Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-09
2002-05-28
Higel, Floyd D. (Department: 1745)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S430000, C549S453000, C548S517000
Reexamination Certificate
active
06395911
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention provides an improved process for cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine which is an intermediate for the preparation of (−)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol which is useful for the treatment of osteoporosis.
2. Description of the Related Art
A preparation of (−)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthhalene-2-ol is described in U.S. Pat. No. 5,552,241 which is hereby incorporated by reference. This compound is an estrogen agonist and is useful for treatment of conditions caused by estrogen difficiency. U.S. Pat. No. 5,552,241 also describes the synthesis of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine by hydrogeneration of nafoxidine.
Lednicer, et al.,
J. Med. Chem
., 12, 881 (1969) described estrogen antagonists of the structure
wherein R
2
is phenyl or cyclopentyl and R
3
is H,
or —CH
2
CHOHCH
2
OH.
Bencze, et al.,
J. Med. Chem
., 10, 138 (1967) prepared a series of tetrahydronaphthalenes intended to achieve separation of estrogenic, antifertility and hypocholesterolemic activities. These structures are the general formula
wherein R
1
is H or OCH
3
; R
2
is H, OH, OCH
3
, OPO(OC
2
H
5
)
2
, OCH
2
CH
2
N(C
2
H
5
)
2
, OCH
2
COOH or OCH(CH
3
) COOH.
U.S. Pat. No. 3,234,090 refers to compounds which have estrogenic and antifungal properties of the formula
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic carbocyclic aryl group substituted by tertiary amino-lower alkyl-oxy, in which tertiary amino is separated from oxy by at least two carbon atoms, R is hydrogen, an aliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical or a heterocyclic aryl aliphatic radical, the group of the formula —(C
n
H
2n-2
)— stands for an unbranched alkylene radical having from three to five carbon atoms and carrying the groups Ar and R, salts, N-oxides, salts of N-oxides or quaternary ammonium compounds thereof, as well as procedure for the preparation of such compounds.
U.S. Pat. No. 3,277,106 refers to basic ethers with estrogenic, hypocholesterolemic and antifertility effects which are of the formula
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic aryl radical substituted by at least one amino-lower alkyl-oxy group in which the nitrogen atom is separated from the oxygen atom by at least two carbon atoms, R is an aryl radical, and the portion —(C
n
H
2n-2
)— stands for lower alkylene forming with Ph a six— or seven-membered ring, two of the ring carbon atoms thereof carry the groups Ar and R, salts, N-oxides, salts of N-oxides and quaternary ammonium compounds thereof.
Lednicer, et al., in J. Med. Chem. 10, 78 (1967) and in U.S. Pat. No. 3,274,213 refer to compounds of the formula
wherein R
1
and R
2
are selected from the class consisting of lower alkyl and lower alkyl linked together to form a 5 to 7 ring member saturated heterocyclic radical. References
1. Kanapure, S. P.; Das, K. G.; Bhawal, B. M.
Synth. Comm
. 1984, 14, 1205-1211.
2. Lexa, D.; Saveant, J. M.; Zickler, J.
J. Amer. Chem. Soc
. 1977, 99, 2786-2790.
3. Chan, T. H.; Brook, M. A.; Chaly, T.
Synthesis
1983, 203-205.
4. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J.
Tet. Lett
. 1986, 27, 279-282.
5. McMurry, J. E.; Kees, K. L.
J. Org. Chem
. 1977, 42, 2655-2656.
SUMMARY OF THE INVENTION
This invention provides intermediate compounds which are useful for the preparation of (−)cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol. These compounds include: 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one; 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane; 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one; and 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene; and (4-Benzyloxy-phenyl)-({4-methoxy-2-[2-(2-phenyl-[1,3]dioxolan-2-yl)-ethyl]-phenyl }-methanone.
This invention also provides a method of preparing Cis-1-{4-[6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenoxy]ethyl}pyrrolidine which comprises the following steps:
1) 2-Bromo-5-methoxy-toluene is brominated to provide 1-bromo-2-bromomethyl-4-methoxybenzene;
2) The product of step 1 is used to alkylate benzoyl acetate ethyl ester followed by decarboxylation to provide 3-(2-bromo-5-methoxyphenyl)-1-phenyl-propan-1-one;
3) The product of step 2 is reacted with ethylene glycol to produce 2-[2-(2-bromo-5-methoxyphenyl)-ethyl]-2-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane;
4) The product of step 3 undergoes metal-halogen exchange with n-butyl lithium and is reacted with 4-benzyloxy benzonitrile to produce 2-[2-(2-(4-benzyloxybenzoyl)-5-methoxy phenyl)-ethyl]-2-phenyl-[1,3]-dioxolane which is subjected to acid hydrolysis of the 1,3 dioxolane to provide 3-[2-(4-benzyloxy-benzoyl)-5-methoxyphenyl]-1-phenyl propan-1-one;
5) The product of step 4 is treated with titanium (III) chloride and zinc-copper couple to produce 4-(4-benzyloxyphenyl)-7-methoxy-3-phenyl-1,2-dihydronaphthalene;
6) The product of step 5 is hydrogenated and treated with triphenyl phosphine, DEAD and 1-(2-hydroxyethyl)pyrolidine to produce 1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)-ethyl}-pyrolidine.
This invention also provides a method of reacting
to produce
wherein R is a protected phenol or
which comprises reacting 2-[2-(2-bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane with butyl lithium followed by reaction with
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a new synthesis of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine as shown below.
Acronyms used in this description are defined as follows:
NBS
N-bromosuccinimide
AIBN
2,2′-Azobisisobutyronitrile
TMSCI
Trimethyl chloro silane
THF
tetrahydrofuran
PPTS
pyridine p-toluene sulfonate
DEAD
Diethyl azodicarboxylate
DME
Dimethoxy ethane
The term “protected phenol” includes optional benzyloxy groups substituted with alkoxy, nitro or halogen, and other acceptable alcohol protecting groups.
Synthesis of CIS-1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-Tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine
The synthesis begins with bromination
1
of 2-bromo-5-methoxy-toluene to provide the benzyl bromide 1-Bromo-2-bromomethyl-4-methoxy-benzene. Alkylation of ethyl benzoylacetate
2
with the benzyl bromide followed by decarboxylation leads to the ketone 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one, which is protected
3
as the ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane. Metal-halogen exchange of ketal 2-[2-Bromo-5-methoxy-phenyl)-2-phenyl-[1,3]dioxolane provides an aryl-lithium species, which adds readily to either 4-benzyloxy-benzoate or 4-benzoxy-benzontrile
4
and furnishes the diketone 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one upon acidic work-up. The diketone undergoes a titanium mediated McMurry type coupling
5
to provide the alkene 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene, which possesses the carbon framework of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine with all the functional groups in place. A palladium catalyzed hydrogenation achieves the reduction of the olefinic double bond and deprotection of the benzyl ether in one pot. The introduction of the N-ethyl-pyrrolidino side-chain is achieved under Mitsunobu conditions to afford 1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-phenoxy]-ethyl}-pyrrolidine, t
Benson Gregg C.
Crissey Todd M.
Higel Floyd D.
Pfizer Inc.
Richardson Peter C.
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