Indian Patents. 242166:A PROCESS FOR THE SYNTHESIS OF SECONDARY AMINO ALKOXY DERIVATIVES OF SUBTITUTED DIARYL 1,2,3,4-TETRAHYDRO NAPHTHYL METHANE

Title of Invention	A PROCESS FOR THE SYNTHESIS OF SECONDARY AMINO ALKOXY DERIVATIVES OF SUBTITUTED DIARYL 1,2,3,4-TETRAHYDRO NAPHTHYL METHANE
Abstract	This invention relates to a process for the synthesis of secondary amino alkoxy derivatives of subti-tuted diaryl 1,2,3,4- tetrahydro naphthyl methane as fertility regulating agents.

Full Text	This invention relates to a process for the synthesis of secondary amino alkoxy derivatives of subti-tuted diaryl 1,2,3,4- tetrahydro naphthyl methane 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 havi'ng 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 alkyl group as defined above. 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.231/DEL/98. The main object of the present invention is to provide a process of synthesis of secondary amino alkoxy derivatives of substituted diaryl 1,2,3,4 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 molecule using easily available chemicals. Accordingly, the present invention provides a process for the synthesis of secondary amino alkoxy derivatives of subtituted diaryl 1,2,3,4 tetrahydro naphthyl methane of 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 such as methyl, ethyl, n-propyl, isopro-pyl, n-butyl, tert butyl, n- amyl, n- hexyl, 2- ethyl butyl in case of lower alkyl and also as the alkyl subtituent constituting the lower alkyl group, R is H, or a lower alkyl group as defined above useful as fertility regulating agents which comprises reacting diaryl 1,2,3,4 tetrahydro naphthyl methane derivatives of general formula I wherein R1, R2 R3 & R4 has the meaning given above with epichlorohydrin in the presence of an acid binding agent (a base) in an organ- ic solvent at a temperature in the range of 2 0 - 12 0 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 obtained above with aromatic and or aliphatic primary amine in the presence of alcohol at a temperature in the range of 50 - 80°C recovering the compound of general formula III wherein R, R1, , R2 R3, R4 are as stated above, by known method and purifying the product by known method. In an embodiment of the present invention the epichlorohydrin used may be such as epichlorohydrin or epibromohydrin. In another embodiment of the invention the acid binding agent used may be such as K2CO3, Na2CO3, 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 synthesised 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 -hydrxypropyloxyphenyl) 1,2,3,4tetrahydro-napth -1-yl-methane active at 2.5mg/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-Methoxy phenyl)-(4-(2,3-epoxy) propyloxy) pheny) 1,2,3,4 tetrahydro- naphth-1-yl methane . A mixture of compound (4-methoxy phenyl) (4-hydroxy phenyl) 1,2,3,4 tetrahydro naphthyl methane (l.0gm, 0.29mmol) anhydrousK2CO3 (4.Ogm,0.28mol) , epi-chlorohydrin (20ml) was refluxed at 100-120°C for 8-10 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. yield 1.lgm 94.8%). Example 2 (4- Methoxyphenyl)-(3-methyl -4-(2,3- epoxy) propyloxy) pheny) 1,2,3,4 tetra hydro-1-naphth-l-yl methane A mixture ofcompound (4-methoxy phenyl) (3-methyl-4-hydroxy phenyl) 1,2,3,4 tetrahydro naphthyl methane (600mg, 0.0016mol),epichlorohydrin (25ml)and anhydrous K2CO3 (4.0gm, 0.028mol) was refluxed at 120°C for 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. yield 610mg(88.4%). Example 3 (4-Methoxy phenyl)-(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)1,2,3,4tetrahydro- naphth-1-yl methane (300mg, .0007mol), di butyl amine ( 1.0ml, ) and ethanol ( 10ml ) was refluxed for 10-12 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 4 (4-Methoxy phenyl)-(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 (400mg0mg, .OOlmol), n- butyl amine ( 1.0ml, .Olmol ) and ethanol( 10ml ) was refluxed for 8-9 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 5 (4-Methoxyphenyl)-(3-methyl-4-(2-hydroxy-3-n-butylami-no)propoxy)phenyl)1,2,3,4 tetrahydro- naphth -1-yl methane A mixture of (4-Methoxyphenyl)-(3-methyl -4-(2,3-epoxy)propyloxy)pheny)1,2,3,4tetrahydro naphth-1-yl methane (30Omg,0.0007 mol),n-butyl amine (1.0m, 0. Olmol) and ethanol (15ml) was refluxed for 8-10 hrs. Ethanol was distillled off and residue was passed through basic alumina column using hexane ethyl acetate as eluant.Yield 212mg, (60.05%). We claim: 1. A process for the synthesis of secondary amino alkoxy derivatives of subtituted diaryl 1,2,3,4 tet-rahydro naphthyl methane of 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 such as methyl, ethyl, n-pro-pyl, isopropyl, n-butyl, tert butyl, n- amyl, n- hexyl, 2- ethyl butyl in case of lower alkyl and also as the alkyl subtituent constituting the lower alkyl group, R is H, or a lower alkyl group as defined above useful as fertility regulating agents which comprises reacting diaryl 1,2,3,4 tetrahydro naphthyl methane derivatives of general formula I wherein R1, R2 R3 & 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 - 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 obtained above with aromatic and or aliphatic primary amine in the presence of alcohol at a temperature in the range of 50 - 80°C recovering the compound of general formula III wherein R, R1, R2 R3, R4 are as stated above, by known method and purifying the product by known method. 2. A process as claimed in claim 1, wherein the acid binding agent is K2CO3 NaOH,or KOH. 3. A process as claimed in claim 1 and 2, wherein the solvent used is such as acetone, cyclohexanone, dimethyl sulphoxide. 4. A process as claimed in claim 1-3, where in aromatic and aliphatic primary amine used is such as propyl amine, butyl amine, cyclo propyl amine or cyclo-hexyl amine. 5. A process for the preparation of secondary amino alkoxy derivatives of substituted diaryl 1,2,3,4 tet-rahydro naphthyl methane substantially as here in described with reference to the examples and the drawing accompanying this specification.

Full Text

This invention relates to a process for the synthesis of secondary amino alkoxy derivatives of subti-tuted diaryl 1,2,3,4- tetrahydro naphthyl methane 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 havi'ng 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 alkyl group as defined above.
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.231/DEL/98.
The main object of the present invention is to provide a process of synthesis of secondary amino alkoxy derivatives of substituted diaryl 1,2,3,4 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 molecule using easily available chemicals.
Accordingly, the present invention provides a process for the synthesis of secondary amino alkoxy derivatives of subtituted diaryl 1,2,3,4 tetrahydro naphthyl methane of 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 such as methyl, ethyl, n-propyl, isopro-pyl, n-butyl, tert butyl, n- amyl, n- hexyl, 2- ethyl butyl in case of lower alkyl and also as the alkyl subtituent constituting the lower alkyl group, R is H, or a lower alkyl group as defined above useful as fertility regulating agents which comprises reacting diaryl 1,2,3,4 tetrahydro naphthyl methane derivatives of general formula I wherein R1, R2 R3 & R4 has the meaning given above with epichlorohydrin in the presence of an acid binding agent (a base) in an organ-
ic solvent at a temperature in the range of 2 0 - 12 0 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 obtained above with aromatic and or aliphatic primary amine in the presence of alcohol at a temperature in the range of 50 - 80°C recovering the compound of general formula III wherein R, R1, , R2 R3, R4 are as stated above, by known method and purifying the product by known method.
In an embodiment of the present invention the epichlorohydrin used may be such as epichlorohydrin or epibromohydrin.
In another embodiment of the invention the acid binding agent used may be such as K2CO3, Na2CO3, 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 synthesised 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 -hydrxypropyloxyphenyl) 1,2,3,4tetrahydro-napth -1-yl-methane active at 2.5mg/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-Methoxy phenyl)-(4-(2,3-epoxy) propyloxy) pheny) 1,2,3,4 tetrahydro- naphth-1-yl methane .
A mixture of compound (4-methoxy phenyl) (4-hydroxy phenyl) 1,2,3,4 tetrahydro naphthyl methane (l.0gm, 0.29mmol) anhydrousK2CO3 (4.Ogm,0.28mol) , epi-chlorohydrin (20ml) was refluxed at 100-120°C for 8-10 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. yield 1.lgm 94.8%).
Example 2 (4- Methoxyphenyl)-(3-methyl -4-(2,3- epoxy) propyloxy) pheny) 1,2,3,4 tetra hydro-1-naphth-l-yl methane
A mixture ofcompound (4-methoxy phenyl) (3-methyl-4-hydroxy phenyl) 1,2,3,4 tetrahydro naphthyl methane (600mg, 0.0016mol),epichlorohydrin (25ml)and anhydrous K2CO3 (4.0gm, 0.028mol) was refluxed at 120°C for 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. yield 610mg(88.4%).
Example 3 (4-Methoxy phenyl)-(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)1,2,3,4tetrahydro- naphth-1-yl methane
(300mg, .0007mol), di butyl amine ( 1.0ml, ) and
ethanol ( 10ml ) was refluxed for 10-12 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 4
(4-Methoxy phenyl)-(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 (400mg0mg, .OOlmol), n- butyl amine ( 1.0ml, .Olmol ) and ethanol( 10ml ) was refluxed for 8-9 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 5 (4-Methoxyphenyl)-(3-methyl-4-(2-hydroxy-3-n-butylami-no)propoxy)phenyl)1,2,3,4 tetrahydro- naphth -1-yl methane
A mixture of (4-Methoxyphenyl)-(3-methyl -4-(2,3-epoxy)propyloxy)pheny)1,2,3,4tetrahydro naphth-1-yl methane (30Omg,0.0007 mol),n-butyl amine (1.0m, 0. Olmol) and ethanol (15ml) was refluxed for 8-10 hrs. Ethanol was distillled off and residue was passed through basic alumina column using hexane ethyl acetate as eluant.Yield 212mg, (60.05%).

We claim:
1. A process for the synthesis of secondary amino alkoxy derivatives of subtituted diaryl 1,2,3,4 tet-rahydro naphthyl methane of 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 such as methyl, ethyl, n-pro-pyl, isopropyl, n-butyl, tert butyl, n- amyl, n- hexyl, 2- ethyl butyl in case of lower alkyl and also as the alkyl subtituent constituting the lower alkyl group, R is H, or a lower alkyl group as defined above useful as fertility regulating agents which comprises reacting diaryl 1,2,3,4 tetrahydro naphthyl methane derivatives of general formula I wherein R1, R2 R3 & 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 - 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 obtained above with aromatic and or aliphatic primary amine in the presence of alcohol at a temperature in the range of 50 - 80°C recovering the compound of general formula III wherein R, R1, R2 R3, R4 are as stated above, by known method and purifying the product by known method.
2. A process as claimed in claim 1, wherein the acid binding agent is K2CO3 NaOH,or KOH.
3. A process as claimed in claim 1 and 2, wherein the solvent used is such as acetone, cyclohexanone, dimethyl sulphoxide.
4. A process as claimed in claim 1-3, where in aromatic and aliphatic primary amine used is such as propyl amine, butyl amine, cyclo propyl amine or cyclo-hexyl amine.
5. A process for the preparation of secondary amino alkoxy derivatives of substituted diaryl 1,2,3,4 tet-rahydro naphthyl methane substantially as here in described with reference to the examples and the drawing accompanying this specification.

Documents:

232-del-1998-abstract.pdf

232-del-1998-claims.pdf

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

232-del-1998-correspondence-others.pdf

232-del-1998-correspondence-po.pdf

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

232-del-1998-drawings.pdf

232-del-1998-form-1.pdf

232-del-1998-form-2.pdf

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Patent Number

242166

Indian Patent Application Number

232/DEL/1998

PG Journal Number

34/2010

Publication Date

20-Aug-2010

Grant Date

17-Aug-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	NEETA SRIVASTAVA	CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA.
2	MAN MOHAN SINGH	CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA.
3	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