CA2555051C - Process for cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine - Google Patents

Abstract

This invention provides compounds 3-[2-(4- benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one and (4-benzyloxy-phenyl)-{4-methoxy-2-[2-(2-phenyl- [1,3]dioxolan-2-yl)-ethyl]-phenyl}-methanone, and a method of producing a compound of the formula: wherein R is a protected hydroxyl group or

Description

''.72222-405E

Process for Cis-1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-Tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine This application is a divisional application of Canadian Patent Application No. 2,308,922 filed May 19, 2000.

Field of the Invention This invention provides an improved process for producing cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-l-yl)phenoxy]ethyl}pyrrolidine which is an intermediate for the preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol which is useful for the treatment of osteoporosis.

The subject-matter of this divisional application is restricted to the compounds 3-[2-(4-benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-l-one and (4-benzyloxy-phenyl) - {4-methoxy-2- [2- (2-phenyl- [1, 3] dioxolan-2-yl) -ethyl]-phenyl}-methanone, and a method of producing a compound of the formula:

R

O

O O
\__J

-la-It is to be understood that reference to "the invention" or the like used in the specification of this divisional application encompasses not only the subject-matter of this divisional application, but that of the parent and another divisional application also.
Description of the Related Art A preparation of (-)cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol is described in U.S. Patent 5,552,241.

This compound is an estrogen agonist and is useful for treatment of conditions caused by estrogen difficiency.
U.S. Patent 5,552,241 also describes the synthesis of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-l-yl)phenoxy]ethyl}pyrrolidine by hydrogeneration of nafoxidine.

Lednicer, et al., J. Med. Chem., 12, 881 (1969) described estrogen antagonists of the structure:

CH3Owherein R2 is phenyl or cyclopentyl and R3 is H, or -CH2CHOHCH2OH.

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 i R
wherein R' is H or OCH3; R2 is H, OH, OCH3, OPO(OC2H5)2, OCH2CH2N(C2H5)2, OCH2COOH or OCH(CH3) COOH.
U.S. Patent No. 3,234,090 refers to compounds which have estrogenic and antifungal properties of the formula Ar ~I h CnH2n_2) R

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 -(CnH2n_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. Patent No. 3,277,106 refers to basic ethers with estrogenic, hypocholesterolemic and antifertility effects which are of the formula ,--~Ar Ph C2H2n_2 L ---%'R

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 -(CnH2n_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 United States Patent No. 3,274,213 refer to compounds of the formula OCnH2õK,RL

(alkoxy)X

wherein R, and R2 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-l-one; 2-[2-(2-b romo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane; 3-[2-(4-benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-l-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- {2- [4- ( 6-methoxy-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 alkylated with 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 (I11) chloride and zinc-copper couple to produce 4-(4-benzyloxyphenyl)-7-methoxy-3-phenyl-1,2-dihydronaphthalene; and 6) t'he product of step 5 is hydrogenated and treated with triphenyl phosphine, DEAD and 1-(2-hydroxyethyl)pyrolidine to produce 1-{2-[4-(6-methoxy-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)-ethyl}-pyrolidine.

~ R
This invention also provides a method of reacting NC~~
Br ~ ~ .
or with CH3Oov CIC
R
U to produce CH3~ 0 ~ wherein R is a protected hydroxy or -OCH2CH2-NC-) which comprises reacting 2-[2-(2-bromo-5-methoxy-phenyl)-5. ethyl]-2-phenyl-[1,3]dioxolane with butyl lithium followed by reaction with ~ R ( ~ R
~~ or ~
NC CIc Detailed Description of the Invention This invention provides a new synthesis of cis-1-t2-[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 hydroxy" includes benzyloxy optionally 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 Br OH OH
MeO Me HO2C(/
NC
~

NaOH/PhCH2CI
K2CO ,/PHCH2CI EtOH
NBS/AIBN bMF
CICHZCHZCI 50% (1 crop) \ OBn I \ OBn HO I /
\ Br NC~
O
MeO / Br SOCI2 i. NaOEUEtOH ~
Et0 ~ I OBn H. HZSO4 \ Br Me0 /

HOCHZCHZOH OBn cat. TMSCI

rrBuLi \ Br / -78 CITHF \ p /
/ \ ( NHqClquench ' / \ ( Me0 MeO
0 0 v PPTS
acetone/water OBn 0'-~ OBn I\ 1. H2/Pd(OH)2 TiCl3/Zn-Cu 2. Ph3P/DEAD r.t./DME 0 \ HOCH2CH2Pyrro \ I
MeO
Me0 I Me0 0 The synthesis begins with bromination' of 2-bromo-5-methoxy-toluene to provide the benzyl bromide 1 -Bromo-2-bromomethyl-4-methoxy-benzene.
Alkylation of ethyl benzoylacetate2 with the benzyl bromide followed by decarboxylation leads to the ketone 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one, which is protected3 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 benzyloxy-benzoate or 4-benzoxy-benzontrile4 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 coupling5 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}-pyrro(idine, the key precursor to cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine. This compound is converted to cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol with HBr as described in U.S. 5,552,241.

Examples Example 1 1 -Bromo-2-bromomethyl-4-methoxy-benzene Reference: Synthetic Communications, 1984, 1205-1211 To a solution of 2-bromo-5-methoxytoluene (50g, 0.25 mol) in dichloroethane (375 ml), N-bromosuccinimide (48.8g, 0.275 mol) and AIBN (1.36g) were added and the reaction was refluxed for 4 h. The cooled solution was filtered and the solvent was evaporated to give a weight of 44.8 g crude 1 -Bromo-2-bromomethyl-4-methoxy-benzene (64% yield).
This compound was used in next step without further purification.
Example 2 3-(2-Bromo-5-methoxy-phenyl)1-phenyl-propan-1-one Reference: JACS, 1977,2786 To sodium ethoxide (5.72g, 84 mmol) in 50 ml of anhydrous ethanol was added 14.8 g (77 mmol) of ethyl benzoylacetate with stirring. The reaction mixture was then brought to a gentle ref lux and 19.6g (70 mmol) of 1 -Bromo-2-bromomethyl-4-methoxy-benzene in 20 ml of ethanol was added over 20 min. The reaction mixture was refluxed for 2 h. The reaction mixture was cooled, filtered and concentrated.
The concentrated mixture was subjected to acid hydrolysis and decarboxylation by refluxing for overnight in a solution containing 40 ml of glacial acetic acid, 5 mi of concentrated sulfuric acid, and 10 mi of water. The reaction mixture was then neutralized with 10% NaOH and extracted with methylene chloride. The extracts were concentrated to give a weight of 19.43 g crude 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-l-one (yield: 87%). This compound was used in next step without further purification.
Example 3 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane Reference: Synthesis, 1983,203 To a solution of crude 3-(2-Bromo-5-methoxy-phenyl)-1-phenyl-propan-1-one (1 9.43g, 61 mmol) in dry ethylene glycol (300 ml) under a N2 atmosphere was added chlorotrimethylsilane (31 ml, 0.25 mol). The reaction was stirred at room temperature for 1 h. A 5% aqueous NaHCO3 (300 ml) was added. The mixture was extracted with diisopropyl ether, and the extracts were washed with brine. The combined ether extracts were dried with Na2SO4 and the solvent was removed under reduced pressure to produce a weight of 21.52 g crude 2-(2-(2-Bromo-5-methoxy-phenyl)-ethyl)-2-phenyl-[1,3]dioxolane (yield: 97%).
Example 4 4-Benzyloxy-benzonitrile Reference: Tetrahedron Lett. 1986, 279-282 To a solution of 4-cyanophenol (25 g, 0.21 mol) and K2C03 (138 g, 1 mol) in DMF (300 ml) was added benzyl chloride (27.91 g, 0.22 mol) in one portion. The resulting mixture was stirred at room temperature overnight. The suspension was filtered and the filtrate was poured into iced water. The resulting solid was collected to provide a weight of 43.5 g product (yield: 99%).
Example 5 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1 -phenyl-propan-1 -one A solution of 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane (0.9 g, 2.5 mmol) in 10 ml of dry THF was cooled to -780 C and n-BuLi (2.5 M
in hexane, 1 ml) was added dropwise. The solution was stirred at -780C for 2 h and 4-benzyloxy-benzonitrile (0.575 g, 2.75 mmol) in 2 ml of THF was added. The mixture was allowed to warm to room temperature and refluxed overnight. The solution was then quenched with sat. NH4C1 and the solvent was evaporated. A solution of the residue in 20 ml of wet acetone, 5 ml of H20 containing PPTS (188 mg, 0.75 mmol) was refluxed overnight. Regular workup and column purification afforded an unoptimized weight of 0.8 g 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1 -phenyl-propan-1 -one.
Example 6 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene Reference: JOC, 1977, 2656 TiC13 (2.062 g, 13 mmol) and Zn-Cu couple (2.02 g, 30.8 mmol) were placed in a 200 ml round bottom flask under N2. Anhydrous dimethoxyethane (40 ml) was added and the mixture was ref luxed for 1 h.
Note: The Zn-Cu couple is prepared by adding zinc dust (9.8 g, 150 mmol) to 40 ml of deoxygenated water, purging the slurry with N2 gas for 15 min, and than adding CuSO4 (0.75 g, 4.7 mmol). The black slurry was filtered under N2, washed with deoxygenated H20, acetone, ether, and then stored under N2.
3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one (540 mg, 1.2 mmol) in 80 ml of DME was added to the refluxing slurry and the resulting mixture was refluxed for 15 min. The suspension was filtered and the solvent was evaporated to give a weight of 0.45 g 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene (yield: 90%, structure was confirmed by X-ray).
Example 7 1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl}-pyrrolidine 4-(4-Benzyloxy-phenyl)-7-methoxy-3-phenyl-1,2-dihydro-naphthalene (0.45g, 1.08 mmol) was dissolved in a mixture of EtOH (15 ml) in a Paar bottle.
Pd.(OH)2 (0.3 g) in 2 ml of H20 was added and the mixture was shaken under H2 (50 psi) at room temperature. The solution was filtered and treated with same equivalent of triphenylphosphine, DEAD and 1-(2-hydroxyethyl)pyrrolidine. Normai workup gave {2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl}-pyrrolidine.

Claims (4)

CLAIMS:

1. The compound 3-[2-(4-benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one.

2. The compound (4-benzyloxy-phenyl)-{4-methoxy-2-[2-(2-phenyl-[1,3]dioxolan-2-yl)-ethyl]-phenyl}-methanone.

3. A method of producing a compound of the formula:

wherein R is a protected hydroxyl group or which comprises reacting 2-[2-(2-bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane of the formula:

with butyl lithium followed by reaction with a compound of the formula:

wherein R is as defined above.

4. The method of claim 3, wherein R is the protected hydroxyl group and is benzyloxy.