Title of Invention

A PROCESS FOR THE PREPARATION OF SECONDARY AMINO ALKOXY DERIVATIVES OF SUBTITUTED DIARYL 5,6,7,8-TETRAHYDRO NAPHTHYL METHANE

Abstract A process for the preparation of secondary amino alkoxy derivatives of subtituted diaryl 5,6,7,8 tet-rahydro naphthylmethane of formula III as shown in the drawing accompanying this specification wherein R1,R2,R, 3,R4 are H, OH, or a lower alkyl or a lower alkoxy group having a straight or a branched chain radical containing 1 to 6 carbon atoms for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n-amyl, n- hexyl, 2- ethyl butyl alkyl substituent constituting the lower alkyl group, R is H, or lower alkoxy group having 1 to 6 carbon atoms useful as fertility regulating agents which comprises reacting diaryl 5,6,7,8 tetrahydro naphthyl methane derivatives of general formula I wherein R1,R2,R,3,R4 has the meaning given above with epichlorohydrin in the presence of an acid binding agent (a base) in an organic solvent at a temperature in the range of 2 0 - 120°C for a period in the range of 4 - 12 hrs, isolating the epoxy compound of formula II wherein R1,R2,R,3,R4 are as stated above, reacting epoxy compound of formula II as obtained above with aliphatic and aromatic primary amine in the presence of alcohol at a temperature in the range of 50 - 80°C recovering the compound of general formula III R1,R2,R,3,R4 are as stated above, R is H or a lower alkyl group as defined above and purifying the product by known method.
Full Text This invention relates to a process for the preparation of secondary amino alkoxy derivatives of subti-tuted diaryl 5,6,7,8 - tetrahydro naphthyl methane useful as fertility regulating agents.
Particularly this invention relates to a process for the preparation of compound of general formula III of the drawing accompanying this specification, wherein R1,R2,R3,R4 are H,OH, or a lower alkyl or a lower alkoxy group having a straight or a branched chain radical containing 1 to 6 carbon atoms for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n- amyl, n- hexyl, 2- ethyl butyl in case of lower alkyl and also as the alkyl substituent constituting the lower alkyl group, R is H, or lower alkoxy group having 1 to 5 carbon atoms.
The compounds prepared by the process of this invention are novel therefore no prior art methods are available .
The compounds of general formula (III) have been carried out from compounds of formula I which are prepared by the process as described and claimed in our copending application no.. 232/D/98.
The main object of the present invention is to provide a process of synthesis of secondary amino alkoxy derivatives of substituted diaryl 5,6,7,8 tetrahydro naphtyl methane useful as fertility regulating agents.

Another object of the invention is to provide a process for the preparation of the compound which possess high order of antifertility activity.
Yet another object Is to provide a process for the introduction of antiestrogen binding side in the mole-cule using easily available chemicals.
Accordingly,the present invention provides a process for the preparation of secondary amino alkoxy derivatives of subtituted diaryl 5,6,7,8 tetrahydro naphthylmethane of formula III as shown in the drawing accompanying this specification wherein R1,R2,R3,R4 are H,OH, or a lower alkyl or a lower,alkoxy group having a straight or a branched chain radical containing 1 to 6 carbon atoms for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n- amyl, n~ hexyl, 2 - ethyl butyl alkyl substituent constituting the lower alkyl group, R is H, or lower alkoxy group having 1 to 6 carbon atoms useful as fertility regulating agents which comprises reacting diaryl 5,6,7,8 tetrahydro naphthyl methane derivatives of general formula I wherein R1,R2,R3,R4 has the meaning given above wrth epichlorohydrin in the presence of an acid binding agent (a base) in an organic solivent at a tern perature in the range of 2 0 ~ 120°C for a period in the range of 4 - 12 hrs, isolating the epoxy compound of formula II wherein R1,R2,R3,R4 are as stated above, reacting epoxy compound of formula II as ob-
tained above with aliphatic and aromatic primary amine in the presence of alcohol at a temperature in the range of 50 - 80 "^ C recovering the compound of general formula III R1,R2,R3,R4 are as stated above, R is H or a lower alkyl group as defined above and purifying the product by known method.
In an embodiment of the present invention the epichlo-rohydrin used may be replaced by epibromohydrin.
In another embodiment of the invention the base used may be such as K2CO3, Na2C03' NaOH, KOH.
In another embodiment of the invention the organic solvent used may be such as acetone, cyclohexanone, dimethylsulphoxide.
In still another embodiment of the invention the primary amine used may be such as n-butyl amine, n-propyl amine, cyclo propyl amine, cyclo hexyl amine, ethyl amine.
The compounds gynthesised by the above process were tested for antifertility activity in female albino rats , A number of these compounds showed cent percent prevention of pregnency at doses of 10 mg /kg or below when administered orally to rats on days 1-7 p.c. or on a single day shedule. The most active compound of the series is (4-methoxyphenyl)-(4-(3-n'butylamino-2-hydrxypropylcxyphenyl) 5,6,7,8 tetrahydro-napth -1-yl-methane active at 2.Sma/kg dose..
The invention as described above is -illustrated by examples given below which should not however, be construed to limit the scope of the invention.

Example 1 (4-Metlioxy phenyl) - (4-(2,3-epoxy) propyloxy)pheny) 5,6,7,8 tetxahydro- naphth-l-yl methane .
A mixture of compound (4-methoxy phenyl) - (4 -hydroxy phenyl) 5,6,7,8 tetrahydro naphthyl methane {450gm, 0.0013 mol) anhydrous K2CO3 (2.8 gm,1.44 mol) , epichlorohydrin (20ml.) was refluxed at 100-120°C for 10-12 hrs. The reaction mixture was filtered and filtrate was cocentrated. The residue was dissolved in ethylacetate, and washed with water, dried .over sodium sulphate and cocentrated to give an oil.The oil was chromatographed over silica gel . The, epoxide was eluted with 20 % hexane chloroform to give pure epoxide as an oil, yield 410 gm (78.39%).
Example 2 (4- Methoxyphenyl) - (3-methyl -4- (2,3- epoxy) propyloxy) pheny) 5,6,7,8 tetrahydro-l-maphth-l-yl miethane
A mixture ofcompound (4-methoxy:. phenyl) (3-methyl-4-hydroxy phenyl) 5,6,7,8 tetrahydro naphthyl methane (410mg, 0 . 0011 mol) ,epichlorohydrin (25ml)and anhydrous K2CO3 (2.0gm, 0.014 mol) was refluxed at 120°C fox 6-8 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 chromatograpphed over silica gel using hexane -chloroform as eluant, yield 388 mg(82.37%).
Example 3 (4-Methoxy phenyl)-(4- (2-hydroxy- 3-n- butylamino) propoxy)phenyl-5,6,7,8 tetxahydro- naphth-l- yl methane
A mixture of (4-Methoxy phenyl)-(4-(2,3- epoxy) propyloxy)pheny) 5,6,7,8 tetrahydro- naphth-1-yi methane (350mg, 0.004 mol), n butyl amine ( 1.0ml, 0.01mol) and ethanol( 10ml ) was refluxed for 5-6 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 286 mg( 69.75%)
Example 4 (4-Methoxy phenyl) - {3-methyl-4-(2-hydroxys 3-n-butyl-amino) prc^poxy) phenyl 5,6,7,8 tetxahydro - naphth-1-yl
methane
A mixture of (4-Methoxy phenyl)-(3~methyl'4-(2,3-epoxy) propyloxy)pheny) 5,6,7,8 tetrahyro naphth-1-yl methane (380mg, 00.0009mol), n- butyl amine ( 1.0ml, O.Olmol ) and ethanol was refluxed for 4-6 hrs. Ethanol was distilled off and the residue was passed through basic alumina column using hexane ethyl acetate as eluent. Solvent was distilled off. Yield 236mg(52.79%).





We claim :
1. A process for the preparation of secondary amino alkoxy derivatives of subtituted diaryl 5,6,7,8 tet-rahydro naphthylmethane of formula III as shown in the drawing accompanying this specification wherein R1, R2 -R3,R4 are H,OH, or a lower alkyl or a lower alkoxy group having a straight or a branched chain radical containing 1 to 6 carbon atoms for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert butyl, n-arayl, n- hexyl, 2- ethyl butyl alkyl substituent constituting the lower alkyl group, R is H, or lower alkoxy group having 1 to 5 carbon atoms useful as fertility regulating agents which comprises reacting diaryl 5,6,7,8 tetrahydro naphthyl methane derivatives of general formula I wherein R1,R2,R,3,R4 has the meaning given above with epichlorohydrin in the presence of an acid binding agent {a base) in an organic solvent at a temperature in the range of 20 - 12 0 °C for a period in the range of 4 - 12 hrs, isolating the epoxy compound of formula II wherein R1,R2,R,3,R4 are as stated above, reacting epoxy compound of formula II as obtained above with ali{Dhatic and aromatic primary amine in the presence of alcohol at a temperature in the range of 50 - 80 ° C recovering the compound of general formula III R1,R2,R,3,R4 are as stated above, R is H or a lower alkyl group as defined above and purifying the product by known method.
2. A process as claimed in claim 1, wherein the acid binding agent (a base) used is K2CO3, NaOH,or KOH.
3. A process as claimed in claims 1 to 2, wherein the solvent used is such as acetone, cyclohexanone, dimethyl sulphoxide.
4. A process as claimed in claims 1 to 3, wherein primary amine used is such as propyl amine, butyl amine, cycle propyl amine or cyclohexyl amine.
5. A process for the preparation of secondary amino alkoxy derivatives of substituted diaryl. 5,6,7,8 tet-rahydro naphthyl methane substantially as here in described with reference to the examples and the drawing accompanying this specification.

Documents:

233-del-1998-abstract.pdf

233-del-1998-claims.pdf

233-del-1998-complete specification (granted).pdf

233-del-1998-correspondence-others.pdf

233-del-1998-correspondence-po.pdf

233-del-1998-description (complete).pdf

233-del-1998-drawings.pdf

233-del-1998-form-1.pdf

233-del-1998-form-2.pdf


Patent Number 243701
Indian Patent Application Number 233/DEL/1998
PG Journal Number 45/2010
Publication Date 05-Nov-2010
Grant Date 01-Nov-2010
Date of Filing 28-Jan-1998
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 MAN MOHAN SINGH CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA
2 SUPRABHAT RAY CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA
PCT International Classification Number C07C 39/15
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA