Title of Invention

"A PROCESS FOR THE PREPARATION OF DIARYL NAPHTHYL METHANES"

Abstract Process for the preparation of diaryl naphthyl methanes The invention relates to novel diaryl naphthyl methane compounds having general formula I useful in the treatment of esterogen related disease or syndrome . The process for the preparation of the said novel methane derivatives has been described which comprises reacting a compound of formula II with a phenolic compound under the conventional Friedel Crafts reaction conditions to get the novel diaryl naphthyl methane compounds having general formula I.
Full Text FIELD OF THE INVENTION
This invention relates to a process for perparation of novaldiaryl naphthyl methanes and a process for preparation of said methane
derivatives. The present invention particularly relates to a process or preparation of substituted secondary and tertiary amino alkoxy diaryl naphthyl methane derivatives, preparation of pharmaceutical comnoeitio", containing such compounds as active ingredients and their use as contraceptives, in to treatment and prophylaxes of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial disorders and in estrogen replacement therapy (ERT).
BACKGROUND OF THE INVENTION
Estrogen agonists as well as antagonists act through their interaction with estrogen receptor. This
estrogen receptor protein has an active site where the ligand binds. It has been visualized as
composed of two units, one having a shape complimentary to the structure of estradiol where
estradiol finds a proper fit for producing estrogen agonistic activity. The second site provides binding
of structural unit such as a substituted amino alkoxy anyI group thereby causing interference with the
initiation of the hormonal activity as observed with estrogen antagonists. Based on this visualization,
estrogen receptor model has been proposed easier. This present work utilizes the receptor model
towards designing of novel estrogen antagonists.
OBJECTS OF THE INVENTION
The main object of the invention is to provide novel diarylnaphthyl methane compounds having
structural Formula 1 and their derivatives, useful in the treatment of estrogen related diseases such
as breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial
disorders and in estrogen replacement therapy (ERT).
Another object is to provide pharmaceutical compositions containing the novel diarylnaphthyl
methane compounds having structural formula 1.
Yet another object is to provide methods for the preparation of novel diarylnapththyl methane
compounds and their derivatives.
Summary of the invention
In accordance with the above and other objectives, the invention provides novel substituted diaryl naphthyl methane compounds having structural formula 1 and its derivatives, being a novel group of non-steroidal compounds and exhibiting estrogenic, antiestrogenic and contraceptive activities. The invention also provides methods for the preparation of the said novel diaryl naphthyl methane compounds and their derivatives. The invention also provides pharmaceutical compositions containing said novel diaryl naphthyl methane compounds and their derivatives.
Detailed description of the invention
Accordingly the invention provides novel diaryl naphthyl methane compounds having general formula 1 as shown herein below,
(Formula Removed)wherein,
R1.R2.R3.R4.R5 represent H, OH, lower alkyl, lower alkoxy group having straight or branched chain radical containing 1-6 carbon atoms selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group, substituted alkoxy groups, epoxy alkoxy, alkyl/dialkyl amino alkoxy, cyclic alkyl amino alkoxy, the dotted indicate 1,2,3,4-tetrahydro naphthyl ring or 5,6,7,8-tetrahydronaphthyl ring, said compounds exhibiting estrogenic, antiestrogenic and contraceptive activities.
Substituted diaryl naphthyl methane derivatives, a novel group of non-steroidal compounds is showing promising estrogenic, antiestrogenic and contraceptive activities. The hormonal profile of such compounds is suitable for the treatment and prophylaxes of breast cancer, osteoporosis, hypercholesteremia, enaometriosis, vasoconstriction,

endometrial disorders and in estrogen replacement therapy.
The invention provides a novel substituted aminoalkoxy diaryl naphthyl methane derivatives thereof, represented by general formula 1 as shown hereinbelow:
(Formula Removed)
Wherein R1.R2.R3.R4.R5 are H,OH, lower alkyl, a substituted lower alkoxy group having a straight or branched chain radical containing 1-6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group. Substitutent on the alkyl chain of alkoxy radical can be H or OH, a substituted amino lower alkoxy group wherein the lower alkoxy substituent is as defined above, the substituent on the nitrogen atom is H, or a lower alkyl radical as defined above or constitutes a cyclic polymethyline system containing nitrogen atom, i.e. N(CH2)n wherein n=2-8. The naphthyl residue can be a substituted naphthyl, substituted 1,2,3,4-tetra hydro naphthyl or a substituted 5,6,7,8-tetrahydro naphthyl.
The compounds synthesized were tested for estrogenic, antiestrogenic activies in rats. A number of these compounds showed cent percent prevention of pregency at doses 10 mg per kg or below when administered orally to female albino rats on days 1-7 p.c. or on single day schedule.
The most preferred compounds, represented by formula 1 are given below:
1. (4-Methoxypheny!)-(4-pyrro!idinoethoxyphenyl}-naphth-1 -yl-methane HCI
2. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-naphth-1-yl-methane
3. (4-Methoxyphenyl)-(3-methyl-4-piperidinoethoxyphenyl)-naphth-1-yl-methane
4. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-1,2,3,4-tetrahydro-naphth-1-
yl- methane
5. (4-Methoxyphenyl}-(4-pyrrolidinoethoxypheny!)-5,6,7,8-tetrahydro-naphth-1-
yl- methane HCI
6. (4-Methoxyphenyl)-(4-(2-hydroxy-3-cyclopropylamino)-propoxy)-phenyl-
naphth-1-yl- methane
7. (4-Methoxyphenyl)-(4-(2-hydroxy-3-n-butyiamino-propoxy)phenyl)-1,2,3,4-
tetrahydronaphth-1-yl-methane
The most preferred compounds belonging to the class of diaryl naphthyl methanes represented by formula la are given below.
(Formula Removed)
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-naphth-1-yl-methane HCI
2. {4-Methoxyphenyl}-(4-piperidinoethoxyphenyl)-naphth-1-yi-methane
3. (4-Methoxypheny!)-(3-methyl-4-piperidinoethoxyphenyl)-naphth-1-yi-methane
The invention includes within the scope partially reduced substituted naphthalene residue to provide derivatives of substituted diaryl 1,2,3,4- tetrahydro
naphthyl methane represented by the general formula Ib wherein R1.R2.R3.R4.R5 have the meaning as stated above.

(Formula Removed)
Preferred compounds belonging to Ib are:
1. (4-Methoxyphenyl)-(4-piperidinoethoxy phenyl)- 1,2,3,4-tetrahydronapth-1-yl
methane.
2. (4-methoxyphenyl)-(3-methyl-4-piperidinoethoxyphenyl)-1,2,3,4-
tetrahydronaphth-1 -yl-methane.
3. (4-Methoxyphenyl);(4-(2-hydroxy-3-n-dibutylaminopropoxy)phenyl-1,2,3,4-
tetrahydronaphth-1 -yl-methane.
In yet another modification included within the scope are the partially reduced naphthalene residue containing derivatives of substituted diaryl 5,6,7,8- tetra hydro naphthyl methane represented by the general formula Ic.
(Formula Removed)

wherein R1.R2.R3.R4.R5 have the meanings as stated above.
Preferred compounds of 1c are :
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxy phenyl)-5,6,7,8-tetrahydronaphth-1-yl-
methane hydrochloride.
2. (4-Methoxyphenyl)-(4-N,N-diethylamino-ethoxyphenyl)-5,6,7,8-tetrahydro-
naphth-1-yl-methane.
The preparation of compounds shown in formula 1, wherein R1.R2.R3.R4.R5 are as defined above is described hereinbelow. The process comprises the steps of conducting Friedel-Crafts reaction of substituted cc-naphthoic acid with the substituted phenol in the presence of Lewis acid to give a naphthophenone derivative which is reduced by a metal hydride in a protic solvent to the corresponding alcohol which is subjected to a second Friedel-Crafts reaction with a phenol derivative in the presence of a Lewis acid under low temperature to produce compound of formula 1 wherein one of the substituent Ri,R2,R3,R4,Rs is a hydroxy group which is reacted with a tertiary amino alkyl chloride to produce corresponding tertiary amino alkoxy compound or alternatively treated with epichlorohydrin under basic condition either neat or in organic solvent such as acetone, DMSO to produce corresponding 2,3-epoxy-propyloxy derivatives which on treatment with an amine produce hydroxy substituted corresponding secondary amino alkoxy derivatives.
PHARMACEUTICAL COMPOSITION
Typical composition includes a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluents or be diluted or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the composition, conventional techniques for the preparation of pharmaceutical composition may be used, for example the active compound will usually be mixed with a carrier, or diluted by a carrier, enclosed within a container, which may be in the form of an ampoule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid or liquid material which act as a vehicle, excipient, or medium of the active compound. The active compound can be adsorbed on a granular solid. Some examples of suitable carriers are water, salt solution, alcohol, polyethyleneglycol, polyhydroxyethoxylated castor oil, gelatine, lactose, amylase, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty
acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulation may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents . The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers , salt for influencing osmotic pressure , buffers and/ or colouring substances and the like , which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compounds dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
The compound according to this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferably, the animal is a vertebrate. Most preferably a compound according to this invention shall be administrated to a mammal. It is especially preferred that the animal is a domestic animal or a human. The most preferred mammal is a human. For such purposes, a compound of this invention may be administrated as a feed additive or in bulk form.
The preparation of the novel compounds and its derivatives are described in the following non-imitative examples.
Novel diaryl naphthyl methanes of formula I have been prepared
(Formula Removed)
Accordingly the present invention provides a process for the preparation of novel diaryl naphthyl methane compound useful in the treatment of estrogen related disease or syndrome and having general formula I as shown in the
accompanying this specification with a phenolic compound under the
drawing accompanying this specification wherein R1, R2, R3, R4, R5 are H, OH, lower alkyl, lower alkoxy group having straight or branched chain radical containing 1 - 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group, substituted alkoxy groups, epoxy alkoxy, alkyl/dialkyl amino alkoxy, cyclic alkyl aminoalkoxy, hydroxyl substituted alkyl/dialkyl/cyclic alkyl aminoalkoxy, the dotted lines indicate 1,2,3,4-tetrahydronaphthyl ring or 5,6,7,8-tetrahydronaphthyl ring, said process comprises the steps of: (i) reacting a compound of formula II as shown in the drawing
(Formula Removed)
Novel diaryl naphthyl methanes of formula I have been prepared

(Formula Removed)
Accordingly the present invention provides a process for the preparation of novel diaryl naphthyl methane compound useful in the treatment of estrogen related disease or syndrome and having general formula I as shown in the

drawing accompanying this specification wherein R1, R2, R3, R4, R5 are H, OH, lower alkyl, lower alkoxy group having straight or branched chain radical containing 1 - 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group, substituted alkoxy groups, epoxy alkoxy, alkyl/dialkyl amino alkoxy, cyclic alkyl aminoalkoxy, hydroxyl substituted alkyl/dialkyl/cyclic alkyl aminoalkoxy, the dotted lines indicate 1,2,3,4-tetrahydronaphthyl ring or 5,6,7,8-tetrahydronaphthyl ring, said process comprises the steps of: (i) reacting a compound of formula II as shown in the drawing
(Formula Removed)accompanying this specification with a phenolic compound under the wherein the preferred compounds are represented below
1 (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-naphth-1-yl-methane HCI
2. (4-Methoxyphenyl)-(4-piperidmoethoxyphenyl)-naphth-1-yl-methane
3. (4-Methoxyphenyl)-(3-methyl-4-piperidinoethoxyphenyl)-naphth-1-yl-methane
4. (4-Methoxyphenyl)-(4-pyrrolidinoethnoxyphenyl)-1,2,3,4-tetrahydro-naphth-1 -
yl- methane
5. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-5,6,7,8-tetrahydro-naphth-1-
yl-methane HCI
6. (4-Methoxyphenyl)-(4-2-hydroxy-3-cyclopropylamino)-propoxy)-phenyl-
naphth-1-yl- methane
7. (4-Methoxyphenyl)-(4-(2-hydroxy-3-n-butylamino-propoxy)phenyl)-1,2,3,4-
tetrahydronaphth -1-yl-methane
In an embodiment of the present invention the catalyst used for Friedel- Crafts reaction is such as AICI3, SnCI4, (CH3)3 SiCI.
In another embodiment of the present invention the solvent used for Friedel-Crafts reaction is hydrocarbon solvents such as benzene, tolune, hexane pentane.
In another embodiment of the present invention the reaction is effected at a temperature in the range of-20°C to 100°C for a period in the range of 1 to 10 hr.
In still another embodiment of the present invention the catalyst used for hydrogenation is such as Raney Ni, Pd/C, Pt2O.
In yet another embodiment of the present invention the hydrogenation is effected at a pressure in the range of 30 to 60 psi at a temperature in the range of 25° to 60°C in presence of solvent such as methanol, ethanol, THF.
In yet another embodiment of the present invention the alkylating agent used is such as epichlorohydrine, CICH2 CH2 N(CH2)3 CICH2CH2 N(CH2)5, CICH2CH2 N-phenyl piperazine, CICH2CH2 n Bu, Cl CH2CH2 N(CH2)3, CICH2CH2 N-isopropyl.
In yet another embodiment of the present invention the alkylation is carried out neat or in a non polar solvent, such as acetone, DMSO, in the presence of a base such as K2CO3 NaOH, KOH, organic base.
In yet another embodiment of the present invention the amine used is such as primary or secondary amine containing carbon atoms 2 to 6.
In yet another embodiment of the present invention the reaction in step (iv) in carried out neat (without solvent) or in presence of polar solvent such as methanol, ethanol, THF.
In yet another embodiment of the present invention the salts of formula 1 in such as hydrochloride, tartrates, citrate, succinate.
In yet another embodiment of the present invention the pharmaceutical composition comprises a compound of formula 1 in an appropriate amount in admixture with a pharmaceutical carrier or a diluant.
In yet another embodiment of the present invention the use of compound prepared is for prevention and treatment of estrogen related disease or syndromes
EXAMPLES Example 1
(4- Methoxyphenyl)-(4-hydroxyphenyl)- naphth -1-yl methane
A solution of compound (4-methoxyphenyl)-naphth-1-yl-carbmol of formula II (3.0 gm, 0.011 mol) and phenol (5.4 gm, 0.057 mol) in a mixture of dry benzene and dry hexane (40.0 ml), 1:1) was gradually added to a mixture of phenol (1 5 gm, 0.061 mol) and anhydrous aluminium chloride (1.5 gm, 0.011 mol) at 0°C under stirring . After the addition was over the stirring was continued at room temperature for 3 hrs, the reaction was decomposed by adding crushd ice with conc.HCI (0.5 ml) and extracted with ethyl acetate. The organic layer was washed with water , 5% NaOH, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel to yield title compound of formula I. Yield 2.3 gm (59.3%).
Example 2.
(4-Methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-naphth-1-yl-methane
To a stirred solution of (4- methoxy phenyl)-naphth-1-yl carbinol of formula II (5.0 gm, 0.018 mol )and o-cresol (2.4ml, 0.022 mol) in a mixture of dry benzene and dry pentane (50ml, 1:1) AICI3 (2.5gm) was gradually added , after addition stirring was continued for 5-6 hrs at 0-4 °C. The reaction mixture was decomposed by adding crushed ice with cone HCI (0.5 ml) and extracted with ethyl acetate. The organic layer was washed successively with water, dried over Na2SO4 and concentrated to give an oil , which was chromatographed over silica gel using benzene-hexane as eluant to give title compound of formula III, yield 4.5 gm (67.16%)
Example 3
(4-Methoxyphenyl)-(4-pyrrolidinoethoxy phenyl)- naphth -1-yl methne hydrochloride
A mixture of (4- methoxy phenyl ) -(4-hydroxy phenyl) -naphth -1-yl -methane of formula 1(2.3 gm,0.007 mol), anhydrous K2C03 (4.43 gm), 1-(2-chloroethtyl)pyrrolidine hydrochloride (3.0gm, 0.018mol) and dry acetone(200ml), was refluxed for 8-10 hrs .K2CO3 was filtered off, acetone was distilled off and residue was diluted with water The reaction mixture was extracted with ethyl acetate .washed with water, dried over Na2SO4 and concentrated to give an oil This oil was passed through basic alumina using benzene as eluant. Solvent was distilled off. The oil thus obtained was treated with ethanolic HCl.The solvent was evaporated and compound was crystallized with absolute alcohol and dry ether to give title compound as a salt of general formula I.Yield 0.75 gm(66%).
Example 4
(4-Methoxyphenyl)-(3-methyl-4-pyrrolidinoethoxy phenyl)-naphth-1-yl-
methane hydrochloride
A mixture of (4-methoxyphenyl)-(3- methyi-4-hydroxyphenyl)-naphtha-1-yl- methane (0.3 gm,0.008 mol) anhydrous K2CO3 (2.0 gm), 1-(2-chloroethtyljpyrrolidine hydrochloride (O.Sgm, 0.0017mol) and dry acetone (25ml) was refluxed for 10 hrs .K2C03 was filtered off , acetone was distilled off and residue was diluted with water The reaction mixture was extracted with ethyl acetate .washed with water, dried over Na2SO4 and concentrated to give an oil This oil was passed through basic alumina using benzene as eluant. Solvent was distilled off. The oil thus obtained was treated with ethanolic HCl.The solvent was evaporated and compound was crystallized with absolute alcohol and dry ether to give the title compound as a salt of general formula I..Yield 170mg(46%).

Example 5
(4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-napth-1-yl-methane
A mixture of (4- methoxy phenyl ) -(4-hydroxy phenyl) -naphth -1-yl -methane of formula l(0.3gm,0.001 mol), anhydrous K2CO3 (1.5gm), 1-{2-chloroethtyl)piperidine hydrochloride (0.276gm, 0.002 mol) and dry acetone(100 ml) was refluxed for 8-10 hrs .K2CO3 was filtered off, acetone was distilled off and residue was diluted with water The reaction mixture was extracted with ethyl acetate .washed with water, dried over Na2SO4 and concentrated to give an oil This oil was purified by column chromatography over basic alumina using benzene as eluant. Solvent was distilled off to give the title compound of general formula I as an oil. Yield 0.3 gm(67%).
Example 6.
(4-Methoxyphenyl)-(4-(2,3- epoxy propyloxy)pheny)-i- naphth-1-yl methane
A mixture of (4-methoxyphenyl}-(4-hydroxypheny)-l- naphth-1-yl methane of formula I (2.6g, 0.29mmol) anhydrous K2CO3(2.8gm,1.44mmol)lepichlorohydrin (20ml) was refluxed at 100°C for 10 hrs. The reaction mixture was filtered and filtrate was concentrated. The residue was dissolved in ether .washed with aq NaOH(10%) and thenwith water to neutral, dried over sodium sulphate and solvent distilled off. The oil was chromatographed over silica gel. The epoxide was eluted with 20% hexane- chloroform to give pure title epoxide of formula I as an oil , yield 1.98gm(65.38%).
Example 7
(4- Methoxyphenyl)-{3-methyl -4-{2,3- epoxypropy!oxy)pheny))-l-naphth-1-y! methane
A mixture of (4- methoxyphenyl)-(3-methyl -4-hydroxy pheny)-!-naphth-1-yl methane{1.0gm, 0.002mol), epichlorohydrin (25ml)and anhydrous K2C03 (4.0gm) was refluxed at 120°C for 8 hrs. K2CO3 was filtered off and fitrate was concentrated. The residue obtained was dissolved in ethyl acetate and washed with water .dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel using hexane -chloroform as eluant to give title compound of general formula I, yield .75gm(66%)
Example 8
(4-Methoxy phenyl)-{4- {2- hydroxy - 3-n- butylaminopropoxy)phenyl- naphth-1-yl methane, hydrochloride
A mixture of (4-methoxy phenyl)-(4-(2,3- epoxy propyloxypheny)) -1 - naphth-1-yl methane { 3.96 gm, 0.01 mol) , n- butyl amine ( 1.gm, 0.014 mol) and ethanol (10ml ) was refluxed for 6 hrs. Ethanol was distilled off and the residue was passed through basic alumina using benzene- hexane as eluant. The solvent was distilled off yielding the free base compound of formula II as an oil. The oil thus obtained was treated with ehanolic HCI. The solvent was evaporated and compound was crystallized with absolute alcohol and dry ether to give compound of general formula II as hydrochloride salt.Example 9
(4-Methoxy phenyl)-(3-methyl-4-(2-hydroxy-3-n-butylamino)propoxy)phenyl)-naphth -1-yl methane, hydrochloride
A mixture of (4- methoxyphenyl)-(3-methyl -4-(2.3- epoxypropyloxy)pheny)-l-naphth-1-yl methane of formula I (O.Sgm,0.001 mol), n-butyl amine (1 .Oml. 0.014 mol) and ethanol was refluxed for 6 hrs. Ethanol was distilled off and residue was passed through basic alumina column using hexane- ethyl acetate as eluent.Solvent was distilled off. The oil thus obtained was treated with ethanolic HCl.The solvent was evaporated and title compound of formula II obtained as a salt was crystallized with absolute alcohol and dry ether. Yield 0.25gm (41.26%).
Example 10
{4-Methoxyphenyl)-(4-hydroxyphenyl)-1,2,3,4-tetrahydro-napth -1-yl methane
A mixture of.(4- methoxy phenyl}-(4-hydroxy phenyl )- naphthyl -1-yl-methane (3.0gm,.008 mol) in methanol(25 ml) and (3.0 gm) of Raney Ni was hydrogenated at 60 psi pressure for 8 hrs Then catalyst was filtered off and solvent was distilled off . This crude product was purified on silica gel (flash) by using hexane and ethyl acetate as eluant to give compound of formula [..Yield 0.9gm (29%).
Example 11
(4-Methoxyphenyl)-(4-hydroxyphenyl)- 5,6,7,8- tetrahydro-napth -1-yl methane.
A mixture of of.(4- methoxy phenyl) (4-hydroxy phenyl ). naphthyl -1yl-methane (3.0gm,.008 mol) in methanol (25 mi)'and (3.0 gm) of Raney Ni was hydrogenated at 60 psi pressure for 8 hrs Then catalyst was filtered off and solvent was distilled off . This crude product was purified on silica gel (flash) by using
hexane and ethyl acetate as eluant to give title compound for formula I. Yield. 8gm . (26%).
Example 12
(4-Methoxyphenyl)-{ 3-methyl-4-hydroxyphenyl)-1,2,3,4-tetrahydro-napth -1-yl
methane.
A mixture of .(4- methoxy phenyl) (3- methyl-4-hydroxy phenyl- . naphth -1-yl-methane (3.8gm,.010 mo!) in methanol (25 ml) and (3.0 gm) of Raney Ni was hydrogenated at 60 psi pressure for 8 hrs Then catalyst was filtered off and solvent was distilled off . This crude product was purified on silica gel (flash) by using hexane and ethyl acetate as eluant to give compound of formula I. Yield 1.2gm (31.5%).
Example 13
(4-Methoxyphenyl)-(3- methyl-4-hydroxyphenyl)- 5,6,7,8- tetrahydro-napth -1-yl methane
A mixture of.(4- methoxy phenyl) (3- methyl-4-hydroxy phenyl ). naphthyl -1-yl-methane in (3.8gm,.010 mol) of methanol (25 ml) and (3.0 gm) of Raney Ni was hydrogenated at 60 psi pressure for 9 hrs .Then catalyst was filtered off and solvent was distilled off. This crude product was purified on silica gel (flash) by using hexane and ethyl acetate as eluant to give title compound of formula I.Yield.6gm . (15.78%).
Example14
(4-Methoxy phenyl)(4-pyrolidinoethoxy. phenyl)-1,2,3,4 tetrahydro-napth -1-yl methane hydrochloride
A mixture of (4- methoxy phenyl)- (4-hydroxy phenyl )-1,2,3,4 tetrahydro naphth-1-yl- methane (400 mg ,.001 mol), anhydrous. K2CO3(2.0gm, 0.14mol),1-(2-
chloro ethyl )pyrrolidine hydrochloride(400mg, .002) and dry acetone (25.0 ml) was refluxed for 10 hrs. K2CO3 was filtered off .acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil .which was filtered through basic alumina column using benzene as eluant, concentrated. The oil thus obtained was treated with ethanolic HCI. The solvent was evoporated and compound was crytallised with absolute alcohol and dry ether filtered under anhydrous condition and dried to give title compound of formula I. Yield 350 mg.(68.35%).
Example 15
(4-Methoxy phenyl)-(3- methyl- 4-pyrrolidinoethoxy- phenyl)- 1,2,3,4-tetrahydro-napth -1-yl -methane hydrochloride
A mixture of (4- methoxy phenyl)- ( 3-methyl-4-hydroxy phenyl )-1,2,3,4-tetrahydro naphthyi-l-yl- methane (322 mg ,.009 mol), anhydrous. K2CO3(2.0gm, 0.14mol),1-(2-chloro ethyl )pyrrolidine hydrochloride(300mg, .0017) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off ,acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water , dried over sodium sulphate and concentrated to give an oil .which was filtered through basic alumina column by using benzene as eluant concentrated The oil thus obtained was treated with ethanolic HCI. The solvent was evaporated and compound was crytallised with absolute alcohol and dry ether filtered under anhydrous condition to give title compound of formula I. Yield 190 mg.(44%).
Example 16
(4-Methoxy phenyl)-(4-pyrrolidinoethoxy-pheny!}-1,2,3,4-tetrahydro-napth-1 -yl-methane.
A mixture of (4- methoxy phenyl)- (4-hydroxy phenyl)- 1,2,3,4 -tetrahydro naphth-1-yl- methane (400 mg .0011 mol), anhydrous. K2CO3(2.0gm, 0.014mo!),1-(2-chloro ethyl) piperidine hydrochloride (400mg, 002) and dry acetone (25 0 ml) was refluxed for 10 hrs, K2CO3 was filtered off .acetone was distilled off and residue was diluted with water . The reaction mixture was extracted with ethyl acetate washed with water , dried over sodium sulphate and concentrated to give an oil .which was filtered through basic alumina column by using benzene as eluant concentrated. The oil thus obtained was treated with ethanolic HCI. The solvent was evaporated and compound was crytallised with absolute alcohol and dry ether filtered under anhydrous conditionto give title compound of formula I. Yield 310 mg.(58.6%).
Example 17
{4-Methoxy phenyl)-( 3-methyl-4-pyrrolidinoethoxy- phenyl)- 1,2,3,4-tetrahydro-napth -1-yl methane.
A mixture of .(4- methoxy phenyl) (3-methyl -4-hydroxy phenyl )-1,2,3,4-tetrahydro naphth-1-yl- methane (345 mg ,.001 mol), anhydrous K2CO3(2.0gm, 0.014mol), and 1-(2-chloro ethyl )pipendine hydrochloride(400mg, ,002ml) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off .acetone was distilled off and residue was diluted with water . The reaction mixture was extracted with ethyl acetate, washed with water , dried over sodium sulphate and cocentrated to give an oil .which was filtered through basic alumina column by using benzene as eluant concentrated to give title compound of formula I Yield 324 mg (72%),
Example 18
(4-Methoxy phenyl))-(4-pyrrolidinoethoxy-phenyl)-5,6,7,8-tetrahydro-napth-1-yl methane hydrochloride
A mixture of (4- methoxy phenyl)- (4-hydroxy phenyl)- 5,6,7,8- tetrahydro naphth-1-yl-methane (300mg, 0.001 mol), anhydrous. K2CO3(2.0gm, 0.01 4moi),1 -(2-chloroethyl)pyrrolidine hydrochloride (400mg, 002ml) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off .acetone was distilled off and residue was diluted with water The reaction mixture was extracted with ethyl acetate, washed with water , dried over sodium sulphate and cocentrated to give an oil .which was filtered through basic alumina column by using benzene as eluant The oil thus obtained was treated with ethanolic HCI. The solvent was evaorated and compound was crytallised with absolute alcohol and dry ether filtered under anhydrous condition to give title compound of formula I. Yield 176 mg (42.30%).
Example19
(4-Methoxy phenyl)-{3- methyl- 4-pyrrolidinoethoxy- phenyl)- 5,6,7,8-tetrahydro-napth -1-y I methane hydrochloride
A mixture of (4- methoxy phenyl)- ( 3-methyl-4-hydroxy phenyl ) -5,6,7,8-tetrahydro naphthyl-1-yl- methane (330 mg .001 mol), anhydrous K2C03(2.0gm,0.14mol),1-(2-chloroethyl )pyrrolidine hydrochloride(400mg, .002 mol) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and cocentrated to give an oil , which was filtered through basic alumina column using benzene as eluant . The oil thus obtained was treated with ethanolic HCI The solvent was evaporated and compound was crytallised with absolute alcohol and dry ether filtered under anhydrous condition to give title compound of formula I Yield 220 mg.{48.5%).
Example 20
( 4-Methoxy phenyl)-(4-pyrrolidinoethoxy-phenyl)-5,6,7,8-tetrahydro-napth-1 -yl- methane.
A mixture of (4- methoxy phenyl)- (4-hydroxy phenyl}- 5,6,7,8- tetrahydro naphth-1-yl-methane (300mg,0.001mol), anhydrousK2C03(2.0gm,0.014mol),1-(2-chloroethyl)piperidine hydrochloride (300mg,0.0015mol ) and dry acetone (25-0 ml) was refluxed for 10 hrs, K2CO3 was filtered off .acetone was distilled off and residue was diluted with water , The reaction mixture was extracted with ethyl acetate, washed with water , dried over sodium sulphate and cocentrated to give an oil ,which was filtered through basic alumina column by using benzene as eluant and concentrated to give tile compound of formula I .Yield 218 mg.(55.89 %).
Example 21
(4-Methoxy phenyl)-(3- methyl- 4-pyrrolidinoethoxy- phenyl)- 5,6,7,8-tetrahydro-napth -1-yl methane.
A mixture of (4- methoxy phenyl)- ( 3-methyl~4-hydroxy- phenyl)- 5,6,7,8-tetrahydro- naphth-1-yl -methane (330 mg,.001 mol), anhydrous. K2CO3(2.0gm,0.14mol),1-(2-ch!oroethyl )pipridine hydrochloride(400mg, .002mol) and dry acetone (25.0 ml) was refluxed forlO hrs, K2C03 was filtered off .acetone was distilled off and residue was diluted with water . The reaction mixture was extracted with ethyl acetate, washed with water , dried over sodium sulphate and cocentrated to give an oil .which was filtered through basic alumina column by using benzene as eluant to give title compound if formula I Yield 210 mg.( 47 19%)
Example 22.
(4-Methoxy phenyl)-(4-(2,3- epoxy- propyloxy)pheny-1,2,3,4- tetrahydro-naphth-1-yl methane
A mixture of (4-methoxy phenyl)- (4-hydroxy phenyl)- 1,2,3,4- tetrahydronaphth-1-yl-methane(1 .Ogm,0.29mmol),anhydrous K2CO3 (4.0gm,0.28mol),epichlorohydrin (20ml) was refluxed at 100-120°C for 8 hrs. The reaction mixture was filtered and filtrate was concentrated. The residue was dissolved in ethylacetate.and washed with water, dried over sodium sulphate and concentrated to give an oil.The oil was chromatographed over silica gel, to give title compound. Yield 1.1gm 94.8%).
Example 23
(4-Methoxypneny!)-(3-methyl-4-(2,3-epoxypropyloxy-pheny)-1,2,3,4-tetrahydro-l-naphth-1 -yl -methane
A mixture of (4-methoxy phenyl)- (3- methyl-4-hydroxy phenyl)- 1,2,3,4-tetrahydro naphth-1-yl-methane {SOOmg, 0.002mol),epichlorohydrin (25rnl)and anhydrous K2CO3 (4.0gm, 0.028mol) was refluxed at 120°C for 8 hrs. K2CO3 was filtered off and fitrate was concentrated. The residue obtained was dissolved in ethyl acetate and washed with water .dried over sodium sulphate and concentrated to give title compound as an oil. yield 610mg(88.4%).
Example 24
(4-Methoxyphenyl)-{4- (2-hydroxy-3-di-butylamino- propoxy-phenyl)-1,2,3,4-tetrahydro- naphth-1- yl- methane
A mixture of (4-Methoxy phenyl)-(4-(2,3- epoxy- propyloxy)pheny)-1,2,3,4-tetrahydro- naphth-1-yl- methane (300mg, .001 mol), dibutyl amine (1.0ml) and ethanol( 10ml ) was refluxed for 12 hrs Ethanol was distilled off and the residue
was passed through basic alumina using benzene ethylacetate as eluant.The solvent was distilled off yielding the required product. Yield 192mg( 49.23%)
Example 25.
(4-Methoxyphenyl)-(4-{2-hydroxy - 3-n- butylamino propoxy)phenyl)-1,2,3,4-tetrahydro- naphth-1- yl- methane
A mixture of (4-Methoxy phenyl}-(4-{2,3- epoxy propyloxy)pheny)- 1,2,3,4- tetrahyro naphth-1-yl -methane (400mg, .OOlmol), n- butyl amine ( 1.0ml, .01mol ) and ethanol( 10ml ) was refluxed for 8 hrs. Ethanol was distilled off and the residue was passed through basic alumina using benzene- ethylacetate as eluant.The solvent was distilled off yielding the required product.Yield 230mg(48.93%)
Example 26
(4-Methoxyphenyl)-(3-methyl-4-(2-hydroxy-3-n-butylaminopropoxy)phenyl-1,2,3,4- tetrahydro- naphth -1-yl- methane
A mixture of (4-methoxyphenyl)-(3-methyl -4-(2,3- epoxypropyloxy)pheny)-1,2,3,4-tetrahydro naphth-1-yl- methane (300mg,0.001 mol),n-butyl amine (1.0m, O.OImol) and ethanol (15ml) was refluxed for 8 hrs. Ethanol was distillled off and residue was passed through basic alumina column using hexane- ethyl acetate as eluant. Sovent was distilled off to give the title compound .Yield 212mg, (60.05%).
Example 27
(4-Methoxy phenyl)-{4-(2,3- epoxy- propyloxy)pheny)-5,6,7,8- tetrahydro naphth-1-yl- methane
A mixture of (4-Methoxy phenyl)-(4-.hydroxy pheny)-5,6,7,8-
tetrahydro naphth-1-yl-methane (450 mg, 0.0013mol) anhydrous
K2CO3(2.8gm,1.44mmol),epichlorohydrin (20ml) was refluxed at 100-120°C for 12
hrs. The reaction mixture was filtered and filtrate was concentrated. The residue was dissolved in ethylacetate .washed with water, dried over sodium sulphate and concentrated to give an oil The oil was chromatographed over silica gel: using 20% hexane chloroform as eluant desired compound to give pure epoxide as an oil , yield 410mg (78.39%).
Example 28
(4-Methoxyphenyl)-{3-methyl-4-(2,3-epoxypropyloxy)pheny)-5,6,7,8-tetrahydro naphth-1-yl- methane
A mixture of (4- methoxyphenyl)-(3-methyl -4-hydroxy pheny)-5,6,7,8-tetrahydro naphth-1-yl- methane (410 mg,0.001mol),epichlorohydrin (25ml) and anhydrous K2CO3 (2.0gm, 0.014mol) was refluxed at 120°C for 6hrs. K2CO3 was filtered off and Titrate was concentrated. The residue obtained was dissolved in ethyl acetate and washed with water .dried over sodium sulphate and concentrated to give an oil which was chromatograpphed over silica ge! using hexane -chloroform as eluant to give title compound . Yield 388mg ( 82.37%).
Example 29
(4-methoxy phenyl)-(4-(2- hydroxy - 3-n- butylaminopropoxy)-phenyl-5,6,7,8-tetrahydro naphth-1- yl-methane
A mixture of (4-methoxy phenyl)-(4-(2,3- epoxy propy(oxy)pheny)- 5,6,7,8-tetrahydro-!- naphth-1-yl- methane ( 350mg, 0.004 mol ) ,n- butyl amine ( 1.0ml,0.01mol) and ethanol (10m! ) was refluxed for for 6 hrs. Ethanol was distilled off and the residue was passed through basic alumina using benzene-ethyl acetate as eluant.The solvent was distilled off yielding the required product.Yield 286mg (69.75 % )

Example 30
(4-Methoxy phenyl)-( 3-methyl- 4- (2- hydroxy - 3-n- butylamino) propoxy)phenyl-5,6,7,8 tetrahydro naphth-1-yl-methane
A mixture of (4-methoxyphenyl)-(3-methyl -4-(2,3-epoxypropyloxy)-pheny)5,6,7,8 tetrahydro -l-naphth-1-yl- methane (380mg,00.001 mol),n-butyl amine (1.0ml,0.01mol) and ethanol was refluxed for 6 hrs. Ethanol was distillled off and residue was passed through basic alumina column using hexane-ethyl acetate as eluent.Solvent was distilled off to give the title compound. . Yield 236mg (52.79 %).




We Claim:
1. A process for the preparation of novel diaryl naphthyl methane compound useful in the treatment of estrogen related disease or syndrome and having general formula I as shown in the drawing accompanying this specification wherein RI, RZ, RS, R4, RS are H, OH, lower alkyl, lower alkoxy group having straight or branched chain radical containing 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group, substituted alkoxy groups, epoxy alkoxy, alkyl/dialkyl amino alkoxy, cyclic alkyl aminoalkoxy, hydroxyl substituted alkyl/dialkyl/cyclic alkyl aminoalkoxy, the dotted lines indicate 1,2,3,4-tetrahydronaphthyl ring or 5,6,7,8-tetrahydronaphthyl ring, said process comprises the steps of:
(i) reacting a compound of formula II as shown in the drawing accompanying this specification with a phenolic compound under the conventional Friedel Crafts reaction conditions to produce the compound of Formula I as defined above
(ii) optionally subjecting the compound of formula I as obtained above in step (I) to the conventional hydrogenation conditions to give the tetrahydronaphthyl compound of formula I wherein dotted lines in one ring of the naphthyl group show the presence of double bonds; (iii) reacting compound of formula I with an alkylating agent in the presence of a base at a temperature in the range 300° to 120°C for a period in the range of 1 - 12 hrs and recovering the alkylated product of formula I wherein R5 is alkoxy, epoxy alkoxy, alkyl or dialkyl amino alkoxy, cyclic
alkyl aminoalkoxy, cyclic alkyl amino alkoxy,
(iv) reacting compound of formula I wherein R5 is epoxy alkoxy with an amine at a temperature in therange of 30° to 120°C for a period in the range of 1 to 12 hr and recovering the compound diaryl napthyl methane of formula I and converting the amino compounds of formula I to their salts by known methods.
2. The process as claimed in claim 1, wherein in step (a), the Lewis acid is
selected from the group consisting of AICI3, SnCI4 and (CH3)3 SiCI.
3. The process as claimed in claims 1 & 2 wherein in step (a), the
hydrocarbon solvent is selected from the group consisting of benzene,
toluene, pentane and hexane.
4. The process as claimed in claims 1 to 3 wherein the hydrogenation
reaction of step (e) is performed and the hydrogenation is effected at a
pressure in the range of 30 to 60 psi and at a temperature ranging from
25°C to 60°C.
5. The process as claimed in claims 1-4, wherein in the hydrogenation
reaction of step (e), the suitable catalyst is selected from the group
consisting of Raney nickel, palladium charcoal (Pd/C) and platinum oxide
(PtO2).
6. The process as claimed in claims 1-5, wherein in the hydrogenation
reaction of step (e), the solvent is selected from the group consisting of
methanol, ethanol and tetrahydrofuran.
7. The process as claimed in claims 1-6. wherein the tertiary amino alkyl
halide is selected from the group consisting of CICH2 CH2 HN-cyclopropyl,
2-chloro-n-butyl amine, N-chloromethylpiperidine, N-chloromethyl

pyrrolidine, and chloroethyl dimethylamine, and wherein the epoxy alkyl halide is epichlorohydrin.
8. The process as claimed in claims 1-7, wherein in step (d), the base is
selected from the group consisting of K2CO3, NaOH and KOH.
9. The process as claimed in claims 1-8, wherein in step (d), the solvent is
selected from the group consisting of acetone and dimethyl sulfoxide.
10.The process as claimed in claims 1-9, wherein in step (d), the amine is at least one selected from the group consisting of a substituted or unsubstituted straight chain or cyclic aliphatic, aromatic and heterocyclic amine.
11.The process as claimed in claims 1-10, wherein in step (f), the acid is at least one selected from the group consisting of hydrochloric acid, tartaric acid, citric acid and succinic acid.
12.A process for preparation of diaryl naphthyl methane compounds substantially as herein described with reference to the examples.

Documents:


Patent Number 197502
Indian Patent Application Number 767/DEL/2000
PG Journal Number 41/2007
Publication Date 12-Oct-2007
Grant Date 08-Oct-2007
Date of Filing 29-Aug-2000
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DLEHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 SUPRABHAT RAY CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P), INDIA.
2 JANAK DULARI DHAR CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P), INDIA.
3 MAN MOHAN SINGH CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P), INDIA.
4 ATUL KUMAR CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P), INDIA.
5 SANGITA CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P), INDIA.
6 NEETA SRIVASTAVA CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P), INDIA.
7 ARVIND GROVER CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P), INDIA.
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA