U.S. patent application number 10/834749 was filed with the patent office on 2004-11-18 for novel method and intermediates for preparing 19-norsteroid compounds.
This patent application is currently assigned to Aventis Pharma S.A.. Invention is credited to Benedetti, Francoise, Moratille, Christian, Nait-Bouda, Lahlou, Prat, Denis.
Application Number | 20040229853 10/834749 |
Document ID | / |
Family ID | 33155512 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040229853 |
Kind Code |
A1 |
Prat, Denis ; et
al. |
November 18, 2004 |
Novel method and intermediates for preparing 19-norsteroid
compounds
Abstract
The subject of the invention is a method for preparing compounds
of general formula (I): 1 in which A, Z, R.sub.3 are as defined in
the description, and the intermediate compounds for carrying out
this method.
Inventors: |
Prat, Denis; (Pantin,
FR) ; Moratille, Christian; (Bry Sur Marne, FR)
; Benedetti, Francoise; (Rosny Sous Bois, FR) ;
Nait-Bouda, Lahlou; (Bondy, FR) |
Correspondence
Address: |
ROSS J. OEHLER
AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
Aventis Pharma S.A.
Antony Cedex
FR
|
Family ID: |
33155512 |
Appl. No.: |
10/834749 |
Filed: |
April 29, 2004 |
Current U.S.
Class: |
514/176 ;
514/182; 540/107; 552/626 |
Current CPC
Class: |
A61P 19/10 20180101;
A61K 31/58 20130101; A61K 31/566 20130101 |
Class at
Publication: |
514/176 ;
514/182; 540/107; 552/626 |
International
Class: |
C07J 043/00; A61K
031/58; A61K 031/56; C07J 001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 29, 2003 |
FR |
0305221 |
Claims
What is claimed is:
1) A method for preparing compounds of general formula (I):
55wherein Z is a linear alkyl radical or a group R.sub.4 of the
formula: 56 wherein n is an integer from 2 to 8, and R.sub.1 and
R.sub.2 are identical or different and independently of each other
selected from benzyl, linear, branched or cyclic
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkenyl or
C.sub.1-C.sub.8alkynyl; or R.sub.1 and R.sub.2 taken together with
the nitrogen atom to which they are attached form a saturated or
unsaturated, aromatic or nonaromatic 5- to 6-membered heterocycle
optionally containing from 1 to 3 additional heteroatoms and
optionally fused with another ring; A is a keto functional group or
a group CH--X, wherein X is a halogen atom; R.sub.3 is hydrogen or
a hydroxyl protecting group; comprising: a) subjecting a mixture of
the compounds of formulae (IIIa) and (IIIb): 57 wherein .dbd.K is a
protected keto functional group selected from ketal, thioketal or a
mixed ketal, to an alkylation reaction with an organocuprate
derivative derived from an organometallic compound of formula
R.sub.5MgHal or R.sub.5Li, Hal being a halogen atom and generated
catalytically or stoichiometrically, wherein R.sub.5 is: 58 wherein
Z is as defined above, the bonding taking place on the phenyl; and
reacting with a suitable deprotecting agent so as to obtain the
compounds of formulae (Va), (Vb) and (Vc) 59b) treating the
compounds of formulae (Va), (Vb) and (Vc) with a aromatization
agent so as to obtain a mixture of the compounds of formulae (VI)
and (I): 60which continue to undergo aromatization so as to obtain
the compound of formula (I) wherein R.sub.3 is as defined
above.
2) A method for preparing compounds of general formula (I):
61wherein Z is a linear alkyl radical or a group R.sub.4 of the
formula: 62 wherein n is an integer from 2 to 8; and R.sub.1 and
R.sub.2 are identical or different and independently of each other
selected from benzyl, linear, branched or cyclic
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkenyl or
C.sub.1-C.sub.8alkynyl; or R.sub.1 and R.sub.2 taken together with
the nitrogen atom to which they are attached form a saturated or
unsaturated, aromatic or nonaromatic 5- to 6-membered heterocycle
optionally containing from 1 to 3 additional heteroatoms and
optionally fused with another ring; A is a keto functional group or
a group CH--X, wherein X is a halogen atom; R.sub.3 is hydrogen or
a hydroxyl protecting group; comprising: a) subjecting a compound
of formula (IIIb): 63 wherein .dbd.K is a protected keto functional
group selected from ketal, thioketal or a mixed ketal, to an
alkylation reaction with an organocuprate derivative derived from
an organometallic compound of formula R.sub.5MgHal or R.sub.5Li,
Hal being a halogen atom and generated catalytically or
stoichiometrically, wherein R.sub.5 is: 64wherein Z is as defined
above, the bonding taking place on the phenyl; and reacting with a
suitable deprotecting agent so as to obtain the compounds of
formulae (Vb) and (Vc): 65b) treating the compounds of formulae
(Vb) and (Vc) with a aromatization agent so as to obtain the
mixture of the compounds of formulae (VI) and (I): 66which continue
to undergo aromatization so as to obtain the compound of formula
(I) wherein R.sub.3 is as defined above.
3) The method as set forth in claim 1, wherein the compounds of
general formula (I) in which A is a keto functional group are
prepared comprising the following steps: a) epoxidizing a compound
of formula (II): 67 wherein .dbd.K is a protected keto functional
group selected from ketal, thioketal or a mixed ketal, so as to
obtain the mixture of the alpha and beta isomers of formulae
(III'a) and (III'b): 68b) subjecting the mixture of the compounds
of formulae (III'a) and (III'b) to an alkylation reaction with an
organocuprate derivative derived from an organometallic compound of
formula R.sub.5MgHal or R.sub.5Li, Hal being a halogen atom and
R.sub.5 is as defined in claim 1, the bonding taking place on the
phenyl; and reacting with a suitable deprotecting agent so as to
obtain the compounds of formulae (V'a), (V'b) and (V'c): 69c)
treating the compounds of formulae (V'a), (V'b) and (V'c) with a
aromatization agent so as to obtain a mixture of the compounds of
formulae (VI') and (I) in which A is a keto functional group: 70
which continue to undergo aromatization so as to obtain the
compound of formula (I) in which A is a keto functional group; d)
deprotecting, where appropriate, the product obtained in step c so
as to obtain a compound of formula (I) in which A is a keto
functional group and R.sub.3 is hydrogen; and optionally e) forming
a salt of the compound of formula (I) by subjecting it to a
salinification reaction.
4) The method as set forth in claim 2, wherein the compounds of
general formula (I) in which A is a keto functional group are
prepared comprising the following steps: a) epoxidizing a compound
of formula (II): 71 wherein .dbd.K is a protected keto functional
group selected from ketal, thioketal or a mixed ketal, so as to
obtain the beta isomer of formula (III'b): 72b) subjecting the
compound of formula (III'b) to an alkylation reaction with an
organocuprate derivative derived from an organometallic compound of
formula R.sub.5MgHal or R.sub.5Li, Hal being a halogen atom and
R.sub.5 is as defined in claim 2, the bonding taking place on the
phenyl; and reacting with a suitable deprotecting agent so as to
obtain the compounds of formulae (V'b) and (V'c): 73c) treating the
compounds of formulae (V'b) and (V'c) with a aromatization agent so
as to obtain a mixture of the compounds of formulae (VI') and (I)
in which A is a keto functional group: 74which continue to undergo
aromatization so as to obtain the compound of formula (I) in which
A is a keto functional group; d) deprotecting, where appropriate,
the product obtained in step c so as to obtain the compound of
formula (I) in which A is a keto functional group and R.sub.3 is
hydrogen; and optionally e) forming a salt of the compound of
formula (I) by subjecting it to a salinification reaction.
5) The method as set forth in claim 3, wherein the alkylation
reaction is accompanied by an enolization reaction.
6) The method as set forth in claim 4, wherein the alkylation
reaction is accompanied by an enolization reaction.
7) The method as set forth in claim 3, further comprising a step of
treating the compounds of formulae (III'a) and (III'b) with a
silylating agent in the presence of a base so as to obtain a
mixture of silylated enols of formulae (IVa) and (IVb): 75wherein,
Ra, Rb and Rc, which are identical or different, represent
C.sub.1-C.sub.4alkyl or phenyl; and reacting the compounds of
formulae (IVa) and (IVb) with an organocuprate derivative as
defined in claim 3, the bonding taking place on the phenyl, so as
to obtain the compounds of formulae (IV'a) and (IV'b) which are
isolated or not isolated: 76deprotecting said products so as to
obtain respectively the compounds of formulae (V'a), (V'b) and
(V'c) as defined in claim 3.
8) The method as set forth in claim 4, further comprising a step of
treating the compound of formula (III'b) with a silylating agent in
the presence of a base so as to obtain the silylated enol of
formula (IVb): 77wherein Ra, Rb and Rc, which are identical or
different, represent C.sub.1-C.sub.4alkyl or phenyl; and reacting
the compound of formula (IVb) with an organocuprate derivative as
defined in claim 4, the bonding taking place on the phenyl, so as
to obtain the compound of formula (IV'b) which is isolated or not
isolated: 78deprotecting said product so as to obtain respectively
the compounds of formulae (V'b) and (V'c) as defined in claim
4.
9) The method as set forth in claim 7, wherein Ra, Rb and Rc are
identical and represent a methyl.
10) The method as set forth in claim 8, wherein Ra, Rb and Rc are
identical and represent a methyl.
11) The method as set forth in claim 3, wherein .dbd.K is a cyclic
ketal.
12) The method as set forth in claim 3, wherein .dbd.K is
3,3-ethylenedioxy.
13) The method as set forth in claim 4, wherein .dbd.K is a cyclic
ketal.
14) The method as set forth in claim 4, wherein .dbd.K is
3,3-ethylenedioxy.
15) The method as set forth in claim 3, wherein (ZO--) is at the
para-position and Z is R.sub.4, with n equal to 2.
16) The method as set forth in claim 4, wherein (ZO--) is at the
para-position and Z is R.sub.4, with n equal to 2.
17) The method as set forth in claim 15, wherein R.sub.1 and
R.sub.2 are identical and represent a linear alkyl group, chosen
from methyl or ethyl.
18) The method as set forth in claim 16, wherein R.sub.1 and
R.sub.2 are identical and represent a linear alkyl group, chosen
from methyl or ethyl.
19) The method as set forth in claim 3, wherein (ZO--) is at the
meta or para position, and Z is methyl.
20) The method as set forth in claim 4, wherein (ZO--) is at the
meta or para position, and Z is methyl.
21) The method as set forth in claim 1, wherein compounds of
formula (I) in which A is CH--X and Z is R.sub.4, are prepared
comprising the following steps: a) subjecting a compound of formula
(II): 79 wherein .dbd.K is a protected keto functional group
selected from ketal, thioketal or a mixed ketal, to the action of
an agent reducing the keto at the 17-position so as to obtain a
compound of formula (VII): 80b) treating the compound of formula
(VII) with a halogenating agent so as to obtain a compound of
formula (VIII): 81wherein X is halogen; c) subjecting the compound
of formula (VIII) to the action of an epoxidation reagent so as to
obtain the mixture of the compounds of formulae (III"a) and (III"b)
82d) subjecting the compounds of formulae (III"a) and (III"b) to an
alkylation reaction with an organocuprate derivative derived from
an organometallic compound of formula R.sub.5MgHal or R.sub.5Li,
Hal being a halogen atom and R.sub.5 is of the formula: 83wherein
R.sub.4 is as defined in claim 1, the bonding taking place on the
phenyl; and subjecting to the action of a deprotecting agent so as
to obtain the compounds of formulae (V"a), (V"b) and (V"c): 84e)
treating the compounds of formulae (V"a), (V"b) and (V"c) with a
aromatization agent so as to obtain the mixture of the compounds of
formulae (VI") and (I) in which A represents a group CH--X and Z
represents a group R.sub.4, 85which continue to undergo
aromatization so as to obtain the compound of formula (I) as
defined above; f) deprotecting, where appropriate, the product
obtained in step e so as to obtain a compound of formula (I) in
which A represents a group CH--X, Z represents a group R.sub.4, and
R.sub.3 is hydrogen; and optionally forming a salt of the compound
of formula (I) by subjecting it to a salinification reaction and
neutralization.
22) The method as set forth in claim 21, wherein .dbd.K is a cyclic
ketal.
23) The method as set forth in claim 21, wherein .dbd.K is
3,3-ethylenedioxy.
24) The method as set forth in claim 21, wherein X is fluorine.
25) The method as set forth in claim 21, wherein R.sub.1 and
R.sub.2 taken together with the nitrogen atom to which they are
attached form a group: 86and wherein n is equal to 2.
26) The method as set forth in claim 1, wherein the aromatization
agent is acetyl bromide in the presence of acetic anhydride.
27) The method as set forth in claim 2, wherein the aromatization
agent is acetyl bromide in the presence of acetic anhydride.
28) The method as set forth in claim 21, wherein the aromatization
agent is acetyl bromide in the presence of acetic anhydride.
29) The method as set forth in claim 1, wherein the deprotecting
agent used to obtain the compounds of formulae (Va), (Vb), or (Vc)
is an agent allowing acid hydrolysis, such as hydrochloric acid or
perchloric acid.
30) The method as set forth in claim 2, wherein the deprotecting
agent used to obtain the compounds of formulae (Vb) or (Vc) is an
agent allowing acid hydrolysis, such as hydrochloric acid or
perchloric acid.
31) A compound of general formula (IV'b): 87wherein Z is a linear
alkyl radical or a group R.sub.4 of the formula: 88wherein n is an
integer from 2 to 8, and R.sub.1 and R.sub.2 are identical or
different and independently of each other selected from benzyl,
linear, branched or cyclic C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8alkenyl or C.sub.1-C.sub.8alkynyl; or R.sub.1 and
R.sub.2 taken together with the nitrogen atom to which they are
attached form a saturated or unsaturated, aromatic or nonaromatic
5- to 6-membered heterocycle optionally containing from 1 to 3
additional heteroatoms and optionally fused with another ring;
.dbd.K is a protected keto functional group selected from ketal,
thioketal or a mixed ketal; and Ra, Rb and Rc are each methyl.
32) The compound as set forth in claim 31 wherein (ZO--) is at the
para position.
33) A compound of general formula (VI') as set forth in claim 3,
wherein R.sub.3 is an acyl group.
34) The compound as set forth in claim 33, wherein (ZO--) is at the
para position.
35) A compound of general formula (VIII) as set forth in claim 21,
wherein .dbd.K is 3,3-ethylenedioxy and X is fluorine.
36) A compound of general formulae (III"a) or (III"b) as set forth
in claim 21, wherein .dbd.K is 3,3-ethylenedioxy and X is
fluorine.
37) A compound of general formulae (V"a), (V"b) or (V"c) as set
forth in claim 21, wherein X is fluorine, n is equal to 2, and
R.sub.1 and R.sub.2 taken together with the nitrogen atom to which
they are attached form a group 89
38) A compound of general formula (VI") as set forth in claim 21,
wherein R.sub.3 is an acyl group, X is fluorine, n is equal to 2,
and R.sub.1 and R.sub.2 taken together with the nitrogen atom to
which they are attached form a group 90
39) A compound of general formula (I) as set forth in claim 1,
wherein R.sub.3 is an acyl group, X is fluorine, n is equal to 2,
and R.sub.1 and R.sub.2 taken together with the nitrogen atom to
which they are attached form a group 91
Description
[0001] This application claims the benefit of priority of French
Patent Application No. 03/05,221, filed Apr. 29, 2003.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The subject of the present invention is a method for
preparing 19-norsteroid compounds, and the intermediate compounds
prepared during the use of this method.
[0004] 2. Description of the Art
[0005] Osteoporosis is a bone disease which affects 50 million
people worldwide, more particularly women. Its development is
linked to age and begins most often after the menopause. This
disease is characterized by a reduction in bone density, causes
deformations, vertebral compression and in time spontaneous
fractures. Osteoporosis therefore represents a serious challenge
for public health. The main treatment consists in taking estrogens
regularly, which reduces bone loss but which, nevertheless, may be
accompanied by certain side effects (bleeding, hot flushes, risk of
breast cancer, and the like). A novel series of molecules called
SERM (Selective Estrogen Receptor Modulator) allows the treatment
of osteoporosis while avoiding some of the side effects
(WO98/45316, WO99/67274, WO98/28324, WO99/25725, EP605193,
WO02/100880).
[0006] The subject of the present application is the development of
a novel method for preparing a key intermediate (compound of
formula I) in the synthesis of certain estrogen derivatives having
a dissociated activity.
[0007] All of the references described herein are incorporated
herein by reference in their entirety.
SUMMARY OF THE INVENTION
[0008] The subject of the invention is a method for preparing
compounds of general formula (I): 2
[0009] in which
[0010] Z represents a linear alkyl radical or a group R.sub.4 of
the formula: 3
[0011] in which n is an integer from 2 to 8, and
[0012] either R.sub.1 and R.sub.2, which are identical or
different, represent a benzyl group or a linear, branched or cyclic
alkyl, alkenyl or alkynyl radical containing from 1 to 8 carbon
atoms,
[0013] or R.sub.1 and R.sub.2 taken together with the nitrogen atom
to which they are attached form a saturated or unsaturated,
aromatic or nonaromatic 5- to 6-membered heterocycle optionally
containing from 1 to 3 additional heteroatoms and optionally fused
with another ring,
[0014] A represents a keto functional group or a group CH--X,
[0015] X representing a halogen atom,
[0016] R.sub.3 represents a hydrogen atom or a group protecting the
hydroxyl functional group,
[0017] comprising the following steps
[0018] a) the mixture of the compounds of formulae (IIIa) and
(IIIb): 4
[0019] wherein .dbd.K representing a keto functional group
protected in particular in ketal, thioketal or mixed ketal
form,
[0020] is subjected to an alkylation reaction with an organocuprate
derivative derived from an organometallic compound of formula
R.sub.5MgHal or R.sub.5Li, Hal being a halogen atom and generated
catalytically or stoichiometrically, in which R.sub.5 represents
the group: 5
[0021] Z being as defined above, the bonding taking place on the
phenyl,
[0022] and then to the action of a deprotecting agent so as to
obtain the compounds of formulae (Va), (Vb) and (Vc): 6
[0023] b) the compounds of formulae (Va), (Vb) and (Vc) are treated
with an aromatization agent so as to obtain the mixture of the
compounds of formulae (VI) and (I): 7
[0024] which continue to undergo aromatization so as to obtain the
compound of formula (I), R.sub.3 being as defined above.
[0025] The subject of the invention is also a method for preparing
compounds of general formula (I) 8
[0026] in which
[0027] Z represents a linear alkyl radical or a group R.sub.4 of
the formula: 9
[0028] in which n is an integer from 2 to 8, and
[0029] either R.sub.1 and R.sub.2, which are identical or
different, represent a benzyl group or a linear, branched or cyclic
alkyl, alkenyl or alkynyl radical containing from 1 to 8 carbon
atoms,
[0030] or R.sub.1 and R.sub.2 taken together with the nitrogen atom
to which they are attached form a saturated or unsaturated,
aromatic or nonaromatic 5- to 6-membered heterocycle optionally
containing from 1 to 3 additional heteroatoms and optionally fused
with another ring,
[0031] A represents a keto functional group or a group CH--X,
[0032] X representing a halogen atom,
[0033] R.sub.3 represents a hydrogen atom or a group protecting the
hydroxyl functional group,
[0034] comprising the following steps
[0035] a) the compound of formula (IIIb): 10
[0036] wherein .dbd.K representing a keto functional group
protected in particular in ketal, thioketal or mixed ketal
form,
[0037] is subjected to an alkylation reaction with an organocuprate
derivative derived from an organometallic compound of formula
R.sub.5MgHal or R.sub.5Li, Hal being a halogen atom and generated
catalytically or stoichiometrically, in which R.sub.5 represents
the group 11
[0038] Z being as defined above, the bonding taking place on the
phenyl,
[0039] and then to the action of a deprotecting agent so as to
obtain the compounds of formulae (Vb) and (Vc): 12
[0040] b) the compounds of formulae (Vb) and (Vc) are treated with
an aromatization agent so as to obtain the mixture of the compounds
of formulae (VI) and (I) 13
[0041] which continue to undergo aromatization so as to obtain the
compound of formula (I), R.sub.3 being as defined above.
[0042] The group (ZO--) may be at the ortho, meta or para
position.
DETAILED DESCRIPTION OF THE INVENTION
[0043] As an example of a linear alkyl radical which Z may
represent, there may be mentioned methyl, ethyl, propyl, butyl,
pentyl, hexyl and octyl radicals. The linear alkyl radical which Z
may represent is preferably methyl.
[0044] As an example of a linear or branched alkyl radical
containing from 1 to 8 carbon atoms which R.sub.1 and R.sub.2 may
represent, there may be mentioned methyl, ethyl, propyl, butyl,
pentyl, hexyl and octyl radicals, and the branched isomers of these
radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl,
3-methylpentyl, sec-butyl, tert-butyl and tert-pentyl. The
preferred alkyl radicals are methyl and ethyl.
[0045] As an example of a cyclic alkyl radical which R.sub.1 and
R.sub.2 may represent, there may be mentioned cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
radicals which may be substituted for example with an alkyl group
containing from 1 to 4 carbon atoms.
[0046] As an example of an alkenyl radical which R.sub.1 and
R.sub.2 may represent, there may be mentioned allyl, butenyl and
3-methyl-2-butenyl radical. As an example of alkynyl radicals,
there may be mentioned the propargyl radical. Of course these
alkenyl or alkynyl radicals contain at least 2 carbon atoms and are
attached to the nitrogen atom via a group --CH.sub.2--.
[0047] As an example of a heterocycle which R.sub.1 and R.sub.2 may
form together with the nitrogen atom to which they are attached,
there may be mentioned in particular mono- or bicyclic heterocycles
optionally containing another heteroatom chosen from oxygen and
nitrogen, such as the following unsaturated heterocycles: pyrrolyl,
imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
thiazolyl, oxazolyl, furazolinyl, pyrazolinyl; or such as the
following saturated heterocycles: morpholinyl, pyrrolidinyl,
piperidinyl, oxazolidinyl, thiazolidinyl. It will be preferably the
group: 14
[0048] As an example of a halogen atom which Hal may represent,
there may be mentioned chlorine, iodine or bromine.
[0049] As an example of a halogen atom which X may represent, there
may be mentioned chlorine, bromine, iodine or fluorine. It is
preferably fluorine.
[0050] As an example of a protecting group which R.sub.3 may
represent, there may be mentioned in particular a group
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl-CO-- such as
CH.sub.3CO or benzoyl, benzyl, phenyl-(C.sub.1-C.sub.6)-alkyl such
as benzyl, and all the protecting groups known to persons skilled
in the art, for example those described in Greene, Wuts, Protective
Groups in Organic Synthesis 3rd edition, Wiley & sons, 1999.
Preferably R.sub.3, by way of a protecting group, is an acyl
group.
[0051] As an example of a group protecting the keto at the
3-position of the steroid which .dbd.K may represent, there may be
mentioned
[0052] cyclic ketals such as --O--(CH.sub.2).sub.m--O--,
--O--(CH.sub.2).sub.n--S--, --S--(CH.sub.2).sub.m--S--,
--O--CH.sub.2--C(C.sub.1-4-alkyl).sub.2--CH.sub.2--
[0053] O--, wherein m is an integer from 1 to 4.
[0054] acyclic ketals such as (CH.sub.3O).sub.2, (EtO).sub.2,
[0055] as well as all the groups protecting the keto group which
are known to persons skilled in the art, for example those
described in Greene, Wuts, Protective Groups in Organic Synthesis
3rd edition, Wiley & sons, 1999. Preferably, .dbd.K is a cyclic
ketal, and in particular a 3,3-ethylenedioxy group.
[0056] As used herein the term "salinification" means subjecting
the compound under consideration to a salt forming reaction so as
to obtain a salt of said compound.
[0057] The subject of the invention is more particularly a method
for preparing, as defined above, compounds of general formula (I)
in which A is a keto functional group, comprising the following
steps
[0058] a) a compound of formula (II) 15
[0059] .dbd.K representing a keto functional group protected in
particular in ketal, thioketal or mixed ketal form, is subjected to
the action of an epoxidation reagent so as to obtain the mixture of
the alpha and beta isomers of formulae (III'a) and (III'b) 16
[0060] b) the mixture of the compounds of formulae (III'a) and
(III'b) is subjected to an alkylation reaction with an
organocuprate derivative derived from an organometallic compound of
formula R.sub.5MgHal or R.sub.5Li, Hal being a halogen atom and
R.sub.5 being as defined above, the bonding taking place on the
phenyl,
[0061] and then to the action of a deprotecting agent so as to
obtain the compounds of formulae (V'a), (V'b) and (V'c): 17
[0062] c) the compounds of formulae (V'a), (V'b) and (V'c) are
treated with a aromatization agent so as to obtain the mixture of
the compounds of formulae (VI') and (I) in which A is a keto
functional group: 18
[0063] which continue to undergo aromatization so as to obtain the
compound of formula (I) in which A is a keto functional group,
[0064] d) where appropriate, the product obtained in step c is
deprotected so as to obtain a compound of formula (I) in which A is
a keto functional group and R.sub.3 represents a hydrogen atom,
[0065] which is subjected, where appropriate, to a salinification
reaction.
[0066] The subject of the invention is more particularly a method
for preparing, as defined above, compounds of general formula (I)
in which A is a keto functional group, comprising the following
steps
[0067] a) a compound of formula (II): 19
[0068] .dbd.K representing a keto functional group protected in
particular in ketal, thioketal or mixed ketal form, is subjected to
the action of an epoxidation reagent so as to obtain the beta
isomer of formula (III'b) 20
[0069] b) the compound of formula (III'b) is subjected to an
alkylation reaction with an organocuprate derivative derived from
an organometallic compound of formula R.sub.5MgHal or R.sub.5Li,
Hal being a halogen atom and R.sub.5 being as defined above, the
bonding taking place on the phenyl,
[0070] and then to the action of a deprotecting agent so as to
obtain the compounds of formulae (V'b) and (V'c): 21
[0071] c) the compounds of formulae (V'b) and (V'c) are treated
with an aromatization agent so as to obtain the mixture, of the
compounds of formulae (VI') and (I) in which A is a keto functional
group: 22
[0072] which continue to undergo aromatization so as to obtain the
compound of formula (I) in which A is a keto functional group,
[0073] d) where appropriate, the product obtained in step c is
deprotected so as to obtain a compound of formula (I) in which A is
a keto functional group and R.sub.3 represents a hydrogen atom,
[0074] which is subjected, where appropriate, to a salinification
reaction.
[0075] The epoxidation reaction is a standard reaction which is
carried out according to methods known to persons skilled in the
art. It may be carried out in particular in the presence of
hexachloroacetone, dichloromethane and hydrogen peroxide.
[0076] The alkylation reaction with an organocuprate derivative
derived from an organometallic compound of formula R.sub.5MgHal or
R.sub.5Li, Hal and R.sub.5 being as defined above, is carried out
according to standard methods known to persons skilled in the
art.
[0077] The deprotection reaction which makes it possible to obtain
the compounds of formulae (V'a), (V'c), or (V'b) is carried out
according to standard methods known to persons skilled in the art.
The deprotecting agent used is in particular an agent allowing acid
hydrolysis, such as hydrochloric acid or perchloric acid.
[0078] The aromatization reaction is a standard reaction which is
carried out in particular according to the methods described in EP
298,020. This aromatization may be carried out by catalysis with
palladium, or preferably in the presence of acetyl bromide and
acetic anhydride.
[0079] The deprotection of the acetyl group formed at the
3-position, where appropriate, is carried out in general in the
presence of a strong base such as sodium hydroxide or potassium
hydroxide, in an alcohol solvent, such as methanol or ethanol. It
is preferably carried out in the presence of sodium hydroxide in
methanol.
[0080] The salinification reaction is carried out by conventional
methods known to persons skilled in the art.
[0081] The subject of the invention is most particularly a method
as defined above, characterized in that the alkylation reaction is
accompanied by an enolization reaction of the keto functional group
at the 17-position. The enolization reaction is carried out
according to standard conditions known to persons skilled in the
art. It is carried out in particular by the action of an additional
equivalent of a Grignard reagent.
[0082] The subject of the invention is most particularly a method
as defined above, characterized in that the compounds of formulae
(III'a) and (III'b) are treated with a silylating agent in the
presence of a base so as to obtain the mixture of silylated enols
of formulae (IVa) and (IVb): 23
[0083] in which, Ra, Rb and Rc, which are identical or different,
represent an alkyl radical containing from 1 to 4 carbon atoms, or
a phenyl radical,
[0084] which is reacted with an organocuprate derivative as defined
above, the bonding taking place on the phenyl, so as to obtain the
compounds of formulae (IV'a) and (IV'b) which are either isolated
or used as such in the next step: 24
[0085] said products then being deprotected so as to obtain the
compounds of formulae (V'a), (V'b), (V'c) as defined above.
[0086] The subject of the invention is most particularly a method
as defined above, characterized in that the compound of formula
(III'b) is treated with a silylating agent in the presence of a
base so as to obtain the silylated enol of formula (IVb) 25
[0087] in which Ra, Rb and Rc, which are identical or different,
represent an alkyl radical containing from 1 to 4 carbon atoms, or
a phenyl radical, which is reacted with an organocuprate derivative
as defined above, the bonding taking place on the phenyl, so as to
obtain the compound of formula (IV'b) which is either isolated or
used as such in the next step: 26
[0088] said product then being deprotected so as to obtain the
compounds of formulae (V'b), (V'c) as defined above.
[0089] As silylating agent, there may be mentioned all the agents
capable of silylating enols or enolates known to persons skilled in
the art and cited in the monograph Van Look, G.; Simchen, G.;
Heberle, J., Silylating Agents; Fluka Chimica, Fluka Chemie AG;
Buchs, Switzerland, 1995. It may preferably be a chlorosilane such
as trimethylchlorosilane.
[0090] This silylation reaction is generally carried out in the
presence of a strong base such as Li-HMDS
((Me.sub.3Si).sub.2N--Li), or LDA ((iPr).sub.2N--Li).
[0091] The solvents used are known to persons skilled in the art
for this type of reaction. Protic or enolizable solvents should be
avoided. Preferably, the silylation reaction will be carried out
with ClSiMe.sub.3 in the presence of LDA or Li-HMDS in a mixture of
THF and solvents such as pentane, hexanes, cyclohexane, heptane and
toluene.
[0092] The alkylation reaction is carried out by coupling of the
organometallic compound of formula R.sub.5MgHal or R.sub.5Li with
the silylated derivatives of formulae (IVb) and/or (IVa) according
to standard conditions known to persons skilled in the art.
[0093] The subject of the invention is more particularly a method
as defined above, characterized in that the silylated derivative is
a trimethylsilyl derivative which makes it possible to obtain the
silylated enols of formulae (IVb) and/or (IVa) in which Ra, Rb and
Rc are identical and represent a methyl.
[0094] The subject of the invention is more particularly a method
as defined above, characterized in that .dbd.K represents a keto
functional group protected in the form of a cyclic ketal, such as
3,3-ethylenedioxy.
[0095] The subject of the invention is more particularly a method
as defined above, characterized in that (ZO--) is at the para
position and Z represents a group R.sub.4, with n equal to 2.
[0096] The subject of the invention is more particularly a method
as defined above, characterized in that R.sub.1 and R.sub.2 are
identical and represent a linear alkyl group, such as the methyl or
ethyl radicals.
[0097] The subject of the invention is most particularly a method
as defined above, characterized in that (ZO--) is at the meta or
para position, and Z represents a linear alkyl radical such as the
methyl radical.
[0098] The subject of the invention is also a method for preparing,
as defined above, compounds of formula (I) as defined above in
which A represents a group CH--X and Z represents a group R.sub.4,
comprising the following steps:
[0099] a) a compound of formula (II): 27
[0100] wherein .dbd.K representing a keto functional group
protected in particular in ketal, thioketal or mixed ketal
form,
[0101] is subjected to the action of an agent reducing the keto at
the 17-position so as to obtain a compound of formula (VII): 28
[0102] b) the compound of formula (VII) is treated with a
halogenating agent so as to obtain a compound of formula (VIII):
29
[0103] in which X represents a halogen atom,
[0104] c) the compound of formula (VIII) is subjected to the action
of an epoxidation reagent so as to obtain the mixture of the
compounds of formulae (III"a) and 30
[0105] d) the compounds of formulae (III"a) and (III"b) are
subjected to an alkylation reaction with an organocuprate
derivative derived from an organometallic compound of formula
R.sub.5MgHal or R.sub.5Li, Hal being a halogen atom and R.sub.5
representing the group: 31
[0106] R.sub.4 being as defined above, the bonding taking place on
the phenyl,
[0107] and then to the action of a deprotecting agent so as to
obtain the compounds of formulae (V"a), (V"b) and (V"c): 32
[0108] e) the compounds of formulae (V"a), (V"b) and (V"c) are
treated with a aromatization agent so as to obtain the mixture of
the compounds of formulae (VI") and (I) in which A represents a
group CH--X and Z represents a group R.sub.4, 33
[0109] which continue to undergo aromatization so as to obtain the
compound of formula (I) as defined above,
[0110] f) where appropriate, the product obtained in step e is
deprotected so as to obtain a compound of formula (I) in which A
represents a group CH--X, Z represents a group R.sub.4, and R.sub.3
represents a hydrogen atom,
[0111] which is subjected, where appropriate, to salinification and
neutralization.
[0112] The reduction of the 17-keto to an alcohol is carried out
according to standard methods, in particular by the action of an
alkali metal borohydride such as sodium borohydride in methanol or
ethanol or by the action of lithium aluminum hydride in THF. This
reaction makes it possible to obtain in particular the alcohol at
the 17beta-position.
[0113] The halogenation reaction which follows is carried out in
particular with reagents such as XSO.sub.2C.sub.4F.sub.9 in the
presence of a hindered base such as DBU (diazabicycloundecene), X
is preferably fluorine. Other methods known to persons skilled in
the art may also be used.
[0114] The halogenation reaction may be carried out in particular
in the presence of perfluorobutanesulfonyl fluoride, hydrofluoric
acid/triethylamine complex ((HF).sub.3/TEA) and DBU.
[0115] The alkylation reaction with an organocuprate derivative
derived from an organometallic compound R.sub.5MgHal or R.sub.5Li,
Hal and R.sub.5 being as defined above, is carried out according to
standard methods known to persons skilled in the art.
[0116] The aromatization reaction followed by the saponification
reaction is carried out according to standard methods as described
in European patent 0097572. This aromatization may be preferably
carried out in the presence of acetyl bromide and acetic
anhydride.
[0117] Where appropriate, the deprotection of the formed acetyl
group is carried out in general in the presence of a strong base,
such as sodium hydroxide or potassium hydroxide, in an alcohol,
such as methanol or ethanol.
[0118] The salinification and neutralization reactions are carried
out by standard methods known to persons skilled in the art.
[0119] The subject of the invention is more particularly a method
as defined above, characterized in that .dbd.K represents a keto
functional group protected in cyclic ketal form, such as
3,3-ethylenedioxy.
[0120] The subject of the invention is more particularly a method
as defined above, characterized in that X represents a fluorine
atom.
[0121] The subject of the invention is most particularly a method
as defined above, characterized in that R.sub.1 and R.sub.2 taken
together with the nitrogen atom to which they are attached form a
group: 34
[0122] and wherein n is equal to 2.
[0123] The compounds of formula (II) are compounds which are known
or easily accessible to persons skilled in the art. In particular,
the compounds of formula (II) in which .dbd.K is a
3,3-ethylenedioxy group are described in the article Crocq, V. et
al.; Org. Process. Res. Dev. 1997, 1, 2.
[0124] The compounds of formulae (IIIa) and (IIIb) are known
compounds. In particular, the compounds of formulae (IIIa) and
(IIIb) in which .dbd.K is a 3,3-ethylenedioxy group and A
represents a keto functional group, are described in the article
Larkin, J. P. et al.; Org. Process. Res. Dev. 2002, 6, 20.
[0125] The subject of the invention is also, as novel intermediate
products,
[0126] the compound of general formula (IV'b) as defined above and
in which Ra, Rb and Rc are identical and represent a methyl,
[0127] the compound of general formula (VI') as defined above and
in which R.sub.3 represents an acyl group.
[0128] The subject of the invention is more particularly, as novel
intermediate products,
[0129] the compound of general formula (IV'b) as defined above in
which (ZO--) is at the para position,
[0130] the compound of general formula (VI') as defined above in
which (ZO--) is at the para position.
[0131] The subject of the invention is also, as novel intermediate
compounds,
[0132] the compound of general formula (VIII) in which .dbd.K
represents 3,3-ethylenedioxy, n is equal to 2, and X represents a
fluorine atom,
[0133] the compounds of general formulae (III"a) and (III"b) in
which .dbd.K represents 3,3-ethylenedioxy, n is equal to 2, and X
represents a fluorine atom,
[0134] the compounds of general formulae (V"a), (V"b) and (V"c) in
which X represents a fluorine atom, n is equal to 2, and R.sub.1
and R.sub.2 taken together with the nitrogen atom to which they are
attached form a group 35
[0135] the compound of general formula (VI") in which R.sub.3
represents an acyl group, X represents a fluorine atom, n is equal
to 2, and R.sub.1 and R.sub.2 taken together with the nitrogen atom
to which they are attached form a group 36
[0136] the compound of general formula (I) in which R.sub.3
represents an acyl group, X represents a fluorine atom, n is equal
to 2, and R.sub.1 and R.sub.2 taken together with the nitrogen atom
to which they are attached form a group 37
[0137] as defined above.
[0138] This invention is further illustrated by the following
examples which are provided for illustration purposes and in no way
limit the scope of the present invention.
EXAMPLES
Example 1
11.beta.-(4-(2-(diethylamino)ethoxy)phenyl)estra-1,3,5(10)-trien-3-ol-17-o-
ne hydrochloride
[0139] Preparation 1: 4-(2-(diethylamino)ethoxy)phenylmagnesium
bromide was prepared as follows. Initially, about 25 ml solution of
4-(2-(diethylamino)ethoxy)-benzene bromide (74 g; MW=272.2)
dissolved in 250 ml of THF was added to magnesium (turnings;
MW=24.3; 7.5 g; 1.13 eq.) at around 20.degree. C., with stirring.
The mixture was stirred at around 60.degree. C. until the Grignard
reagent (exothermic; gray color) was obtained. The remainder of the
solution was then carefully added over about 60 min at around
58.degree. C., and the suspension was stirred for 60 min at the
same temperature, and then allowed to cool. The concentration of
the magnesium compound in solution was about 1.0 M.
[0140] Step a: 3,3-ethylenedioxy-5(10)-epoxyestr-9(11)-ene-17-one
(about 2/1 mixture of 5(10)-alpha and 5(10)-beta isomers). 38
[0141] 3,3-Ethylenedioxyestra-5(10),9(11)-diene-17-one (50 g; M:
314.4; 0.159 mol), hexachloroacetone (98%; 2.5 ml; 0.1 eq.),
pyridine (0.25 ml), hydrogen peroxide at 50% (about 18 M; 15 ml;
1.7 eq) and dichloromethane (250 ml) were vigorously stirred for 18
h at 20-25.degree. C. After reduction in the presence of aqueous
sodium thiosulfate, washes (water) and extractions
(dichloromethane), the organic phase was concentrated to a total
volume of about 150 ml. Next, the dichloromethane was replaced with
isopropyl ether by continuous distillation at constant volume,
until the internal temperature reached 68.degree. C. The mixture
was cooled to around 20.degree. C.--a spontaneous precipitation of
the mixture of epoxides was observed. The suspension was cooled and
then stirred for 1 h at 0.degree. C., and the product was filtered,
and dried under vacuum for 18 h at around 40.degree. C. (44.6 g
white solid; yield: 84.9%; HPLC purity: 97%; about 67/33 alpha/beta
mixture): C.sub.20H.sub.26O.sub.4; MW: 330.4.
[0142] The alpha-epoxide was obtained in pure state (white solid)
by crystallization from acetonitrile or ethyl acetate: m.p.:
154.degree. C.; [.alpha.].sub.D: +133.+-.2.5 (c=1% in
chloroform).
[0143] The beta-epoxide was obtained in pure state (white solid) by
chromatography (eluent system: heptane 50, ethyl acetate 50,
pyridine 0.1): m.p.: 143.degree. C., and it was recrystallized from
a mixture of ethyl acetate and isopropyl ether: m.p.:
162-163.degree. C.; [.alpha.].sub.D: +101.5.+-.2 (c=1% in
chloroform); IR (CHCl.sub.3, cm.sup.-1): 1735, 1640; .sup.1H NMR
(CDCl.sub.3, ppm): 0.86 (s, 3H); 3.92 (m, 4H); 5.86 (m, 1H)
[0144] Step b: Silylated enol ether:
3,3-ethylenedioxy-5,10-epoxy-17-trime-
thylsilyloxyestra-9(11),16(17)-diene (about 2/1 mixture of
5,10-alpha and 5,10-beta isomers). 39
[0145] n-Butyllithium (solution at 17% in cyclohexane; 68 g; 1.2
eq.) was added over 30 min to a stirred solution of
diisopropylamine (M: 101.2; d: 0.714; 30 ml; 1.4 eq.) in anhydrous
THF (100 ml), at -10.degree. C. The lithium diisopropylamine
solution thus obtained was added over 30 min at around 0.degree. C.
to a solution of epoxide prepared in step A (50 g; 0.151 mol) in
THF (150 ml), and the mixture was stirred for 5 min at around
0.degree. C.
[0146] Trimethylchlorosilane (M: 108.6; d: 0.856; 27 ml; 1.4 eq.)
was added over 15 min at 0.degree. C., and the mixture was stirred
for 1 h at around 0.degree. C. Methanol (M: 32; d: 0.792; 5 ml; 0.8
eq.) was added at around 0.degree. C. and the medium was stirred
for 30 min at around 10.degree. C. and then poured into the stirred
mixture of sodium dihydrogen phosphate dihydrate (M: 156; 26 g; 1.1
eq.), water and toluene. After decantation and washing with water,
the toluenic phase was dried over sodium sulfate and concentrated
under vacuum to a final volume of about 100 ml. The silylated enol
ether was used in this form in the next step, but an isolation by
dry extract is possible: C.sub.23H.sub.34O.sub.4Si; MW: 402.6.
[0147] The alpha-epoxide (amorphous solid, m.p. <40.degree. C.)
was obtained in pure state by the same procedure, but starting with
pure alpha-epoxide, which is obtained in accordance with the
procedures as set forth in step A:
[0148] IR (CHCl.sub.3, cm.sup.-1): 1621, 1254, 849
[0149] .sup.1H NMR (CDCl.sub.3, ppm): 0.19 (s, 9H); 0.80 (s, 3H);
3.85-4.00 (m, 4H); 4.47 (dd, J=1.5 and 1 Hz, 1H); 6.03 (m, 1H)
[0150] MS (m/z): 402 (M.sup.+), 387 (M.sup.+-CH.sub.3), 99.
[0151] The beta-epoxide (oil) was obtained in pure state by the
same procedure, but starting with pure beta-epoxide, which is
obtained in accordance with the procedures as set forth in step A:
.sup.1H NMR (CDCl.sub.3, ppm): 0.19 (s, 9H); 0.78 (s, 3H); 1.12 (m,
1H); 2.34 (d, J=15 Hz, 1H); 3.90 (m, 4H); 4.48 (m, 1H); 5.84 (m,
1H).
[0152] Step c: Mixture of
11-(4-(2-(diethylamino)ethoxy)-phenyl)estra-5(10-
),9(11)-diene-3,17-dione and
11-alpha-(4-(2-(diethylamino)ethoxy)phenyl)es-
tra-4,9-diene-3,17-dione. 40
[0153] Copper (I) chloride (MW=99.0; 509 mg; 0.17 eq.) was added at
around 20.degree. C. to a solution of silylated enol ether (pure
beta isomer) as prepared above (step B) (12.2 g; 30.3 mmol) in THF
(30 ml). The medium was cooled to around -3.degree. C. and the
solution of the magnesium compound as described above (preparation
1) (61 ml; about 1 M; 2 eq) was added while maintaining the
temperature at -3.sup.2C. The medium was stirred for about 3 h at
around 20.degree. C., and then poured into a mixture of ammonium
chloride (50 g) in water (200 ml). The medium was extracted with
dichloromethane. The organic phase was then washed with water and
concentrated under vacuum. Dichloromethane (80 ml) and water (30
ml) were added. The mixture was cooled at 0-5.degree. C. and
hydrochloric acid at 36% (12 ml; 4.75 eq.) was added over 20 min.
The biphasic medium was vigorously stirred for 2 h at about
0.degree. C., and then diluted with water (50 ml). The organic
phase was separated by decantation and washed with water. The
amine-containing by-products were removed in the acidic aqueous
phase while the hydrochloric acid salts of the enones remain in
dichloromethane. The organic phase was neutralized by washing with
an aqueous sodium hydrogen carbonate solution (50 ml), washed with
water, dried over sodium sulfate and then concentrated under
vacuum. The residue (11 g) is chromatographed on a silica column
(eluent: n-heptane 50, ethyl acetate 45, triethylamine 5). The
fractions were concentrated to dryness to obtain: -800 mg of
11-(4-(2-(diethylamino)-eth-
oxy)phenyl)estra-5(10),9(11)-diene-3,17-dione:
C.sub.30H.sub.39NO.sub.3; MW: 461.6; IR (CHCl.sub.3, cm.sup.-1):
1733, 1712, 1607, 1568, 1508;
[0154] .sup.1H NMR (CDCl.sub.3, ppm): 1.03 (s, 3H); 1.12 (t, J=7
Hz, 6H) and 2.72 (q, J=7 Hz, 4H); 2.94 (t, J=6 Hz, 2H); 4.09 (t,
J=6 Hz, 2H); 6.82 and 7.07 (m, 4H); from 1.0 to 2.9 (m, 18H);
[0155] MS (EI, m/z): 461 (M.sup.+); and
[0156] 444 mg of
11-alpha-(4-(2-(diethylamino)ethoxy)phenyl)-estra-4,9-die-
ne-3,17-dione: C.sub.30H.sub.39NO.sub.3; MW: 461.6:
[0157] .sup.1H NMR (CDCl.sub.3, ppm): 1.02 (s, 3H); 1.12 (t, J=7
Hz, 6H) and 2.69 (q, J=7 Hz, 4H); 2.91 (t, J=7 Hz, 2H); 4.05 (m,
3H); 5.72 (s, 1H); 6.79 and 6.95 (m, 4H); from 1.0 to 2.8 (m,
16H);
[0158] MS (ESP, m/z): 426 (MH.sup.+).
[0159] Step c: Mixture of
11-beta-(4-(2-(diethylamino)ethoxy)-phenyl)estra-
-4,9-diene-3,17-dione,
11-(4-(2-(diethylamino)ethoxy)phenyl)estra-5(10),9(-
11)-diene-3,17-dione and
11-alpha-(4-(2-(diethylamino)ethoxy)phenyl)-estra-
-4,9-diene-3,17-dione. 41
[0160] Copper (I) chloride (MW=99.0; 2.24 g; 0.25 eq.) was added at
around 20.degree. C. to a solution of the magnesium compound as
described above (preparation 1) (182 ml; about 1 M; 2.0 eq). The
medium was stirred for 15 min at around 20.degree. C. and then a
solution of silylated enol ether (about 2/1 beta-alpha mixture) as
prepared above (step B) (36.5 g; 90.7 mmol) was introduced with THF
(120 ml). The medium was stirred for about 1 h at around 20.degree.
C., and then poured into a mixture of ammonium chloride (150 g) in
water (600 ml). The medium was extracted with dichloromethane. The
organic phase was then washed with water and concentrated under
vacuum. Dichloromethane (150 ml) and water (75 ml) were added. The
mixture was cooled to 0-5.degree. C. and hydrochloric acid at 36%
(45 ml; 6 eq.) was added over 45 min. The biphasic medium was
vigorously stirred for 1.5 h at around 0.degree. C., and then
diluted with water (150 ml). The organic phase was separated by
decantation and washed with water. The organic phase was
neutralized by washing with a saturated aqueous sodium hydrogen
carbonate solution (150 ml), washed with water, dried over sodium
sulfate and then concentrated under vacuum.
[0161] The product thus obtained was an orange-colored resin: 36 g;
yield: 86%: C.sub.30H.sub.39NO.sub.3; MW: 461.6.
[0162]
11-Beta-(4-(2-(diethylamino)ethoxy)phenyl)estra-4,9-diene-3,17-dion-
e was isolated by crystallization from isopropyl ether (which
crystallization was all the more efficient as the alpha/beta ratio
in the initial mixture of epoxides was high).
[0163]
11-(4-(2-(Diethylamino)ethoxy)phenyl)estra-5(10),9(11)-diene-3,17-d-
ione and
11-alpha-(4-(2-(diethylamino)ethoxy)phenyl)estra-4,9-diene-3,17-d-
ione was isolated by chromatography on silica as described in the
preceding example.
[0164]
11-Beta-(4-(2-(diethylamino)ethoxy)phenyl)estra-4,9-diene-3,17-dion-
e: m.p.=188.degree. C.;
[0165] IR (CHCl.sub.3, cm.sup.-1): 1735, 1658, 1609, 1581,
1509;
[0166] .sup.1H NMR (CDCl.sub.3, ppm): 0.56 (s, 3H); 1.06 (t, J=7
Hz, 6H) and 2.63 (q, J=7 Hz, 4H); 2.85 (t, J=6 Hz, 2H); 4.01 (t,
J=6 Hz, 2H); 4.38 (dl, J=7 Hz, 1H); 5.80 (bs, 1H); 6.82 and 7.07
(AA'BB', 4H); from 1.4 to 2.9 (m, 16H); MS (EI, m/z): 461
(M.sup.+)
[0167] Step d: Mixture of
3-acetyl-11-beta-(4-(2-(diethylamino)ethoxy)phen-
yl)estra-1,3,5(10)-trien-17-one hydrochloride and
3-acetyl-11-(4-(2-(dieth-
ylamino)ethoxy)phenyl)estra-3,5(10),9(11)-trien-17-one
hydrochloride. 42
[0168] To a solution of
11-beta-(4-(2-(diethylamino)ethoxy)-phenyl)estra-4-
,9-diene-3,17-dione prepared in step c (10 g; 21.6 mmol) in
dichloromethane (40 ml) were added acetic anhydride (MW=102.1;
d=1.09; 6.1 ml; 3 eq.) and, and over 5 min, acetylbromide
(MW=123.0; d=1.66; 6.1 ml; 3.8 eq.), at 20-25.degree. C. The brown
solution was stirred for 1 h at 20-25.degree. C. The solution was
poured over in about 30 min into a suspension of sodium hydrogen
carbonate (24.4 g) in water (100 ml) at around 20.degree. C.
(emission of carbon dioxide). The mixture was vigorously stirred
for 30 min at around 20.degree. C., and then the organic phase was
separated by decantation, washed with water, dried over sodium
sulfate and then concentrated to dryness under vacuum. The residue
(18 g) was chromatographed on a silica column (eluent:
cyclohexane/ethyl acetate/triethylamine 75/20/5). Each fraction was
concentrated to dryness separately, taken up in dichloromethane and
acidified to pH=1 with 1 N aqueous hydrochloric acid. The organic
phase was separated by decantation, dried over sodium sulfate and
concentrated to dryness. The least polar fraction thus acidified
gave 3-acetyl-11-(4-(2-(diethylamino)-
ethoxy)-phenyl)estra-3,5(10),9(11)-trien-17-one hydrochloride (1.3
g; yellow solid; 10%): C.sub.32H.sub.42NO.sub.4Cl; MW: 540.1.
[0169] IR (CHCl.sub.3, cm.sup.-1): .nu. 1736, 1664, 1606, 1570,
1507;
[0170] .sup.1H NMR (CDCl.sub.3, ppm): .delta. 1.02 (s, 3H); 1.47
(td, J=7 Hz, 6H) and 3.27 (m, 4H); 2.10 (s, 3H); 3.47 (m, 2H); 4.51
(m, 2H); 5.52 (d, J=1.5 Hz, 1H); 6.79 and 7.12 (AA'BB', 4H); 12.4
(bs, 1H, active); from 1.0 to 2.6 (m, 16H); MS (EI; m/z): 503
(M.sup.+); 461; 100; 86; 38 and 36 (HCl).
[0171] The acidified more polar fraction gave
3-acetyl-11-beta-(4-(2-(diet-
hylamino)ethoxy)phenyl)estra-1,3,5(10)-trien-17-one hydrochloride
(6.09 g; white solid; 52%): C.sub.32H.sub.42NO.sub.4Cl; MW:
540.1.
[0172] IR (CHCl.sub.3, cm.sup.-1): .nu. 1734, 1610, 1582, 1512,
1494;
[0173] .sup.1H NMR (CDCl.sub.3, ppm): .delta. 0.45 (s, 3H); 1.43
(t, J=7 Hz, 6H) and 3.22 (m, 4H); 2.25 (s, 3H); 3.39 (m, 2H); 4.40
(m, 2H); 4.04 (d, J=4.5 Hz, 1H); 6.63 and 6.99 (AA'BB', 4H); 6.65
(dd, J=8.5 and 1.5 Hz, 1H); 6.86 (d, J=1.5 Hz, 1H); 6.94 (d, J=8.5
Hz, 1H); 12.3 (bs, 1H, active); from 0.85 to 3.5 (m, 13H);
[0174] MS (EI; m/z): 503 (M.sup.+), 86, 38 and 36 (HCl)
[0175] Step e:
3-Acetyl-11-beta-(4-(2-(diethylamino)ethoxy)-phenyl)estra-3-
,5(10),9(11)-trien-17-one. 43
[0176] To the solution of enones prepared in step c (35 g; 75.8
mmol) in dichloromethane (250 ml) were added acetic anhydride
(MW=102.1; d=1.09; 7.1 ml; 1 eq.) and, over a period of about 20
min, acetylbromide (MW=123.0; d=1.66; 14 ml; 2.5 eq.), at
20-25.degree. C. (exothermic addition). The brown solution thus
obtained was stirred for 5 h at 20-25.degree. C. The disappearance
of the 3-acetyltriene was monitored by HPLC (Hypersil DBS 3 microns
CN, 150.times.4.6 mm; eluent: water containing 0.1% of
trifluoroacetic acid, acetone, methanol 65/30/5; UV 210 nm). The
solution was poured over in about 30 nm into a suspension of sodium
hydrogen carbonate (93 g) in water (350 ml) at around 20.degree. C.
(emission of carbon dioxide). The mixture was vigorously stirred
overnight at around 20.degree. C., and then the organic phase was
separated by decantation, washed with 1N sodium hydroxide (175 ml)
and water and then concentrated to a final volume of 100 ml.
[0177] Dichloromethane was replaced with methanol at constant
volume by distillation under gradual vacuum at about 40.degree. C.
The product was stored in solution in methanol.
C.sub.32H.sub.41NO.sub.4; MW: 503.7.
[0178] Step f:
11-Beta-(4-(2-(diethylamino)ethoxy)phenyl)estra-1,3,5(10)-t-
rien-3-ol-17-one hydrochloride.
[0179] A solution of potassium hydroxide (MW=56.0; 6.3 g; 1.5 eq.)
in methanol (70 ml) was added over in about 10 min, at around
0.degree. C., to the
3-acetyl-11-beta-(4-(2-(diethylamino)ethoxy)phenyl)estra-3,5(10),9-
(11)-trien-17-one solution in methanol obtained in step e. The
medium was stirred for 2 h at 0-5.degree. C., and then poured into
water (175 ml) and dichloromethane (175 ml). The organic phase was
separated by decantation and washed with water. Water (175 ml) and
hydrochloric acid at 36% (16 ml; 2.5 eq.) were added and the medium
was stirred for about 5 min while monitoring the pH (<2). The
organic phase was separated by decantation, dried over sodium
sulfate, filtered and concentrated until a final volume of 175 ml
was obtained. The medium was then distillated while the volume was
kept constant by gradual introduction of 2-butanone. The expected
product crystallized spontaneously. The temperature at the end of
the exchange was about 78.degree. C. The medium was stirred, while
allowing it to cool in about 1 h, and then the stirring continued
for 1 h at about 20.degree. C. The product was filtered, washed
with 2-butanone and then dried under vacuum at around 70.degree. C.
(24.4 g beige solid; m.p.=179.degree. C.; yield: 64.6%):
C.sub.30H.sub.40ClNO.sub.3; MW: 498.1;
[0180] IR (CHCl.sub.3, cm.sup.-1): .nu. 3601, 2456, 1733, 1610,
1584, 1511; .sup.1H NMR (CDCl.sub.3, ppm): .delta. 0.42 (s, 3H),
1.31 (m, 6H), 3.16 (m, 4H), 3.31 (m, 2H), 3.96 (bt, 1H), 4.17 (m,
2H), 6.51 (m, 1H), 6.68 (m, 1H), 6.73 (m, 1H), 6.51 and 6.95
(AA'BB', 4H), 11.36 (bs; 1H);
[0181] MS (EI; m/z): 461 (M.sup.+), 446, 362, 86, 38 and 36
(HCl).
Example 2
11.beta.-(4-(2-(Diethylamino)ethoxy)phenyl)estra-1,3,5(10)-trien-3-ol-17-o-
ne hydrochloride
[0182] Step c: Mixture of
11-beta-(4-(2-(diethylamino)ethoxy)-phenyl)estra-
-4,9-diene-3,17-dione,
11-(4-(2-(diethylamino)ethoxy)phenyl)estra-5(10),9(-
11)-diene-3,17-dione and
11-alpha-(4-(2-(diethylamino)ethoxy)phenyl)-estra-
-4,9-diene-3,17-dione. 44
[0183] Initially, about 25 ml solution of
4-(2-(diethylamino)-ethoxy)benze- ne bromide (123.6 g; MW=272.2; 3
eq.) in THF (250 ml) was added to magnesium (turnings; MW=24.3;
11.8 g; 3.2 eq.) at around 20.degree. C., with stirring. The
mixture was stirred at around 60.degree. C. until the Grignard
reagent was formed (exothermic; gray color). The remainder of the
solution was then carefully added over about 60 min at around
58.degree. C., and the suspension was stirred for 60 min at the
same temperature, and then allowed to cool. Copper (I) chloride
(MW=99.0; 3.75 g; 0.25 eq.) was added at around 20.degree. C. and
the suspension obtained was stirred for about 15 min at around
20.degree. C. The mixture of epoxides (step A) (50 g; 0.151 mol)
solubilized in THF (300 ml) was added over 30 min at around
20.degree. C. to the suspension. The mixture was stirred for 1 h at
around 20.degree. C., and then poured into a mixture of ammonium
chloride (125 g) in water (600 ml). The medium was extracted with
dichloromethane. The organic phase was then washed with water and
concentrated under vacuum. Dichloromethane (600 ml) and water (125
ml) were added. The mixture was cooled at 0-5.degree. C. and
hydrochloric acid at 36% (100 ml; 7.7 eq.) was added over 20 min.
The biphasic medium was vigorously stirred for 2 h at around
0.degree. C., and then diluted with water (250 ml). The organic
phase was separated by decantation and washed with water. The
amine-containing by-products were removed in the acidic aqueous
phase while the hydrochloric acid salts of the enones remained in
dichloromethane. The organic phase was neutralized by washing with
an aqueous sodium hydrogen carbonate solution (25 g; 2 eq.), washed
with water, dried over sodium sulfate and then concentrated under
vacuum. The product thus obtained was in semicrystalline form: 65.3
g; yield: 93.5% (from the epoxide 2): C.sub.30H.sub.39NO.sub.3; MW:
461.6.
[0184] Step e:
3-Acetyl-11-beta-(4-(2-(diethylamino)ethoxy)-phenyl)estra-3-
,5(10),9(11)-trien-17-one. 45
[0185] To a solution of enones prepared in step c (65.3 g; 0.141
mol) in dichloromethane (250 ml) were added acetic anhydride
(MW=102.1; d=1.09; 14.2 ml; 1.1 eq.) and, over 15 min, acetyl
bromide (MW=123.0; d=1.66; 28 ml; 2.7 eq.), at 20-25.degree. C.
(exothermic addition). The brown solution was stirred for 5 h at
20-25.degree. C. The disappearance of the 3-acetyltriene was
monitored by HPLC (Hypersil DBS 3 microns CN, 150.times.4.6 mm;
eluent: water containing 0.1% of trifluoroacetic acid, acetone,
methanol 65/30/5; UV 210 nm). The solution was poured over a
suspension of sodium hydrogen carbonate (127 g) in water (500 ml)
at around 20.degree. C. (emission of carbon dioxide) in about 30
min. The mixture was vigorously stirred overnight at around
20.degree. C., and then the organic phase was separated by
decantation, washed with 1 N sodium hydroxide (250 ml) and water
(3.times.250 ml) and then concentrated to a final volume of 150 ml.
The dichloromethane is replaced with methanol at constant volume by
distillation under gradual vacuum at about 40.degree. C. The
product was stored in solution in methanol.
C.sub.32H.sub.41NO.sub.4; MW: 503.7.
[0186] Step f:
11-Beta-(4-(2-(diethylamino)ethoxy)phenyl)estra-1,3,5(10)-t-
rien-3-ol-17-one hydrochloride.
[0187] A solution of potassium hydroxide (MW=56.0; 12.7 g; 1.6 eq.)
in methanol (100 ml) was added over 10 min at around 0.degree. C.
to the solution of
3-acetyl-11-beta-(4-(2-(diethylamino)ethoxy)phenyl)estra-3,5(-
10),9(11)-trien-17-one in methanol obtained in step e. The medium
was stirred for 1.5 h at 0-5.degree. C., and then poured into water
(250 ml) and dichloromethane (250 ml). The organic phase was washed
with water. The medium was acidified by adding water and
hydrochloric acid at 36% (26 ml; 2.2 eq.) and stirred for about 5
min while monitoring the pH (<2). The organic phase was
separated by decantation, dried over sodium sulfate, filtered and
concentrated until a final volume of 300 ml was obtained. The
medium was then distilled while maintaining the volume constant by
gradual introduction of 2-butanone. The expected product
crystallized spontaneously. The temperature at the end of the
exchange was about 78.degree. C. The medium was stirred, while
allowing it to cool over about 1 h, and then for 1 h at around
20.degree. C. The product was filtered, washed with 2-butanone and
then dried under vacuum at around 70.degree. C. (48 g beige solid;
m.p.=179.degree. C.; yield: 68.3%, HPLC purity: 95%):
C.sub.30H.sub.40ClNO.sub.3; MW: 498.1. Same spectral data were
observed as those set forth in Example 1, step f.
Example 3
11-Beta-(4-(2-(dimethylamino)ethoxy)phenyl)-estra-1,3,5(10)-trien-3-ol-17--
one.
[0188] Preparation 2: 4-(2-(Diethylamino)ethoxy)phenylmagnesium
bromide.
[0189] A solution of 4-(2-(dimethylamino)ethoxy)benzene bromide
(18.3 g; MW=244.1) in THF (90 ml) was added dropwise, with stirring
at 35-40.degree. C., to magnesium (turnings; MW=24.3; 2.2 g; 1.2
eq.), after having initiated the reaction with a few drops of
dibromoethane, in 10 ml of anhydrous THF. After the end of the
introduction, the gray solution obtained was stirred for 90 min at
the same temperature, and then allowed to cool. The concentration
of the magnesium compound thus formed in solution is about 0.55 M
(titer by iodometry).
[0190] Step c: 3,3-Ethylenedioxy-11-alpha-(4-(2-(dimethylamino)
ethoxy)phenyl)estr-9-en-5-beta-ol-17-one. 46
[0191] A solution of magnesium compound prepared above (preparation
2) (82.5 ml; 0.55 M; 3 eq.) was added to a suspension of anhydrous
copper (I) chloride (MW=99; 0.5 g; 0.33 eq.) in anhydrous THF (20
ml) stirred for 10 min at 20.degree. C. The mixture was cooled in
an ice bath. A solution of
3,3-ethylenedioxy-5-beta,10-beta-epoxyestr-9(11)-en-17-one (4.95 g;
M: 330.42; 15 mmol) in anhydrous THF (50 ml) was added thereto,
with stirring, at around 0.degree. C. and over 20 min. After
stirring for 4 h, the mixture was poured over an ice-cold,
saturated aqueous ammonium chloride solution, and the product was
extracted with ethyl acetate. The organic phase was washed with
salt water, dried over sodium sulfate and then concentrated under
vacuum. The residue (14 g) was then chromatographed on a silica
column (eluent: cyclohexane 40, ethyl acetate 40, triethylamine
20). The fractions were concentrated to dryness so as to
obtain:
[0192] 5.7 g of
3,3-ethylenedioxy-11-alpha-(4-(2-(dimethylamino)ethoxy)phe-
nyl)estr-9-en-5-beta-ol-17-one, yield: 77%,
C.sub.30H.sub.41NO.sub.5; MW: 495.6.
[0193] By crystallization (dissolution in a small volume of
dichloromethane and then addition of isopropyl ether and slight
concentration under vacuum), draining and drying at 50.degree. C.
under vacuum, there were obtained:
[0194] 4.24 g of white crystals, m.p.=122.degree. C.
[0195] IR (CHCl.sub.3, cm.sup.-1): 3510, 1735, 1609, 1578,
1510.
[0196] Step d:
11-Alpha-(4-(2-(dimethylamino)ethoxy)phenyl)-estra-4,9-dien-
e-3,17-dione and
11-(4-(2-(dimethylamino)ethoxy)phenyl)estra-5(10),9(11)-d-
iene-3,17-dione. 47
[0197] Method a: 2 N hydrochloric acid (1 ml) was slowly added,
with stirring, to a solution of
3,3-ethylenedioxy-11-alpha-(4-(2-(dimethylamin-
o)ethoxy)phenyl)estr-9-en-5-beta-ol-17-one prepared in step c (0.55
g; 1.1 mmol) in methanol (6 ml). After stirring for 1 h 30 min, the
solution was concentrated under vacuum and the residue was
dissolved in water and then made alkaline with a saturated aqueous
sodium bicarbonate solution. The product was extracted with ethyl
acetate. The organic phase was washed with salt water, dried over
sodium sulfate and then concentrated under vacuum. The residue (0.5
g) was chromatographed on a silica column (eluent: cyclohexane 40,
ethyl acetate 40, triethylamine 20). The fractions were
concentrated to dryness so as to obtain:
[0198] 0.325 g of
11-(4-(2-(dimethylamino)ethoxy)phenyl)estra-5(10),9(11)--
diene-3,17-dione, yield: 67%, C.sub.28H.sub.35NO.sub.3; MW:
433.6.
[0199] IR (CHCl.sub.3, cm.sup.-1): 1730, 1705, 1600;
[0200] 0.025 g of
11-alpha-(4-(2-(dimethylamino)ethoxy)-phenyl)estra-4,9-d-
iene-3,17-dione, identical to the product obtained by method b,
yield: 5%, C.sub.28H.sub.35NO.sub.3; MW: 433.6.
[0201] Method b: Perchloric acid at 55.degree. C. (2 ml) was slowly
added with stirring to a solution of
3,3-ethylenedioxy-11-alpha-(4-(2-(dimethyl-
amino)ethoxy)phenyl)estr-9-en-5-beta-ol-17-one prepared in step c
(0.5 g; 1 mmol) in acetic acid (1 ml). After 1 h 45 min of contact,
the mixture was slowly poured, while cooling, into a saturated
aqueous sodium bicarbonate solution. The product was extracted with
ethyl acetate. The organic phase was washed with salt water, dried
over sodium sulfate and then concentrated under vacuum. The residue
(0.5 g) was chromatographed on a silica column (eluent: cyclohexane
40, ethyl acetate 40, triethylamine 20). The fractions were
concentrated to dryness so as to obtain:
[0202] 0.16 g of
11-alpha-(4-(2-(dimethylamino)ethoxy)phenyl)-estra-4,9-di-
ene-3,17-dione, yield: 36%, C.sub.28H.sub.35NO.sub.3; MW:
433.6.
[0203] IR (CHCl.sub.3, cm.sup.-1): 1739, 1652, 1609, 1580,
1510;
[0204] .sup.1H NMR (CDCl.sub.3, ppm): 1.03 (s, 3H); 2.32 (s, 6H);
2.71 (t, J=6 Hz, 2H); 4.03 (t, J=6 Hz, 2H); 4.06 (t, J=9 Hz, 1H);
5.72 (s, 1H); 6.83 and 6.99 (AA'BB', 4H).
[0205] Step e:
11-Beta-(4-(2-(dimethylamino)ethoxy)phenyl)-estra-1,3,5(10)-
-trien-3-ol-17-one. 48
[0206] The
11-alpha-(4-(2-(dimethylamino)ethoxy)phenyl)estra-4,9-diene-3,1-
7-dione (0.2 g; 0.46 mmol) prepared in step d was dissolved in dry
methylene chloride (2 ml). The solution was cooled to 0.degree. C.
and then acetic anhydride (0.2 ml; 2.11 mmol; 4.5 eq.) was added
dropwise thereto at this temperature followed by acetyl bromide
(0.1 ml; 1.34 mmol; 3 eq.). The solution obtained was stirred at
room temperature for 1 h 45 min. It was carefully made alkaline by
adding a saturated aqueous sodium bicarbonate solution. The product
was extracted with dichloromethane. The organic phase was washed
with salt water, dried over sodium sulfate and then concentrated
under vacuum. The residue (0.21 g) was dissolved in methanol (5
ml). 2 N sodium hydroxide was added and then the medium was stirred
at room temperature for 45 min. The mixture was then acidified with
2 N hydrochloric acid, and then again alkalinized with a saturated
aqueous sodium bicarbonate solution. The product was extracted with
dichloromethane. The organic phase was washed with salt water,
dried over sodium sulfate and then concentrated under vacuum. The
residue (0.19 g) was chromatographed on a silica column (eluent:
cyclohexane 40, ethyl acetate 40, triethylamine 20). The fractions
were concentrated to dryness so as to obtain:
[0207] 0.13 g of
11-beta-(4-(2-(dimethylamino)ethoxy)phenyl)-estra-1,3,5(1-
0)-trien-3-ol-17-one, yield: 65%, C.sub.28H.sub.35NO.sub.3; MW:
433.6.
[0208] IR (CHCl.sub.3, cm.sup.-1): 3595, 1735, 1610, 1580,
1512;
[0209] .sup.1H NMR (CDCl.sub.3, ppm): 0.47 (s, 3H); 2.33 (s, 6H);
3.94 (m, 2H); 3.99 (t, J=4.5 Hz, 1H); 6.37 (dd, J=2.5 and 8.5 Hz,
1H); 6.49 (d, J=2.5 Hz, 1H); 6.77 (d, J=8.5 Hz, 1H); 6.50 and 6.96
(AA'BB', 4H).
Example 4
11-Beta-(4-(2-(1-piperidinyl)ethoxy)phenyl)-17-alpha-fluoroestra-1,3,5(10)-
-trien-3-ol
[0210] Step a: Reduction
[0211] 3,3-ethylenedioxyestra-5(10),9(11)-diene-17-ol 49
[0212] Sodium borohydride (MW=37.8; 18.9 g; 500 mmol) dissolved in
0.5 N sodium hydroxide (100 ml) was introduced over about 5 min at
around 2.degree. C. into a suspension of
3,3-ethylenedioxyestra-5(10),9(11)-dien- e-17-one (MW=314.4; 100 g;
318 mmol) in methanol (1 liter). The medium was stirred for 2 h at
around 2.degree. C. and then acetone (100 ml) was introduced over
about 15 min at around 5.degree. C. The medium was stirred for 1 h,
and poured at around 20.degree. C. into the stirred mixture of
water (2 liters), sodium chloride (500 g) and ethyl acetate (400
ml). The medium was separated by decantation and the aqueous phase
was re-extracted with ethyl acetate. The combined organic phases
were washed with water, dried over sodium sulfate and concentrated
at atmospheric pressure at 500 ml. The distillation is continued
while the volume is kept constant by gradual introduction of
1,2-dimethoxyethane (DME). The temperature at the end of the
exchange is 83.degree. C. The solution was used as it is in the
next step, but a dry extract gave the expected product (resin).
C.sub.20H.sub.28O.sub.3; MW=316.4.
[0213] IR (CHCl.sub.3, cm.sup.-1): .nu. 3613, 1638.
[0214] .sup.1H NMR (CDCl.sub.3, ppm): .delta. 0.74 (s, 3H), 2.29
(bs, 2H), 3.78 (t, J=8.5 Hz, 1H), 3.98 (m, 4H), 5.57 (m, 1H), from
0.85 to 2.6 (m, 16H).
[0215] Step b: Fluorination
[0216] 3,3-Ethylenedioxy-17-alpha-fluoroestra-5(10),9(11)-diene
50
[0217] Perfluorobutanesulfonyl fluoride (MW=302.1; 41.4 g; 137
mmol) was introduced over about 5 min at around -10.degree. C. into
the solution of 3,3-ethylenedioxyestra-5(10),9(11)-diene-17-ol
(MW=316.4; 20 g; 63.2 mmol) in DME (100 ml) obtained in the
preceding step. The suspension was cooled to around -40.degree. C.
and the 3HF.TEA complex (MW=161.2; 10.2 g; 63.3 mmol) was
introduced over about 30 min at this temperature. The medium was
stirred for about 15 min at around -40.degree. C. and then
1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)(MW=152.2; 38.4 g; 252
mmol) was introduced over about one hour at this temperature. The
yellow suspension was stirred for 15 min at around -40.degree. C.
and then for 3 h at around 2.degree. C. The medium was poured into
the stirred mixture of water (400 ml), ammonium chloride (80 g) and
ethyl acetate (140 ml), at around 10.degree. C. The medium was
stirred for 30 min, separated by decantation and re-extracted with
ethyl acetate. The combined organic phases were washed with water
and 1N sodium hydroxide, and dried over sodium sulfate. The medium
was concentrated under vacuum and then dichloromethane (300 ml) was
introduced. Silica (Merck Si 60; 60 g) was introduced into the
solution. The medium was stirred for one hour at around 20.degree.
C., the silica was filtered and rinsed with dichloromethane (80
ml). The filtrate was concentrated at atmospheric pressure to 80
ml. The distillation was continued while the volume was kept
constant by gradual introduction of isopropanol. The temperature at
the end of the exchange was 82.degree. C. The solution was brought
to around 20.degree. C., the crystallization was initiated at
around 63.degree. C. The suspension was stirred for one hour at
around 20.degree. C. The white product was drained at 20.degree. C.
and dried under vacuum overnight at around 40.degree. C.: 12.34 g;
C.sub.20H.sub.27O.sub.2F; MW=318.4. Yield=61.3%. m.p.=100.degree.
C.
[0218] IR (CHCl.sub.3, cm.sup.-1): .nu. 1640, 1610;
[0219] .sup.1H NMR (CDCl.sub.3, ppm): .delta. 0.66 (d, J=2.5 Hz,
3H), 3.99 (bs, 4H), 4.59 (dd, J=55 and 5 Hz; 1H), 5.60 (m, 1H),
from 0.8 to 2.6 (m, 18H);
[0220] MS (EI; m/z): 318 (M.sup.+), 298 (M.sup.+-HF)
[0221] Step c: Epoxidation
[0222] 3,3-Ethylenedioxy-17-alpha-fluoro-5(10)-epoxyestr-9(11)-ene
51
[0223] 3,3-Ethylenedioxy-17-alpha-fluoroestra-5(10),9(11)-diene
(100 g; M: 318.4; 0.314 mol), hexafluoroacetone (trihydrate; 8.75
ml; 0.2 eq.), pyridine (0.1 ml), hydrogen peroxide at 50% (about 18
M; 30 ml; 1.7 eq) and dichloromethane (1000 ml) were vigorously
stirred for 18 h at 20-25.degree. C. After reduction in the
presence of aqueous sodium thiosulfate, washes (water) and
extractions (dichloromethane), the organic phase was concentrated
to a total volume of about 400 ml. Next, the dichloromethane was
replaced with tetrahydrofuran by continuous distillation at
constant volume, until the internal temperature reaches 66.degree.
C. The solution obtained was cooled and used as it is in the next
step. (HPLC purity: 97%; about 70/30 alpha/beta mixture):
C.sub.20H.sub.27O.sub.3F; MW: 334.4. After concentrating to
dryness, the alpha-epoxide was crystallized from heptane, and the
beta-epoxide was isolated by chromatography on silica of the mother
liquors (eluent: cyclohexane 90-ethyl acetate 10). Alpha-epoxide
(m.p.=115.degree. C.).
[0224] IR (CHCl.sub.3, cm.sup.-1): .nu. 1642;
[0225] .sup.1H NMR (CDCl.sub.3, ppm): .delta. 0.66 (d, J=2 Hz, 3H),
3.85 to 3.97 (m, 4H), 4.58 (dd, J=55 and 5 Hz, 1H), 6.07 (dt, J=5.5
and 2.5 Hz, 1H), from 1.15 to 2.57 (m, 18H).
[0226] Beta-Epoxide (Oil):
[0227] IR (CHCl.sub.3, cm.sup.-1): .nu. 1642;
[0228] .sup.1H NMR (CDCl.sub.3, ppm): .delta. 0.64 (d, J=1.5 Hz,
3H), 3.86 to 3.97 (m, 4H), 4.59 (dd, J=55 and 5 Hz; 1H), 5.88 (dt,
J=5.5 and 2 Hz, 1H), from 0.98 to 2.51 (m, 18H).
[0229] Step d: Alkylation
[0230] Mixture of
17-alpha-fluoro-11-beta-(4-(2-(1-piperidinyl)ethoxy)phen-
yl)estra-4,9-dien-3-one and
17-alpha-fluoro-11-(4-(2-(1-piperidinyl)ethoxy-
)phenyl)-estra-5(10),9(11)-dien-3-one. 52
[0231] 14.4 g of magnesium (turnings; MW=24.3; 593 mmol) were
introduced into a reactor, followed by 100 ml of a
1-bromo-4-(2-(1-piperidinyl)ethox- y)benzene solution (153.3 g;
MW=284.2; 539 mmol) in THF (560 ml). The medium was heated to
around 58.degree. C. and as soon as the medium became gray, the
remainder of the solution was introduced at about 58.degree. C.
over about 1.5 h, and then further maintained for 2 h at this
temperature. The solution was brought to 20.degree. C. and stirred
for 18 h. Copper (I) chloride (4.43 g; MW=99.0; 44.7 mmol) was
introduced, the medium was stirred for about 15 min at about
20.degree. C. and then the solution of
3,3-ethylenedioxy-17-alpha-fluoro-5(10)-epoxy- estr-9(11)-ene (7/3
alpha/beta mixture)(100 g; MW=334.4; 299 mmol) in THF described in
the preceding step (step c) was introduced over 30 min at around
20.degree. C. The medium was stirred for one hour at around
20.degree. C. and it was poured over the stirred mixture of
ammonium chloride (500 g), water (2 liters) and dichloromethane (1
liter), at around 10.degree. C. The aqueous phase was separated by
decantation and re-extracted with dichloromethane. The combined
organic phases were washed with water, and then concentrated under
vacuum to about 200 ml. The solution was cooled to around 2.degree.
C., water (250 ml) and concentrated hydrochloric acid (36%; 150 ml)
were introduced, while maintaining the temperature at around
2.degree. C. The medium was stirred for 1.5 h at around 2.degree.
C. and then diluted further with water (500 ml), separated by
decantation and washed with water to pH>4. The medium was poured
over in about 30 min (formation of foam) over a stirred mixture at
around 20.degree. C. of sodium bicarbonate (47 g; MW=84.0; 559
mmol) in water (500 ml). The medium was stirred for 30 min and
separated by decantation. The aqueous phases were re-extracted with
dichloromethane, washed with water and dried over sodium sulfate.
The solution was decolorized by adding alumina (around 200 g). The
medium was stirred at around 20.degree. C., filtered and rinsed
with dichloromethane. The filtrate was concentrated at atmospheric
pressure to about 700 ml, and then the distillation was continued
while keeping the volume constant by gradual introduction of
isopropyl ether. The temperature at the end of the exchange was at
68.degree. C. The crystallization started at around 63.degree. C.
The medium was allowed to cool to around 20.degree. C. and the
stirring was continued for a further 2 h at around 20.degree. C.
The beige product (61.9 g; yield: 43%):
17-alpha-fluoro-11-beta-(4-(2-(1-piperidinyl)ethoxy)phenyl)estra-4,9-dien-
-3-one is drained: C.sub.31H.sub.40FNO.sub.2; MW: 477.7;
m.p.=160.degree. C.; IR (CHCl.sub.3, cm.sup.-1): 1656, 1608,
1508;
[0232] .sup.1H NMR (CDCl.sub.3, ppm): 0.35 (d, J=2 Hz, 3H); 1.44
(m, 2H) 1.60 (m, 4H); 2.50 (bt, J=6 Hz, 4H); 2.76 (t, 6 Hz, 2H);
4.07 (t, 6 Hz, 2H); 4.39 (m, 1H); 4.46 (dd, J=55.5 and 5 Hz, 1H);
5.76 (bs, 1H); 6.82 and 7.07 (AA'BB', 4H); from 1.2 to 4.1 (m,
18H);
[0233] MS (EI; m/z): 477 (M.sup.+); 457 (M.sup.+-HF); 366; 346;
98.
[0234] By chromatography of the mother liquors on silica (eluent:
heptane 55-ethyl acetate 40-triethylamine 5),
17-alpha-fluoro-11-(4-(2-(1-piperid-
inyl)ethoxy)phenyl)-estra-5(10),9(11)-dien-3-one is obtained:
C.sub.31H.sub.40FNO.sub.2; MW: 477.7
[0235] IR (CHCl.sub.3, cm.sup.-1): 1710, 1606, 1572, 1507;
[0236] .sup.1H NMR (CDCl.sub.3, ppm): 0.81 (d, J=2 Hz, 3H); 1.46
(m, 2H); 1.62 (m, 4H); 2.53 (m, 4H); 2.80 (m, 2H); 4.10 (t, J=6 Hz,
2H); 4.65 (dd, J=55 and 5, 1H); 6.82 (m, 2H); 7.07 (m, 2H); from
1.1 to 2.85 (m, 18H);
[0237] MS (m/z): 478 (MH.sup.+); 112.
[0238] Step e: Aromatization
[0239]
3-Acetyl-11-beta-(4-(2-(1-piperidinyl)ethoxy)phenyl)-17-alpha-fluor-
oestra-1,3,5(10)-triene. 53
[0240] To a solution of
17-alpha-fluoro-11-beta-(4-(2-(1-piperidinyl)ethox-
y)phenyl)estra-4,9-dien-3-one (38 g; MW=477.7; 79.5 mmol) (step d)
in dichloromethane (152 ml) were added acetic anhydride (MW=102.1;
d=1.09; 7.5 ml; 1.0 eq.) and, over 15 min, acetyl bromide
(MW=123.0; d=1.66; 14.7 ml; 2.5 eq.) at 20-25.degree. C.
(exothermic addition). The brown solution was stirred for 5 h at
20-25.degree. C. The solution was poured over in about 30 min into
a sodium hydrogen carbonate suspension (45 g) in water (380 ml) at
around 20.degree. C. (emission of carbon dioxide). The mixture was
vigorously stirred overnight at around 20.degree. C., and then the
organic phase was separated by decantation, washed with 1 N sodium
hydroxide (190 ml) and water, and then concentrated to a final
volume of 114 ml. The dichloromethane was replaced with methanol at
constant volume by distillation under gradual vacuum at about
40.degree. C. The product was stored in solution in methanol.
C.sub.33H.sub.42FNO.sub.3; MW: 519.8.
[0241] Step f: Saponification
[0242]
11-Beta-(4-(2-(1-piperidinyl)ethoxy)phenyl)-17-alpha-fluoroestra-1,-
3,5(10)-trien-3-ol hydrochloride 54
[0243] A solution of potassium hydroxide (MW=56.0; 6.7 g; 1.5 eq.)
in methanol (76 ml) was added over in about 10 min at around
0.degree. C. to the solution of the fluorinated derivative in
methanol obtained in the preceding step e. The medium was stirred
for 45 min at 0-5.degree. C., and then poured into water (190 ml)
and dichloromethane (190 ml). The organic phase was washed with
water. It was acidified by addition of methanol (76 ml), water (190
ml) and hydrochloric acid at 36% (17 ml; 2.2 eq.) and stirred for
about 5 min while monitoring the pH (<2). The organic phase was
separated by decantation, dried over sodium sulfate, filtered and
concentrated until a final volume of 190 ml was obtained. The
medium was then distilled at ordinary pressure while keeping the
volume constant by gradual introduction of dichloromethane. The
expected product crystallized spontaneously. The medium was stirred
while allowing it to cool over about 1 h, and then for 2 h, to
around 20.degree. C. The product was filtered, washed with
dichloromethane and then dried under vacuum at around 40.degree. C.
(30.8 g beige solid; yield: 75.3%, HPLC purity: 98%):
C.sub.31H.sub.41ClFNO.sub.2; MW: 514.1;
[0244] IR (CHCl.sub.3, cm.sup.-1): .nu.=3599; 2467; 1609; 1583;
1511.
[0245] .sup.1H NMR (CDCl.sub.3, ppm): 0.22 (d, J=1.5 Hz, 3H); 3.09
(m, 1H); 3.21 (m, 1H); 3.87 (m, 1H); 3.99 (m, 1H); 4.25 (m, 1H);
4.43 (dd, J=56 and 5 Hz, 1H); 6.43 and 6.95 (AA'BB', 4H); 6.60 (dd,
J=8.5 and 1.5 Hz, 1H); 6.67 (d, J=1.5 Hz, 1H); 6.78 (d, J=8.5 Hz,
1H); 11.4 (bs, 1H, active); from 0.9 to 3.4 (m, 14H).
[0246] MS (ESP; m/z): 478 (MH.sup.+)
[0247] Step g: Neutralization
[0248]
11-Beta-(4-(2-(1-piperidinyl)ethoxy)phenyl)-17-alpha-fluoroestra-1,-
3,5(10)-trien-3-ol
[0249] Sodium carbonate (MW=106.0; 6.1 g) in aqueous solution (112
ml) was introduced at around 20.degree. C. into a suspension of
11-beta-(4-(2-(1-piperidinyl)ethoxy)phenyl)-17-alpha-fluoroestra-1,3,5(10-
)-trien-3-ol hydrochloride (28 g; MW=514.1; 54.5 mmol) (step f) in
dichloromethane (224 ml). The medium was stirred for 30 min at
around 20.degree. C., separated by decantation and washed with
water. The organic phase was dried over sodium sulfate, filtered
and the filtrate was concentrated to a residual volume of 140 ml.
It was brought to 20.degree. C. and acetone (280 ml) was
introduced, followed by silica (Merck Si 60; 42 g). The medium was
stirred for one hour at around 20.degree. C., filtered and rinsed
with a 2/1 acetone-dichloromethane mixture. The filtrate was
concentrated until a final volume of 224 ml was obtained. It was
then distilled at atmospheric pressure while the volume was kept
constant by gradual introduction of isopropanol. The product
crystallized continuously. The medium was stirred while allowing it
to cool over about 1 h, and then for 2 h to around 0.degree. C. The
product was filtered, washed with isopropanol at around 0.degree.
C. and then dried under vacuum at around 40.degree. C. (21.3 g of
white solid; m.p.=180.degree. C.; yield: 82.1% HPLC purity: 99%):
C.sub.31H.sub.40FNO.sub.2; MW: 477.7;
[0250] IR (CHCl.sub.3, cm.sup.-1): .nu.=3598, 1610, 1581, 1512;
[0251] .sup.1H NMR (CDCl.sub.3, ppm): 0.16 (d, J=2.5 Hz, 3H); 1.34
(m, 2H); 1.44 (m, 4H); 2.37 (m, 4H); 2.56 (t, J=6 Hz, 2H); 3.91 (m,
2H); 3.95 (m, 1H); 4.44 (dd, J=56 and 5 Hz, 1H); 6.31 (dd, J=8.5
and 3 Hz, 1H); 6.46 (d, J=3 Hz, 1H); 6.63 and 6.97 (AA'BB', 4H);
6.71 (d, J=8.5 Hz, 1H); 8.95 (bs, 1H, active); from 0.9 to 3.0 (m,
13H).
[0252] Although the invention has been illustrated by certain of
the preceding examples, it is not to be construed as being limited
thereby; but rather, the invention encompasses the generic area as
hereinbefore disclosed. Various modifications and embodiments can
be made without departing from the spirit and scope thereof.
* * * * *