Process for the synthesis of estrogen receptor modulators

Details Process for the synthesis of estrogen receptor modulators Process for the synthesis of estrogen receptor modulators

2003-10-15

2004-10-05

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S315000, C568S326000, C549S416000, C556S436000

Reexamination Certificate

active

06800785

ABSTRACT:

BACKGROUND OF THE INVENTION
Naturally occurring and synthetic estrogens have broad therapeutic utility, including: relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostatic cancer, treatment of hot flashes and prevention of cardiovascular disease. Because estrogen is very therapeutically valuable, there has been great interest in discovering compounds that mimic estrogen-like behavior in estrogen responsive tissues.
This invention relates to processes for making intermediates of estrogen receptor modulator compounds. The processes involve new methods for annelating 5-, 6- and 7-membered cycloalkenones onto an indanone.
SUMMARY OF THE INVENTION
The present invention relates to processes for the synthesis of compounds of formula I:
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to processes for the synthesis of compounds of formula I:
wherein R
1
is hydrogen, C
1-10
alkyl, C
3-7
cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, (heteroaryl)alkyl or SiR
a
R
b
R
c
wherein said alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with 1, 2 or 3 groups selected from fluoro, chloro, bromo, iodo, OR
d
, NR
e
R
f
, O(C═O)NR
e
R
f
, NR
e
(C═O)R
f
, NR
e
(C═O)OR
f
, SR
e
, S(O)R
e
, SO
2
R
e
, SO
2
NR
e
R
f
, LR
g
or MLR
g
;
R
2
is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF
3
;
R
3
is hydrogen, C
1-10
alkyl, benzyl or a removable hydroxyl protecting group;
R
4
is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF
3
;
R
5
is hydrogen, C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, C
3-6
cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl or (hetereoaryl)alkyl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl and (heteroaryl)alkyl groups are optionally substituted with bromo, iodo, OR
d
, SR
e
, 1-3 C
1-3
alkyl, 1-3 chloro or 1-5 fluoro;
R
a
, R
b
, and R
c
are independently selected from C
1-8
alkyl, O(C
1-8
alkyl) and phenyl;
R
d
is a removable hydroxyl protecting group, C
1-10
alkyl, benzyl or phenyl, wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C
1-4
alkyl, O(C
1-4
alkyl), NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
or halo;
R
e
is C
1-10
alkyl or phenyl, wherein said alkyl group is optionally substituted with a group selected from O(C
1-4
alkyl), NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
, phenyl or 1-5 fluoro, and wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C
1-4
alkyl, O(C
1-4
alkyl), NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
or halo;
R
f
is C
1-10
alkyl or phenyl, wherein said phenyl group is substituted with 1-3 substituents independently selected from C
1-4
alkyl, O(C
1-4
alkyl), NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
or halo;
or R
e
and R
f
, whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;
R
g
is NR
e
R
f
, OR
d
, NR
e
(C═O)R
f
, CONR
e
R
f
, SO
2
NR
e
R
f
or a 4-9 membered mono- or bicyclic N-heterocycloalkyl ring that can be optonally substituted with 1-3 C
1-3
alkyl and can be optionally interrupted by O, S or NR
e
;
L is CH
2
, CR
e
R
f
, or C
2-6
alkylene, wherein said alkylene linker can be optionally interrupted by O, S or NR
e
;
M is O, S, NR
e
, NR
e
(C═O) or (C═O)NR
e
;
and n is one, two or three.
The first step in the synthesis of compounds of formula I comprises alkylating of an indanone of formula II to yield an intermediate of formula III.
The alkylation is performed with an alkylating agent of formula VII in the presence of a base,
wherein X is Br, Cl, I, OMs, OTs or OTf, and n is as defined above. Suitable bases include, but are not limited to sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or sodium bis(trimethylsilyl)amide.
It is also possible to control the absolute stereochemistry of the chiral center which is generated in this alkylation reaction (indicated by an asterik in formula II). In this case, sodium or potassium hydroxide is used as a base in the presence of a chiral phase transfer catalyst. Suitable chiral phase transfer catalysts include, but are not limited to, N-benzylcinchoninium bromide, N-(p-trifluorobenzyl)cinchoninium bromide, N-(3,4-dichlorobenzyl)cinchoninium chloride, N-benzylcinchonidinium bromide, N-(p-trifluorobenzyl)cinchonidinium bromide or N-(3,4-dichlorobenzyl)cinchonidinium chloride.
Next, adding a nucleophile to an intermediate of formula III to yields a diene of formula IV.
The nucleophilic addition can be performed with an alkenyl metal species of formula VIII,
wherein M′ is MgBr, Li or Ce, and R
1
is as defined above.
The next step is cyclizing the compound of formula IV via a ring closing olefin metathesis reaction to yield an allylic alcohol of formula V.
The ring closing olefin metathesis reaction is performed in the presence of a transition metal catalyst. Suitable transition metal catalysts include, but are not limited to:
wherein
A preferred transition metal catalyst is
tricyclohexylphosphine[1,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydro-imidazol-2-ylidene]benzylidine ruthenium(IV) dichloride
wherein
Other suitable catalysts for this ring closing olefin metathesis reaction are known in the art and are described in the following literature references [
Angew. Chem. Int. Ed
. 2002, 41, 794
; J. Am. Chem. Soc
. 2002, 124, 7061
; Angew. Chem. Int. Ed
. 2002, 41, 2403
; J. Am. Chem. Soc
. 2000, 122, 8168
; Org. Lett
. 2001, 3, 3225].
Alternatively, a chiral metathesis catalyst can be used during the ring closing olefin metathesis reaction. Suitable chiral metathesis catalysts include, but are not limited to:
wherein
The following step comprises rearranging the compound of formula I via an allylic oxidative rearrangement to yield the enone of formula VI.
The allylic oxidative rearrangement is performed with a chromium (IV) oxidant. Suitable chromium (IV) oxidants include, but are not limited to, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide and chromium trioxide-pyridine complex.
Depending on the R
3
chosen, the compound of formula VI may be equivalent to a compound of formula I. In the case where R
3
is hydrogen, final deprotection may be required to give a compound of formula I.
Another embodiment of the present invention relates to a process for the synthesis of estrogen receptor modulator compounds of formula IA:
wherein R
1
is hydrogen, C
1-10
alkyl, C
3-7
cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, (hetereoaryl)alkyl or SiR
a
R
b
R
c
wherein said alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with 1, 2 or 3 groups selected from fluoro, chloro, bromo, iodo, OR
d
, NR
e
R
f
, O(C═O)NR
e
R
f
, NR
e
(C═O)R
f
, NR
e
(C═O)OR
f
, SR
e
, S(O)R
e
, SO
2
R
e
, SO
2
NR
e
R
f
, LR
g
or MLR
g
;
R
2
is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF
3
;
R
3
is hydrogen, C
1-10
alkyl, benzyl or a removable hydroxyl protecting group;
R
4
is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF
3
;
R
a
, R
b
, and R
c
are independently selected from C
1-8
alkyl, O(C
1-8
alkyl) and phenyl;
R
d
is a removable hydroxyl protecting group, C
1-10
alkyl, benzyl or phenyl, wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C
1-4
alkyl, O(C
1-4
alkyl), NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
or halo;
R
e
is C
1-10
alkyl or phenyl, wherein said alkyl group is optionally substituted with a group selected from O(C
1-4
alkyl), NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
, phenyl or 1-5 fluoro, and wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C
1-4
alkyl, O(C
1-4
alkyl), NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
or halo;
R
f
is C
1-10
alkyl or phenyl, wherein said phenyl group is substituted with 1-3 substituents independently selected from C
1-4
alk

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