Indian Patents. 256123:"A PROCESS FOR THE PREPARATION OF CHIRAL 2,3-SUBSTITUTED PROPYLOXY SUBSTITUTED-2,2-DIALKYL-3,4-DIARYLCHROMANS AND THEIR SALTS"

Title of Invention	"A PROCESS FOR THE PREPARATION OF CHIRAL 2,3-SUBSTITUTED PROPYLOXY SUBSTITUTED-2,2-DIALKYL-3,4-DIARYLCHROMANS AND THEIR SALTS"
Abstract	A process for the preparation of Chiral 2, 3 substituted Propyloxy substituted 2,2, dialkyl-3,4-diarylchromans and their salts comprises. ating a mixture of 2,2-dialkyl-3,4-diarylchromans with chiral compounds and then treating. the chiral compounds with an alkyl or cycloalkyl amine in a protic solvent at a period of 15 min to 10 hr.

Full Text	This invention relates to a process for the preparation of chiral 2,3-substituted propyloxy substituted-2,2-dialkyl-3,4-diarylchromans and their salts.More particularly the present invention is directed to 2,2-di-lower alkyl-3,4-di arylchromans bearing a 3-lower alkylamino -2-hydroxy-propyloxy group on either one of the aryl groups or the benzenoid portion of the chroman nucleus. Such compounds have significant pharmacological activity as antiestrogens and high order of antifertility activity. Synthesis of racemic mixture of 3-alkylamino-2-hydroxy- propyloxy substituted-2,2-dialkyl-3,4diarylchroman has been reported by Ray et al.(Contraception,Vol.35,pp283-287).such compounds possess many fold higher antifertility activity as compared to corresponding conventional tertiary aminoalkoxy substituted derivatives. Since chirality of ligands is known to affect their binding to chiral estrogen receptors for initiating estrogenic activity, hence the importance of preparation of R-and S-3-alkyl-amino-2-hydroxy-propyloxy substituted-2,2- dialkyl-3,4-diaryl-chromans. As used throughout the specification and in the claim, the terms lower alkyl and lower alkoxy embrace both straight and branched chain alkyl and alkoxy radicals respectively,containing from 1 to 6 carbon atoms,for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, in the case of lower alkyl and methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert.butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy, cyclopropyloxy, cyclobutyloxy, cyclopentoxy, cyclohexyloxy, in the case of lower alkoxy . The main objective of the invention is to provide a process for the preparation of chiral 2,3-substituted propyloxy substituted -2,2-dialkyl-3,4-diarylchromans and their salts. Another objective of the invention is to introduce the chirality in the antiestrogen binding site of the molecule which may selectively bind to the chiral estrogen receptor and produce the final biological response. Accordingly the present invention provides a process for the preparation of chiral2,3-substituted propyloxy substituted 2,2-dialkyl-3,4- diarylchromans and their salts of general formula II accompanying this specification wherein R1, R2, are H, lower alkyl, cycloalkyl, OH, lower alkoxy and R3 is 3-(2,3-epoxypropyloxy) or a 3-substituted amino -2-hydroxypropyloxy group ( OCH2CH(OH)CH2NR6 R7, wherein R6 and R7 are H or a lower alkyl) and R4 R5 are H or a lower alkyl, X=nil or anion which comprises (i) reacting a mixture of 2,2-dialkyl-3,4-diaryl chromans of general formula I of the drawing accompanying this specification wherein R1, R2, R4, R5, are as defined above and R3 is a hydroxy group with chiral compound epi-chlorohydrin to give compounds of general formula I of the specification wherein R1, R2, R4. R5 are as defined above and R3 is a chiral 2,3-epoxypropyloxy group (ii), treating the above said chiral compound with an alkyl or cycloalkyl amine in a protic solvent such as alkanol & water at a temperature in the range of 30 to 100°C for a period of 15 min to 10 hr, to form the compound of formula II of the drawing wherein R1 R2, R4, R5, are as defined above and R3 is an optically active 3-substituted amino-2- hydroxy-propyloxy group as defined above, X=nil, recovering and converting the said free compound to salt of general formula II of the accompanying drawing wherein R1, R2, R3, R4, R5 are as defined above and X is an anion, by known methods. In an embodiment of the invention the amine used in the reaction may be such as lower alkyl amine of carbon atom ranging from C1 to C10, cyclopropyl amine, pyrrolidine, piperidine. In another embodiment of the invention the protic solvent used may be methanol, ethanol, propanol, water. In still another embodiment of the invention, the salt of compound of formula II is hyrochloride, tartarate, succinate salts. Reaction of chromene compounds of general formula I having hydroxyl group at any phenyl ring prepared by known methods ( Indian Patent No. 129188, filed on 12.11.1970, Synthesis,68-70, 1988) with chiral epichlorohydrin in presence of a base in an organic solvent for a time range of 2 hr to 48 hr at a temperature in the range of ambient to 120°C. Organic solvent used in the reaction may be such as acetone,cyclohexenone, dimethyl sulfoxide. Epoxide ring opening of the compound of general formula II as obtained above may be carried out on reaction with an amine in a protic solvent at a temperature in the range of 30 to 100°C for a period of 15 min to 10 hr. Solvent is removed by distillation,residue obtained was taken up in a water immenible solvent and washed with water ,dried over dehydrating agent,solvent was distilled off and if desired residue obtained was purified on basic alumina column to give chiral aminohydrin of general formula I wherein R1 R2 ,R4 ,R5 , as defined above and R is an optically active-3-substituted amino-2-hydroxy-proplyoxy group X=nil. The aminohyrin as obtained above may be converted to their salts by treatment with HCl or tartaric acid or succinic acid at a temperature in the range of room temperature to 100°C, followed by crystallization of residue with anhydrous alcohol and dry ether to give corresponding crystalline compound of general formula II Following examples are given by way of illustration and should not be construed to limit the scope of the present invention. Example 1 A mixture of 3,4- trans-2,2-dimethyl-3-phenyl-4-(p- hydroxy)phenyl-7-methoxy chroman of formula I (3.0g, 8.3 mmol), R(-) epichlorohydrin (2 ml, 25.5 mmol), anhydrous potassium carbonate (8g) in dry dimethylsulphoxide (30 ml ) was stirred at 0 50 C for 10 hrs. Reaction mixture was poured onto cold water 200 ml and then extracted with ethylacetate, washed with water, dried over anhydrous sodium sulphate,ethylacetate was distilled off to give an oil which was crystallised with hexane-benzene to give 3,4- trans -2,2-dimethyl 3-phenyl-4-(p-(R)-epoxyalkoxy) phenyl-7- 0 methoxy chroman,yield 2.13 gm (61.40%), m.p. 129 C. Example 2 A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-( p-(R) - 2,3-epoxyprop1oxy phenyl)-7-methoxychroman (800 mg, 1.92 mmo1), n-butylamine ( 0.4ml, 4.01mmol ) and ethanol (3 0 ml) was refluxed for 2 hrs. Ethanol was distilled off and the residue obtained was purified by passing through basic alumina column using hexane- benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans - 2,2-dimethyl- 3-phenyl-4-(p-(R)-(3-n-butylamino-2-hydroxy-proploxy)phenyl)-7- methoxy chroman hydrochloride of formula II, yield 564 mg (60.02%), m.p.170° C. Example 3 A mixture of 3,4- trans-2,2-dimethyl-3-phenyl-4-(p-hydroxy) phenyl-7-methoxy chroman (2.0g, 5.56 mmol), S(+) epi- chlorohyrin (1.1 ml, 10.0 mmol ), anhydrous potassium carbonate 0 (5g ) in dry dimethylsulphoxide (20 ml) was stirred at 60 C for 8 hrs. Reaction mixture was poured onto cold water 200 ml and then extracted with ethylacetate,washed with water, dried over anhydrous sodium sulphate,ethylacetate was distilled off to give an oil which was crystallised with methanol to give 3,4- trans -2,2-dimethyl -3-phenyl-4-(p-(S)-epoxyalkoxy) phenyl-7-methoxy chroman, Yield 1.5g (65.00%), m.p. 135°C. Example 4 A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-(p-(S)-2,3-epoxyproploxy phenyl)-7-methoxychroman (lg, 2.40mmol), n-butylamine ( 0.5 ml, 5.03 mmol ) and ethanol (50 ml) was refluxed for 2 hrs. Ethanol was distilled off and the residue obtained was purified by passing through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield trans S(+) 2,2-dimethyl-3-phenyl-4-(p-(3-n-butylamino-2hydroxy-proploxy)phenyl)-7-methoxy chroman hydrochloride of formula II, yield 735 (62.60%). Example 5 A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-(p-(R)-2,3-epoxyproploxy phenyl)-7-methoxychroman (lg, 2.04 mmol), dibutylamine ( 0.8 ml, 4.74 mmol ) and ethanol (50 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans 2,2-dimethyl-3-phenyl-4-(p-(R)-(3-di-butylamino-2hydroxy-p- roploxy)phenyl)-7-methoxy chroman hydrochloride of formula II, yield 734 mg (56.05%), m.p. 150° C Example 6 A mixture of 3,4-trans -2,2 dimethyl-3-phenyl-4-(p-(S)-2,3-epoxyproploxy phenyl)-7-methoxychroman (lg, 2.04 mmol), dibutylamine ( 0.8 ml, 4.74 mmol ) and ethanol (50 ml) was re-fluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans 2,2-dimethyl-3-phenyl-4-(p-(S)-(3-di-butylamino-2hydroxy-p- roploxy)phenyl)-7-methoxy chroman hydrochloride of formula II , yield 760 mg(58.02%), m.p.145°C . Example 7 A mixture of 3,4-trans -2,2dimethyl-3-phenyl-4-(p-(R)-2,3-epoxyproploxy phenyl)-7-methoxychroman (500 mg, 1.20 mmol) , cyclopropylamine ( 0.2 ml, 2.87 mmol ) and ethanol (50 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans -2,2-dimethyl-3-phenyl-4-(p-(R)-(3-cyclopropylamino-2hydroxy-proploxy)phenyl)-7-methoxy chroman hydrochloride of formula II , yield 309 mg(54.09%). Example 8 A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-(p-(S) -2,3-epoxyproploxy phenyl)-7-methoxychroman (500 mg, 1.20 mmol), cyclopropylamine ( 0.2 ml, 2.87 mmol ) and ethanol (50 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans -2,2-dimethyl-3-phenyl-4-(p-(S)-(3-cyclopropylamino-2hydroxy-proploxy)phenyl)-7-methoxy chroman hydrochloride of formula II yield 315mg(55.50%). Advantages : 1. By use of chiral epichlorohydrine in alkylation, pure enentio-men is obtained without the contamination of other • enentiomer' which excludes the method of resolution. 2.The compounds prepared by the method of present invention possessing high order of antifertility activity. 3. The compounds obtained by this method are in high yield. We claim : 1. A process for the preparation of chiral 2,3-substituted propyloxy substituted 2,2-dialkyl-3,4- diarylchromans and their salts of general formula II accompanying this specification wherein R1, R2, are H, lower alkyl, cycloalkyl, OH, lower alkoxy and R3 is 3-(2,3-epoxypropyloxy) or a 3-substituted amino -2-hydroxypropyloxy group ( OCH2CH(OH)CH2NR6 R7, wherein R6 and R7 are H or a lower alkyl) and R4 R5 are H or a lower alkyl, X=nil or anion which comprises (i) reacting a mixture of 2,2-dialkyl-3,4-diaryl chromans of general formula I of the drawing accompanying this specification wherein R1, R2, R4, R5, are as defined above and R3 is a hydroxy group with chiral compound epichlorohydrin to give compounds of general formula I of the specification wherein R1, R2, R4, R5 are as defined above and R3 is a chiral 2,3-epoxypropyloxy group (ii), treating the above said chiral compound with an alkyl or cycloalkyl amine in a protic solvent such as alkanol & water at a temperature in the range of 30 to 100°C for a period of 15 min to 10 hr, to form the compound of formula II of the drawing wherein R1, R2, R4, R5, are as defined above and R3 is an optically active 3- substituted amino-2- hydroxy-propyloxy group as defined above, X=nil, recovering and converting the said free compound to salt of general formula II of the accompanying drawing wherein R1, R2, R3, R4, R5 are as defined above and X is an anion, by known methods. 2. A process as claimed in claim 1 wherein the alkyl amine used is containing carbon atom in the range of C1 to C10 and cycloalkyl amine of carbon ranging C1 to C5. 3. A process as claimed in claims 1 and 2 wherein the alkanol used as protic solvent is methanol, ethanol, propanol. 4. A process as claimed in claims 1 to 3 wherein the salt of compound of formula II is hydrochloride, tartarate, succinate. 5. A process for the preparation of chiral 2,3-substituted proplyoxy substituted- 2,2-dialkylchromene and their salts of formula II substantially as herein described with reference to the drawings and the examples.

Full Text

This invention relates to a process for the preparation of chiral 2,3-substituted propyloxy substituted-2,2-dialkyl-3,4-diarylchromans and their salts.More particularly the present invention is directed to 2,2-di-lower alkyl-3,4-di arylchromans bearing a 3-lower alkylamino -2-hydroxy-propyloxy group on either one of the aryl groups or the benzenoid portion of the chroman nucleus. Such compounds have significant pharmacological activity as antiestrogens and high order of antifertility activity.
Synthesis of racemic mixture of 3-alkylamino-2-hydroxy-
propyloxy substituted-2,2-dialkyl-3,4diarylchroman has been
reported by Ray et al.(Contraception,Vol.35,pp283-287).such
compounds possess many fold higher antifertility activity as
compared to corresponding conventional tertiary aminoalkoxy
substituted derivatives.
Since chirality of ligands is known to affect their binding to chiral estrogen receptors for initiating estrogenic activity, hence the importance of preparation of R-and S-3-alkyl-amino-2-hydroxy-propyloxy substituted-2,2- dialkyl-3,4-diaryl-chromans.
As used throughout the specification and in the claim, the terms lower alkyl and lower alkoxy embrace both straight and branched chain alkyl and alkoxy radicals respectively,containing from 1 to 6 carbon atoms,for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, in the case of lower alkyl and
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert.butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy, cyclopropyloxy, cyclobutyloxy, cyclopentoxy, cyclohexyloxy, in the case of lower alkoxy .
The main objective of the invention is to provide a process for the preparation of chiral 2,3-substituted propyloxy substituted -2,2-dialkyl-3,4-diarylchromans and their salts.
Another objective of the invention is to introduce the chirality in the antiestrogen binding site of the molecule which may selectively bind to the chiral estrogen receptor and produce the final biological response.
Accordingly the present invention provides a process for the preparation of chiral2,3-substituted propyloxy substituted 2,2-dialkyl-3,4- diarylchromans and their salts of general formula II accompanying this specification wherein R1, R2, are H, lower alkyl, cycloalkyl, OH, lower alkoxy and R3 is 3-(2,3-epoxypropyloxy) or a 3-substituted amino -2-hydroxypropyloxy group ( OCH2CH(OH)CH2NR6 R7, wherein R6 and R7 are H or a lower alkyl) and R4 R5 are H or a lower alkyl, X=nil or anion which comprises (i) reacting a mixture of 2,2-dialkyl-3,4-diaryl chromans of general formula I of the drawing accompanying this specification wherein R1, R2, R4, R5, are as defined above and R3 is a hydroxy group with chiral compound epi-chlorohydrin to give compounds of general formula I of the specification wherein
R1, R2, R4. R5 are as defined above and R3 is a chiral 2,3-epoxypropyloxy group (ii), treating the above said chiral compound with an alkyl or cycloalkyl amine in a protic solvent such as alkanol & water at a temperature in the range of 30 to 100°C for a period of 15 min to 10 hr, to form the compound of formula II of the drawing wherein R1 R2, R4, R5, are as defined above and R3 is an optically active 3-substituted amino-2- hydroxy-propyloxy group as defined above, X=nil, recovering and converting the said free compound to salt of general formula II of the accompanying drawing wherein R1, R2, R3, R4, R5 are as defined above and X is an anion, by known methods.
In an embodiment of the invention the amine used in the reaction may be such as lower alkyl amine of carbon atom ranging from C1 to C10, cyclopropyl amine, pyrrolidine, piperidine.
In another embodiment of the invention the protic solvent used may be methanol, ethanol, propanol, water.
In still another embodiment of the invention, the salt of compound of formula II is hyrochloride, tartarate, succinate salts.
Reaction of chromene compounds of general formula I
having hydroxyl group at any phenyl ring prepared by
known methods ( Indian Patent No. 129188, filed on 12.11.1970,
Synthesis,68-70, 1988) with chiral epichlorohydrin in presence of
a base in an organic solvent for a time range of 2 hr to 48 hr at
a temperature in the range of ambient to 120°C. Organic solvent
used in the reaction may be such as acetone,cyclohexenone, dimethyl sulfoxide. Epoxide ring opening of the compound of general formula II as obtained above may be carried out on reaction
with an amine in a protic solvent at a temperature in the range
of 30 to 100°C for a period of 15 min to 10 hr. Solvent is removed by distillation,residue obtained was taken up in a water immenible solvent and washed with water ,dried over dehydrating agent,solvent was distilled off and if desired residue obtained was purified on basic alumina column to give chiral aminohydrin
of general formula I wherein R1 R2 ,R4 ,R5 , as defined above and R
is an optically active-3-substituted amino-2-hydroxy-proplyoxy
group X=nil. The aminohyrin as obtained above may be converted to
their salts by treatment with HCl or tartaric acid or succinic
acid at a temperature in the range of room temperature to 100°C,
followed by crystallization of residue with anhydrous alcohol and
dry ether to give corresponding crystalline compound of general
formula II
Following examples are given by way of illustration
and should not be construed to limit the scope of the present
invention.
Example 1
A mixture of 3,4- trans-2,2-dimethyl-3-phenyl-4-(p-
hydroxy)phenyl-7-methoxy chroman of formula I (3.0g, 8.3 mmol),
R(-) epichlorohydrin (2 ml, 25.5 mmol), anhydrous potassium
carbonate (8g) in dry dimethylsulphoxide (30 ml ) was stirred at
0 50 C for 10 hrs. Reaction mixture was poured onto cold water 200
ml and then extracted with ethylacetate, washed with water, dried
over anhydrous sodium sulphate,ethylacetate was distilled off to
give an oil which was crystallised with hexane-benzene to give
3,4- trans -2,2-dimethyl 3-phenyl-4-(p-(R)-epoxyalkoxy) phenyl-7-
0 methoxy chroman,yield 2.13 gm (61.40%), m.p. 129 C.
Example 2
A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-( p-(R) -
2,3-epoxyprop1oxy phenyl)-7-methoxychroman (800 mg, 1.92 mmo1),
n-butylamine ( 0.4ml, 4.01mmol ) and ethanol (3 0 ml) was refluxed
for 2 hrs. Ethanol was distilled off and the residue obtained was
purified by passing through basic alumina column using hexane-
benzene as eluant.The free base obtained was converted into its
hydrochloride by treating with methanolic-HCl and crystallized
with dry ethanol-diethylether to yield 3,4- trans - 2,2-dimethyl-
3-phenyl-4-(p-(R)-(3-n-butylamino-2-hydroxy-proploxy)phenyl)-7-
methoxy chroman hydrochloride of formula II, yield 564 mg
(60.02%), m.p.170° C.
Example 3
A mixture of 3,4- trans-2,2-dimethyl-3-phenyl-4-(p-hydroxy) phenyl-7-methoxy chroman (2.0g, 5.56 mmol), S(+) epi-
chlorohyrin (1.1 ml, 10.0 mmol ), anhydrous potassium carbonate
0 (5g ) in dry dimethylsulphoxide (20 ml) was stirred at 60 C for 8
hrs. Reaction mixture was poured onto cold water 200 ml and then extracted with ethylacetate,washed with water, dried over anhydrous sodium sulphate,ethylacetate was distilled off to give an oil which was crystallised with methanol to give 3,4- trans
-2,2-dimethyl -3-phenyl-4-(p-(S)-epoxyalkoxy) phenyl-7-methoxy
chroman, Yield 1.5g (65.00%), m.p. 135°C.
Example 4
A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-(p-(S)-2,3-epoxyproploxy phenyl)-7-methoxychroman (lg, 2.40mmol), n-butylamine ( 0.5 ml, 5.03 mmol ) and ethanol (50 ml) was refluxed for 2 hrs. Ethanol was distilled off and the residue obtained was purified by passing through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield trans S(+) 2,2-dimethyl-3-phenyl-4-(p-(3-n-butylamino-2hydroxy-proploxy)phenyl)-7-methoxy chroman hydrochloride of formula II, yield 735 (62.60%).
Example 5
A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-(p-(R)-2,3-epoxyproploxy phenyl)-7-methoxychroman (lg, 2.04 mmol),
dibutylamine ( 0.8 ml, 4.74 mmol ) and ethanol (50 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans 2,2-dimethyl-3-phenyl-4-(p-(R)-(3-di-butylamino-2hydroxy-p-
roploxy)phenyl)-7-methoxy chroman hydrochloride of formula II,
yield 734 mg (56.05%), m.p. 150° C
Example 6
A mixture of 3,4-trans -2,2 dimethyl-3-phenyl-4-(p-(S)-2,3-epoxyproploxy phenyl)-7-methoxychroman (lg, 2.04 mmol), dibutylamine ( 0.8 ml, 4.74 mmol ) and ethanol (50 ml) was re-fluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans 2,2-dimethyl-3-phenyl-4-(p-(S)-(3-di-butylamino-2hydroxy-p-
roploxy)phenyl)-7-methoxy chroman hydrochloride of formula II ,
yield 760 mg(58.02%), m.p.145°C .
Example 7
A mixture of 3,4-trans -2,2dimethyl-3-phenyl-4-(p-(R)-2,3-epoxyproploxy phenyl)-7-methoxychroman (500 mg, 1.20 mmol) , cyclopropylamine ( 0.2 ml, 2.87 mmol ) and ethanol (50 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans -2,2-dimethyl-3-phenyl-4-(p-(R)-(3-cyclopropylamino-2hydroxy-proploxy)phenyl)-7-methoxy chroman hydrochloride of formula II , yield 309 mg(54.09%).
Example 8
A mixture of 3,4- trans -2,2dimethyl-3-phenyl-4-(p-(S) -2,3-epoxyproploxy phenyl)-7-methoxychroman (500 mg, 1.20 mmol), cyclopropylamine ( 0.2 ml, 2.87 mmol ) and ethanol (50 ml) was refluxed for 3 hrs. Ethanol was distilled off and the residue obtained was purified by passins through basic alumina column using hexane-benzene as eluant.The free base obtained was converted into its hydrochloride by treating with methanolic-HCl and crystallized with dry ethanol-diethylether to yield 3,4- trans -2,2-dimethyl-3-phenyl-4-(p-(S)-(3-cyclopropylamino-2hydroxy-proploxy)phenyl)-7-methoxy chroman hydrochloride of formula II yield 315mg(55.50%).
Advantages :
1. By use of chiral epichlorohydrine in alkylation, pure enentio-men is obtained without the contamination of other • enentiomer' which excludes the method of resolution.
2.The compounds prepared by the method of present invention possessing high order of antifertility activity. 3. The compounds obtained by this method are in high yield.

We claim :
1. A process for the preparation of chiral 2,3-substituted propyloxy substituted
2,2-dialkyl-3,4- diarylchromans and their salts of general formula II accompanying
this specification wherein R1, R2, are H, lower alkyl, cycloalkyl, OH, lower alkoxy
and R3 is 3-(2,3-epoxypropyloxy) or a 3-substituted amino -2-hydroxypropyloxy
group ( OCH2CH(OH)CH2NR6 R7, wherein R6 and R7 are H or a lower alkyl) and R4
R5 are H or a lower alkyl, X=nil or anion which comprises (i) reacting a mixture of
2,2-dialkyl-3,4-diaryl chromans of general formula I of the drawing accompanying
this specification wherein R1, R2, R4, R5, are as defined above and R3 is a hydroxy
group with chiral compound epichlorohydrin to give compounds of general
formula I of the specification wherein R1, R2, R4, R5 are as defined above and R3 is
a chiral 2,3-epoxypropyloxy group (ii), treating the above said chiral compound
with an alkyl or cycloalkyl amine in a protic solvent such as alkanol & water at a
temperature in the range of 30 to 100°C for a period of 15 min to 10 hr, to form the
compound of formula II of the drawing wherein R1, R2, R4, R5, are as defined
above and R3 is an optically active 3- substituted amino-2- hydroxy-propyloxy
group as defined above, X=nil, recovering and converting the said free compound
to salt of general formula II of the accompanying drawing wherein R1, R2, R3, R4,
R5 are as defined above and X is an anion, by known methods.
2. A process as claimed in claim 1 wherein the alkyl amine used is containing
carbon atom in the range of C1 to C10 and cycloalkyl amine of carbon ranging C1
to C5.
3. A process as claimed in claims 1 and 2 wherein the alkanol used as protic
solvent is methanol, ethanol, propanol.
4. A process as claimed in claims 1 to 3 wherein the salt of compound of formula II
is hydrochloride, tartarate, succinate.
5. A process for the preparation of chiral 2,3-substituted proplyoxy substituted-
2,2-dialkylchromene and their salts of formula II substantially as herein described
with reference to the drawings and the examples.

Documents:

3072-del-1997-abstract.pdf

3072-del-1997-claims.pdf

3072-del-1997-correspondence-others.pdf

3072-del-1997-correspondence-po.pdf

3072-del-1997-description (complete).pdf

3072-del-1997-drawings.pdf

3072-del-1997-form-1.pdf

3072-del-1997-form-13.pdf

3072-del-1997-form-2.pdf

abstract.jpg

« Previous Patent

Next Patent »

Patent Number

256123

Indian Patent Application Number

3072/DEL/1997

PG Journal Number

19/2013

Publication Date

10-May-2013

Grant Date

05-May-2013

Date of Filing

24-Oct-1997

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110001,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SACHI TRIPATHI	CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA.
2	INDRA DWIVEDY	CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA
3	MAN MOHAH SINGH	CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA
4	SUPRABHAT RAY	CENTRAL DRUG RESEARCH INSTITUTE, LUCKNOW, INDIA

PCT International Classification Number

C07D 309/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA