Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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The present invention relates to the production of
D steroids.
In applicants copending application No. 263,032 filed
October 8, 1976 Q15-steroids having the ~eneral ormula I
~ ~ 2
/ ` (I)
in which, Rl represents a hydrogen atom, a trialkyl silyl group
or an acyl group and R represents an ethynyl group, a chloro-
ethynyl group or a propynyl group are inter alia described.
Acyl radicals of physiological compatible acids are suitable as
acyl radicals Rl. Preferred acids are organic carboxylic and
sulphonic acids containing 1 to 16, particularly 1 to 11 carbon
atoms, which belong to the aliphatic, cycloaliphatic, aromatic~
aromatic-aliphatic or heterocyclic series. These acids can also
be saturated or unsaturated, monobasic or polybasic and/or sub-
stituted in the usual manner. Alkyl, hydroxy, alkoxy, oxo or
amino groups or halogen atoms are mentioned as examples of the
substituents.
Each of the alkyl groups of the trialkyl silyl group
must contain 1 to 4 carbon atoms, the trimethyl silyl group
being preferred.
The ~15-steroids having the general formula I have
valuable steroid-hormone properties and can be used as pharma-
ceutics.
According to copending Application Ser. No. 263,032
the ~15-steroids having the general formula I are produced by
introducing the R2 radical into a 17-oxo steroid having the
- 1- ~
591
~eneral formula II
B
A
~ ` ~ ~ (II)
wherein Y represents a free keto group or a ketalised keto group
and one of the ---- bonds in the 4, 5-, 5, 6- or 9, 10- position,
is a carbon-carbon double bond and each of the other carbon-
carbon single bonds and A-B represents a carbon-carbon double
bond or the grouping C15 - C16, wherein R represents a hydrogen
OR
atom, a silyl, acyl, sulphonyl or nitro group, by means of con-
ventional methods with the aid of an agent yielding the radical
R2, while forming a tertiary carbinol group at the 17-carbon
atom, HORl being split off in the 15, 16-double bond, any
primarily introduced protective group being split off and depen-
din~ on the eventually desired meanin~ of Rl in the final pro-
duct, the 17-hydroxy group is esterified if required, either
prior to or after splitting off the protective group.
Trialkyl silyl radicals, particularly trimethyl silyl
radicals or dialkyl silyl radicals, particularly dimethyl
silyl radicals are suitable as silyl radicals Rl.
The radicals of organic carboxylic acids are suitable
as acyl radicals Rl. Acyl radicals containing approximately 1
to 10 carbon atoms, for example, the acetyl, trifluoro-acetyl,
propionyl, butyryl, valeryl, heptanoyl and benzoyl radical, are
particularly suitable. Again, for example, the mesyl, ethane-
sulphonyl, propionyl-sulphonyl and p-tosyl radical are suitable
sulphonyl radicals R .
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The introduction of the radical R can be carried out
by conventional methods with an organo-metallic ethynyl, chloro-
ethynyl or propynyl compound. Such organo-metallic compounds
are, for example, alkali metal acetylides, such as for example,
potassium and lithium acetylide or potassium and lithium chloro-
or methyl acetylide.
The organo-metallic compound can also be formed in
situ and reacted with the 17-ketone having the for~ula II.
Thus, for example, acetylene and an alkali metal, particularly
potassium, sodium or lithium, can be allowed to act on the 17-
ketone in a suitable so'vent, in the presence of a C4- or C5-
alcohol or of ammonia, or in the form of e.g. butyl lithium.
Li-thium chloro-acetylide can be formed from 1, 2-dichloro
ethylene and an ethereal lithium-methyl solution. Ethinyl-
magnesium or ethinyl-zinc halides, particularly ethinyl-magnes-
ium bromide or iodide, are also suitable as organo-metallic
ethinyl compounds. Dialkyl ether, tetrahydrofuran, dioxane,
benzene and toluene are suitable solvents.
Accordin~ to copending application NQ . 263,032 in a
! 20 preferred method the reaction of the 17-oxo steroid is carried
' out with the aid of an agent yielding the radical R when the 3-
; keto group is present as a protected ketal. The ketal radicals
are derived from the alcohols usually used for the protection
of oxo groups. Ethylene glycol and 2,2-dimethyl-1,3-propane-
diole are mentioned as examples.
; It has now been found that the formation of ketal in
the 3 position is particularly favourable if the 3,17-diketone
is reacted with ethane dithiol-(1,2~.
The present invention thus is a development of the
process of applicantscopending Application No.263,032 for
producing ~15-steroids having the general formula I by R -
alkinylation of compounds having the general formula II, in
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which ~ in formula II represent a keto group protected with
ethane dithiol-(1,2) and that the carbon-carbon double bond ~s
in the 4, 5-position.
a The advantages of the process o the present invention
lie in that the 3,3-dithio~thylene ketal is formed in almost
~ quantitative yields and that a compound with a stable protec-
¦ tive group is formed which can be easily split off again after
; the R -~lkinylation.
In tne protection of the 3-keto group with ethane
dithiol-(1,2) according to the invention a homogenous compouna
having a 4-en structure is formed. This compound can be puri-
fied in a simple manner by crystallization. In the process of
the copending application a substance mixture having 5(6)- and
5(10)-en structure in formed by protection of the 3-keto group
with 2,2-dimethyl-1,3-propane diol. This substance mixture
must be purified by chromatography.
' According to "Synthesis" 1974, page 32 the thioketal
is formed in polar solvents, as for example, in a lower alcohol,
particularly methanol, or in a lower carboxylic acid, particul-,
arly glacial acetic-acid, in the presence of an acid, catalyst,
as for example, boron trifluorid~ etherate, at temperatures of
approximately o to 50C.
! According to "Tetrahedron letters" 1972, page 1989 the
thioketal is split with methyl iodide in an aqueous lower alcohol
while adding calcium carbonate.
~ The process according to the invention is further
described followed by the Examples:
Example 1
50.0 g of 15~-hydroxy-18-methyl~4-oestren-3,17-dione
~ 30 in 750 ml of methanol are mixed with 25 ml of ethane diol-(1,2)t and 10 ml of boron trifluoride etherate under argon at room
temperature. A portion of the product crystallizes out wi~hin
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an hour while the remaining substance is crystallized by cooling
with ice/water. The crystallizate is filtered with suction,
washed with waterr dried in vacuo and recrystallized from
acetone/hexane. 54 0 g o~ 3,3-ethylene dithio-15a-hydroxy-18-
methyl-4-oestren-17-one are obtained.
Melting point: 213.5C
Example 2
15 ml of methane sulphonyl chloride are slowly added
dropwise to 14.6 g of 3,3-ethylene-dithio-15a-hydroxy-18-methyl-
4-oestren-17-one in 75 ml of pyridine while cooling with ice and
stirring. After 1.5 hours 75 ml of dimethyl formamide and 45 g
of anhydrous sodium acetate are added. The mixtute is stirred
for 28 hours at room temperature, whereupon it is put in ice/
water. The precipitated product is ~iltered with suction, dis-
solved in acetic ester and dried over sodium sulphate. The
solution is treated with active carbon. 12.1 g of 3,3-ethylene-
dithio-18-methyl-4,15-oestradien-17-one are obtained. A sample
recrystallized from acetone/hexane had a melting point of
215.8C.
Example 3
Acetylene is passed through an ice/water-cooled
solution of 140 ml of butyl lithium (15% in hexane) in 450 ml of
tetrahydrofuran, whereupon 12.1 g of 3,3-ethylene~dithio-18-
methyl-4,15-oestradien-17-one in 450 ml of tetrahydrofuran are
added dropwise, followed by stirring for 30 minutes at room
! . temperature. The solution is then carefully mixed with satur-
! ated ammonium-chloride solution dilutedwith acetic ester, washed
with water and dried over sodium sulphate. The crude product i5
purified in acetone with active carbon. 12.0 g of 17~-ethynyl-
3,3-ethylene-dithio-18-methyl-4,15-oestradien-17~-ol are obtain-
ed. A sample recrystallized from acetone/hexane has a melting
point of 152.2C.
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Example 4
7.4 g of 17~ ethynyl-3r3 ethylene-dioxy-18-methyl-4,
15-oestradien-17~-ol in 200 ml of a 95~ aqueous methanol are
stirred with 20 ml of methyl iodide and 3.5 g of calcium
carbonate for 19 hours with reflux. The reaction mixture is
concentrated in vacuo, the resiaue is dissolved in acetic ester,
washed with water and dri~d over sodium sulphate. After chro-
matographing the crude product on silica gel with 15 to 20~ of
acetone/hexane 4.7 g of 17a-ethynyl-17~-hydroxy-18-methyl-4,15-
oestradien-3-one having a melting point of 198C are obtained.
Example 5
320 ml of a 5% ethereal lithium-methyl solution are
added dropwise to 65 ml of 1,2-dichloro-ethylene in 325 ml of
ether at 0C while injecting argon. After 1 hour 28.2 g of 3.3-
ethylene-dithio-18-methyl-4,15-oestradien-17-one in 700 ml of
tetrahydrofuran are added, followed by stirring at room temper-
ature. After 2.5 hours the solution is carefully mixed with
saturated ammonium-chloride solution, diluted with acetic ester,
washed with water and dried over sodium sulphate. After concen-
trating in vacuo, 33.2 g of 3,3-ethylene-dithio-17~-chloro-
ethynyl-18-methyl-4,15-oestradien-17~-ol are obtained a~ an oily
product.
~]D = -115.2C
Example 6
33.2 g of 3.3-ethylene-dithio-17~-chloro-ethynyl-18-
methyl-4,15-oestradien-17~-ol in 500 ml of 95% methanol are
` stirred with 70 ml of methyl iodide and 15 g of calcium carbon-
ate for 22 hours with reflux. The reaction mixture is concen-
, trated in vacuo, the residue is dissolved in acetic ester,
! 30 washed with water and dried over sodium sulphate. After chroma
tographing the crude product on silica gel with 13 to 15% of
acetone/hexane 16.5 g of 17~-chloro-ethynyl-17~-hydroxy-18-
~ Z59~
methyl-4,15-oestradien-3-one having a melting poin~ of 155C
are obtained.
Example 7
Methyl acetylene is passed through an ice-water-cooled
solution of 50 ml of n-butyl lithium (15~ in hexane~ in 100 ml
of tetrahydrofuran for 30 minutes. After stirring and injecting
argon 2.0 g of 3;3-ethylene-dithio-18-methyl-4,15-oestradien-17-
one in 20 ml of tetrahydrofuran are added. After 1.5 hours the
solution is carefully mixed with a saturated ammonium-chloride
io solution, diluted with acetic ester, washed with water until
neutral and dried over sodium sulphate. The crude product is
chromatographed on silica gel. With 10% of acetone in hexane
1.9 g of 3,3-ethylene-dithio-18-methyl-17a-propyn-1-yl-4,15-
oestradien-17~-ol are extracted as an oily product.
[a]D = -66C
Example 8
1.0 g of 3,3-ethylene-dithio-18-methyl-17a-propyn-1-
yl-4,15-oestradien-17~-ol in 40 ml of 95~ aqueous methanol are
reacted with methyl iodide and calcium carbonate and further
treated analogously to example 6. After recrystallizing the
crude product from acetone/isopropyl ether 320 mg of 17~-hydroxy-
18 -methyl-17a-propyn-1-yl-4,15-oestradien-3-one having a melt-
ing point of 82C are obtained.
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