~ -10a-epoxy 17 ~ - (prop-1-ynyl) estr-9 (11 ~ -in 17 ~ -ol du-stade A of the example 7 with 200 mg of cupric chloride. We stir at 0, + 5C, then add 50 cm3 of the magnesium solution in 15 minutes obtained above. Then stirred for 1 hour at 20C, poured into a saturated aqueous solution of ammonium chloride nium, extracted with ether, dries the organic phase and evaporates re the solvent. The residue is chromatographed on silica in eluting with the toluene-ethyl acetate mixture (7-3) and obtains 5.3 g of expected productO
~ a ~ D ~ -56 ~ 2 ~ c = 0.8% chloroform).
Analysis C35 H49 NO4 (547 ~ 75) Calculated: C% 76.74 H% 9.02 N ~ 2.56 Found: 76.6 9.2 2.5 Stage B: Application of the compound previously obtained to the preparation of 17 ~ hydroxy ~ 4- (N, N-dipropylamino) pheny ~ 7 17 ~ - (prop-1-ynyl3_ estra 4,9-dièn-3-one.
To a solution of 5.83 g of product obtained at stage A in 80 cm3 of methanol 10 cm3 of acid are added hydrochloric 2N e ~ stirred at 20C for 50 minutes. We neutralized by adding sodium hydroxide, evaporates the solvent under reduced pressure and takes up the residue with methylene. The organic phase is washed with water, dried and evaporates the solvent. The residue is chromatographed on silica, eluting with a toluene-ethyl acetate mixture (75-25 : and obtains 3.81 g of expected product.
IR (chloroform) sector Absorption at 3600 cm 1 tOH ?, 1654 cm 1 [C = O), 1610-1595-1558 and 1517 cm 1 ~ 4.9 + aromatic bands), 2240 cm 1 ~ C = C).

Claims (5)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of a compound of general formula (II):

(II) in which K represents a blocked ketone group in the form of ketal, thiocetal, oxime or methyloxime, R1 represents an organic radical containing from 1 to 18 atoms carbon, containing at least one nitrogen atom, phosphorus or silicon, the atom immediately adjacent to the carbon in 11 being a carbon atom, R2 represents a hydro-containing 1 to 8 carbon atoms and X represents the unsubstituted pentagonal or hexagonal ring residue or substituted and possibly carrying unsaturation, characterized in that it is prepared by submitting a compound of formula general (III):

(III) in which K, R2 and X retain the same meaning as previously, to the action of a compound chosen from the group consisting of the compounds of formula (R1) 2 Cu Li, of formula R1Mg Hal and of formula R1Li, in which R1 retains the same meaning as before and Hal represents an atom halogen, where appropriate, in the presence of cuprous halide, to obtain the compound of formula (II) sought. 2. Process for the preparation of a compound of general formula (II '):

(II ') in which K represents a keto group blocked in the form of a ketal, thiocetal, oxime or methyloxime, R1 represents an organic radical containing from 1 to 18 carbon atoms, containing at least one nitrogen atom, phosphorus or silicon, the immediately adjacent atom with carbon and 11 being a carbon atom, R2 represents a hydrocarbon radical containing 1 to 8 carbon atoms, R'3 represents a hydroxy radical or an ORc radical, in which Rc represents the remainder alc4 of an ether group or COalc5 of an ester group, alc4 and alc5 representing a alkyl radical containing 1 to 8 carbon atoms or aralkyl containing from 7 to 15 carbon atoms and R'4 represents smells of a hydrogen atom or an alkenyl or alkynyl radical containing from 2 to 8 carbon atoms, characterized in that it is prepared by submitting a compound of general formula (IV):

(IV) in which K and R2 are defined as above, at the action of a compound chosen from the group consisting of compounds of formula (R1) 2CULi, of formula R1MgHal and of formula R1Li, in which R1 is defined as above and Hal represents a halogen atom, if any, in the presence of copper halide, to obtain the compound of formula (V):

(V) in which K, R1 and R2 retain the same meaning that previously, that we submit - either to the action of a reduction agent for obtain the corresponding 17-hydroxy compound, - either by the action of a magnesian suitable for obtain the corresponding 17.beta.-hydroxy 17.alpha.-substituted compound, - either to the action of an organometallic derivative for obtain the corresponding 17.beta.-hydroxy 17.alpha.-substituted compound, - either to the action of a cyanidation agent to obtain the compound 17.beta.-cyano 17.alpha.-hydroxy corresponding, which one protects the hydroxy function, then to the action of an organo derivative metallic to obtain the compound 17.beta.-hydroxy 17.alpha. - substituted corresponding, and that, if applicable, we submit one or the other of the 17-hydroxy compounds obtained above, with the action an esterification or etherification agent, and that, the if necessary, one or the other of the compounds 17-substituted obtained above, wherein the substituent in 17 includes a triple bond, to the action of a reduction, to obtain the corresponding ethylenic. 3. Method according to claim 2, characterized in what the organometallic derivative is chosen from the group including lithians or potassium derivatives. 4. Compounds of formula (II):

(II) in which K represents a blocked ketone group in the form of ketal, thiocetal, oxime or methyloxime, R1 represents an organic radical containing from 1 to 18 atoms carbon, containing at least one nitrogen atom, phosphorus or silicon, the atom immediately adjacent to the carbon in 11 being a carbon atom, R2 represents a hydro-carbon containing 1 to 8 carbon atoms and X represents the remainder of an unsubstituted pentagonal or hexagonal ring, or substituted and possibly carrying unsaturation, each time that they are obtained by a process according to claim 1 or its obvious chemical equivalents. 5. Compounds corresponding to the general formula (II '):

(II ') in which K represents a keto group blocked under form of ketal, thiocetal, oxime or methyloxime, R1 represents an organic radical containing from 1 to 18 carbon atoms, containing at least one nitrogen atom, of phosphorus or silicon, the atom immediately adjacent to the carbon in 11 being a carbon atom, R2 represents a hydrocarbon radical containing 1 to 8 carbon atoms, R'3 represents a hydroxy radical or an ORc radical in which Rc represents the remainder alc4 of an ether group or COalc5 of an ester group, alc4 and alc5 representing an alkyl radical containing from 1 to 8 carbon atoms or aralkyl containing 7 to 15 carbon atoms, and R'4 represents has a hydrogen atom or an alkenyl radical or alkynyl having 2 to 8 carbon atoms, each once they are obtained by a process according to claim 2 or its obvious chemical equivalents.