PROCESS FOR THE PREPARATION OF 11.beta.-HYDROXY-18-ALKYL-ESTRANE COMPOUNDS

PREPARATION DE COMPOSES DE 11.beta.-HYDROXY-18-ALKYLESTRANE

English Abstract

Abstract of the Disclosure
The present invention relates to a novel process for
the preparation of 11.beta.-hydroxy-18-alkyl-estrane compounds
by reacting an 11.beta.-hydroxy-13-methyl-gonane compound with
an acylhypoiodite to give an 11.beta.-hydroxy-13-iodomethyl-
gonane compound and reacting the latter compound with an
alkylhalide in the presence of an alkali metal or with an
alkali metal alkyl compound or with dimethylformamide in
the presence of an alkali metal alkyl compound followed
by a treatment with a proton donor, whereafter in the
latter case the 18-carbaldehyde obtained is reduced to
the 18-methyl compound or is reacted with a trialkyl- or
triaryl-alkylidene phosphorane (Wittig reagent), followed
by a reduction of the thus-obtained 18-alkenyl compound
to the corresponding 18-alkyl-compound, and to novel
intermediates of the subject compounds.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a 11.beta.-hydroxy-18-alkyl steroid of
the estrane series having the formula:
<IMG> (I)
wherein R1 = H2, H(OR3), O or ketalised O;
R2 = O, ketalised O, H(OR4) or (.alpha.-alkyl)(.beta.-OR4), wherein the alkyl
group has 1 to 4 carbon atoms, R3 and R4 are the same or different and
represent hydrogen atoms or an acyl or alkyl protecting group, R is a lower
alkyl group and the dotted lines represent optional double bonds, which
comprises either:-
(a) reacting a corresponding 18-iodo compound of the formula:
<IMG>
(II)
or a corresponding compound having a protecting group in the 11-position,
wherein R1 and R2 are as hereinbefore defined with an alkyl halide of the
formula:
R Hal
wherein Hal is a halogen atom and R is as hereinbefore defined in the presence
of an alkali metal or with an organo metallic compound:
R Alk
wherein Alk represents an alkali metal and R is as hereinbefore defined; or
(b) reducing a compound of the formula:
19

<IMG>
(III)
or a cyclic hemi-acetal thereof and where the 11-hydroxy group is either
free or protected and R1 and R2 and the dotted lines are as hereinbefore
defined: or
(c) reducing a compound of the formula:
<IMG> (IV)
wherein X is a lower alkenyl group, the 11-hydroxy group is free
or protected and R1, R2 and the dotted lines are as defined above; and where
any of steps (a), (b) or (c) can be followed by the additional step of
removing any protecting group present in the 3, 11 or 17-positions.
2. Process according to claim 1(a) in which R1 and R2 are ketal groups;
the 11-hydroxy group is protected by silylation, the compound of formula II
is reacted with methyl lithium or butyl lithium and the resulting compound is
hydrolysed to produce a free keto group in the 3- and 17-positions and a free
hydroxy group in the 17-position.
3. Process according to claim 1(b) in which R1 and R2 are ketal groups;
a cyclic hemi-acetal of a compound of formula III is used as one of the
reactants and the reduction is effected by reaction with a mixture of
hydrazine hydrate and hydrazine dihydrochloride.
4. Process according to claim 1(c) in which R1 and R2 are ketal groups
and the reduction is effected by means of catalytic hydrogenation.

5. Process according to claim 1 in which R is methyl, R1 and R2 are
oxygen atoms and a double bond is present in the 4,5-position.
6. Process according to claim 1 in which 11.beta.-hydroxy-18-methyl-.DELTA.4-
estrene-3,17-dione is prepared by reacting 11.beta.-hydroxy-18-iodo-.DELTA.5-estrene-
3,17-dione 3,17-diethylene ketal 11.beta.-trimethylsilyl ether with methyllithium
and hydrolysing the 11.beta.-hydroxy-18-methyl-.DELTA.5-estrene-3,17-diethylene ketal
11.beta.-trimethylsilyl ether so obtained.
7. Process according to claim 1 in which R is n-butyl, R1 and R2 are
oxygen atoms and a double bond is present in the 4,5-position.
8. Process according to claim 1 in which 11.beta.-hydroxy-18-n-butyl-.DELTA.4-
estrene-3,17-dione is prepared by reacting 11.beta.-hydroxy-18-iodo-.DELTA.5-estrene-
3,17-dione 11.beta.-trimethylsilyl ether 3,17-diethylene ketal with n-butyllithium
and hydrolysing the 11.beta.-hydroxy-18-n-butyl-.DELTA.5-estrene-3,17-dione 3,17-
diethylene ketal 11.beta.-trimethylsilyl ether so obtained.
9. Process according to claim 1 in which R is methyl, R1 and R2 are
ethylene ketal groups and a double bond is present in the 5,6-position.
10. Process according to claim 1 in which 11.beta.-hydroxy-18-methyl-.DELTA.5-
estrene-3,17-dione 3,17-diethylene ketal is prepared by reducing the cyclo-
hemi-acetal of 11.beta.-hydroxy-18-formyl-.DELTA.5-estrene-3,17-dione 3,17-diethylene
ketal.
11. Process according to claim 10 in which the reduction is effected by
reaction with a mixture of hydrazine hydrate and hydrazine dihydrochloride.
12. Process according to claim 1 in which R is ethyl, R1 and R2 are
ethylene ketal groups and a double bond is present in the 5,6-position.
13. Process according to claim 1 in which 11.beta.-hydroxy-18-ethyl-.DELTA.5-
estrene-3,17-dione 3,17-diethylene ketal is prepared by reducing 11.beta.-hydroxy-
18-vinyl-.DELTA.5-estrene-3,17-dione 3,17-diethylene ketal.
21

14. Process according to claim 13 in which the reduction is effected
by means of catalytic hydrogenation.
15. Process for the preparation of a compound of the formula:
(IIA)
<IMG>
where R1 is an iodine atom, a <IMG> group or lower alkenyl group,
X is a hydrogen atom or a trialkylsilyl group
R1 = H2, H(OR3), O or ketalised O;
R2 = O, ketalised O, H(OR4) or (.alpha.-alkyl).beta.-OR4), wherein R3 and
R4 are the same or different and represent hydrogen atoms or acyl or alkyl
protecting group, the dotted lines represent optional double bonds, and
where X is hydrogen and R1 is <IMG> the two groups can form a cyclohemi-
acetal group; which comprises either:-
(a) reacting a compound of the formula:
(V)
<IMG>
where X, R1, R2 and the dotted lines have the same significance as above,
with an acyl hypoiodite; or
(b) reacting a compound of the formula:-
(VI)
<IMG>
22

wherein X, R1, R2 and the dotted lines have the same significance as above,
with dimethyl formamide in the presence of an alkali metal alkyl compound
followed by treatment with a proton donor; or
(c) reacting a compound of the formula:
<IMG> (VII)
wherein X, R1, R2 and the dotted lines have the same significance as above,
with a trialkyl- or triaryl- alkylidene phosphorane compound (a Wittig
reagent); and where any of steps (a), (b) or (c) can be followed by the
additional step of removing any protecting group present in the 3,11 or
17-position.
16. A compound of the formula IIA as defined in claim 15 whenever
prepared by the process of claim 15 or by an obvious chemical equivalent
thereof.
17. Process according to claim 15(a) in which the acyl hypoiodite is
formed in situ by the reaction of iodine with an acylate of a heavy metal.
18. Process according to claim 15(a) in which the acyl hypoiodite is
formed in situ by the reaction with iodine with lead tetra acetate.
19. Process according to claim 17 in which 0.5 to 1.5 g mol iodine and
at least an equivalent amount of a heavy metal acylate per g mol of steroid.
20. Process according to claim 19 in which 1.5 to 3 g mol of heavy
metal acylate is used per g mol of iodine.
21. Process according to claim 15(a) in which the reaction is performed
in the presence of a radical initiator.
23

22. Process according to claim 21 in which the radical initiator is
azoisobutyrodinitrile.
23. Process according to claim 15(b) in which water is used as the
proton donor.
24. Process according to claim 15(b) or 23 in which the alkali metal
alkyl compound used is methyllithium or butyllithium.
25. Process according to claim 15(c) in which the Wittig reagent is
triphenylmethylene phosphorane or triphenylethylidene phosphorane.
26. Process according to claim 25 in which the Wittig reagent is
prepared in situ by reaction of the appropriate triphenylalkylphosphonium
halide with a base.
27. Process according to claim 26 in which the base is dimsylsodium.
28. Process according to claim 15(a) in which R1 and R2 are ethylene
ketal groups, X is hydrogen or a trimethylsilyl group and the double bond
is present in the 5,6-position.
29. Process according to claim 15(a) in which 11.beta.-hydroxy-18-iodo-.DELTA.5-
estrene-3,17-dione 3,17-diethylene ketal and the corresponding trimethylsilyl
ether are prepared by reacting 11.beta.-hydroxy-.DELTA.5-estrene-3,17-dione-3,17-
diethylene ketal with a mixture of lead tetra acetate and iodine in the
presence of azoisobutyrodinitrile and when the trimethylsilyl ether is
required reacting the product so obtained with trimethylchlorosilane.
30. 11.beta.-Hydroxy-18-iodo-.DELTA.5-estrene-3,17-dione 3,17-diethylene ketal
and the corresponding trimethylsilyl ether whenever prepared by the process
of claim 29 or by an obvious chemical equivalent thereof.
31. Process according to claim 15(b) in which R1 and R2 are ethylene
ketal groups, X is a trimethylsilyl group and a double bond is present in
the 5,6-position.
24

32. Process according to claim 15(b) in which 11.beta.-hydroxy-18-formyl-.DELTA.5-
estrene-3,17-dione 3,17-diethylene ketal cyclohemiacetal is prepared by react-
ing 11.beta.-hydroxy-18-iodo-.DELTA.5-estrene-3,17-dione 3,17-diethylene ketal 11.beta.-
trimethylsilyl ether with dimethyl formamide and butyllithium followed by
reaction with water.
33. 11.beta.-Hydroxy-18-formyl-.DELTA.5-estrene-3,17-dione 3,17-diethylene ketal
cyclohemiacetal whenever prepared by the process of claim 32 or by an obvious
chemical equivalent thereof.
34. Process according to claim 15(c) in which X is a hydrogen atom,
R1 and R2 are ethylene ketal groups and a double bond is present in the
5,6-position.
35. Process according to claim 15(c) in which 11.beta.-hydroxy-18-vinyl-.DELTA.5-
estrene-3,17-dione 3,17-diethylene ketal is prepared by reacting triphenyl-
methylidene phosphorane with 11.beta.-hydroxy-18-formyl-.DELTA.5-estrene-3,17-dione
3,17-diethylene ketal.
36. Process according to claim 35 in which the triphenylmethylidene
phosphorane used as reactant is prepared in situ by reaction of methyltri-
phenylphosphonium bromide with dimsylsodium.
37. 11.beta.-Hydroxy-18-vinyl-.DELTA.5-estrene-3,17-dione 3,17-diethylene ketal
whenever prepared by the process of claim 35 or 36 or by an obvious chemical
equivalent thereof.
38. Process for the preparation of 11.beta.-hydroxy-18-alkyl steroids of
the estrane series, characterized in that a 11.beta.-hydroxy-13-methyl-gonane
compound is reacted with an acylhypoiodite and the thus obtained 11.beta.-hydroxy-
13-iodomethyl-gonane compound after protecting the 11.beta.-hydroxy group is reacted
with an alkyl halide in the presence of an alkali metal or with an alkali
metal alkyl compound or with dimethyl formamide in the presence of an alkali
metal alkyl compound followed by a treatment with a proton donor, whereafter
in the latter case the thus obtained 18-carbaldehyde group is reduced or

reacted with Wittig reagent, followed by reduction of the thus obtained
18-alkenyl group.
39. Process according to claim 38 characterized in that the starting
11.beta.-hydroxy-13-methyl-gonane compound has the formula
<IMG> , wherein
R1 = H2, H(OR3), O or ketalised O;
R2 = O, ketalised O, H(OR4) or (.alpha.-alkyl)(.beta.-OR4), the alkyl group
having 1-4 C-atoms and R3 and R4 being H or a protecting group such as acyl
or alkyl; and a double bond is present in the position 4,5 or 5,6.
40. Process according to claim 39 characterized in that in the formula
R1 = H2, H(Oacetyl) or ethylenedioxy; and
R2 = ethylenedioxy, .alpha.H(.beta.Oacetyl) or (.alpha.-alkyl 1-4 C) (.beta.Oacetyl).
41. Process according to claim 38 haracterized in that the acyl
hypoiodite is formed in situ from iodine and an acylate of a heavy metal.
42. Process according to claim 41 characterized in that lead tetra
acetate is used as acylate of a heavy metal.
43. Process according to claim 41 characterized in that per g mol
steroid 0.5-1.5 g mol iodine is used and at least an equivalent amount of
lead tetra acylate.
44. Process according to claim 43 characterized in that per g mol
iodine 1.5-3 g mol of lead tetra acylate is used.
45. Process according to claim 38, 39 or 40 characterized in that
cyclohexane is used as solvent.
26

46. Process according to claim 38 characterized in that in the first
step the reaction is performed in the presence of a radical initiator.
47. Process according to claim 46 characterized in that azoisobutyro-
dinitrile is used as radical initiator.
48. Process according to claims 38-40 characterized in that in the
11.beta.-hydroxy-13-iodo-methyl-compound the 11.beta.-hydroxy group is temporarily
protected in the form of the trimethylsilylether.
49, Process according to claim 38, 39 or 40 characterized in that an
alkyllithium compound with 1-4 C-atoms is used as alkali metal alkyl compound.
50. Process according to claim 38 characterized in that water is used
as proton donor.
51. Process according to claims 38-40 characterized in that an 18-
carbaldehyde compound is reacted with a triarylalkylidene phosphorane
(Wittig reagent) and the 18-alkenyl compound formed is reduced with hydrogen
in the presence of a noble metal catalyst to the corresponding 18-alkyl
compound.
27

52. Process for the preparation of a compound of the formula:
<IMG> IIB
wherein R6 is an iodine atom, a <IMG> group or lower alkenyl group; R5 is a
free or etherified or esterified hydroxyl group; R1 = H2, H(OR3), O or
ketalised O; R2 = 0, ketalised O, H(OR4) or (.alpha.-alkyl)(.beta.-OR4) wherein R3
and R4 are the same or different and represent hydrogen atom or acyl or
alkyl protecting groups, the dotted lines represent optional double bonds,
and where R5 is hydroxy and R6 is <IMG> the two groups can form a cyclo-
hemiacetal group; which comprises either:-
(a) reacting a compound of the formula:
<IMG> (V)a
wherein , R2, R5 and the dotted lines have the same significance as above,
with an acyl hypoiodite; or
(b) reacting a compound of the formula:
(VI)a
<IMG>
wherein R1, R2 and R5 and the dotted lines have the same significance as
above, with dimethylformamide in the presence of an alkali metal alkyl
28

compound followed by treatment with a proton donor; or
(c) reacting a compound of the formula:
<IMG>
(VII)a
wherein R1, R2 and R5 and the dotted lines have the same significance as
above, with a trialkyl- or triaryl- alkylidene phosphorane (a Wittig
reagent); and where any of steps (a), (b) or (c) can be followed by the
additional step of removing any protecting group present in the 3-, 11- or
17-position.
53. A compound of the formula IIB as defined in claim 52 whenever
prepared by the process of claim 52 or by an obvious chemical equivalent
thereof.
29

Description

~0~2~47
.
The present invention relates to a novel process for
the preparation of llp-hydroxy-18-alkyl-estrane compounds
and novel intermediates thereof.
18-Alkyl-estrane compounds are pharmacologically im-
portant 19-nor-steroids. An example of such a compound
is norgestrel (= 17a-ethinyl-l7B-hydroxy-l8-methyl-~4
estren-3-one) which has found application as an oral
progestative and is used i.a. as progestational constit-
, uent in contraceptives. In literature many 18-alkyl-
10 estrane compounds are described with various hormono-
mimetic properties. These compounds are usually found to
have a stronger activity than the corresponding 13 methyl
~,
compounds.
The natural steroid hormones have a methyl group in
,
;~, 15 the 13-position. It is only by way of exception that
this methyl group is substituted, such as in aldosterone.
~! Most synthetic l9-nor-steroids that have found therapeutic
~; application, are prepared on an industrial scale by starting
from natural steroids, modifying and/or eliminating the
20 substituents present in the steroid skeleton and/or
introducing substituents into the steroid and/or
-' introducing or saturating double bonds. In these reactions
the 13-methyl group is left unaffected. Up to now the 18-
alkyl-estrane compounds have been obtained by total
; 25 synthesis whereby the steroid skeleton is built up from
X smaller molecules and the 18-alkyl group is built in by
., .
" proper choice of the starting substances. The total
synthesis is a long and laborious procedure, particularly
due to the presence of the many asymmetric carbon atoms
30 in the steroid skeleton. It is true that many synthetic

106ZZ4 7
problems haYe heen solved by a suitable choice of starting substances and by
finding stereospecific reactions, but nevertheless many isomer separations
and purification steps are still imperative, owing to which the yields are
low and the costprice relatively high. This might likewise be a reason why
18-alkyl-estrane compounds in spite of the promising properties and strong
activities which are mentioned in literature for these compounds, have in
fact found so little actual application.
~he novel process for the preparation of ll~-hydroxy-18-alkyl-
estrane compounds consists therein that (a) the starting substance is an
11~-hydroxy-13-methyl-gonane compound, (b) this steroid is reacted with an
acylhypOiodite and (c) the thus obtained ll~-hydroxy-13-iodo-methyl-gonane
compound, after protection of the ll~-hydroxy group, is reacted with an
alkylhalide in the presence of an alkali metal or with an alkali metal alkyl
compound or with dimethylformamide in the presence of an alkali metal alkyl
compound followed by a treatment with a proton-donor, whereafter in the latter
case the 18-carbaldehyde obtained is reduced to the 18-methyl compound or is
reacted with a trialkyl- or triaryl- alkylidene phosphorane (Wittig reagent),
followed by a reduction of the thus obtained 18-alkenyl-compound to the
corresponding 18-alkyl-compound.
In this manner ll~-hydroxy-18-alkyl-estrane compounds can be pre-
pared in an elegant and simple way without stereoisomeric problems and with
good to excellent yields, which compounds hitherto could only be prepared
- along the more difficult route of the total synthesis.
This invention also relates to a process for the preparation of
a ll~-hydroxy-18-alkyl steroid of the estrane series having the formula:
CH2R
H0 ~ 2
(I) -
~ ~ -2-
.- , . : ~ -

10~;~2247
wherein Rl = H2, ll(OR3), 0 or ketalised 0;
R2 ~ , ketalised 0, H~OR4~ or ~ -alkyl) ~ -OR4), wherein the alkyl
group has l to 4 carbon atoms, R3 and R4 are the same or different and
represent hydrogen atoms or an acyl or alkyl protecting group, R is a lower
alkyl group and the dotted lines represent optional double bonds, which
: comprises either:-
" (a) reacting a corresponding 18-iodo compound of the formula:
H0 ~ 2
(II)
~ \~ \/
: R ~
-~ or a corresponding compound having a protecting group in the ll-position,
wherein Rl and R2 are as hereinbefore defined with an al~ ~ 1 halide of the
formula:
R Hal
wherein Hal is a halogen atom and R is as hereinbefore defined in the presence
of an alkali metal or with an organo metallic compound: :
R Alk
wherein Alk represents an alkali metal and R is as hereinbefore defined; or
:~ (b) reducing a compound of the formula:
H0 ~ _______ c~R2
~ I
~ V (III)
or a cyclic hemi-acetal thereof and where the ll-hydroxy group is either free
.
or protected and Rl and R2 and the dotted lines are as hereinbefore defined;
or
(c~ reducing a compound of the formula:
~ 2a-

106Z247
CH2X
H ~ R2 ~IV~
- ':
.
wherein X is a lower alkenyl group~ the ll hydroxy group is free or protected
and Rl, R2 and the dotted lines are as defined above; and where any of steps
. (a), (b) or ~c) can be followed by ~he additional step of removing any
~: protecting group present in the 3, 11 or 17-positions.
According to ~nother embodiment of this invention there is provided
a process for the prepara~ion of a compound of the formula:
- CH2Rl
'~ XO ~ R2
~ ~IIA)
1~ `
-. where Rl is an iodine atom, a -C~ group or lower alkenyl group,
X is a hydrogen atom or a trialkylsilyl group
Rl = H2, H~OR3), O or ketalised O;
. R2 = . ketalised O, H(OR4) or (~-alkyl)(~-OR4), wherein R3 and
: R4 are the same or different and represent hydrogen atoms or acyl or alkyl ~-
protecting group, the dotted lines represent optional double bonds, and
where X is hydrogen and Rl is -C~ the two groups can form a cyclohemi-
acetal group; which comprises either:
. ~a) reacting a compound of the formula:
CH3
2 CV)
. R ~
E~ ~ -2b-
.. ~ .. .. . . . . .. .. .

~06Z;~47
where X, Rl, R2 and the dotted lines have the same significance as above,
with an acyl hypoiodite; or
(b) reacting a compound of the formula:-
CH I
XO ~L~,, ,
¦ l l (VI)
~' ~
: I I
Rl~ .,
wherein X, Rl, R2 and the dotted lines have the same significance as above,
with dimethyl formamide in the presence of an alkali metal alkyl compound
followed by treatment with a proton donor; or
~` (c) reacting a compound of the formula:
XO~ CII~U~
~VII)
Rl~
., .
wherein X, Rl, R2 and the dotted lines have the same significance as above,
with a trialkyl- or triaryl- alkylidene phosphorane compound (a Wittig
reagent); and where any of steps (a), (b) or (c) can be followed by the
additional step of removing any protecting group present in the 3,11 or
17-position.
Finally, according to yet another embodiment of the invention
there is provided a process for the preparation of a compound of the formula:
R16
CH2
R5 ~ R2 IIB
~ '1~
D'
- ~ -2c-
: -~ . . .
,

1062Z47
wherein R6 is an iodine atom, a -C~ group or lower alkenyl group; R5
is a free or etherified or esterified hydroxyl group; Rl = H2, ~(OR3), O or
ketalised O; R2 = , ketalised O, H(OR4) or (~-alkyl)(~-OR4) wherein R3
and R4 are the same or different and represent hydrogen atom or acyl or
alkyl protecting groups, the dotted lines represent optional double bonds,
and where R5 is hydroxy and R6 is -C~ the two groups can form a
cyclohemiacetal group; which comprises either:-
(a~ reacting a compound of the formula:
5 ~ R2 (V)a
wherein Rl, R2, R5 and the dotted lines have the same significance as above,
with an acyl hypoiodite; or
~b) reacting a compound of the formula:
CH I
2 ~VI~a
~- R
wherein Rl, R2 and R5 and the dotted lines have the same significance as
above, with dimethylformamide in the presence of an alkali metal alkyl
compound followed by treatment with a proton donor; or
(c) reacting a compound of the formula:
. ~
~ ~ -2d-

106ZZ~7
CH2.CHO
R5 ~ R2
~VII)a
: 1`~ .''
wherein Rl, R2 and R5 and the dotted lines have the same significance as
- above, with a trialkyl- or triaryl- alkylidene phosphorane ~a Wittig
reagent); and where any of steps (a), (b) or (c) can be followed by the
additional step of removing any protecting group present in the 3-J 11- or
. 17-position as well as the products of this process.
~', - .
, :
~ . ,
,
~i~
"
~,
:~
..
~,
. .
. ~..i
~ 2e-

106224'7
Advantages of starting with ll~-hydroxy-13-methyl-
gonane compounds are that the presence of the ll~-hydroxy
groups affords the possibility of functionalising the 13-
methyl group by the reaction with an acylhypoiodite and
the possibility of preparing ll-substituted 18-alkyl
compounds in an easier way then by total synthesis.
The ll~-hydroxy-13-methyl-gonane compounds to be used
as starting substances may have substituents in other
positions in the ring-system, such as oxo groups (and
1~ preferably functional derivatives thereof) in the 3 and~
or 17 position; free, esterified or etherified hydroxyl
groups in the 1, 2, 3, 4, 5, 6, 7, 15 and/or 16 position,
` of which the free hydroxyl groups are preferably protected~
during the process of the invention; alkyl groups such as
methyl or ethyl groups in the 1, 6, 7, 9, 11Y and or 16
position; and/or a saturated or unsaturated alkyl group
with 1-4 C-atoms, such as methyl, ethyl, isopropyl,
vinyl, ethynyl, isopropenyl, propadienyl or butenynyl,
in the 17~-position, next to a free, esterified or
~ 20 etherified hydroxyl group in the 17~-position. By func-
; tional derivatives of oxo groups are meant ketalised oxo
groups or oxo groups converted into enol derivatives
thereof such as enol-ethers or enol-esters. Furthermore
! the starting substances may also have double bonds, for
` ~5 example in the 4,5-, 5,6- or 5,10-positions.
Preferred starting substances are ll~-hydroxy-13-
methyl-gonane compounds havin~ the formula:
-- 3 --
. - .. , .. -, ' ' `' , ~ ..

1062Z~7
~0 ~ R~
Rl ~ , wherein
Rl = H2, H(OR3), 0 or ketalised 0;
R2 = ~ ketalised 0, H(OR4) or (a-alkyl) (~OR4), the alkyl
group having 1-4 C-atoms and R3 and R4 being H or a
protecting group such as acyl or alkyl, preferably
acetyl; and
a double bond is present in the position 4, 5 or 5,6.
Specific examples of starting substances are~
hydroxy-~5-estrene-3 t 17-dione 3,17-diethylene ketal,
:~ 15 11~,17~-dihydroxy-~5-estren-3-one 3-ethylene ketal 17-
`~ acetate, ll~-hydroxy-~ -estren-17-one 17-ethylene ketal,
~4-estrene-11~,17~-diol 17-acetate, 11~-hydroxy-~4-estrene-
3,17-dione, 3~ dihydroxy-~5-estren-17-one 3-acetate
17-ethylene ketal, 11~-hydroxy-Q5-estren-17-one 17-
20 ethylene ketal, ~5-estrene-11~,17~-diol 17-acetate,
,17~-dihydroxy-17~-methyl-~5-estren-3-one 3-ethylene
ketal 17-acetate and the corresponding 17a-ethyl compound,
etc.
Known estrane compounds without ll~-hydroxy group can
be easily converted into starting substances for the
process according to the invention by introducing, for
example in a microbiological way, an lla-hydroxyl group,
using e.g. the micro-organism Asperqillus ochraceus,
Rhizopus niqricans or Pestalotia royena and then
oxidizing the lla-hydroxyl group, for example with chromic
.. . .

106Z~47
acid, to the ll-ketone, whereafter the ll-ketone is
converted into the ll~-hydroxy-estrane compound by
reduction, for example, with NaBH4. Thus, l9-nor-
testosterone, for e~ample is converted into 11~-hydroxy-
l9-nor-testosterone via the microbiological route and
last-mentioned compound is reacted with Jones' reagent
to the corresponding 11,17-diketone ~4-estrene-3,11,17-
trione), whereafter this 3,11,17-triketone after
protection of the 3- and 17-oxo group in the form of a
ketal, is converted into 11~-hydroxy-a5-estrene-3,17-
dione 3,17-diketal by reduction with NaBH4.
The 11~-hydroxy group may also be introduced direct-
ly along the microbiological route, for example with the
micro-organism Curvularia lunata.
The ll~-hydroxy-13-methyl-gonane compounds to be
used as starting substances are reacted in the first
- reaction step according to the invention with an acyl
hypoiodite to give an 11~-hydroxy-13-iodo-methylgonane
compound. The acylhypoiodite is preferably formed in
situ from iodine and an acylate of a heavy metal, such
as the acetates, propionates or benzoates of the metals
of the first, second and fourth side-g~oup of the
Periodic System, e.g. the silver, mercury and lead
acylates. Preferably a lead tetra-acylate, such as
; 25 lead tetra acetate, is used, which forms with iodine
a lead di-acylate and an acylhypoiodite. The acylhypo-
~; iodite converts the ll~-hydroxy group into the 11~-
hypoiodite group, whereafter by way of an intramolecular
conversion the ll~-hydroxy-13-iodomethyl compound is
formed.
- 5 -
., . - .

1062Z47
This step is preferably performed by dissolving
or suspending the starting substance in a solvent inert
with regard to the reactants, for example in a hydro-
carbon, such as cyclohexane or methylcyclohexane, or
in a chlorinated hydrocarbon, such as dichloromethane,
carbon tetrachloride or hexachlorobutadiene, adding lead
tetra-acetate and iodine and if necessary a weak alkali,
such as e.g. calcium carbonate, and heating the reaction
mixture while stirring. The reaction can be performed at
normal pressure or raised pressure and, for example, at
the boiling temperature of the solvent under reflux. The
duration of the reaction depends i.a. on the temperature
and on the solvent used. When working with iodine and
lead tetra acetate in cyclohexane under reflux, the
reaction is compl~ted within one hour as a rule. The
temperature is usually kept between 50C and 150C.
An acceleration of the reaction can be achieved by
~ irradiating the reaction mixture with visible and/or
;~ ultra violet light.lHowever, preferably a radical
initiator is added to the reaction mixture for that
purpose. Addition of, for example, azoisobutyrodinitril
turned out to influence the duration of the reaction
very favourably. The amount of radical initiator is not
very critical. With a quantity of 0.1-0.25 gmol per gmol
steroid excellent results are achieved.
i So as to obtain a good yield, the amount of iodine
in the reaction mixture should be such that per gmol
steroid at least 0.5 gmol I2 is present. Preferably a
certain excess of I2 is used, however, usually not
exceeding 1.5 gmol I2 per gmol steroid. The amount of

1062247
lead tetra acylate, expressed in gmol, should at least be
e~ al to the amount o~ I2, but is preferably greater.
Usually 1.5-3 gmol lead tetra acylate is used per gmol I2.
The duration of the reaction is closely connected with
the amount of iodine used. In case of a greater excess or
iodine the reaction time should be shortened to avoid
i that the ll~-hydroxy-13-iodomethyl compound is reacting
again, forming via the ll~-acylhypoiodite thereof the 11~-
hydroxy-13-diiodomethyl compound. The formation of last-
mentioned compound would unfavourably influence the yield
of the desired ll~-hydroxy-13-iodomethyl compound, as a
matter of course.
In boiling cyclohexane and in the presence of a
radical initiator the duration of reaction will, in case
of an amount of 0.5-1.0 gmol I2 per gmol steroid, be
between-about 10 and about 30 minutes; in case of an
amount of about 1.5 gmol I2 per gmol steroid, the
reaction will have been completed in a few minutes.
Of the ll~-hydroxy-13-iodomethyl-gonane compound
obtained in the first step, the ll~-hydroxy group is
then protected temporarily. This can be done effectively
in the form of an ether. Protection as ester is not
effective, because under the circumstances of the next -
reaction step, an ester group will also react.
As protective ether, the trimethylsilylether turned
out to give excellent satisfaction. The etherification
., .
is, for example, performed by reacting the ll~-hydroxy-
steroid with trimethylchlorosilane in a solvent, such as
e.g. pyridine, and at a low temperature.
According to the method of the invention, the 11~-
-- 7 --

1062Z4~
ether of the ll~-hydroxy-13-iodomethyl-gonane compound
is then reacted with an alkylhalide in the presence of
an alkali metal or with an alkali metal alkyl compound
or is reacted with dimethylformamide in the presence of
an alkali metal alkyl compound, followed by a treatment
with a proton-donor.
Preferably an alkyliodide is used as alkylhalide.
The alkali metal is preferably sodium. Examples of
alkyl iodides which are preferably used are the alkyl
iodides with 1-4 C-atoms, such as methyliodide, ethyl-
iodide, propyliodide, butyliodide, isobutyliodide.
As alkali metal alkyl compound, preferably an alkyl-
:^ .
lithium compound is used. Examples of these compounds
preferably used are the alkyllithium compounds with 1-4
C-atoms, such as methyllithium, ethyllithium, butyl-
lithium.
The reaction with the alkylhalide in the presence
of sodium or with the alkyllithium compound is performed
in a solvent under anhydrous conditions at normal
temperatures, for example in dry ether or dry tetra-
hydrofuran, and in a nitrogen atmosphere. In this
manner the ll~-ether of the corresponding ll~-hydroxy-
18-alkyl-estrane compound is obtained from the 11~-
ether of the ll~-hydroxy-13-iodomethyl-gonane compound.
The ether group in the ll-position can be removed
by hydrolysis, for example by treatment with hydro-
chloric acid in acetone.
In case of the reaction with dimethylformamide the
same compounds as mentioned above are used as alkali
metal alkyl compound, for example methyllithium or
,r
- 8 -
' -

106ZZ47
butyllithium. The reaction is performed at room temperature
under anhydrous conditions in an inert solvent, for example
diethylether or hexane. The thus-formed dimethylamino-
carbinol compound in the form of the lithiumalkoxide is
then decomposed to the 18-carbaldehyde by means of a
proton donor. ~s proton donor, water satisfies. ~lso a
diluted ammonium chloride solution can be used or optional-
ly an organic acid, such as oxalic acid. The decomposition
reaction is suitably performed by pouring out the reaction
mixture of the dimethylformamide reaction into water,
optionally containing dissolved ammonium chloride or
oxalic acid. The 18-carbaldehyde is extracted, for example
; with methylene chloride, the extract is evaporated and the
residue is purified, if desired, for example by chromato-
graphy.
`,The 113-hydroxy-18-carbaldehyde compound may also be
present in its isomeric form, the (18a -~ 113)-carbolactol
(the cyclic hemi acetal) with which it is in equilibrium.
The 18-carbaldehyde is then reduced to the 18-methyl
.20 compound or optionally reacted first with Wittig reagent
to give an 18-alkenyl compound, which is then reduced to
the 18-alkyl compound.
The reduction is performed effectively according to
the method of Wolff-Kishner, whereby the carbonyl com-
pound is converted into the hydrazone or semicarbazonethereof and the hydrazone or semicarbazone is decomposed
with alkali. This decomposition is performed with the
aid of potassium hydroxide or with an alkoxide, such
as e.g. sodium ethoxide. Preferably the Huang-Minlon
modification is used, whereby the decomposition is

1062Z47
perfor~ed in a highly boiling solvent, such as diethylene
glycol and the water formed during the reaction is
distilled off.
Tile optional reaction of the 18-carbaldehyde with
Wittig reagent (a triaryl- or trialkyl-alkylidene
phosphorane), for example with triphenylmethylene
phosphorane or triphenylethylidene phosphorane, said
Wittig reagent being prepared in situ from a trialkyl-
- or triarylphosphine, for example triphenylphosphine, and
an alkylhalide, for example methyl- or ethylbromide,
with the aid of a suitable base, such as butyllithium,
ethylmagnesiumbromide, dimethylsodiumamide or dimsyl-
sodium, is performed in a suitable solvent, such as di-
methylsulphoxide, diethylether, dioxane or tetrahydro-
furan.
The thus-obtained 18-alkenyl compound is finally
converted into the alkyl-estrane compound, that can be
done effectively by reduction in a suitable solvent,
`` such as tetrahydrofuran or methanol, with hydrogen in
the presence of a noble metal catalyst, for example Pd/
BaS04 or Adams catalyst (PtO2), preferably also in the
-,;
~ presence of a small amount of acetic acid.
. .,
The ll~-hydroxy-18-alkyl-estrane compounds prepared
by the process of the invention can easily be converted
; 25 into important known compounds such as, for example,
17~-ethinyl-17~-hydroxy-18-methyl-~4-estren-3-one
(= norgestrel) and ll-methylene-17~-ethinyl-17~-hydroxy-
;~ ~ 18-methyl-~4-estren-3-one, both being very active
progestational compounds. For preparing known ll-un-
substituted compounds, the ll~-hydroxy group is oxidised
-- 10 --

106Z247
with chromic acid or by the Oppenauer oxidation method
and the ll-oxo group thus-obtained is reduced by the
method of Wolff-Kishner, whereafter substituents
required elsewhere in the molecule are introduced
` 5 according to methods known per se, such as the introduc-
;; tion of a 17a-ethinyl-17~-hydroxy group in a 17-ketone
` by the well-known reaction with potassium acetylide. Por
preparing ll-methylene compounds, the ll~-hydroxy group
is also oxidised as indicated above and the ll-oxo group
- 10 thus obtained is reacted, for example, with triphenyl-
phosphorylmethylene (Wittig reagent) to give the 11-
methyleen group. (See for example South African Patent
No. 73/9161).
.... .
The 18-iodo and 18-carbaldehyde compounds obtained
according to the invention as intermediates are novel.
~` Thus, the invention therefore also relates to novel
intermediates having the general formula:
. .
~ Q~
~ ~
Rl ~ , wherein
Rl and R2 have the meanings as given hereinbefore;
R5 = a free, esterified or eth~rified hydroxyl group;
R6 = I or C~ ; and
a double bond is present in the 4,5- or 5,6-position.
An ester group that may be present is derived from
an organic carboxylic acid with 1-18 C-atoms. An ether
group, if present, is, for example, the methylether-,
-- 11 --

106~Z47
the ethylether-, the tetrahydropyranylether- or the ~ri-
methylsilylether-group. A ketal group, if present, is,
for example, the ethylene ketal or dimethylketal group.
These novel compounds are not only important
intermediate products for the preparation of pharmacol-
ogically important 18-alkyl-estrane compounds, but have
also interesting estrogenic, progestative, ovulation-
inhibiting and peripheric anti-fertility properties.
The invention will he further illustrated with the
following examples:
Example I
a) 19.8 g of lead tetra acetate (3 x washed with cyclo-
- hexane) and 3.87 g of iodine were suspended in 350 ml
of cyclohexane. The mixture was refluxed for 20
~; minutes and then cooled down to room temperature. Then
9.9 g of ll~-hydroxy-~ -estrene-3,17-dione 3,17-di-
ethylene ketal and 0.69 g of azo-isobutyrodinitril
were added whereafter the mixture was refluxed for
another 20 minutes. The reaction mixture was filtrated
` D~ on hyflo and the filtrate washed with water to neutral.
The organic layer was dried on Na2S04, filtered and
concentrated in vacuo until dry. Weight of the residue:
12.65 g. The residue was taken up in 25 ml of ethanol
and put aside for one night at -20 C. The crystals
- formed were filtered off and dried. In this way 6.21
g of ll~-hydroxy-18-iodo-Q5-estrene-3,17-dione 3,17-
diethylene ketal were obtained. Melting point: 143-
144C.
In a similar manner 11~,17~-dihydroxy-A5-estren-3-one
~)-ademark
- 12 -

106Z247
3-ethylene ketal 17~-acetate, ~4-estrene~ ,17~-diol
17~-acetate, 11~-hydroxy-~5-estren-17-one 17-ethylene
ketal and 11~,17~-dihydroxy-17~-methyl-~ -estren-3-
one 3-ethylene ketal 17~-acetate were converted into
the corresponding 18-iodo compound.
; b) 6.2 g of 11~-hydroxy-18-iodo-~ -estrene-3,17-dione
~- 3~17-diethylene ketal were dissolved in 42 ml of dry
:: .
pyridine. The solution was cooled to 0C and then 6
ml of trimethylchlorosilane were added in one hour.
Subsequently the reaction mixture was stirred for 2
. .
; hours at 0C and then poured out into 0.5 ltr of ice
water. The crystals were filtered off and dried in
vacuo at room temperature on KOH. In this way 6.44 g
~ 15 of 11~-hydroxy-18-iodo-~5-estrene-3,17-dione 11~-
i~ trimethylsilylether 3,17-diethylene ketal were
obtained with a melting point of 153-155C.
~! In a similar manner the other ll~-hydroxy-18-iodo-
compounds mentioned in example I a) were converted
into the corresponding ll~-trimethylsilylethers.
.
,. .
c) To 1.15 g (2 mmol) of 11~-hydroxy-18-iodo-~5-estrene-
3,17-dione 3,17-diethylene ketal ll~-trimethylsilyl-
ether in 20 ml of dry THF, 5 ml of 2 N methyllithium
were added dropwise while the mixture was kept under
N2. After stirring for 4 hours water was added where-
after the etheric layer was separated and the water
layer extracted with ether. The combined organic
layers were dried with Na2S04. After evaporation,the
residue (0.85 g) was chromatographed on 100 g of SiO2
- 13 -
.:,
.. ,............ .. -
, -: ,- . . . . .

1062247
with toluene/ethylacetate 9:1 and 2~ pyridine as
eluent. Obtained: 0.30 g of 11~-hydroxy-18-methyl-~5-
estrene-3,17-dione 3,17-diethylene ketal ll~-tri-
methylsilylether; melting point 168-171 C; Treatment
with concentrated hydrochloric acid in acetone gave
hydroxy-18-methyl-~4-estrene-3,17-dione~
In a similar manner llr~,17~-dihydroxy-~5-estren-3-
one 3-ethylene ketal l~-trimethylsilylether 17~-
acetate, A4-estrene~ ,17~-diol ll~-trimethylsilyl-
ether 17~-acetate, 11~-hydroxy-~5-estren-17-one 17-
ethylene ketal ll~-trimethylsilylether and 11~,17~-
dihydroxy-17~-methyl-~5-estren-3-one 3-ethylene ketal
ll~-trimethylsilylether 17~-acetate gave 11~,17~-di-
hydroxy-18-methyl-~4-estren-3-one, 18-methyl-~4-
estrene-11~,17~-diol, 11~-hydroxy-18-methyl-~ -
estren-17-one and 11~,17~-dihydroxy-17a,18-dimethyl-
-~ ~ -estren-3-one, respectively.
Example II
` 20 500 mg (0.88 mmol) of 11~-hydroxy-18-iodo-~ -estrene-
3,17-dione ll~-trimethylsilylether 3,17-diethylene ketal,
as obtained in Example I b), were dissolved in 30 ml of
dry ether. To this solution 1.0 ml of 20% n-butyllithium
in hexane was added under N2, whereafter the mixture was
stirred for 4 hours at room temperature. Water was added
and the organic layer was separated. After drying of the
organic layer over Na2S04, the mixture was evaporated
and the residue chromatographed on 45 g of silicagel
with toluene/ethylacetate 9:1 + 2~ pyridine as eluent.
The thus-obtained ll~-hydroxy-18-n-butyl-~5-estrene-3,17-
- 14 -

106ZZ47
dione 3,17-diethylene ketal ll~- rimethylsilyle~her was
converted with concentrated hydrochloric acid in acetone
into ll~-hydroxy-18-n-butyl-~4-estrene-3,17-dione;
me]ting point 115-119C.
In a similar manner the other L~-trimethylsilyl-
ethers prcpared in example I b) were converted inro
,17~-dihydroxy-18-n-butyl-~ -estren-3-one, 18-n-
butyl-A4-estrene-llp,17~-diol, 11~-hydroxy-18-n-butyl-
-estren-17-one and 11~,17~-dihydroxy-17~-methyl-18-n-
butyl-a4-estren-3-one, respectively.
:'
Example III
a) 1.15 g of 11~-hydroxy-18-iodo-~5-estrene-3,17-dione
.
~- 3,17-dïethylene ketal ll~-trimethylsilylether were
-~ 15 dissolved in 50 ml diethylether dried on KOH. To this
:
~` solution 2 ml of l.S molar butyllithium in diethyl-
ether were added while the reaction mixture was
` stirred for one hour at room temperature. Then 1.5 ml
:
of distilled dimethylformamide were added. ~ sticky
precipitate was formed immediately. The mixture was
refluxed for another hour. Then the mixture was
- poured out into water and extracted with CH2C12. The
- organic layer was dried on sodium sulphate, filtrated
and evaporated in vacuo until dry. The residue (0.9 g)
was chromatographed on 27 g of SiO2 with toluene/ethyl-
acetate 1:1 + 2% pyridine. In this manner 11~,18a-
.~ epoxy-18a-hydroxy-18-methyl-a5-estrene-3,17-dione
3,17-diethylene ketal (= 11~-hydroxy-18-formyl-~5-
estrene-3,17-dione 3,17-diethylene ketal cyclohemi-
acetal)was obtained; melting point 144-146C (dec.).
- 15 -

1(~62247
In a similar manner the other 18-iodo-11~-trimethyl-
silylethers obtained in example I b) were converted
into the corresponding 11~,18a-epoxy-18a-hydroxy-18-
methyl-compounds.
:`
b) 3.4 9 of 11~-hydroxy-18-formyl-~5-estrene-3,17-dione
3,17-diethylene ketal (cyclohemi-acetal) were
suspended in 33 ml of 100% ethanol, 80 ml of di-
ethylene glycol and 33 ml of hydrazine hydrate. Then
6.8 g of hydrazine-dihydrochloride were added. The ``
mixture was brought at 100 C and kept at this
temperature for 16 hours. After that the reaction
mixture was cooled down to room temperature where-
after 12 g of powdered potassium hydroxide and 240
ml of diethylene glycol were added. The reaction
mixture was brought at 200C while distilling off
- the fractions boiling at lower temperatures. The
mixture was kept at 200 C for l.S hours and then
,~:
cooled down to room temperature, poured out into
2.5 ltr of ice-water while stirring and stirred for
another hour, whereafter the precipitate formed was
filtered off, washed to neutral with water and dried
at 70C in vacuo. After recrystallisation from ethyl-
; acetate 2.4 g of 11~-hydroxy-18-methyl-~ -estrene-
3,17-dione 3,17-diethylene ketal were obtained with
a melting point of 178-181C.
i In a similar manner the other cyclohemi-acetals
obtained in example III a) were converted into the
corresponding ll~-hydroxy-18-methyl-compounds.
.
- 16 -

106Z247
~xam~le IV
a) 1.3 g of sodium hydride (suspension in oil 55_~0D~)
were suspended in 25 ml of dry DMS0. The mixture was
placed in a waterbath of 75 C for one hour and then
cooled down to room temperature. To the cooled mixt~re
a solution of 10.8 g of methyltriphenylphosphonium-
bromide in 35 ml of dry DMS0 was added. After stirring
for 15 minutes at room temperature a suspension of 2.3
g of ll~-hydroxy-18-formyl-~5-estrene-3,17-dione 3,17-
diethylene ketal in 30 ml of dry DMS0 was added. The
whole mixture was stirred for 6 hours in a waterbath
at 50C and then poured out into 1 litre of ice water.
; D The oily residue was filtered off on hyflo~ washed
with water and then a few times with cold methanol/
H20 1:1.
- The filter was washed out with methylene chloride, the
- methylene chloride layer was washed with water, then
dried on Na2S04, filtered off and evaporated in vacuo
to obtain 2.36 g of 11~-hydroxy-18-vinyl-~5-estrene-
3,17-dione 3,17-diethylene ketal.
In a similar manner, the other ll~-hydroxy-18-formyl-
compounds obtained in example III a) were converted
into the corresponding ll~-hydroxy-18-vinyl compounds.
b) 100 mg of platinum-oxide was pre-hydrogenated for half
an hour in a mixture of 40 ml of methanol/tetrahydro-
furan 1:1. rrhen 1 g of 11~-hydroxy-18-vinyl-~5-estrene-
3,17-dione 3,17-diethylene ketal and 0.4 ml of 100%
acetic acid were added. The 18-vinyl-compound was
hydrogenated at room temperature and at 1 ato. ~fter
~ .
T~dema~
- 17 -

1062247
ahsorption of l mol hydrogen pcr mol steroi.d, the
catalyst was filtered off and the reacti.on mixture
evaporated. The residue (0.98 q) was purified by
chromatography on silicagel (toluene/ethyl acetate
9:1 ~ 2% pyridine), to obtain ll~-hydroxy-18-ethyl-
~5-estrene-3,17-dione 3,17-diethylene ketal.
In a similar manner the other 18-vinyl compounds
mentioned in example IV a) were hydrogenated to the
corresponding 18-ethyl compounds.
:.~
...
.
,, ,
i ,
,~,
`,'
.
~ - 18 -